Linear Viscoelasticity and Time—Alcohol Superposition of Chitosan/Hyaluronic Acid Complex Coacervates

Complex coacervation is an associative liquid−liquid phase separation phenomenon resulting from the complexation of oppositely charged macroions. While it is well-known that the phase behavior and rheological character of the resulting coacervates can vary as a function of the identity of the various species present (i.e., macroions, salt, and solution conditions), the effect of solvent quality has been rarely studied. Here, the effect of adding small amounts of either methanol or ethanol to complex coacervates of the natural polymers chitosan and hyaluronic acid is described. The effect of cosolvent addition on the phase behavior and linear viscoelasticity of the resulting coacervates is characterized. Lastly, we explore the potential for using not only time−salt superposition but also time−alcohol and time−salt−alcohol superposition to provide insight into coacervate rheology

Understanding The Electrospinability Of Complex Coacervates

Complex coacervation is an associative, liquid-liquid phase separation that is driven by the electrostatic and entropic interactions between oppositely-charged polymers in water. For many coacervating systems it is possible to transition from the liquid coacervate state to a solid material by removing salt. This ‘saloplasticity’ allows for the processing of materials via methods such as spin coating, extrusion, etc. using the coacervate phase as a liquid precursor. In particular, we have developed an approach that uses complex coacervation as an environmentally friendly method for fabricating ultra-stable electrospun fibers directly from aqueous solutions. We have used this method to electrospin complexes of various synthetic polymers as well as natural biopolymers. These efforts have required the simultaneous exploration of the phase behavior of coacervate formation, as well as the rheology of the liquid coacervates

Electrospinning complex coacervates

As polymer-based materials become ever more integrated into our daily lives, there is an increasing need to develop both materials that are safe for the consumer, and manufacturing strategies that have a minimal impact on the environment. However, the vast majority of polymers require either organic solvents for dissolution, or the use of potentially cytotoxic cross-linking agents to prevent material dissolution. Additionally, many of the chemistries and solution conditions necessary for processing can damage cargo molecules and create biocompatibility issues for subsequent use. Complex coacervation is an associative, liquid-liquid phase separation that has the potential to circumvent many of the challenges associated with processing traditional polymers and encapsulating actives. Complex coacervation is driven by the electrostatic and entropic interactions between oppositely-charged polymers in water. For many coacervating systems, the solid or liquid nature of the complex can be tuned via the concentration of salt present. Additionally, the strength of the electrostatic interactions within the complex are such that in the absence of salt, solid complexes are highly resistant to thermal melting and/or solvent dissolution. Furthermore, complex coacervation has a strong history of use for the encapsulation of a range of cargo. We have taken advantage of this salt-driven plasticity to enable fabrication of ultra-stable electrospun fibers directly from aqueous solutions. These efforts have required the simultaneous characterization of coacervation, as well as the effect of cargo molecules on the phase behavior and rheology of the resulting coacervates/precursor solutions. Furthermore, these materials show tremendous promise for the use of electrospun coacervate-based nanofiber meshes across a range of applications

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase study

Background: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. Methods: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Findings: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0.0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0.43 [95% CI 0.32-0.58]; median progression-free survival 14.6 months [95% CI 10.4-not estimable] vs 6.2 months [4.2-7.9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Interpretation: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma

Clinical application of a template-guided automated planning routine

PURPOSE: Determine the dosimetric quality and the planning time reduction when utilizing a template-based automated planning application. METHODS: A software application integrated through the treatment planning system application programing interface, QuickPlan, was developed to facilitate automated planning using configurable templates for contouring, knowledge-based planning structure matching, field design, and algorithm settings. Validations are performed at various levels of the planning procedure and assist in the evaluation of readiness of the CT image, structure set, and plan layout for automated planning. QuickPlan is evaluated dosimetrically against 22 hippocampal-avoidance whole brain radiotherapy patients. The required times to treatment plan generation are compared for the validations set as well as 10 prospective patients whose plans have been automated by QuickPlan. RESULTS: The generations of 22 automated treatment plans are compared against a manual replanning using an identical process, resulting in dosimetric differences of minor clinical significance. The target dose to 2% volume and homogeneity index result in significantly decreased values for automated plans, whereas other dose metric evaluations are nonsignificant. The time to generate the treatment plans is reduced for all automated plans with a median difference of 9\u27 50″ ± 4\u27 33″. CONCLUSIONS: Template-based automated planning allows for reduced treatment planning time with consistent optimization structure creation, treatment field creation, plan optimization, and dose calculation with similar dosimetric quality. This process has potential expansion to numerous disease sites

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P&lt;0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation

miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ~22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation

Subchondral pre-solidified chitosan/blood implants elicit reproducible early osteochondral wound-repair responses including neutrophil and stromal cell chemotaxis, bone resorption and repair, enhanced repair tissue integration and delayed matrix deposition

Background: In this study we evaluated a novel approach to guide the bone marrow-driven articular cartilage repair response in skeletally aged rabbits. We hypothesized that dispersed chitosan particles implanted close to the bone marrow degrade in situ in a molecular mass-dependent manner, and attract more stromal cells to the site in aged rabbits compared to the blood clot in untreated controls. Methods: Three microdrill hole defects, 1.4 mm diameter and 2 mm deep, were created in both knee trochlea of 30 month-old New Zealand White rabbits. Each of 3 isotonic chitosan solutions (150, 40, 10 kDa, 80% degree of deaceylation, with fluorescent chitosan tracer) was mixed with autologous rabbit whole blood, clotted with Tissue Factor to form cylindrical implants, and press-fit in drill holes in the left knee while contralateral holes received Tissue Factor or no treatment. At day 1 or day 21 post-operative, defects were analyzed by micro-computed tomography, histomorphometry and stereology for bone and soft tissue repair. Results: All 3 implants filled the top of defects at day 1 and were partly degraded in situ at 21 days post-operative. All implants attracted neutrophils, osteoclasts and abundant bone marrow-derived stromal cells, stimulated bone resorption followed by new woven bone repair (bone remodeling) and promoted repair tissue-bone integration. 150 kDa chitosan implant was less degraded, and elicited more apoptotic neutrophils and bone resorption than 10 kDa chitosan implant. Drilled controls elicited a poorly integrated fibrous or fibrocartilaginous tissue. Conclusions: Pre-solidified implants elicit stromal cells and vigorous bone plate remodeling through a phase involving neutrophil chemotaxis. Pre-solidified chitosan implants are tunable by molecular mass, and could be beneficial for augmented marrow stimulation therapy if the recruited stromal cells can progress to bone and cartilage repair