Observation of transition cascades in sheared liquid crystalline polymers.

We report on the shear rheology of liquid crystalline solutions composed of charged, rodlike polymers that form supramolecular assemblies dispersed in water. Under steady shear, we observe shear thickening behavior, followed by a hesitation in the viscosity accompanied by an extremely narrow range of negative first normal stress difference. The Peclet number (Pe, shear rate normalized by rod rotational diffusivity) for the onset of shear thickening is in agreement with previous, high-resolution numerical simulations of the Doi-Edwards-Hess kinetic theory. We interrogate these dynamic responses through shear step-down experiments, revealing a complex evolution of transient responses. Detailed analysis of the stress transients provides compelling evidence that the principal axis of the rod orientational distribution, the nematic director, undergoes a cascade of transitions and coexistence of periodic states known as kayaking, tumbling, and wagging, before transitioning to steady flow alignment above a critical shear rate.

High-Strength Liquid Crystal Polymer-Graphene Oxide Nanocomposites from Water.

We report on the morphology and mechanical properties of nanocomposite films derived from aqueous, hybrid liquid crystalline mixtures of rodlike aggregates of a sulfonated, all-aromatic polyamide, poly(2,2'-disulfonyl-4,4'-benzidine terephthalamide) (PBDT), and graphene oxide (GO) platelets. An isothermal step at 200 °C facilitates in situ partial thermal reduction of GO to reduced GO (rGO) in nanocomposite films. X-ray scattering studies reveal that PBDT-rGO nanocomposites exhibit both higher in-plane alignment of PBDT (the order parameter increases from 0.79 to 0.9 at 1.8 vol % rGO) and alignment along the casting direction (from 0.1 to 0.6 at 1.8 vol % rGO). From dynamic mechanical thermal analysis, the interaction between PBDT and rGO causes the ß-relaxation activation energy for PBDT to increase with rGO concentration. Modulus mapping of nanocomposites using atomic force microscopy demonstrates enhanced local stiffness, indicating reinforcement. From stress-strain analysis, the average Young's modulus increases from 16 to 37 GPa at 1.8 vol % rGO and the average tensile strength increases from 210 to 640 MPa. Despite polymer alignment along the casting direction, an average transverse tensile strength of 230 MPa is obtained.

A mucoadhesive biodissolvable thin film for localized and rapid delivery of lidocaine for the treatment of vestibulodynia.

Vestibulodynia (VBD), an idiopathic pain disorder characterized by erythema and pain of the vulvar vestibule (the inner aspect of the labia minora and vaginal opening), is the most common cause of sexual pain for women of reproductive age. Women also feel discomfort with contact with clothing and tampon use. As most women with this disorder only have pain with provocation of the tissue, topical anesthetics applied to the vestibule are the current first line treatment for temporary pain relief. Treatment options are limited due to anatomical constraints of the vestibular region, poor drug retention time, imprecise dosing, leakage, and overall product messiness. In this study we report a novel approach to treatment of VBD using thin film designed to fit the vulvar vestibule and deliver lidocaine locally. Two use cases for VBD treatment were identified 1) rapid drug release (<5 min), for use prior to intercourse and 2) long-acting release (≥120 min) for prolonged use and relief throughout the day. Cellulose-based mucoadhesive thin films were fabricated using a solvent casting method. Three polymers including hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethycellulose (HMPC), were selected owing to their biocompatibility and ideal properties for film casting. Films casted with HEC, HPC, and HPMC exhibited mucoadhesive properties relative to a control, with the highest mucoadhesive force recorded for films casted with HPC. Effect of media volume, pH, presence of mucin and presence of drug on film dissolution rates were investigated. Dissolution rates were independent of media volume, media pH or drug presence, whereas faster dissolution rates were obtained for all films in presence of mucin. In vitro lidocaine release kinetics were influenced by polymer type, percent drug loading and film casting thickness. Lidocaine release was based on a diffusion mechanism rather than through film dissolution and faster release (∼5 min) was observed for HEC films compared HPC films (∼120 min). Higher drug loading and film thickness resulted in slower and more prolonged release kinetics of lidocaine. All films were biocompatible and exhibited good mechanical properties. Two film formulations (9% w/w HPC with 12% w/w LHC, 5% w/w HEC with 6% w/w LHC) were optimized to meet the two use case scenarios for VBD treatment and moved into in vivo testing. In vivo testing demonstrated the safety of the films in BALB/c mice, and the pharmacokinetic analysis demonstrated the delivery of lidocaine primarily to the vaginal tissue. We demonstrate the ability to develop a mucoadhesive, biodissolvable thin film and fine-tune drug release kinetics to optimize local delivery of lidocaine to the vulva.

Irreversible Shear-Activated Gelation of a Liquid Crystalline Polyelectrolyte.

We report irreversible, shear-activated gelation in liquid crystalline solutions of a rigid polyelectrolyte that forms rodlike assemblies (rods) in salt-free solution. At rest, the liquid crystalline solutions are kinetically stable against gelation and exhibit low viscosities. Under steady shear at, or above, a critical shear rate, a physically cross-linked, nematic gel network forms due to linear growth and branching of the rods. Above a critical shear rate, the time scale of gelation can be tuned from hours to nearly instantaneously by varying the shear rate and solution concentration. The shear-activated gels are distinct in their structure and rheological properties from thermoreversible gels. At a fixed concentration, the induction time prior to gelation decreases exponentially with the shear rate. This result indicates that shear-activated thermalization of the electrostatically stabilized rods overcomes the energy barrier for rod-rod contact, enabling rod fusion and subsequent irreversible network formation.

Strong graphene oxide nanocomposites from aqueous hybrid liquid crystals.

Combining polymers with small amounts of stiff carbon-based nanofillers such as graphene or graphene oxide is expected to yield low-density nanocomposites with exceptional mechanical properties. However, such nanocomposites have remained elusive because of incompatibilities between fillers and polymers that are further compounded by processing difficulties. Here we report a water-based process to obtain highly reinforced nanocomposite films by simple mixing of two liquid crystalline solutions: a colloidal nematic phase comprised of graphene oxide platelets and a nematic phase formed by a rod-like high-performance aramid. Upon drying the resulting hybrid biaxial nematic phase, we obtain robust, structural nanocomposites reinforced with graphene oxide.

Nanofibrillar Ionic Polymer Composites Enable High-Modulus Ion-Conducting Membranes.

Polymer electrolyte membranes (PEMs) with high volume fractions of ionic liquids (IL) and high modulus show promise for enabling next-generation gas separations, and electrochemical energy storage and conversion applications. Herein, we present a conductive polymer-IL composite based on a sulfonated all-aromatic polyamide (sulfo-aramid, PBDT) and a model IL, which we term a PBDT-IL composite. The polymer forms glassy and high-aspect-ratio hierarchical nanofibrils, which enable fabrication of PEMs with both high volume fractions of IL and high elastic modulus. We report direct evidence for nanofibrillar networks that serve as matrices for dispersed ILs using atomic force microscopy and small- and wide-angle X-ray scattering. These supramolecular nanofibrils form through myriad noncovalent interactions to produce a physically cross-linked glassy network, which boasts the best combination of room-temperature modulus (0.1-2 GPa) and ionic conductivity (8-4 mS cm-1) of any polymer-IL electrolyte reported to date. The ultrahigh thermomechanical properties of our PBDT-IL composites provide high moduli (∼1 GPa) at temperatures up to 200 °C, enabling a wide device operation window with stable mechanical properties. Together, the high-performance nature of sulfo-aramids in concert with the inherent properties of ILs imparts PBDT-IL composites with nonflammability and thermal stability up to 350 °C. Thus, nanofibrillar ionic networks based on sulfo-aramids and ILs represent a new design paradigm affording PEMs with exceptionally high moduli at exceedingly low polymer concentrations. This new design strategy will drive the development of new high-performance conductive membranes that can be used for the design of gas separation membranes and in electrochemical applications, such as fuel cells and Li-metal batteries.

Co-Expression of VEGF and IL-6 Family Cytokines is Associated with Decreased Survival in HER2 Negative Breast Cancer Patients: Subtype-Specific IL-6 Family Cytokine-Mediated VEGF Secretion.

Breast cancer cell-response to inflammatory cytokines such as interleukin-6 (IL-6) and oncostatin M (OSM) may affect the course of clinical disease in a cancer subtype-dependent manner. Furthermore, vascular endothelial growth factor A (VEGF) secretion induced by IL-6 and OSM may also be subtype-dependent. Utilizing datasets from Oncomine, we show that poor survival of invasive ductal carcinoma (IDC) breast cancer patients is correlated with both high VEGF expression and high cytokine or cytokine receptor expression in tumors. Importantly, epidermal growth factor receptor-negative (HER2-), but not HER2-positive (HER2+), patient survival is significantly lower with high tumor co-expression of VEGF and OSM, OSMRß, IL-6, or IL-6Rα compared to low co-expression. Furthermore, assessment of HER2- breast cancer cells in vitro identified unique signaling differences regulating cytokine-induced VEGF secretion. The levels of VEGF secretion were analyzed by ELISA with siRNAs for hypoxia inducible factor 1 α (HIF1α) and signal transducer and activator of transcription 3 (STAT3). Specifically, we found that estrogen receptor-negative (ER-) MDA-MB-231 cells respond only to OSM through STAT3 signaling, while ER+ T47D cells respond to both OSM and IL-6, though to IL-6 to a lesser extent. Additionally, in the ER+ T47D cells, OSM signals through both STAT3 and HIF1α. These results highlight that the survival of breast cancer patients with high co-expression of VEGF and IL-6 family cytokines is dependent on breast cancer subtype. Thus, the heterogeneity of human breast cancer in relation to IL-6 family cytokines and VEGF may have important implications in clinical treatment options, disease progression, and ultimately patient prognosis.

Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4).

GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.

Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.

Investigation of interfacial properties of pure and mixed poloxamers for surfactant-mediated shear protection of mammalian cells.

The Poloxamer family of surfactants are commonly used in the biopharmaceutical industry as cell culture media additives to protect cells from the turbulent environment of sparged bioreactors. Despite the widespread use of poloxamers in cell culture, their performance as cell protectants varies depending on their physical structure, molecular weight, and batch-to-batch composition. In this study, the interfacial properties of Poloxamer 188 (P188), Poloxamer 407 (P407), and a mixture of P188 and P407 were characterized to investigate the mechanism of surfactant-mediated shear protection of mammalian cells. The foam stability and equilibrium surface tension of these surfactant systems correlated with their ability to mitigate physical damage to cells in a turbulent environment. We demonstrate that while P188 can function as highly effective shear protectant, the presence of a surface-active contaminant can greatly hinder its protective characteristics. P407 was found to function as such an interfacially active "impurity," disrupting shear protection when mixed with P188 by preferentially adsorbing to the gas-liquid and membrane-liquid interface. Addition of surface-active impurities altered the interfacial properties of the surfactant system and could be detected using an equilibrium surface tension assay. The mechanism of disruption by P407 was determined to be independent of cell-to-bubble attachment, suggesting that poloxamer adsorption to and subsequent reinforcement of the cell membrane may play a key role in protecting cells in high shear environments. This investigation contributes to our understanding of the mechanism of surfactant-mediated shear protection of cells and demonstrates that a surface tension assay can be utilized as a screening tool to ensure that poloxamer lots are free of surface active impurities.

Crystal structure of 2,3-diphenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one 1-oxide.

In the racemic title compound, C20H15NO2S, the planes of the two phenyl substituents form dihedral angles of 48.97 (15) and 69.26 (15)° with that of the fused benzene ring of the parent benzo-thia-zine ring, while the heterocyclic thia-zine ring exhibits a screw-boat pucker. The O atom on the S atom of the ring is pseudo-axial on the thia-zine ring and trans to the 2-phenyl group. In the crystal, mol-ecules are arranged in layers in the ac plane, the layers being linked across b through inter-molecular C-H⋯O hydrogen-bonding inter-actions.

Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4.

Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4'-bipiperidin-1'-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, 28) after addressing an unexpected off-target cardiovascular liability observed from in vivo studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both in vitro and in vivo.

Crystal structure of the 1:1 adduct of 2,3-diphenyl-3,4,5,6-tetra-hydro-2H-1,3-thia-zin-4-one with tri-phenyl-tin chloride.

The title adduct, chlorido-(2,3-diphenyl-3,4,5,6-tetra-hydro-2H-1,3-thia-zin-4-one-κO)tri-phenyl-tin, [Sn(C6H5)3Cl(C16H15NOS)], resulted from reaction of 2,3-diphenyl-3,4,5,6-tetra-hydro-2H-1,3-thia-zin-4-one with tri-phenyl-tin chloride. The thia-zine ring has an envelope conformation with the S atom forming the flap. The mol-ecule has five phenyl rings, two of them attached to the thia-zine ring at positions 2 and 3, and three in coordination with the Sn(IV) atom. The three rings of the tri-phenyl-tin group are involved in intra-molecular inter-actions of different types, C-H⋯O, edge-to-face (or T-type) π-π inter-actions with the 3-phenyl ring of the thia-zine, T-type inter-actions with both phenyl rings of the thia-zine etc. On the other hand, all the phenyl rings participate in inter-molecular π-π inter-actions. There is one instance of a 'parallel-displaced'-type inter-action extending continuously along the a-axis direction and seven instances of T-type inter-actions stabilizing the crystal lattice.

Urethral catheters and medical malpractice: a legal database review from 1965 to 2015.

BACKGROUND: Urethral catheters (UCs) are commonly used in medicine and are associated with complications such as urinary tract infections (UTIs) and trauma. Given UC complications and their ubiquitous usage in healthcare, there is a potential for liability risk. We aim to explore litigation involving UC-related complications. METHODS: The LexisNexis legal database was queried for all state and federal cases from January 1965 through October 2015 using the terms "urethral catheter" or "Foley catheter" in combination with "medical malpractice", "negligence", "medical error", and "trauma". Each case was reviewed for reported medical characteristics and legal aspects, including the outcome of the case. RESULTS: Our search yielded 29 cases. Urologists were the most common providers cited as defendants (21%), all of whom were successful in their defense. The most common malpractice claim was for traumatic insertion (48%). Pain was the most common type of damage claimed by plaintiffs (28%), followed by UTI (24%). Nineteen (66%) cases favored defendants, while 10 (34%) cases favored the plaintiffs, of which 2 (7%) were settled out of the court. In settled cases, the mean settlement received by plaintiffs was $55,750 (range, $25,000-$86,500). The mean award to plaintiffs for cases determined by the court was $112,991 (range, $4,000-$325,000). CONCLUSIONS: Despite widespread usage of UC over a 50-year period, lawsuits centered on UC misuse are rare at the state and federal court levels. Of litigated cases, urologists are commonly involved yet have successful defenses.

Tissue regeneration of the vocal fold using bone marrow mesenchymal stem cells and synthetic extracellular matrix injections in rats.

OBJECTIVES/HYPOTHESIS: To determine the effectiveness of bone marrow mesenchymal stem cell (BM-MSC) transplantation in isolation or within a synthetic extracellular matrix (sECM) for tissue regeneration of the scarred vocal fold lamina propria. METHODS: In vitro stability and compatibility of mouse BM-MSC embedded in sECM was assessed by flow cytometry detection of BM-MSC marker expression and proliferation. Eighteen rats were subjected to vocal fold injury bilaterally, followed by 1 month post-treatment with unilateral injections of saline or sECM hydrogel (Extracel; Glycosan BioSystems, Inc., Salt Lake City, UT), green fluorescence protein (GFP)-mouse BM-MSC, or BM-MSC suspended in sECM. Outcomes measured 1 month after treatment included procollagen-III, fibronectin, hyaluronan synthase-III (HAS3), hyaluronidase (HYAL3), smooth muscle actin (SMA), and transforming growth factor-beta 1(TGF-beta1) mRNA expression. The persistence of GFP BM-MSC, proliferation, apoptosis, and myofibroblast differentiation was assessed by immunofluorescence. RESULTS: BM-MSC grown in vitro within sECM express Sca-1, are positive for hyaluronan receptor CD44, and continue to proliferate. In the in vivo study, groups injected with BM-MSC had detectable GFP-labeled BM-MSC remaining and showed proliferation and low apoptotic or myofibroblast markers compared to the contralateral side. Embedded BM-MSC in the sECM group exhibited increased levels of procollagen III, fibronectin, and TGF-beta1. BM-MSC within sECM downregulated the expression of SMA compared to BM-MSC alone and exhibited upregulation of HYAL3 and no change in HAS3 compared to saline. CONCLUSIONS: Treatment of vocal fold scarring with BM-MSC injected in a sECM displayed the most favorable outcomes in ECM production, hyaluronan metabolism, myofibroblast differentiation, and production of TGF-beta1. Furthermore, the combined treatment had no detectable cytotoxicity and preserved local cell proliferation.