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Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the ‘Warburg effect’, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.

Abstract The activation of mitochondrial large conductance calcium-activated potassium (mitoBKCa) channels increases cell survival during ischemia/reperfusion injury of cardiac cells. The basic biophysical and pharmacological properties of mitoBKCa correspond to the properties of the BKCa channels from the plasma membrane. It has been suggested that the VEDEC splice variant of the KCNMA1 gene product encoding plasma membrane BKCa is targeted toward mitochondria. However there has been no direct evidence that this protein forms a functional channel in mitochondria. In our study, we used HEK293T cells to express the VEDEC splice variant and observed channel activity in mitochondria using the mitoplast patch-clamp technique. For the first time, we found that transient expression with the VEDEC isoform resulted in channel activity with the conductance of 290 ± 3 pS. The channel was voltage-dependent and activated by calcium ions. Moreover, the activity of the channel was stimulated by the potassium channel opener NS11021 and inhibited by hemin and paxilline, which are known BKCa channel blockers. Immunofluorescence experiments confirmed the partial colocalization of the channel within the mitochondria. From these results, we conclude that the VEDEC isoform of the BKCa channel forms a functional channel in the inner mitochondrial membrane. Additionally, our data show that HEK293T cells are a promising experimental model for expression and electrophysiological studies of mitochondrial potassium channels.

In this paper, the current challenges of mitochondrial potassium channels research were critically reviewed. Even though recent progress in understanding K+ traffic in mitochondria has been substantial, some basic issues of this process remain unresolved. Here, we focused on the critical discussion of the molecular identity of various mitochondrial potassium channels. This point helps to clarify why there are different potassium channels in specific mitochondria. We also described interactions of mitochondrial potassium channel subunits with other mitochondrial proteins. Posttranslational modifications of mitochondrial potassium channels and their import are essential but unexplored research areas. Additionally, problems with the pharmacological targeting of mitochondrial potassium channel were illustrated. Finally, the limitation of the techniques used to measure mitochondrial potassium channels was explained. We believe that recognizing these problems may be interesting for readers but will also help to progress the field of mitochondrial potassium channels.

In the inner mitochondrial membrane, several potassium channels that play a role in cell life and death have been identified. One of these channels is the ATP-regulated potassium channel (mitoKATP). The ROMK2 potassium channel is a potential molecular component of the mitoKATP channel. The current study aimed to investigate the pharmacological modulation of the activity of the ROMK2 potassium channel expressed in Escherichia coli bacteria. ROMK2 was solubilized in polymer nanodiscs and incorporated in planar lipid bilayers. The impact of known mitoKATP channel modulators on the activity of the ROMK2 was characterized. We found that the ROMK2 channel was activated by the mitoKATP channel opener diazoxide and blocked by mitoKATP inhibitors such as ATP/Mg2+, 5-hydroxydecanoic acid, and antidiabetic sulfonylurea glibenclamide. These results indicate that the ROMK2 potassium protein may be a pore-forming subunit of mitoKATP and that the impact of channel modulators is not related to the presence of accessory proteins.

Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.

Mitochondria play a fundamental role in the energetics of cardiac cells. Moreover, mitochondria are involved in cardiac ischemia/reperfusion injury by opening the mitochondrial permeability transition pore which is the major cause of cell death. The preservation of mitochondrial function is an essential component of the cardioprotective mechanism. The involvement of mitochondrial K+ transport in this complex phenomenon seems to be well established. Several mitochondrial K+ channels in the inner mitochondrial membrane, such as ATP-sensitive, voltage-regulated, calcium-activated and Na+-activated channels, have been discovered. This obliges us to ask the following question: why is the simple potassium ion influx process carried out by several different mitochondrial potassium channels? In this review, we summarize the current knowledge of both the properties of mitochondrial potassium channels in cardiac mitochondria and the current understanding of their multidimensional functional role. We also critically summarize the pharmacological modulation of these proteins within the context of cardiac ischemia/reperfusion injury and cardioprotection.

Mitochondria play a key role in energy metabolism within the cell. Potassium channels such as ATP-sensitive, voltage-gated or large-conductance Ca2+-regulated channels have been described in the inner mitochondrial membrane. Several hypotheses have been proposed to describe the important roles of mitochondrial potassium channels in cell survival and death pathways. In the current study, we identified two populations of mitochondrial large-conductance Ca2+-regulated potassium (mitoBKCa) channels in human bronchial epithelial (HBE) cells. The biophysical properties of the channels were characterized using the patch-clamp technique. We observed the activity of the channel with a mean conductance close to 285 pS in symmetric 150/150 mM KCl solution. Channel activity was increased upon application of the potassium channel opener NS11021 in the micromolar concentration range. The channel activity was completely inhibited by 1 µM paxilline and 300 nM iberiotoxin, selective inhibitors of the BKCa channels. Based on calcium and iberiotoxin modulation, we suggest that the C-terminus of the protein is localized to the mitochondrial matrix. Additionally, using RT-PCR, we confirmed the presence of α pore-forming (Slo1) and auxiliary β3-β4 subunits of BKCa channel in HBE cells. Western blot analysis of cellular fractions confirmed the mitochondrial localization of α pore-forming and predominately β3 subunits. Additionally, the regulation of oxygen consumption and membrane potential of human bronchial epithelial mitochondria in the presence of the potassium channel opener NS11021 and inhibitor paxilline were also studied. In summary, for the first time, the electrophysiological and functional properties of the mitoBKCa channel in a bronchial epithelial cell line were described.

In this study, we analyzed the mechanical properties of selectively laser melted (SLM) steel obtained via different modifications during and after the manufacturing process. The aim was to determine the effects of precipitation heat treatment on the mechanical properties of elements additively manufactured using three different process parameters. Some samples were additionally obtained using hot isostatic pressing (HIP), while some were treated using two different types of heat treatment and a combination of those two processes. From each manufactured sample, a part of the material was taken for structural analysis including residual stress analysis and microstructural investigations. In the second part of the research, the mechanical properties were studied to define the scleronomic hardness of the samples. Finally, tensile tests were conducted using a digital image correlation (DIC) test and fracture analysis. The treated samples were found to be significantly elongated, thus indicating the advantages of using precipitation heat treatment. Additionally, precipitation heat treatment was found to increase the porosity of samples, which was the opposite compared to HIP-treated samples.

The aim of this research was to investigate the effect of different heat treatment conditions of AA2519 friction stir welded joints on their microstructure and residual stresses. The following welding parameters have been used: 500 rpm tool rotation speed, 150 mm/min tool traverse speed, tool tilt angle 2°, pressure force 17 kN. The welded material was investigated in three different configurations: HT0, HT1, and HT2. The first type of weld (HT-0) was made using AA2519 alloy in non-precipitation hardened state and examined in such condition. The second type of weld (HT-1) has been performed on AA2519-T62, that corresponds to precipitation hardening condition. The last type of weld (HT2) was performed on annealed AA2519 and the obtained welds were subjected to the post-weld precipitation hardening process. The heat treatment was carried out in two stages: solution heat treatment (530 °C/2 h + cooling in cold water) and aging (165 °C/1 0 h). Residual stresses were measured using X-Ray diffraction patterns obtained from Bruker D8 Discover X-ray diffractometer utilizing the concepts of Euler cradle and polycapillary primary beam optics. The conducted research indicates that the best material properties: homogenous microstructure and uniform distribution of microhardness and compressive state of residual stresses were obtained for the HT-2 series samples subjected to heat treatment after the friction stir welding (FSW) process.

Alkali silica reaction (ASR) is a harmful phenomenon occurring as a result of chemical interactions between sodium and potassium hydroxides in the pore solution and reactive minerals contained in the aggregate. Reactive minerals like microcrystalline, cryptocrystalline or strained quartz dissolve in the alkaline solution and form an expansive gel product. Proper selection of concrete constituents is necessary to ensure the durability of concrete structures. The proper recognition of the aggregate mineralogical composition is a very important element in the process of selection of concrete components due to the risk of ASR occurrence. This paper presents the results of detailed microscopic analysis of alkali-silica reactivity of domestic fine aggregates of various origins. Six siliceous sands from different locations in Poland and one limestone sand were tested. Detailed petrographic analysis was performed on thin sections. In all siliceous sands micro- and cryptocrystalline quartz was recognized as a reactive mineral. Digital image analysis was performed for quantitative assessment of the potential of reactivity of sands. It revealed, that siliceous river sands were the most susceptible to an alkali-silica reaction, which was confirmed by mortar bar expansion test performed according to the standard test method.

An increased flux of potassium ions into the mitochondrial matrix through the ATP-sensitive potassium channel (mitoKATP) has been shown to provide protection against ischemia-reperfusion injury. Recently, it was proposed that the mitochondrial-targeted isoform of the renal outer medullary potassium channel (ROMK) protein creates a pore-forming subunit of mitoKATP in heart mitochondria. Our research focuses on the properties of mitoKATP from heart-derived H9c2 cells. For the first time, we detected single-channel activity and describe the pharmacology of mitoKATP in the H9c2 heart-derived cells. The patch-clamping of mitoplasts from wild type (WT) and cells overexpressing ROMK2 revealed the existence of a potassium channel that exhibits the same basic properties previously attributed to mitoKATP. ROMK2 overexpression resulted in a significant increase of mitoKATP activity. The conductance of both channels in symmetric 150/150 mM KCl was around 97 ± 2 pS in WT cells and 94 ± 3 pS in cells overexpressing ROMK2. The channels were inhibited by 5-hydroxydecanoic acid (a mitoKATP inhibitor) and by Tertiapin Q (an inhibitor of both the ROMK-type channels and mitoKATP). Additionally, mitoKATP from cells overexpressing ROMK2 were inhibited by ATP/Mg2+ and activated by diazoxide. We used an assay based on proteinase K to examine the topology of the channel in the inner mitochondrial membrane and found that both termini of the protein localized to the mitochondrial matrix. We conclude that the observed activity of the channel formed by the ROMK protein corresponds to the electrophysiological and pharmacological properties of mitoKATP.

Potassium channel openers (KCOs) have been shown to play a role in cytoprotection through the activation of mitochondrial potassium channels. Recently, in several reports, a number of data has been described as off-target actions for KCOs. In the present study, we investigated the effects of BKCa channel openers CGS7181, CGS7184, NS1619, and NS004 in neuronal cells. For the purpose of this research, we used a rat brain, the mouse hippocampal HT22 cells, and the human astrocytoma U-87 MG cell line. We showed that CGS7184 activated the mitochondrial BKCa (mitoBKCa) channel in single-channel recordings performed on astrocytoma mitoplasts. Moreover, when applied to the rat brain homogenate or isolated rat brain mitochondria, CGS7184 increased the oxygen consumption rate, and can thus be considered a potentially cytoprotective agent. However, experiments on intact neuronal HT22 cells revealed that both CGS7181 and CGS7184 induced HT22 cell death in a concentration- and time-dependent manner. By contrast, we did not observe cell death when NS1619 or NS004 was applied. CGS7184 toxicity was not abolished by BKCa channel inhibitors, suggesting that the observed effects were independent of a BKCa-type channel activity. CGS7184 treatment resulted in an increase of cytoplasmic Ca2+ concentration that likely involved efflux from internal calcium stores and the activation of calpains (calcium-dependent proteases). The cytotoxic effect of the channel opener was partially reversed by a calpain inhibitor. Our data show that KCOs under study not only activate mitoBKCa channels from brain tissue, but also induce cell death when used in cellular models.

The mitochondrial response to changes of cytosolic calcium concentration has a strong impact on neuronal cell metabolism and viability. We observed that Ca2+ additions to isolated rat brain mitochondria induced in potassium ion containing media a mitochondrial membrane potential depolarization and an accompanying increase ofmitochondrial respiration. These Ca2+ effects can be blocked by iberiotoxin and charybdotoxin, well known inhibitors of large conductance potassium channel (BKCa channel). Furthermore, NS1619 – a BKCa channel opener – induced potassium ion–specific effects on brain mitochondria similar to those induced by Ca2+. These findings suggest the presence of a calcium-activated, large conductance potassium channel (sensitive to charybdotoxin and NS1619), which was confirmed by reconstitution of the mitochondrial inner membrane into planar lipid bilayers. The conductance of the reconstituted channel was 265 pS under gradient (50/450 mM KCl) conditions. Its reversal potential was equal to 50 mV, which proved that the examined channel was cation-selective. We also observed immunoreactivity of anti-b4 subunit (of the BKCa channel) antibodies with ~26 kDa proteins of rat brain mitochondria. Immunohistochemical analysis confirmed the predominant occurrence of b4 subunit in neuronal mitochondria. We hypothesize that the mitochondrial BKCa channel represents a calcium sensor, which can contribute to neuronal signal transduction and survival.

Abstract Objective: The main goal of our study was to assess the impact of vascular procedures on the activity of hemostatic and fibrinolytic pathways. Methods: We enrolled 38 patients with ≥ 45 years old undergoing surgery for abdominal aortic aneurysm or peripheral artery disease under general or regional anesthesia and who were hospitalized at least one night after the procedure. Patients undergoing carotid artery surgery and those who had acute bypass graft thrombosis, cancer, renal failure defined as estimated glomerular filtration rate < 30 ml/min/1.73m2, venous thromboembolism three months prior to surgery, or acute infection were excluded from the study. We measured levels of markers of hemostasis (factor VIII, von Willebrand factor:ristocetin cofactor [vWF:CoR], antithrombin), fibrinolysis (D-dimer, tissue plasminogen activator [tPA], plasmin-antiplasmin complexes), and soluble cluster of differentiation 40 ligand (sCD40L) before and 6-12h after vascular procedure. Results: Significant differences between preoperative and postoperative levels of factor VIII (158.0 vs. 103.3, P

The endocytic adaptor protein 2 (AP-2) complex binds dynactin as part of its noncanonical function, which is necessary for dynein-driven autophagosome transport along microtubules in neuronal axons. The absence of this AP-2-dependent transport causes neuronal morphology simplification and neurodegeneration. The mechanisms that lead to formation of the AP-2-dynactin complex have not been studied to date. However, the inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) enhances the transport of newly formed autophagosomes by influencing the biogenesis and protein interactions of Rab-interacting lysosomal protein (RILP), another dynein cargo adaptor. We tested effects of mTORC1 inhibition on interactions between the AP-2 and dynactin complexes, with a focus on their two essential subunits, AP-2β and p150 Glued . We found that the mTORC1 inhibitor rapamycin enhanced p150 Glued -AP-2β complex formation in both neurons and non-neuronal cells. Additional analysis revealed that the p150 Glued -AP-2β interaction was indirect and required integrity of the dynactin complex. In non-neuronal cells rapamycin-driven enhancement of the p150 Glued -AP-2β interaction also required the presence of cytoplasmic linker protein 170 (CLIP-170), the activation of autophagy, and an undisturbed endolysosomal system. The rapamycin-dependent p150 Glued -AP-2β interaction occurred on lysosomal-associated membrane protein 1 (Lamp-1)-positive organelles but without the need for autolysosome formation. Rapamycin treatment also increased the acidification and number of acidic organelles and increased speed of the long-distance retrograde movement of Lamp-1-positive organelles. Altogether, our results indicate that autophagy regulates the p150 Glued -AP-2β interaction, possibly to coordinate sufficient motor-adaptor complex availability for effective lysosome transport., (© 2024. The Author(s).)

A review of the literature on emotion regulation in binge eating disorder (BED) published both in English and Polish between 1990 and 2020. BED might be considered as an impulsive and compulsive disorder associated with altered reward sensitivity and food-related attentional bias. The growing body of research indicated that there were corticostriatal circuitry alterations in BED, comparable to those observed in substance abuse, including altered function of orbitofrontal, prefrontal and insular cortices with the striatum included. Negative emotions and deficits in their regulation play a significant role in BED. Processing of anger, anxiety and sadness appear to be particularly important in this disorder. Research results identified an increase in negative emotions preceding episodes of binge eating. However, there is still inconsistency when it comes to whether these episodes alleviate negative affect. Individuals with BED more often use non-adaptive emotion regulation strategies, such as rumination and suppression of negative sensations. Whereas adaptive ones, for instance, cognitive reappraisal, are used less often. Clinical implications, besides pharmacology, highlight the high effectiveness of enhanced cognitive behavioral therapy (CBT-E), dialectic-behavioral therapy (DBT) and psychodynamic therapy in the treatment of emotional dysregulation in BED. Further studies, including ecological momentary assessment (EMA), should focus on emotional changes related to the binge cycle and the identification of reinforcing factors of BED.

Objectives: To provide real-world data on the impact of autologous hematopoietic stem cell transplantation (AHSCT) on treatment costs of patients with multiple sclerosis (MS) in Poland., Methods: Medical data of 105 patients who underwent AHSCT in the years 2011 to 2016 were obtained from the National Health Fund (NHF) database. Treatment costs were calculated from the public payer's perspective per patient-year for the total available period as well as 12 months before and after AHSCT. The statistical analysis was performed using MATLAB 2016b., Results: Mean treatment-related costs covered by the NHF per patient-year before and after the transplantation were €4314.9 and €1188.8 , respectively. The average cost of disease-modifying drugs per patient was reduced from €2497.9/year before to €65.3/year after AHSCT., Conclusions: Although the initial cost of AHSCT is high, the costs involving AHSCT and post-AHSCT treatment could, according to our analysis, pay off in 3.9 years, when compared to the costs of disease-modifying drug therapy in aggressive MS. The study provides evidence that the AHSCT can lead to significant savings in treatment costs of aggressive MS from the public payer's perspective., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aims: Binge eating disorder (BED) is correlated with substance use. This study aimed to estimate the life-time prevalence of alcohol use disorder (AUD) among individuals with non-compensatory binge eating and determine whether their life-time prevalence of AUD is higher than in non-bingeing controls., Design: A systematic search of databases (PubMed, Embase and Web of Science) for studies of adults diagnosed with BED or a related behavior that also reported the life-time prevalence of AUD was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol was followed. The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO)., Setting: Studies originating in Canada, Sweden, the United Kingdom and the United States., Participants: Eighteen studies meeting the inclusion criteria were found, representing 69 233 individuals., Measurements: Life-time prevalence of AUD among individuals with binge eating disorder and their life-time relative risk of AUD compared with individuals without this disorder., Results: The pooled life-time prevalence of AUD in individuals with binge eating disorder was 19.9% [95% confidence interval (CI) = 13.7-27.9]. The risk of life-time AUD incidence among individuals with binge eating disorder was more than 1.5 times higher than controls (relative risk = 1.59, 95% CI = 1.41-1.79). Life-time AUD prevalence was higher in community samples than in clinical samples (27.45 versus 14.45%, P = 0.041) and in studies with a lower proportion of women (β = -2.2773, P = 0.044)., Conclusions: Life-time alcohol use disorder appears to be more prevalent with binge eating disorder than among those without., (© 2020 Society for the Study of Addiction.)

Background and Objectives: Many consider volunteer blood donors as ideal candidates for unrelated haematopoietic progenitor cell (HPC) donation. However, frequent blood donations could influence the results of HPC mobilization. To our best knowledge, there are no data on the possible impact of repeated blood donation on efficiency of subsequent HPC mobilization by granulocyte colony-stimulating factor (G-CSF)., Materials and Methods: We compared outcomes of HPC mobilization in unrelated donors with and without a history of blood donation. We conducted a prospective study on 287 consecutive donors admitted to the Department of Hematology since January 2016. The final analysis included 153 donors who agreed to take part in the study and had undergone stem cell mobilization with G-CSF., Results: History of blood donations prior to haematopoietic stem cell mobilization with G-CSF does not have a significant impact on the number of collected CD34+ cells in the first leucocytapheresis (516.2 x 10 6 (170-1148) in blood donors vs 490.5 x 10 6 (101-1154) in non-donors) (P = 0.32). In all donors, in this study mobilization of HPC was successful: 87.5% of blood donors and 85.6% of non-donors collected the required cell number in a single apheresis. In blood donors, a higher number of blood donations within 2 and 5 years prior to HPC mobilization correlated significantly with successful donation within one leucocytapheresis (P = 0.014 and P = 0.024, respectively)., Conclusion: Multiple blood donations do not significantly influence the outcome of HPC collection in unrelated donors. Blood donors and non-donors have similar results of HPC collection, so there is no reason to favour either group., (© 2019 International Society of Blood Transfusion.)

Over the past decade, there has been increasing interest in the use of multifunctional nanoparticles (NPs) for cancer treatment. Of importance are systems that can deliver drugs at a sustained rate to target cancer cells, which can result in higher efficiency and reduced systemic toxicity. In this study, we present the route for the synthesis of tantalum pentoxide (Ta 2 O 5 ) NPs with a particle size of 27 nm that were individually coated with poly(acrylic acid) (PAA) with a different layer thickness of 2-8 nm by in-situ polymerization of the acrylic acid monomer. The capability of Ta 2 O 5 -PAA to provide anatomical contrast-enhancing features has been demonstrated via computed tomography. The Ta 2 O 5 -PAA conjugate was further loaded with methotrexate, and the drug release was observed for a total of 72 h at a pH of 3.6, 5.4, 7.4, and 9.4. While the different layer thicknesses did not influence the drug release kinetics, a decrease in pH of the release medium resulted in a slower drug release. The developed nanocomposite particles present a great potential as a theranostic system for biomedical applications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The World Marrow Donor Organization recommends original granulocyte-colony stimulating factor (G-CSF) for the mobilization of stem cells in healthy unrelated hematopoietic stem cell donors. We report the comparison of a biosimilar G-CSF (Zarzio) with two original G-CSFs (filgrastim and lenograstim) in mobilization in unrelated donors. We included data of 313 consecutive donors who were mobilized during the period from October 2014 to March 2016 at the Medical University of Warsaw. The primary endpoints of this study were the efficiency of CD34+ cell mobilization to the circulation and results of the first apheresis. The mean daily dose of G-CSF was 9.1 μg/kg for lenograstim, 9.8 μg/kg for biosimilar filgrastim, and 9.3 μg/kg for filgrastim (p < 0.001). The mean CD34+ cell number per microliter in the blood before the first apheresis was 111 for lenograstim, 119 for biosimilar filgrastim, and 124 for filgrastim (p = 0.354); the mean difference was even less significant when comparing CD34+ number per dose of G-CSF per kilogram (p = 0.787). Target doses of CD34+ cells were reached with one apheresis in 87% donors mobilized with lenograstim and in 93% donors mobilized with original and biosimilar filgrastim (p = 0.005). The mobilized apheresis outcomes (mean number of CD34+ cells/kg of donor collected during the first apheresis) was similar with lenograstim, biosimilar filgrastim, and filgrastim: 6.2 × 10 6 , 7.6 × 10 6 , and 7.3 × 10 6 , respectively, p = 0.06. There was no mobilization failure in any of the donors. Biosimilar G-CSF is as effective in the mobilization of hematopoietic stem cells in unrelated donors as original G-CSFs. Small and clinically irrelevant differences seen in the study can be attributed to differences in G-CSF dose and collection-related factors. Active safety surveillance concurrent to clinical use and reporting to donor outcome registry (e.g., EBMT donor outcome registry or WMDA SEAR/SPEAR) might help to evaluate the possible short- and long-term complications of biosimilar G-CSF.

Aim: The study aim was to evaluate progression-free survival (PFS) and overall survival (OS) in patients with metastatic clear cell renal cell carcinoma on sunitinib (SU) and SU-everolimus treatment., Patients & Methods: After 7 years of enrollment and 9 years of follow-up, 193 consecutively presenting patients (151 men and 42 women) were treated., Results: A total of 157 patients (81.3%) died and 36 patients (18.7%) survived. Median PFS in 193 SU-treated patients was 14.7 months and OS was 28.8 months. Median PFS was 13.98 months and median OS was 26.67 months in 175 patients treated with SU only or on SU-everolimus., Conclusion: The development of SU-induced hypothyroidism, hypertension, neutropenia and edema was a significant predictive and prognostic factor.

In this study, we investigate the toxicity of hematite (α-Fe2O3) nanoparticles on the Madin-Darby Canine Kidney (MDCK) cell line. The oxide particles have been synthesized through two different methods and annealing conditions. These two methods, spray precipitation and precipitation, resulted in particles with rod-like and spherical morphology and feature different particle sizes, surface features, and magnetic properties. Through flow cytometry it was found that particle morphology heavily influences the degree to which the nanomaterials are internalized into the cells. It was also found that the ability of the nanoparticles to generate free radicals species is hindered by the formation of tetrahedrally coordinated maghemite-like (γ-Fe2O3) spinel defects on the surfaces of the particles. The combination of these two factors resulted in variable cytotoxic effects of the hematite nanoparticles synthesized with different conditions. This article highlights the importance on the fabrication method, materials properties, and surface characteristics on the cytotoxicity of hematite nanomaterials.

Background: The Work Disability Functional Assessment Battery (WD-FAB), developed for potential use by the US Social Security Administration to assess work-related function, currently consists of five multi-item scales assessing physical function and four multi-item scales assessing behavioral health function; the WD-FAB scales are administered as Computerized Adaptive Tests (CATs)., Objective: The goal of this study was to evaluate the test-retest reliability of the WD-FAB Physical Function and Behavioral Health CATs., Methods: We administered the WD-FAB scales twice, 7-10 days apart, to a sample of 376 working age adults and 316 adults with work-disability. Intraclass correlation coefficients were calculated to measure the consistency of the scores between the two administrations. Standard error of measurement (SEM) and minimal detectable change (MDC90) were also calculated to measure the scales precision and sensitivity., Results: For the Physical Function CAT scales, the ICCs ranged from 0.76 to 0.89 in the working age adult sample, and 0.77-0.86 in the sample of adults with work-disability. ICCs for the Behavioral Health CAT scales ranged from 0.66 to 0.70 in the working age adult sample, and 0.77-0.80 in the adults with work-disability. The SEM ranged from 3.25 to 4.55 for the Physical Function scales and 5.27-6.97 for the Behavioral Health function scales. For all scales in both samples, the MDC90 ranged from 7.58 to 16.27., Conclusion: Both the Physical Function and Behavioral Health CATs of the WD-FAB demonstrated good test-retest reliability in adults with work-disability and general adult samples, a critical requirement for assessing work related functioning in disability applicants and in other contexts., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To assess the feasibility and psychometric properties of 8 scales covering 2 domains of the newly developed Work Disability Functional Assessment Battery (WD-FAB): physical function (PF) and behavioral health (BH) function., Design: Cross-sectional study., Setting: Community., Participants: Adults (N=973) unable to work because of a physical (n=497) or a mental (n=476) disability., Interventions: Not applicable., Main Outcome Measures: Each disability group responded to a survey consisting of the relevant WD-FAB scales and existing measures of established validity. The WD-FAB scales were evaluated with regard to data quality (score distribution, percentage of "I don't know" responses), efficiency of administration (number of items required to achieve reliability criterion, time required to complete the scale) by computerized adaptive testing (CAT), and measurement accuracy as tested by person fit. Construct validity was assessed by examining both convergent and discriminant correlations between the WD-FAB scales and scores on same-domain and cross-domain established measures., Results: Data quality was good, and CAT efficiency was high across both WD-FAB domains. Measurement accuracy was very good for PF scales; BH scales demonstrated more variability. Construct validity correlations, both convergent and divergent, between all WD-FAB scales and established measures were in the expected direction and range of magnitude., Conclusions: The data quality, CAT efficiency, person fit, and construct validity of the WD-FAB scales were well supported and suggest that the WD-FAB could be used to assess PF and BH function related to work disability. Variation in scale performance suggests the need for future work on item replenishment and refinement, particularly with regard to the Self-Efficacy scale., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Physical and mental impairments represent the 2 largest health condition categories for which workers receive Social Security disability benefits. Comprehensive assessment of physical and mental impairments should include aspects beyond medical conditions such as a person's underlying capabilities as well as activity demands relevant to the context of work. The objective of this article is to describe the initial conceptual stages of developing new measurement instruments of behavioral health and physical functioning relevant for Social Security work disability evaluation purposes. To outline a clear conceptualization of the constructs to be measured, 2 content models were developed using structured and informal qualitative approaches. We performed a structured literature review focusing on work disability and incorporating aspects of the International Classification of Functioning, Disability and Health as a unifying taxonomy for framework development. Expert interviews provided advice and consultation to enhance face validity of the resulting content models. The content model for work-related behavioral health function identifies 5 major domains: (1) behavior control, (2) basic interactions, (3) temperament and personality, (4) adaptability, and (5) workplace behaviors. The content model describing physical functioning includes 3 domains: (1) changing and maintaining body position, (2) whole-body mobility, and (3) carrying, moving, and handling objects. These content models informed subsequent measurement properties including item development and measurement scale construction, and provided conceptual coherence guiding future empirical inquiry. The proposed measurement approaches show promise to comprehensively and systematically assess physical and behavioral health functioning relevant to work., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To build a comprehensive item pool representing work-relevant physical functioning and to test the factor structure of the item pool. These developmental steps represent initial outcomes of a broader project to develop instruments for the assessment of function within the context of Social Security Administration (SSA) disability programs., Design: Comprehensive literature review; gap analysis; item generation with expert panel input; stakeholder interviews; cognitive interviews; cross-sectional survey administration; and exploratory and confirmatory factor analyses to assess item pool structure., Setting: In-person and semistructured interviews and Internet and telephone surveys., Participants: Sample of SSA claimants (n=1017) and a normative sample of adults from the U.S. general population (n=999)., Interventions: Not applicable., Main Outcome Measure: Model fit statistics., Results: The final item pool consisted of 139 items. Within the claimant sample, 58.7% were white; 31.8% were black; 46.6% were women; and the mean age was 49.7 years. Initial factor analyses revealed a 4-factor solution, which included more items and allowed separate characterization of: (1) changing and maintaining body position, (2) whole body mobility, (3) upper body function, and (4) upper extremity fine motor. The final 4-factor model included 91 items. Confirmatory factor analyses for the 4-factor models for the claimant and the normative samples demonstrated very good fit. Fit statistics for claimant and normative samples, respectively, were: Comparative Fit Index=.93 and .98; Tucker-Lewis Index=.92 and .98; and root mean square error approximation=.05 and .04., Conclusions: The factor structure of the physical function item pool closely resembled the hypothesized content model. The 4 scales relevant to work activities offer promise for providing reliable information about claimant physical functioning relevant to work disability., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To develop a broad set of claimant-reported items to assess behavioral health functioning relevant to the Social Security disability determination processes, and to evaluate the underlying structure of behavioral health functioning for use in development of a new functional assessment instrument., Design: Cross-sectional., Setting: Community., Participants: Item pools of behavioral health functioning were developed, refined, and field tested in a sample of persons applying for Social Security disability benefits (N=1015) who reported difficulties working because of mental or both mental and physical conditions., Interventions: None., Main Outcome Measure: Social Security Administration Behavioral Health (SSA-BH) measurement instrument., Results: Confirmatory factor analysis (CFA) specified that a 4-factor model (self-efficacy, mood and emotions, behavioral control, social interactions) had the optimal fit with the data and was also consistent with our hypothesized conceptual framework for characterizing behavioral health functioning. When the items within each of the 4 scales were tested in CFA, the fit statistics indicated adequate support for characterizing behavioral health as a unidimensional construct along these 4 distinct scales of function., Conclusions: This work represents a significant advance both conceptually and psychometrically in assessment methodologies for work-related behavioral health. The measurement of behavioral health functioning relevant to the context of work requires the assessment of multiple dimensions of behavioral health functioning. Specifically, we identified a 4-factor model solution that represented key domains of work-related behavioral health functioning. These results guided the development and scale formation of a new SSA-BH instrument., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To use item response theory (IRT) data simulations to construct and perform initial psychometric testing of a newly developed instrument, the Social Security Administration Behavioral Health Function (SSA-BH) instrument, that aims to assess behavioral health functioning relevant to the context of work., Design: Cross-sectional survey followed by IRT calibration data simulations., Setting: Community., Participants: Sample of individuals applying for Social Security Administration disability benefits: claimants (n=1015) and a normative comparative sample of U.S. adults (n=1000)., Interventions: None., Main Outcome Measure: SSA-BH measurement instrument., Results: IRT analyses supported the unidimensionality of 4 SSA-BH scales: mood and emotions (35 items), self-efficacy (23 items), social interactions (6 items), and behavioral control (15 items). All SSA-BH scales demonstrated strong psychometric properties including reliability, accuracy, and breadth of coverage. High correlations of the simulated 5- or 10-item computer adaptive tests with the full item bank indicated robust ability of the computer adaptive testing approach to comprehensively characterize behavioral health function along 4 distinct dimensions., Conclusions: Initial testing and evaluation of the SSA-BH instrument demonstrated good accuracy, reliability, and content coverage along all 4 scales. Behavioral function profiles of Social Security Administration claimants were generated and compared with age- and sex-matched norms along 4 scales: mood and emotions, behavioral control, social interactions, and self-efficacy. Using the computer adaptive test-based approach offers the ability to collect standardized, comprehensive functional information about claimants in an efficient way, which may prove useful in the context of the Social Security Administration's work disability programs., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To develop and test an instrument to assess physical function for Social Security Administration (SSA) disability programs, the SSA-Physical Function (SSA-PF) instrument. Item response theory (IRT) analyses were used to (1) create a calibrated item bank for each of the factors identified in prior factor analyses, (2) assess the fit of the items within each scale, (3) develop separate computer-adaptive testing (CAT) instruments for each scale, and (4) conduct initial psychometric testing., Design: Cross-sectional data collection; IRT analyses; CAT simulation., Setting: Telephone and Internet survey., Participants: Two samples: SSA claimants (n=1017) and adults from the U.S. general population (n=999)., Interventions: None., Main Outcome Measures: Model fit statistics, correlation, and reliability coefficients., Results: IRT analyses resulted in 5 unidimensional SSA-PF scales: Changing & Maintaining Body Position, Whole Body Mobility, Upper Body Function, Upper Extremity Fine Motor, and Wheelchair Mobility for a total of 102 items. High CAT accuracy was demonstrated by strong correlations between simulated CAT scores and those from the full item banks. On comparing the simulated CATs with the full item banks, very little loss of reliability or precision was noted, except at the lower and upper ranges of each scale. No difference in response patterns by age or sex was noted. The distributions of claimant scores were shifted to the lower end of each scale compared with those of a sample of U.S. adults., Conclusions: The SSA-PF instrument contributes important new methodology for measuring the physical function of adults applying to the SSA disability programs. Initial evaluation revealed that the SSA-PF instrument achieved considerable breadth of coverage in each content domain and demonstrated noteworthy psychometric properties., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)