Emerging therapies for overactive bladder: preclinical, phase I and phase II studies.

INTRODUCTION: Overactive bladder syndrome is a common chronic condition with a significant impact on quality of life and economic burden. Persistence with pharmacologic therapy has been limited by efficacy and side effects. A greater understanding of the pathophysiology of overactive bladder has led to the initial evaluation of several drugs affecting ion channels, the autonomic nervous system, and enzymes which may provide useful alternatives for the management of overactive bladder. AREAS COVERED: A comprehensive review was performed using PubMed and Cochrane databases as well as reviewing clinical trials in the United States. The current standard of care for overactive bladder will be discussed, but this paper focuses on investigational drugs currently in preclinical studies and phase I and II clinical trials. EXPERT OPINION: Current therapies for overactive bladder have limitations in efficacy and side effects. A greater understanding of the pathophysiology of overactive bladder has identified the role(s) of other pathways in the overactive bladder syndrome. Targeting alternative pathways including ion channels and enzymes may provide alternative therapies of overactive bladder and a more tailored approach to the management of overactive bladder.

Multi-Marker Immunofluorescent Staining and PD-L1 Detection on Circulating Tumour Cells from Ovarian Cancer Patients.

Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining protocol was developed and tested using SKOV-3 and OVCA432 OC cell lines. We targeted epithelial (cytokeratin (CK) and EpCAM), mesenchymal (vimentin), and OC-specific (PAX8) markers for detection of CTCs, and CD45/16 and CD31 were used for the exclusion of white blood and vascular endothelial cells, respectively. PD-L1 was used for CTC characterisation. CTCs were enriched using the Parsortix™ system from 16 OC patients. Results revealed the presence of CTCs in 10 (63%) cases. CTCs were heterogeneous, with 113/157 (72%) cells positive for CK/EpCAM (epithelial marker), 58/157 (37%) positive for vimentin (mesenchymal marker), and 17/157 (11%) for both (hybrid). PAX8 was only found in 11/157 (7%) CTCs. In addition, 62/157 (39%) CTCs were positive for PD-L1. Positivity for PD-L1 was significantly associated with the hybrid phenotype when compared with the epithelial (p = 0.007) and mesenchymal (p = 0.0009) expressing CTCs. Characterisation of CTC phenotypes in relation to clinical outcomes is needed to provide insight into the role that epithelial to mesenchymal plasticity plays in OC and its relationship with PD-L1.

Dihalohydration of Alkynols: A Versatile Approach to Diverse Halogenated Molecules.

In this paper we outline how dihalohydration reactions of propargylic alcohols can be used to access a wide variety of useful halogenated building blocks. A novel procedure for dibromohydration of alkynes has been developed, and a selection of dichloro and dibromo diols and cyclic ethers were synthesized. The dihalohydration of homo-propargylic alcohols provides a useful route to 3-halofurans, which were shown to readily undergo cycloaddition reactions under mild conditions. Finally, a novel ring expansion of propargylic alcohols containing a cyclopropylalkyne provides access to halogenated alkenylcyclobutanes.

Unplanned oncology admissions within 14 days of non-surgical discharge: a retrospective study.

AIM: The aim of this study was to identify the incidence, causes, risk factors and interventions for cancer patients requiring unplanned admissions within 14 days of discharge at a large metropolitan private hospital without a co-located emergency department. METHODS: Retrospective data were collected on cancer patients who had an unplanned admission within 14 days of discharge during the period December 1, 2011 and May 31, 2012. Data were collected from the inpatient bed administration database and medical record review. Variables collected included demographics, cancer diagnosis, reasons for admission, interventions, and length of stay. RESULTS: A total of 133 oncology patients required 206 unplanned admissions (UPAs). The most common cancer diagnoses associated with unplanned readmission were upper gastrointestinal (25.4%), colorectal (19.6%), gynaecological (18.8%) and breast (13.8%) cancers. The symptoms most commonly associated with unplanned re-admission were pain (16%); infection not associated with neutropaenia (15.5%); fever and febrile neutropaenia (14.6%); nausea, vomiting and dehydration (13.6%); dyspnoea (8.3%) and altered neurological status (7.8%). The median length of stay (LOS) was 6 days. Length of stay during UPA was decreased for patients with a partner and for those who had a palliative care consult. The need for psychological supports was related to a longer LOS during UPA. CONCLUSION: Cancer patients are at a significant risk of requiring unscheduled care and admission. Strategies and services to limit the burden on patients and the health care system should be reviewed to minimise the incidence of unplanned admission.

Intercepting the Gold-Catalysed Meyer-Schuster Rearrangement by Controlled Protodemetallation: A Regioselective Hydration of Propargylic Alcohols.

The regioselective gold-catalysed hydration of propargylic alcohols to ß-hydroxy ketones can be achieved by diverting the gold-catalysed Meyer-Schuster rearrangement through the addition of a protic additive with a pKa of 7-9 such as p-nitrophenol, boric acid or a boronic acid. This provides an interesting alternative to an aldol reaction when combined with the straightforward addition of an alkyne to an aldehyde or ketone. The gold-catalysed reaction of an electron-deficient, sterically hindered propargylic alcohol with a boronic acid led to the formation of an unusually stable cyclic boron enolate.

A lactate-derived chiral aldehyde for determining the enantiopurity of enantioenriched primary amines.

In this paper we describe the use of a chiral aldehyde derived from lactate esters for determining the enantiopurity of primary amines, via the formation of diastereomeric imines. The method was shown to be suitable for reproducibly determining the enantiopurity of a diverse set of chiral amines. Both enantiomers of the aldehyde can be prepared in two steps from commercially available materials.

Expanding the scope of N → S acyl transfer in native peptide sequences.

Understanding the factors that influence N → S acyl transfer in native peptide sequences, and discovery of new reagents that facilitate it, will be key to expanding its scope and applicability. Here, through a study of short model peptides in thioester formation and cyclisation reactions, we demonstrate that a wider variety of Xaa-Cys motifs than originally envisaged are capable of undergoing efficient N → S acyl transfer. We present data for the relative rates of thioester formation and cyclisation for a representative set of amino acids, and show how this expanded scope can be applied to the production of the natural protease inhibitor Sunflower Trypsin Inhibitor-1 (SFTI-1).

Why did I right that? Factors that influence the production of homophone substitution errors.

Despite considerable research on language production errors involving speech, little research exists in the complementary domain of writing. Two experiments investigated the production of homophone substitution errors, which occur when a contextually appropriate word (e.g., beech) is replaced with its homophone (e.g., beach tree). Participants wrote down auditorily presented sentences containing dominant or subordinate homophones. Homophones were preceded by a lexical prime that overlapped in phonology and orthography (e.g., teacher) or only orthography (e.g., headmaster) with the target homophone. Results showed more substitution errors when the context elicited a subordinate homophone than when it elicited a dominant homophone. Furthermore, both types of primes equivalently increased production of homophone errors relative to control words (e.g., lawyer), suggesting that only orthographic overlap between the prime and target was necessary to influence errors. These results are explained within dual-route models of spelling, which postulate an interaction between lexical and sublexical routes when spelling.