Actions of Octocoral and Tobacco Cembranoids on Nicotinic Receptors

Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as antitumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies

Design and development of a low-cost, electricity-generating cooking Score-Stove™

SCORE (www.score.uk.com) a US$4M, 5 year international collaboration research project aims to improve the life quality of the 1.5 billion people worldwide who cook on an open fire and do not have access to electricity. SCORE market evaluations1 indicate that at the upper-cost target of$120 with 20 Watts of electricity 60 million people would afford the stove. At the lower-cost target of $40 and 100 Watts it would be affordable to over 1 billion people. In November 2010, a wood burning Score-Stove™ prototype successfully developed 23 watts of electricity based on a planar Thermo-Acoustic Engine (TAE) [2],[3],[4],[5],[6] design, indicating that the new Score-Stove™ is now ready to be engaged with manufacturers to gear up for volume production, and therefore to meet the social and cooking requirements of the rural poor people. The development to a large-volume, easy to manufacture, low-cost TAE cooking stove using elements of the formal design methodologies of BS 7000 and TRIZ are discussed. By breaking down the system requirements into cost targets for each module, performing rig testing, and design refinements it is believed that the upper-cost target is achievable with the right level of investment

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment.

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients

Improving trial recruitment through improved communication about patient and public involvement : an embedded cluster randomised recruitment trial

Background: Evidence is emerging that patient and public involvement in research (PPIR) may improve recruitment into randomised controlled trials, but the best methods to achieve improvement are unclear. Although many trials use PPIR to improve design and conduct, many do not communicate their use of PPIR clearly to potential participants. Directly communicating PPIR might encourage participation through increased patient confidence and trust in a trial. We aimed to develop and evaluate the impact on recruitment an intervention communicating PPIR in a trial to potential participants. Methods: This study was embedded in EQUIP, a cluster randomised controlled trial which allocated mental health teams in England to either a training intervention group to improve service user and carer involvement in care planning, or to a control group (no training). We conducted a cluster randomised trial of a recruitment intervention communicating PPIR, embedded within the EQUIP trial. The principles underlying the intervention were informed by a systematic review and a workshop that included mental health service users and trialists. Working with EQUIP PPIR partners (service users and carers) we developed the intervention using a leaflet to advertise the nature and function of the PPIR. Professional graphic design optimised readability and impact. Patients identified as potentially eligible for EQUIP were randomised to receive the leaflet or not, alongside the standard trial information. The primary outcome was the proportion of participants enrolled in EQUIP. The secondary outcome was the proportion expressing interest in taking part. Results: 34 clusters (mental health teams) were recruited, and 8182 potential participants were randomised. Preliminary analyses show that for the primary outcome, 4% of patients receiving the PPIR leaflet were enrolled vs. 5.3% in the control group. For the secondary outcome 7.3% of potential participants receiving the PPIR leaflet responded positively to the invitation to participate, vs. 7.9% in the control group. Future analyses will be by intention-to-treat and use logistic regression to estimate between-group odds ratios (ORs) and corresponding 95% confidence intervals. A planned secondary analysis will explore whether the impact of the intervention is moderated by age and gender. Conclusion: In preliminary analysis of this large trial, communicating PPIR demonstrated no benefits for improving the numbers of potential participants expressing interest in the trial, and reduced trial enrolment. Our findings contrast with the literature suggesting PPIR benefits recruitment. We will discuss the potential reasons for this finding, along with implications for future recruitment practice and research

Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.</p

Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.</p

Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations

Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases

Third-Line Nivolumab Monotherapy in Recurrent Small Cell Lung Cancer : CheckMate 032

Introduction: For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC. Methods: In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results: Between December 4, 2013, and November 30, 2016, 109 patients began receiving third- or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5\u201319.5) with a median duration of response of 17.9 months (range 3.0\u201342.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events. Conclusions: Nivolumab monotherapy provided durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third- or later-line treatment for this patient population