Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?

It is widely acknowledged that there is a considerable number of oncogenic mutations within the Ras superfamily of small GTPases which are the driving force behind a multitude of cancers. Ras proteins mediate a plethora of kinase pathways, including the MAPK, PI3K, and Ral pathways. Since Ras was considered undruggable until recently, pharmacological targeting of pathways downstream of Ras has been attempted to varying success, though drug resistance has often proven an issue.

Worked to the bone: antibody-based conditioning as the future of transplant biology.

Conditioning of the bone marrow prior to haematopoietic stem cell transplant is essential in eradicating the primary cause of disease, facilitating donor cell engraftment and avoiding transplant rejection via immunosuppression. Standard conditioning regimens, typically comprising chemotherapy and/or radiotherapy, have proven successful in bone marrow clearance but are also associated with severe toxicities and high incidence of treatment-related mortality. Antibody-based conditioning is a developing field which, thus far, has largely shown an improved toxicity profile in experimental models and improved transplant outcomes, compared to traditional conditioning.

Recent Progress in Interferon Therapy for Myeloid Malignancies.

Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, caused by abnormalities in haematopoietic stem cells (HSCs) and myeloid progenitor cells that originate in the bone marrow niche. Each of these disorders are unique and present their own challenges with regards to treatment. Acute myeloid leukaemia (AML) is considered the most aggressive myeloid malignancy, only potentially curable with intensive cytotoxic chemotherapy with or without allogeneic haematopoietic stem cell transplantation.

The importance of Ras in drug resistance in cancer.

In this review, we analyse the impact of oncogenic Ras mutations in mediating cancer drug resistance and the progress made in the abrogation of this resistance, through pharmacological targeting. At a physiological level, Ras is implicated in many cellular proliferation and survival pathways. However, mutations within this small GTPase can be responsible for the initiation of cancer, therapeutic resistance and failure, and ultimately disease relapse.

Neonatal screening programme for CF: Results from the Irish Comparative Outcomes Study (ICOS).

The introduction of NBS in Ireland in July 2011, provided a unique opportunity to investigate clinical outcomes using a comparative historical cohort study. Clinical cohort: children clinically diagnosed with CF born 1 July 2008 to 30 June 2011, and NBS cohort: children diagnosed with CF through NBS born 1 July 2011 to 30 June 2016. Clinical data were collected from the CF Registry of Ireland, medical charts, and data on weight/height before diagnosis from public health nurses and family doctors.

Tracheostomy decision making: From placement to decannulation.

Over the last few decades, greater numbers of tracheostomies have been performed in medically complex and fragile children to manage upper airway obstruction, progressive neuromuscular disorders, abnormal ventilatory drive and to facilitate airway clearance. The optimal timing of tracheostomy tube placement and methods to determine suitable patients for the procedure remain unclear. Caring for children with tracheostomies can have a considerable financial and psychosocial impact on a family.

Effects of Advective-Diffusive Transport of Multiple Chemoattractants on Motility of Engineered Chemosensory Particles in Fluidic Environments.

Motility behavior of an engineered chemosensory particle (ECP) in fluidic environments is driven by its responses to chemical stimuli. One of the challenges to understanding such behaviors lies in tracking changes in chemical signal gradients of chemoattractants and ECP-fluid dynamics as the fluid is continuously disturbed by ECP motion. To address this challenge, we introduce a new multiscale numerical model to simulate chemotactic swimming of an ECP in confined fluidic environments by accounting for motility-induced disturbances in spatiotemporal chemoattractant distributions.

Spatial Structure of the Mormon Cricket Gut Microbiome and its Predicted Contribution to Nutrition and Immune Function.

The gut microbiome of insects plays an important role in their ecology and evolution, participating in nutrient acquisition, immunity, and behavior. Microbial community structure within the gut is heavily influenced by differences among gut regions in morphology and physiology, which determine the niches available for microbes to colonize. We present a high-resolution analysis of the structure of the gut microbiome in the Mormon cricket , an insect known for its periodic outbreaks in the western United States and nutrition-dependent mating system.

Development of spiroguanidine-derived α7 neuronal nicotinic receptor partial agonists.

We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N-(6-methyl-1,3-benzoxazol-2-yl)-3',5'-dihydro-4-azaspiro[bicyclo[2.

Design and Synthesis of a New Series of 4-Heteroarylamino-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure-Activity Relationship.

The design and synthesis of a series of quinuclidine-containing spirooxazolidines ("spiroimidates") and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.

The Role of Short-Chain Fatty Acids, Produced by Anaerobic Bacteria, in the Cystic Fibrosis Airway.

Rationale: Anaerobic bacteria are present in large numbers in the airways of people with cystic fibrosis (PWCF). In the gut, anaerobes produce short-chain fatty acids (SCFAs) that modulate immune and inflammatory processes.

Objectives: To investigate the capacity of anaerobes to contribute to cystic fibrosis (CF) airway pathogenesis via SCFAs.

Diagnosis and treatment of sleep related breathing disorders in children: 2007 to 2011.

Sleep related breathing disorders (SRBD) have historically been under-recognised and under-treated. Obstructive sleep apnoea (OSA) affects approximately 3% of children. In line with the increased recognition of SRBD there has been an increase in demand for diagnostic services.

The role of leukotriene receptor antagonists in exercise induced bronchoconstriction in children.

Exercise induced bronchoconstriction (EIB) may complicate childhood asthma. Leukotriene receptor antagonists (LTRAs), such as montelukast, may be beneficial in protecting against EIB. Our aim was to systematically review the role of LTRAs in the treatment of asthmas complicated by exercise induced bronchoconstriction and to assess various clinical factors which may influence the therapeutic outcome.

Lung function over the first 3 years of life in children with congenital diaphragmatic hernia.

Objectives: Infants with congenital diaphragmatic hernia (CDH) have variable degrees of pulmonary hypoplasia at birth. Few reports of lung function over the first years of life exist in this group of children.

Hypothesis: Pulmonary function abnormalities correlate with severity of neonatal disease and intensity of neonatal therapies needed.

Outpatient parenteral antimicrobial therapy: a report of three years experience.

Although outpatient parenteral antimicrobial therapy (OPAT) is practiced internationally, there is a paucity of data regarding outcomes of paediatric OPAT. A retrospective analysis, of 3 years experience (January 2010 to 2013) was performed at a tertiary paediatric Respiratory unit. There were 362 OPAT courses administered to 32 children, of which 30 had cystic fibrosis and the remaining two had recurrent pneumonia.

Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population.

We present a study of five children from three unrelated Irish Traveller families presenting with primary ciliary dyskinesia (PCD). As previously characterized disorders in the Irish Traveller population are caused by common homozygous mutations, we hypothesised that all three PCD families shared the same recessive mutation. However, exome sequencing showed that there was no pathogenic homozygous mutation common to all families.

An association between pulmonary hypertension and impaired lung function in infants with congenital diaphragmatic hernia.

Rationale: Infants with congenital diaphragmatic hernia (CDH) can develop pulmonary hypertension (PH) from decreased number and abnormal muscularization of pulmonary arteries. Normally pulmonary vascular growth and remodeling parallel airspace growth and alveolarization, which exhibits a wide morphologic variation in CDH.

Aim: To assess whether infants with CDH and PH have greater abnormalities in infant pulmonary function testing (IPFT) compared to those without PH.

MK-801 disrupts and nicotine augments 40 Hz auditory steady state responses in the auditory cortex of the urethane-anesthetized rat.

Patients with schizophrenia show marked deficits in processing sensory inputs including a reduction in the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation. Such deficits are not readily demonstrable at other input frequencies. Acute administration of NMDA antagonists to healthy human subjects or laboratory animals is known to reproduce many sensory and cognitive deficits seen in schizophrenia patients.

Pharmacological and behavioral characterization of the novel CRF1 antagonist BMS-763534.

BMS-763534 is a potent (CRF(1) IC(50) = 0.4 nM) and selective (>1000-fold selectivity vs. all other sites tested) CRF(1) receptor antagonist (pA2 = 9.

Productivity, carbon utilization, and energy content of mass in scalable microalgae systems.

This study was designed to examine carbon utilization within scalable microalgae production systems. Neochloris oleoabundans was produced in replicated troughs containing BG11 nutrient formulation. Atmospheric CO(2) was supplemented with ∼5% CO(2) or with NaHCO(3), and the pH of troughs receiving NaHCO(3) was adjusted with HCl or H(3)PO(4).

Pulmonary complications of congenital heart disease.

Cardiac and pulmonary pathophysiologies are closely interdependent, which makes the management of patients with congenital heart disease (CHD) all the more complex. Pulmonary complications of CHD can be structural due to compression causing airway malacia or atelectasis of the lung. Surgical repair of CHD can also result in structural trauma to the respiratory system, e.

Congenital central hypoventilation syndrome in children.

Congenital central hypoventilation syndrome (CCHS) is a rare, lifelong condition wherein control of breathing is abnormal and patients present with symptoms of alveolar hypoventilation. The severity of hypoventilation varies and although most patients present in the neonatal period, late onset cases have been reported. In 2003, it was discovered that mutations in the PHOX2B gene were responsible for CCHS.

Co-morbidity in a cystic fibrosis population attending a regional clinic.

Pulmonary disease remains the major cause of morbidity in patients with cystic fibrosis (CF). However, of 115 patients attending a regional CF clinic we noted 16 cases (14%) with co-morbid conditions. Of this group, 4 of 115 patients (3.

Biomass production and nutrient uptake by Neochloris oleoabundans in an open trough system.

The purpose of this paper is to present biomass and nutrient uptake data from Neochloris oleoabundans production in an open trough system. The growth medium used was BG11, temperature ranged from 16.7 °C to 25.

Using student-generated UV-induced Escherichia coli mutants in a directed inquiry undergraduate genetics laboratory.

We report a thematic sequence of directed inquiry-based labs taking students from bacterial mutagenesis and phenotypic identification of their own self-created mutant, through identification of mutated genes by biochemical testing, to verification of mutant alleles by complementation, and finally to mutant allele characterization by DNA sequence analysis. The lab utilizes UV mutagenesis with wild-type Escherichia coli and a UV-sensitive isogenic derivative optimized for undergraduate use. The labs take advantage of the simplicity of E.