THERAPEUTIC MOLECULES

The present invention relates generally to a ligand for a protein associated with modulating obesity, diabetes and metabolic energy levels in animals including humans. More particularly, the present invention provides a ligand of the protein, Beacon, and its homologs. The identification of a Beacon ligand permits the identification of agents which agonize or antagonize the Beacon-ligand interaction and, hence, the development of therapeutic molecules useful in modulating obesity, diabetes and/or energy imbalance.

THERAPEUTIC MOLECULES

The present invention relates generally to a ligand for a protein associated with modulating obesity, diabetes and metabolic energy levels in animals including humans. More particularly, the present invention provides a ligand of the protein, Beacon, and its homologs. The identification of a Beacon ligand permits the identification of agents which agonize or antagonize the Beacon-ligand interaction and, hence, the development of therapeutic molecules useful in modulating obesity, diabetes and/or energy imbalance.

Therapeutic molecules

The present invention relates generally to a ligand for a protein associated with modulating obesity, diabetes and metabolic energy levels in animals including humans. More particularly, the present invention provides a ligand of the protein, Beacon, and its homologs. The identification of a Beacon ligand permits the identification of agents which agonize or antagonize the Beacon-ligand interaction and, hence, the development of therapeutic molecules useful in modulating obesity, diabetes and/or energy imbalance.

THERAPEUTIC MOLECULES

The present invention relates generally to a ligand for a protein associated with modulating obesity, diabetes and metabolic energy levels in animals including humans. More particularly, the present invention provides a ligand of the protein, Beacon, and its homologs. The identification of a Beacon ligand permits the identification of agents which agonize or antagonize the Beacon-ligand interaction and, hence, the development of therapeutic molecules useful in modulating obesity, diabetes and/or energy imbalance.

The suitability of polycystic ovary syndrome-specific questionnaires for measuring the impact of PCOS on quality of life in clinical trials

Objectives: Generic patient-reported outcome (PRO) measures underestimate the impact of polycystic ovary syndrome (PCOS) on quality of life (QoL). The aim of this review was to identify PCOS-specific QoL measures and establish whether their development history and measurement properties support their use in clinical trials.

Methods: A systematic search was conducted using terms synonymous with “PCOS” and “QoL.” Following identification of measures, further searches were undertaken using the questionnaire name and abbreviation to explore its use, development history, and demonstrated measurement properties.

Results: Of 56 abstracts screened, 21 reported using PRO measures. One PCOS-specific QoL measure was identified: the PolyCystic Ovary Syndrome Questionnaire (PCOSQ). Nine papers show that the PCOSQ’s development history is somewhat incomplete, and that it does not have good content validity. The PCOSQ subscales demonstrate acceptable levels of reliability (0.70–0.97) and partial known-groups validity as well as convergent/divergent validity with other PRO instruments. Responsiveness
to change is variable and minimally important differences have not been established.

Conclusions: The PCOSQ is the only condition-specific measure of the impact of PCOS on QoL. Additional research is required to ensure its comprehensiveness, sensitivity, and to guide interpretation prior to including in clinical trials.

HSP72 preserves muscle function and slows progression of severe muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin¹, ², ³. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca²⁺, which activates inflammatory and muscle degenerative pathways⁴, ⁵, ⁶. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death⁷, ⁸, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca²⁺) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.

The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications

In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness. Features of neuroprogression include poorer symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic–pituitary–adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence-based novel treatments informed by this knowledge are discussed.

Patient-reported outcomes in trials of incretin-based therapies in patients with type 2 diabetes mellitus

Incretin-based therapies have a glucose-dependent mode of action that results in excellent glucose-lowering efficacy with very low risk of hypoglycaemia, and weight neutrality [dipeptidyl peptidase-4 (DPP-4) inhibitors] or weight loss [glucagon-like peptide-1 (GLP-1) receptor agonists], in people with type 2 diabetes mellitus (T2DM). Patient-reported outcomes (PROs) complement physician evaluations of efficacy and tolerability and offer insights into the subjective experience of using modern diabetes treatments. We conducted a systematic search of clinical trials of the GLP-1 receptor agonists liraglutide, exenatide and long-acting exenatide, one of which included the oral DPP-4 inhibitor sitagliptin as a comparator. No other PRO data for DPP-4 inhibitors were identified. This review summarizes PRO data from eight clinical trials, the majority of which used the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and/or Impact of Weight on Quality of Life-Lite (IWQOL-Lite) to evaluate patient experience. People with T2DM were highly satisfied with modern incretin-based therapies compared with traditional therapies. Treatment satisfaction (including perceptions of convenience and flexibility) was high and generally higher with GLP-1 agonists in association with their greater glucose-lowering efficacy and tendency to facilitate weight loss. Weight-related quality of life (QoL) also improved in people using incretin therapies. The glycaemic improvements achieved with GLP-1 receptor agonists, coupled with the low incidence of hypoglycaemia and ability to cause weight loss, seemed to offset potential concern about injections. It is plausible that superior patient-reported benefits found in clinical trials may translate into improved, clinically meaningful, long-term outcomes through increased treatment acceptability. Long-term, prospective data are needed to ascertain whether this is the case in practice.

Patient use of smartphones to communicate subjective data in clinical trials

Purpose. Various methods have been used in clinical trials to collect time-sensitive subjective responses, including study diaries, telephone interviews, and use of text messaging. However, all of these methods are limited by the uncertainty of when the participants enrolled in the study actually record their responses. This technical note reports on the utility of the BlackBerry smartphone to collect such data and why such a system provides advantages over other methods to report subjective ratings in clinical studies.

Methods. The Centre for Contact Lens Research developed an on-line web-enabled system that permits participants to record and immediately transmit subjective rating scores in numerical form directly into a web-enabled database. This, combined with the utility of BlackBerrys, enabled time-specific e-mail requests to be sent to the study participants and then for that data to be simultaneously transmitted to the web-enabled database. This system has been used in several clinical trials conducted at the Centre for Contact Lens Research, in which data were collected at various times and in several specific locations or environments.

Results. In the clinical trials conducted using this system, participants provided responses on 97.5% of occasions to the requests for data generated by the automated system. When the request was for data on a set date, this method resulted in responses of 84.1% of the time.

Conclusions. The series of clinical trials reported here show the benefits of the utilization of the BlackBerry to collect time- or environment-sensitive data via a web-enabled system.

Neuroendocrine neoplasms of the GI tract : the role of cytotoxic chemotherapy

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of neoplasms derived from peptide- and amine-secreting cells of the neuroendocrine system. NENs commonly arise in the GI tract but can arise in most organs of the body. NENs in different organs share many common pathologic features. Although the incidence of NENs is not high, the prevalence is not low because many patients may live relatively long periods without major symptoms from the disease. While many of these tumors lead an indolent clinical course, they constitute a therapeutic challenge when they progress, metastasize and become symptomatic. Treatment requires a multidisciplinary approach including cytotoxic chemotherapy. Almost all clinical trials investigating cytotoxic chemotherapy in NENs are small single-arm studies and guidelines are derived from expert opinion and from extrapolating results from small cell lung cancer studies. This article briefly reviews NENs before focusing on reviewing data on the role of cytotoxic chemotherapy studies in NENs.

Aspirin : a review of its neurobiological properties and therapeutic potential for mental illness

There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory 'braking signals', including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor- and interleukin (IL)--6 , but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.

Prosecutors' perceptions of the utility of 'relationship' evidence in sexual abuse trials

For successful prosecution of sex offences, defined elements that comprise each charge (such as the acts that occurred and offenders’ identities) need to be established beyond reasonable doubt. This study explored the potential benefit (from a prosecution perspective) of eliciting another type of evidence; evidence regarding the relationship between the victim and perpetrator that may explain the victim’s responses.

Fourteen prosecutors representing every major Australian jurisdiction participated in individual interviews or a focus group where they were asked to reflect on the perceived relevance of relationship evidence in sex offence trials, and the potential impact of this evidence on court process and outcomes.

All prosecutors gave strong support for the premise of including relationship evidence in victim and witness statements, as well as in suspect interviews; however, this type of evidence was not routinely being included in interviews or admitted in trials.

The majority of the discussion centred on:

Role of immune-inflammatory and oxidative and nitrosative stress pathways in the etiology of depression: therapeutic implications

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immuneinflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and Nacetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS- targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders.

Bevacizumab for the treatment of high-grade glioma: an update after phase III trials.

Gliomas are highly vascular and rich in VEGF, which promotes angiogenesis. Bevacizumab is a monoclonal antibody against VEGF, inhibiting angiogenesis by preventing receptor activation. Early Phase II clinical trials using bevacizumab in both newly diagnosed and recurrent high-grade gliomas (HGG) showed promising results, but these have not been confirmed in recent Phase III trials. This review is an update including recently reported Phase II and III study results.

Cognitive dysfunction in depression - pathophysiology and novel targets

Major depressive disorder (MDD) is associated with cognitive dysfunction encompassing several domains, including memory, executive function, processing speed and attention. Cognitive deficits persist in a significant proportion of patients even in remission, compromising psychosocial functioning and workforce performance. While monoaminergic antidepressants may improve cognitive performance in MDD, most antidepressants have limited clinical efficacy. The overarching aims of this review were: (1) to synthesize extant literature on putative biological pathways related to cognitive dysfunction in MDD and (2) to review novel neurotherapeutic targets for cognitive enhancement in MDD. We found that reciprocal and overlapping biological pathways may contribute to cognitive dysfunction in MDD, including an hyperactive hypothalamic-pituitary-adrenal axis, an increase in oxidative and nitrosative stress, inflammation (eg, enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins, anti-inflammatory compounds, N-acetylcysteine, omega-3 poliunsaturated fatty acids, erythropoietin, thiazolidinediones, glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium. Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients. Despite having preclinical and/or preliminary evidences from trials suggesting possible efficacy as novel cognitive enhancing agents for MDD, no RCT to date was performed for most of the other therapeutic targets reviewed herein. In conclusion, multiple biological pathways are involved in cognitive dysfunction in MDD. RCTs testing genuinely novel pro-cognitive compounds for MDD are warranted.