Evaluation of the taste-masking effects of (2-hydroxypropyl)-β-cyclodextrin on ranitidine hydrochloride; a combined biosensor, spectroscopic and molecular modelling assessment

Taste assessment in an increasingly important aspect of formulation development, particularly for paediatric medications. Electronic taste sensing systems have the potential to offer a rapid, objective and safe method of taste assessment prior to the use of more costly human panels or animal models. In this study, the ability of the TS-5000Z taste sensing system to assess the taste masking efficiency of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CyD) complexes with ranitidine hydrochloride was evaluated in order to explore the potential of the biosensor approach as a means of assessing taste masking by inclusion complexation. Nuclear magnetic resonance (NMR) spectroscopy and molecular docking studies were employed to identify and examine the interaction between ranitidine hydrochloride and HP-β-CyD. Taste-masking efficiencies were determined by the Euclidean distance between taste-masked formulations and the pure drug substance on a PCA score plot. The results showed that with increasing molarity of HP-β-CyD in the formulation, the distance from ranitidine hydrochloride increased, thus indicating a significant difference between the taste of the formulation and that of the pure drug. NMR studies also provided strong supporting evidence for the complexation between HP-β-CyD and ranitidine hydrochloride, with the H3′ region of the former identified as the most likely binding site for the drug. Molecular docking studies suggested that the dimethylamino and diamine groups of the drug form direct hydrogen bonds with the hydroxyl oxygen atoms of HP-β-CyD, while the furan ring docks in close proximity to H3′. This study has demonstrated that the biosensor system may provide quantitative data to assess bitterness of inclusion complexes with HP-β-CyD, while spectroscopic and modelling studies may provide a mechanistic explanation for the taste masking process. This in turn suggests that there is a role for biosensor approaches in providing early screening for taste masking using inclusion complexation and that the combination with mechanistic studies may provide insights into the molecular basis of taste and taste masking

Is the Fate of Clinical Candidate Arry-520 Already Sealed? Predicting Resistance in Eg5–Inhibitor Complexes

Arry-520 is an advanced drug candidate from the Eg5 inhibitor class undergoing clinical evaluation in patients with relapsed or refractory multiple myeloma. Here we show by structural analysis that Arry-520 binds stoichiometrically to the motor domain of Eg5 in the conventional allosteric loop L5 pocket in a complex that suggests the same structural mechanism as other Eg5 inhibitors. We have previously shown that acquired resistance through mutations in the allosteric binding site located at loop L5 in the Eg5 structure appears to be independent of the inhibitors' scaffold, which suggests that Arry-520 will ultimately have the same fate. When Arry-520 was assessed in two cell lines selected for the expression of either Eg5(D130A) or Eg5(L214A) STLC-resistant alleles, mutations previously shown to convey resistance to this class of inhibitors, it was inactive in both. Surprisingly, when the cells were challenged with ispinesib, another Eg5 inhibitor, the Eg5(D130A) cells were resistant, but those expressing Eg5(L214A) were strikingly sensitive. Molecular dynamics simulations suggest that subtle differences in ligand binding and flexibility in both compound and protein may alter allosteric transmission from the loop L5 site that do not necessarily result in reduced inhibitory activity in mutated Eg5 structures. Whilst we predict that cells challenged with Arry-520 in the clinical setting are likely to acquire resistance through point mutations in the Eg5 binding site, the data for ispinesib suggests that this resistance mechanism is not scaffold independent as previously thought, and new inhibitors can be designed that retain inhibitory activity in these resistant cells

Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults

BACKGROUND: There is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus. METHODS: Records were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded. RESULTS: Two hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used. CONCLUSIONS: Our findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments. PROSPERO REGISTRATION: The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. Registered on 12 March 2015 revised on 15 March 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1399-9) contains supplementary material, which is available to authorized users

Conceptual Frameworks and Methods for Advancing Invasion Ecology

Invasion ecology has much advanced since its early beginnings. Nevertheless, explanation, prediction, and management of biological invasions remain difficult. We argue that progress in invasion research can be accelerated by, first, pointing out difficulties this field is currently facing and, second, looking for measures to overcome them. We see basic and applied research in invasion ecology confronted with difficulties arising from (A) societal issues, e.g., disparate perceptions of invasive species; (B) the peculiarity of the invasion process, e.g., its complexity and context dependency; and (C) the scientific methodology, e.g., imprecise hypotheses. To overcome these difficulties, we propose three key measures: (1) a checklist for definitions to encourage explicit definitions; (2) implementation of a hierarchy of hypotheses (HoH), where general hypotheses branch into specific and precisely testable hypotheses; and (3) platforms for improved communication. These measures may significantly increase conceptual clarity and enhance communication, thus advancing invasion ecology

Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations

Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the Nuclear Receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of PPARγ/NR1C3 and TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARαNR1C1 or PPARδNR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease

Oligodendroglia Are Particularly Vulnerable to Oxidative Damage After Neurotrauma In Vivo.

In the paper "Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo," we determined the extent of oxidative damage to specific cellular subpopulations and structures within regions vulnerable to secondary degeneration and assessed the effect this had on oligodendroglial function. Comparative assessment of oxidative damage demonstrated selective vulnerability of oligodendroglia, specifically oligodendrocyte progenitor cells (OPCs) to DNA oxidation in vivo. Immunohistochemical fate mapping along the oligodendroglial lineage showed a transient susceptibility of these cells to DNA oxidation, protein nitration, and lipid peroxidation, with mature oligodendrocytes derived immediately after injury more vulnerable to DNA oxidation than their counterparts existing at the time of injury or later derived. In situ hybridization demonstrated a reduction in myelin regulatory factor (MyRF) messenger RNA (mRNA) fluorescence in newly derived mature oligodendrocytes, suggesting a compromise in the production and maintenance of the myelin sheath in these cells. The data imply a deficit in the normal differentiation of OPCs to myelinating oligodendrocytes, associated with a transient increase in oxidative damage, which may contribute to the dysmyelinating phenotype seen at chronic time points after injury. Identifying and understanding the sources of this oxidative damage is integral for the development of therapeutic interventions for neurotrauma

Epstein Barr Virus-positive large T-cell lymphoma presenting as acute appendicitis 17 years after cadaveric renal transplant: a case report

<p>Abstract</p> <p>Introduction</p> <p>The majority of post-transplant lymphoproliferative disorders in renal transplant patients are of the B-cell phenotype, while the T-cell phenotype is rare. We report a case of Epstein Barr Virus-positive, T-cell lymphoma in a renal transplant patient, presenting unusually as acute appendicitis.</p> <p>Case presentation</p> <p>A 45-year-old Hispanic male renal transplant patient presented with right-side abdominal pain 17 years after transplant. The laboratory studies were unremarkable. Laparoscopic exploration showed an inflamed appendix so a laparoscopic appendectomy was performed. Pathology of the appendix showed large cells positive for CD3, CD56 and Epstein Barr Virus-encoded RNA staining, and negative for CD20 and CD30. The tissue tested positive for T-cell receptor gene rearrangement by polymerase chain reaction analysis. Treatment management involved reduction of immunosuppression and initiation of chemotherapy with cisplatin, etoposide, gemcitabine, and solumedrol followed by cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone). He recovered and the allo-grafted kidney is fully functional.</p> <p>Conclusion</p> <p>We report a rare case of post-renal transplant large T-cell lymphoma, with an unusual presentation of acute appendicitis and Epstein Barr Virus-positivity, which responded well to chemotherapy.</p

Modular synthesis of functional libraries by accelerated SuFEx click chemistry

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery

Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina

Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD.NON-H2-nb1 at embryonic day 18.5 (E18.5) and postnatal day 30.5 (P30.5). Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases

Integrated Information in Discrete Dynamical Systems: Motivation and Theoretical Framework

This paper introduces a time- and state-dependent measure of integrated information, φ, which captures the repertoire of causal states available to a system as a whole. Specifically, φ quantifies how much information is generated (uncertainty is reduced) when a system enters a particular state through causal interactions among its elements, above and beyond the information generated independently by its parts. Such mathematical characterization is motivated by the observation that integrated information captures two key phenomenological properties of consciousness: (i) there is a large repertoire of conscious experiences so that, when one particular experience occurs, it generates a large amount of information by ruling out all the others; and (ii) this information is integrated, in that each experience appears as a whole that cannot be decomposed into independent parts. This paper extends previous work on stationary systems and applies integrated information to discrete networks as a function of their dynamics and causal architecture. An analysis of basic examples indicates the following: (i) φ varies depending on the state entered by a network, being higher if active and inactive elements are balanced and lower if the network is inactive or hyperactive. (ii) φ varies for systems with identical or similar surface dynamics depending on the underlying causal architecture, being low for systems that merely copy or replay activity states. (iii) φ varies as a function of network architecture. High φ values can be obtained by architectures that conjoin functional specialization with functional integration. Strictly modular and homogeneous systems cannot generate high φ because the former lack integration, whereas the latter lack information. Feedforward and lattice architectures are capable of generating high φ but are inefficient. (iv) In Hopfield networks, φ is low for attractor states and neutral states, but increases if the networks are optimized to achieve tension between local and global interactions. These basic examples appear to match well against neurobiological evidence concerning the neural substrates of consciousness. More generally, φ appears to be a useful metric to characterize the capacity of any physical system to integrate information