Outcomes of patients aged ≥26 years with relapsed or refractory B-cell acute lymphoblastic leukemia in ZUMA-3 and historical trials.

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the USA and European Union (EU) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL; aged ≥26 years in EU). Here, outcomes for patients with R/R B-ALL aged ≥26 years in ZUMA-3 treated with brexu-cel were compared with historical standard-of-care (SOC) therapy. After median follow-up of 26.8 months, the overall complete remission (CR) rate among patients treated with brexu-cel in Phase 2 (N = 43) was 72% and median overall survival (OS) was 25.4 months (95% CI, 15.9-NE). Median OS was improved in Phase 2 patients versus matched historical SOC-treated patients. Compared with aggregate historical trial data, Phase 1 and 2 patients had improved OS versus blinatumomab, inotuzumab, and chemotherapy in a matching-adjusted indirect comparison (MAIC) study. These data demonstrate clinical benefit of brexu-cel relative to SOC in patients ≥26 years with R/R B-ALL.

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor.

INTRODUCTION: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. METHODS: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. CONCLUSIONS: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma.

The SCHOLAR-2 retrospective study highlighted poor overall survival (OS) with standard of care (SOC) regimens among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who failed a covalent Bruton tyrosine kinase inhibitor (BTKi). In the ZUMA-2 single-arm trial, brexucabtagene autoleucel (brexu-cel; autologous anti-CD19 CAR T-cell therapy) demonstrated high rates of durable responses in patients with R/R MCL who had previous BTKi exposure. Here, we compared OS in ZUMA-2 and SCHOLAR-2 using three different methods which adjusted for imbalances in prognostic factors between populations: inverse probability weighting (IPW), regression adjustment (RA), and doubly robust (DR). Brexu-cel was associated with improved OS compared to SOC across all unadjusted and adjusted comparisons. Hazard ratios (95% confidence intervals) were 0.38 (0.23, 0.61) for IPW, 0.45 (0.28, 0.74) for RA, and 0.37 (0.23, 0.59) for DR. These results suggest a substantial survival benefit with brexu-cel versus SOC in patients with R/R MCL after BTKi exposure.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

INTRODUCTION: Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. METHODS: Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12 months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). RESULTS: The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. CONCLUSION: Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Decreasing Water Activity Using the Tetrahydrofuran Electrolyte Additive for Highly Reversible Aqueous Zinc Metal Batteries.

Aqueous zinc metal batteries show great promise in large-scale energy storage. However, the decomposition of water molecules leads to severe side reactions, resulting in the limited lifespan of Zn batteries. Here, the tetrahydrofuran (THF) additive was introduced into the zinc sulfate (ZnSO4) electrolyte to reduce water activity by modulating the solvation structure of the Zn hydration layer. The THF molecule can play as a proton acceptor to form hydrogen bonds with water molecules, which can prevent water-induced undesired reactions. Thus, in an optimal 2 M ZnSO4/THF (5% by volume) electrolyte, the hydrogen evolution reaction and byproduct precipitation can be suppressed, which greatly improves the cycling stability and Coulombic efficiency of reversible Zn plating/stripping. The Zn symmetrical cells exhibit ultralong working cycles with a wide range of current density and capacity. The THF additive also enables a high Coulombic efficiency in the Zn||Cu cell with an average value of 99.59% over 400 cycles and a high reversible capacity with a capacity retention of 97.56% after 250 cycles in the Zn||MnO2 full cells. This work offers an effective strategy with high scalability and low cost for the protection of the Zn metal electrodes in aqueous rechargeable batteries.

Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR-2 retrospective chart review study.

Mantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR-2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi-based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6-20.0) in the overall cohort, 5.5 months (95% CI 3.9-8.2) in 91 patients without post-BTKi therapy, and 23.8 months (95% CI 18.9-30.1) in 149 patients who received post-BTKi therapy (excluding chimeric antigen receptor T-cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post-BTKi therapy, with lenalidomide-containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post-BTKi therapy was 9.7 months (95% CI 6.3-12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure.

Li-Ion Permeability of Holey Graphene in Solid State Batteries: A Particle Dynamics Study.

Lithium (Li)-ion permeability of holey graphene (hG) for use as an electrically conducting scaffold in solid-state battery electrodes is explored through the means of a particle dynamics simulation model. While carbon materials do not typically exhibit Li-ion conductivity, the unique structural motif of hG, which consists of two-dimensional nanosheets with arrays of through-thickness holes, may present an opportunity for Li-ion conductors (i.e., solid electrolyte (SE) particles) to make contacts through the holes. In our model, the SE is presented as a system of hard elastic spheres conductive to Li-ions. The SE spheres are in contact with each other through compression between two plane current collectors. One hG layer is inserted between the current collectors and parallel to them. Randomly distributed circular holes in the hG allow for contact between the SE particles on both sides of the hG layer. By solving the Li-ion conducting network formed between the electrodes through the contact points of all the particles, the overall conductivity of the system was calculated as a function of SE particle size and the size and number of the hG holes (i.e., hG porosity). A critical ratio of around 4 between the SE particle size and the pore size was found. Below this critical value, the hG layer becomes practically transparent for Li-ions. This study helps to guide the design of highly efficient solid-state electrode composition and architectures using hG as a unique electrically conducting scaffold.

Achieving High Pseudocapacitance Anode by An In Situ Nanocrystallization Strategy for Ultrastable Sodium-Ion Batteries.

Conversion/alloying type anodes have shown great promise for sodium-ion batteries (SIBs) because of their high theoretical capacity. However, the poor structural stability derived from the large volume expansion and short lifetime impedes their further practical applications. Herein, we report a novel anode with a pomegranate-like nanostructure of SnP2O7 particles homogeneously dispersed in the robust N-doped carbon matrix. For the first time, we make use of in situ self-nanocrystallization to generate ultrafine SnP2O7 particles with a short pathway of ions and electrons to promote the reaction kinetics. Ex situ transmission electron microscope (TEM) shows that the average particle size of SnP2O7 decreases from 66 to 20 nm successfully based on this unique nanoscale-engineering method. Therefore, the nanoparticles together with the N-doped carbon contribute a high pseudocapacitance contribution. Moreover, the N-doped carbon matrix forms strong interaction with the self-nanocrystallization ultrafine SnP2O7 particles, leading to a stable nanostructure without any particle aggregation under a long-cycle operation. Benefiting from these synergistic merits, the SnP2O7@C anode shows a high specific capacity of 403 mAh g-1 at 200 mA g-1 and excellent cycling stability (185 mAh g-1 after 4000 cycles at 1000 mA g-1). This work presents a new route for the effective fabrication of advanced conversion/alloying anodes materials for SIBs.

Use of Patient-Reported Outcomes to Understand & Measure the Patient Experience of Novel Cell and Gene Therapies.

Patient reported outcomes (PROs) are the gold standard for assessing patients' experience of treatment in oncology, defined in the 21st Century Cures Act as information about patients' experiences with a disease or condition, including the impact of a disease or condition, or a related therapy or clinical investigation on patients' lives; and patient preferences with respect to treatment of their disease or condition [1]. PROs provide a comprehensive assessment of the benefits and risks of new medical products, as well as essential data to inform real-world use. Although RCTs are the ultimate source for information for evaluating products in development, they are not always feasible for rare diseases with few or no effective treatment options available. Thus, it is important to consider other measures that can help to improve the strength of evidence for cell and gene therapies targeting rare indications. While collection of PROs and other patient experience endpoints does not resolve the difficulty of conducting trials in small populations, doing so contributes empirical evidence that informs both product development and patient access. Additionally, including routine collection of PROs in registries may provide supplemental data to further characterize the benefit:risk profile of cell and gene therapies at follow-up times that would be infeasible to operationalize in a clinical trial setting.

Polymer-free versus durable polymer drug-eluting stents in patients with coronary artery disease: A meta-analysis.

BACKGROUND: Polymer-free drug-eluting stents (PF-DES) were introduced with the aim of reducing the risk of stent thrombosis associated with durable polymer drug-eluting stents (DP-DES). The comparison of safety and efficacy profiles between these two stent platforms remains unclear. MATERIALS AND METHODS: We conducted electronic database searches for randomized controlled trials (RCTs) comparing patients treated with either PF-DES or DP-DES. Outcomes included definite or probable stent thrombosis (ST), myocardial infarction (MI), cardiac death, all-cause death, target lesion revascularization (TLR), and target vessel revascularization (TVR). A random-effects model was used to derive risk ratios (RRs) with 95% confidence intervals (CIs). Subgroup analyses based on different variables were also performed. After screening a total of 1026 articles, the present meta-analysis included 13 RCTs comprising 8021 patients. RESULTS: No significant differences were found for the risks of definite or probable ST (RR, 0.94; 95% CI, 0.62-1.43; P = 0.77), MI (RR, 1.06; 95% CI, 0.85-1.33; P = 0.61), cardiac death (RR, 0.98; 95% CI, 0.80-1.21; P = 0.88), all-cause death (RR, 0.87; 95% CI, 0.76-1.00; P = 0.06), TLR (RR, 1.12; 95% CI, 0.94-1.33; P = 0.22), and TVR (RR, 1.18; 95% CI, 0.87-1.61; P = 0.29). Similarly, no significant differences were found for all outcomes regardless of anti-proliferative drug, except for an increased risk of TLR for polymer-free paclitaxel-eluting stents compared with DP-DES (RR, 2.32, 95% CI, 1.30-4.14; P = 0.005). CONCLUSIONS: Our findings showed that PF-DES and DP-DES confer equivalent safety and efficacy profiles, with similar rates of stent thrombosis.

A Review of the Ultrathin Orsiro Biodegradable Polymer Drug-eluting Stent in the Treatment of Coronary Artery Disease.

Drug-eluting stents (DES) have revolutionised the treatment of coronary artery disease (CAD) in patients undergoing percutaneous coronary intervention. In recent years, there has been a focus on a new generation of DES, such as biodegradable polymer DES (BP-DES). This novel stent platform was developed with the hope of eliminating the risk of very late stent thrombosis associated with the current gold-standard durable polymer DES (DP-DES). Ultrathin Orsiro BP-DES (Biotronik, Bülach, Switzerland) are based on a cobalt-chromium stent platform that is coated with a bioresorbable polymer coating containing sirolimus. These devices have one of the thinnest struts available in the current market and have the theoretical benefit of reducing a chronic inflammatory response in the vessel wall. In 2019, the United States Food and Drug Administration (FDA) approved the use of Orsiro BP-DES in patients with CAD based on promising results in recent landmark trials, such as BIOFLOW V and BIOSTEMI. The aim of the present review article was to discuss the history of stent technology and the continued opportunities for improvements, focusing on the potential benefits of Orsiro BP-DES.

Biodegradable polymer versus second-generation durable polymer drug-eluting stents in patients with coronary artery disease: A meta-analysis.

AIMS: Biodegradable polymer drug-eluting stents (BP-DES) were developed in hopes of reducing the risk of stent thrombosis. The comparison of this new stent platform with second-generation durable polymer drug-eluting stents (DP-DES) has not been well described. We, therefore, performed a meta-analysis to evaluate the safety and efficacy profiles of BP-DES versus second-generation DP-DES in patients with coronary artery disease. METHODS AND RESULTS: Electronic database searches were conducted, from their dates of inception to June 2018, to identify randomized controlled trials (RCTs) comparing patients with either BP-DES or second-generation DP-DES. Risk estimates were expressed as risk ratios (RRs) with 95% confidence intervals (CIs). We also performed a landmark analysis beyond 1 year and sensitivity analyses based on different variables. A total of 24,406 patients from 19 RCTs were included in the present meta-analysis. There were no significant differences between BP-DES and second-generation DP-DES for the risks of definite or probable stent thrombosis (RR 0.88; 95% CI, 0.69-1.12; P = 0.29), myocardial infarction (RR 0.97; 95% CI, 0.86-1.09; P = 0.59), cardiac death (RR 1.08; 95% CI, 0.92-1.28; P = 0.34), all-cause death (RR 1.02; 95% CI, 0.91-1.13; P = 0.77), target lesion revascularization (RR 1.05; 95% CI, 0.94-1.17; P = 0.38), and target vessel revascularization (RR 1.05; 95% CI, 0.95-1.16; P = 0.36). Similar outcomes were observed regardless of anti-proliferative drug and duration of dual antiplatelet therapy (all P > 0.05). CONCLUSION: Our findings demonstrate similar safety and efficacy profiles between BP-DES and second-generation BP-DES, with comparable rates of stent thrombosis.

Transabdominal Pre-Peritoneal Versus Open Repair for Primary Unilateral Inguinal Hernia: A Meta-analysis.

BACKGROUND: Recent NICE guidelines recommend open surgical approaches for the treatment of primary unilateral inguinal hernias. However, many surgeons perform a laparoscopic approach based on the advantages of less post-operative pain and faster recovery. Our aim was to examine current evidence comparing transabdominal pre-peritoneal (TAPP) laparoscopic repair and open surgical repair for primary inguinal hernias. METHODS: A systematic search of six electronic databases was conducted for randomised controlled trials (RCTs) comparing TAPP and open repair for primary unilateral inguinal hernia. A random-effects model was used to combine the data. RESULTS: A total of 13 RCTs were identified, with 1310 patients receiving TAPP repair and 1331 patients receiving open repair. There was no significant difference between the two groups for rates of haematoma (RR 0.92; 95% CI 0.49-1.71; P = 0.78), seroma (RR 1.90; 95% CI 0.87-4.14; P = 0.10), urinary retention (RR 0.99; 95% CI 0.36-2.76; P = 0.99), infection (RR 0.61; 95% CI 0.29-1.28; P = 0.19), and hernia recurrence (RR 0.67; 95% CI 0.42-1.07; P = 0.10). TAPP repair had a significantly lower rate of paraesthesia (RR 0.20; 95% CI 0.08-0.50; P = 0.0005), shorter bed stay (2.4 ± 1.4 vs 3.1 ± 1.6 days, P = 0.0006), and shorter return to normal activities (9.5 ± 7.9 vs 17.3 ± 8.4 days, P < 0.00001). CONCLUSIONS: Our findings demonstrated that TAPP repair did not have higher rate of morbidity or hernia recurrence and is an equivalent approach to open repair, with the advantages of faster recovery and reduced paraesthesia.

Mechanical Versus Bioprosthetic Aortic Valve Replacement in Middle-Aged Adults: A Systematic Review and Meta-Analysis.

The choice of a bioprosthetic valve (BV) or mechanical valve (MV) in middle-aged adults undergoing aortic valve replacement is a complex decision that must account for numerous prosthesis and patient factors. A systematic review and meta-analysis was performed to compare long-term survival, major adverse prosthesis-related events, anticoagulant-related events, major bleeding, reoperation, and structural valve degeneration in middle-aged patients receiving a BV or MV. A comprehensive search from six electronic databases was performed from their inception to February 2016. Results from patients aged less than 70 years undergoing aortic valve replacement with a BV or MV were included. There were 12 studies involving 8,661 patients. Baseline characteristics were similar. There was no significant difference in long-term survival among patients aged 50 to 70 or 60 to 70 years. Compared with MVs, BVs had significantly fewer long-term anticoagulant-related events (hazard ratio [HR] 0.54, p = 0.006) and bleeding (HR 0.48, p < 0.00001) but significantly greater major adverse prosthesis-related events (HR 1.82, p = 0.02), including reoperation (HR 2.19, p < 0.00001). The present meta-analysis found no significant difference in survival between BVs and MVs in patients aged 50 to 70 or 60 to 70 years. Compared with MVs, BVs have reduced risk of major bleeding and anticoagulant-related events but increased risk of structural valve degeneration and reoperation. However, the mortality consequences of reoperation appear lower than that of major bleeding, and recent advances may further lower the reoperation rate for BV. Therefore, this review supports the current trend of using BVs in patients more than 60 years of age.

Computational and Experimental Study of Li-Doped Ionic Liquids at Electrified Interfaces.

We evaluate the influence of Li-salt doping on the dynamics, capacitance, and structure of three ionic liquid electrolytes, [pyr14][TFSI], [pyr13][FSI], and [EMIM][BF4], using molecular dynamics and polarizable force fields. In this respect, our focus is on the properties of the electric double layer (EDL) formed by the electrolytes at the electrode surface as a function of surface potential (Ψ). The rates of EDL formation are found to be on the order of hundreds of picoseconds and only slightly influenced by the addition of Li-salt. The EDLs of three electrolytes are shown to have different energy storage capacities, which we relate to the EDL formation free energy. The differential capacitance obtained from our computations exhibits asymmetry about the potential of zero charge and is consistent with the camel-like profiles noted from mean field theories and experiments on metallic electrodes. The introduction of Li-salt reduces the noted asymmetry in the differential capacitance profile. Complementary experimental capacitance measurements have been made on our three electrolytes in their neat forms and with Li-salt. The measurements, performed on glassy carbon electrodes, produce U-like profiles, and Li-salt doping is shown to strongly affect capacitance at high magnitudes of Ψ. Differences in the theoretical and experimental shapes and magnitudes of capacitance are rationalized in terms of the electrode surface and pseudocapacitive effects. In both neat and Li-doped liquids, the details of the computational capacitance profile are well described by Ψ-induced changes in the density and molecular orientation of ions in the molecular layer closest to the electrode. Our results suggest that the addition of Li+ induces disorder in the EDL, which originates from the strong binding of anions to Li+. An in-depth analysis of the distribution of Li+ in the EDL reveals that it does not readily enter the molecular layer at the electrode surface, preferring instead to be localized farther away from the surface in the second molecular layer. This behavior is validated through an analysis of the free energy of Li+ solvation as a function of distance from the electrode. Free energy wells are found to coincide with localized concentrations of Li+, the depths of which increase with Ψ and suggest a source of impedance for Li+ to reach the electrode. Finally, we make predictions of the specific energy at ideal graphite utilizing the computed capacitance and previously derived electrochemical windows of the liquids.

Surgery for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetically determined cardiac disease characterised by otherwise unexplained myocardial hypertrophy of the left ventricle, and may result in left ventricular outflow tract obstruction. It is the most common cause of sudden cardiac death in young adults due to arrhythmias. Septal myectomy is a surgical treatment for HCM with moderate to severe outflow tract obstruction, and is indicated for patients with severe symptoms refractory to medical therapy. The surgical approach involves obtaining access to the interventricular septum via transaortic, transapical or transmitral approaches, and excising a portion of the hypertrophied myocardium to relieve the outflow tract obstruction. Large, contemporary series from centres experienced in septal myectomy patients have demonstrated a low early mortality of <2 %, excellent long-term survival that matches the general population, and durable relief of symptoms.

Computational and experimental investigation of Li-doped ionic liquid electrolytes: [pyr14][TFSI], [pyr13][FSI], and [EMIM][BF4].

We employ molecular dynamics (MD) simulation and experiment to investigate the structure, thermodynamics, and transport of N-methyl-N-butylpyrrolidinium bis(trifluoromethylsufonyl)imide ([pyr14][TFSI]), N-methyl-N-propylpyrrolidinium bis(fluorosufonyl)imide ([pyr13][FSI]), and 1-ethyl-3-methylimidazolium boron tetrafluoride ([EMIM][BF4]), as a function of Li-salt mole fraction (0.05 ≤ xLi(+) ≤ 0.33) and temperature (298 K ≤ T ≤ 393 K). Structurally, Li(+) is shown to be solvated by three anion neighbors in [pyr14][TFSI] and four anion neighbors in both [pyr13][FSI] and [EMIM][BF4], and at all levels of xLi(+) we find the presence of lithium aggregates. Pulsed field gradient spin-echo NMR measurements of diffusion and electrochemical impedance spectroscopy measurements of ionic conductivity are made for the neat ionic liquids as well as 0.5 molal solutions of Li-salt in the ionic liquids. Bulk ionic liquid properties (density, diffusion, viscosity, and ionic conductivity) are obtained with MD simulations and show excellent agreement with experiment. While the diffusion exhibits a systematic decrease with increasing xLi(+), the contribution of Li(+) to ionic conductivity increases until reaching a saturation doping level of xLi(+) = 0.10. Comparatively, the Li(+) conductivity of [pyr14][TFSI] is an order of magnitude lower than that of the other liquids, which range between 0.1 and 0.3 mS/cm. Our transport results also demonstrate the necessity of long MD simulation runs (∼200 ns) to converge transport properties at room temperature. The differences in Li(+) transport are reflected in the residence times of Li(+) with the anions (τ(Li/-)), which are revealed to be much larger for [pyr14][TFSI] (up to 100 ns at the highest doping levels) than in either [EMIM][BF4] or [pyr13][FSI]. Finally, to comment on the relative kinetics of Li(+) transport in each liquid, we find that while the net motion of Li(+) with its solvation shell (vehicular) significantly contributes to net diffusion in all liquids, the importance of transport through anion exchange increases at high xLi(+) and in liquids with large anions.

A rice-derived recombinant human lactoferrin stimulates fibroblast proliferation, migration, and sustains cell survival.

Human lactoferrin (hLF), a glycoprotein of the transferrin family, has recently been shown to stimulate wound repair through its antimicrobial effect and inflammation modulation. A recent study with several non-skin cell lines indicated that hLF may also have a stimulatory effect on cell proliferation. To explore the role of hLF in wound healing, we used recombinant human lactoferrin (holo-rhLF), derived from transgenic rice, to examine the effects of holo-rhLF on cell proliferation, migration, attachment, and survival in a human primary skin fibroblast culture system. This study revealed that holo-rhLF not only significantly stimulates fibroblast proliferation but also has synergistic effects with fibroblast growth factor-2 and antagonistic effects with transforming growth factor-beta1 on cell proliferation. Furthermore, using a chamber migration assay, our results demonstrate that holo-rhLF promotes fibroblast migration in a dosage-dependent manner. More importantly, holo-rhLF significantly increased cell viability and protected cells from death when they were stressed by either serum depletion or 12-O-tetradecanoylphorbol-13-acetate exposure. No significant effect was observed on cell attachment. In conclusion, these findings reveal the multiple functions of holo-rhLF in human skin fibroblasts and indicate its potential application in wound therapy by enhancing cell proliferation and migration as well as protecting cells from apoptosis.

Noninvasive electromagnetic fields on keratinocyte growth and migration.

BACKGROUND: Although evidence has shown that very small electrical currents produce a beneficial therapeutic result for wounds, noninvasive electromagnetic field (EMF) therapy has consisted mostly of anecdotal clinical reports, with very few well-controlled laboratory mechanistic studies. In this study, we evaluate the effects and potential mechanisms of a noninvasive EMF device on skin wound repair. MATERIALS AND METHODS: The effects of noninvasive EMF on keratinocytes and fibroblasts were assessed via proliferation and incisional wound model migration assays. cDNA microarray and RT-PCR were utilized to assess genetic expression changes in keratinocytes after noninvasive EMF treatment. RESULTS: In vitro analyses with human skin keratinocyte cultures demonstrated that noninvasive EMFs have a strong effect on accelerating keratinocyte migration and a relatively weaker effect on promoting keratinocyte proliferation. The positive effects of noninvasive EMFs on cell migration and proliferation seem keratinocyte-specific without such effects seen on dermal fibroblasts. cDNA microarray and RT-PCR performed revealed increased expression of CRK7 and HOXC8 genes in treated keratinocytes. CONCLUSIONS: This study suggests that a noninvasive EMF accelerates wound re-epithelialization through a mechanism of promoting keratinocyte migration and proliferation, possibly due to upregulation of CRK7 and HOXC8 genes.

N-linked oligosaccharides affect the enzymatic activity of CD39: diverse interactions between seven N-linked glycosylation sites.

Rat CD39, a membrane-bound ectonucleoside triphosphate diphosphohydrolase that hydrolyzes extracellular nucleoside tri- and diphosphates, has seven potential N-glycosylation sites at asparagine residues 73, 226, 291, 333, 375, 429, and 458. To determine their roles in the structure and function of CD39, we mutated these sites individually or in combination by replacing asparagine with serine or glutamine and analyzed the surface expression and the enzymatic activity of the mutants. The results indicate that rat CD39 can be glycosylated at all seven sites when expressed in COS7 cells. Glycosylation sites 73 at the N terminus, 333 in the middle, and 429 and 458 at the C terminus were principally required for cell surface appearance of enzymatically active CD39. Whereas deletion of these sites individually had modest effects on surface ATPase activity, some double deletions of these sites had major effects on both surface activity and expression. The importance of these N-glycosylation sites is recognizable in other members of the ectonucleoside triphosphate diphosphohydrolase family.