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. Most antibody-based conditioning therapies involve monoclonal/naked antibodies, such as alemtuzumab for graft-versus-host disease prophylaxis and rituximab for Epstein-Barr virus prophylaxis, which are both in Phase II trials for inclusion in conditioning regimens. Nevertheless, alternative immune-based therapies, including antibody-drug conjugates, radio-labelled antibodies and CAR-T cells, are showing promise in a conditioning setting. Here, we analyse the current status of antibody-based drugs in pre-transplant conditioning regimens and assess their potential in the future of transplant biology.

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. Often termed "undruggable," Ras is notoriously difficult to target directly, due to its structure and intrinsic activity. Thus, Ras-mediated drug resistance remains a considerable pharmacological problem. However, with advances in both analytical techniques and novel drug classes, the therapeutic landscape against Ras is changing. Allele-specific, direct Ras-targeting agents have reached clinical trials for the first time, indicating there may, at last, be hope of targeting such an elusive but significant protein for better more effective cancer therapy. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

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. In comparison, patients diagnosed with chronic myeloid leukaemia (CML) and treated with tyrosine kinase inhibitors (TKIs) have a high rate of long-term survival. However, drug resistance and relapse are major issues in both these diseases. A growing body of evidence suggests that Interferons (IFNs) may be a useful therapy for myeloid malignancies, particularly in circumstances where patients are resistant to existing front-line therapies and have risk of relapse following haematopoietic stem cell transplant. IFNs are a major class of cytokines which are known to play an integral role in the non-specific immune response. IFN therapy has potential as a combination therapy in AML patients to reduce the impact of minimal residual disease on relapse. Alongside this, IFNs can potentially sensitize leukaemic cells to TKIs in resistant CML patients. There is evidence also that IFNs have a therapeutic role in myeloproliferative neoplasms (MPNs) such as polycythaemia vera (PV) and primary myelofibrosis (PMF), where they can restore polyclonality in patients. Novel formulations have improved the clinical effectiveness of IFNs. Low dose pegylated IFN formulations improve pharmacokinetics and improve patient tolerance to therapies, thereby minimizing the risk of haematological toxicities. Herein, we will discuss recent developments and the current understanding of the molecular and clinical implications of Type I IFNs for the treatment of myeloid malignancies.

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. SPSS was used for analysis. A total of 232 patients were recruited (response 93%) (93 clinically diagnosed, 139 NBS-detected). Following exclusions of meconium ileus (MI) (40), diagnosis outside Ireland (4), and being designated as CFSPID (2), a total of 77 clinically diagnosed patients and 109 NBS detected children were included in analysis. Over half were homozygous for F508del mutation. Being clinically diagnosed was independently associated with hospitalization for infective exacerbation of CF < 36 months (OR, 2.80; 95%CI 1.24-6.29). Diagnosis to first acquisition of Pseudomonas aeruginosa was significantly longer in NBS than clinically detected; from birth there was no significant difference. Weight and length/height were significantly greater in NBS cohort at 6 and 12 months. We provide evidence of improved growth, reduced hospitalization for acute exacerbations, and delayed P. aeruginosa acquisition (from diagnosis) to age 3 for the NBS cohort. Screening practices likely account for the non-significant difference in P. aeruginosa acquisition from birth.

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. Pediatric patients with tracheostomies have a 2-3 fold greater morbidity and mortality compared to adult patients. Clinicians should provide as much clarity as possible for families on the positive and negative aspects of pediatric tracheotomies and long term mechanical ventilation prior to tracheostomy placement. Tracheostomies are often placed as a bridge, whilst time for healing, growth and other therapies are needed to help overcome the indication for tracheostomy. Suitable investigations used to determine the optimal timing of decannulation remain physician and institution dependent.

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. METHODS: Samples of 109 PWCF were processed using anaerobic microbiological culture with bacteria present identified by 16S RNA sequencing. SCFA levels in anaerobic supernatants and bronchoalveolar lavage (BAL) were determined by gas chromatography. The mRNA and/or protein expression of two SCFA receptors, GPR41 and GPR43, in CF and non-CF bronchial brushings and 16HBE14o(-) and CFBE41o(-) cells were evaluated using reverse transcription polymerase chain reaction, Western blot analysis, laser scanning cytometry, and confocal microscopy. SCFA-induced IL-8 secretion was monitored by ELISA. MEASUREMENTS AND MAIN RESULTS: Fifty-seven (52.3%) of 109 PWCF were anaerobe positive. Prevalence increased with age, from 33.3% to 57.7% in PWCF younger (n = 24) and older (n = 85) than 6 years of age. All evaluated anaerobes produced millimolar concentrations of SCFAs, including acetic, propionic, and butyric acids. SCFA levels were higher in BAL samples of adults than in those of children. GPR41 levels were elevated in CFBE41o(-) versus 16HBE14o(-) cells; CF versus non-CF bronchial brushings; and 16HBE14o(-) cells after treatment with cystic fibrosis transmembrane conductance regulator inhibitor CFTR(inh)-172, CF BAL, or inducers of endoplasmic reticulum stress. SCFAs induced a dose-dependent and pertussis toxin-sensitive IL-8 response in bronchial epithelial cells, with a higher production of IL-8 in CFBE41o(-) than in 16HBE14o(-) cells. CONCLUSIONS: This study illustrates that SCFAs contribute to excessive production of IL-8 in CF airways colonized with anaerobes via up-regulated GPR41.

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. We also hypothesized that longitudinal measurements of lung function over the usual period of rapid lung growth would lend some insight into how the lung remodels in CDH infants. METHODOLOGY: Ninety-eight infants with CDH between 11 days and 44 months of age underwent pulmonary function testing (PFT) on 1-5 occasions using the raised volume rapid thoracic compression technique. Demographic data were also collected. MAIN RESULTS: Forced expiratory flows were below normal. Total lung capacity was normal, but residual volume and functional residual capacity were elevated. Children requiring patch closure, ECMO, or pulmonary vasodilators generally had lower lung functions at follow up. Additionally, longer duration of mechanical ventilation correlated with worse lung function. CONCLUSIONS: Lung functions of survivors of CDH remain abnormal throughout the first 3 years of life. The degree of pulmonary function impairment correlated both with markers of the initial degree of pulmonary hypoplasia and the duration of mechanical ventilation. Understanding the relationship between the phenotypic presentation of CDH and the potential for subsequent lung growth could help refine both pre- and postnatal therapies to optimize lung growth in CDH infants.

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. METHODS: We reviewed results of IPFTs and echocardiograms performed on infants with CDH from 2004 to June 2011. Lung volumes, forced flows and tidal mechanics were standardized according to available reference values. Comparisons between infants with and without PH were performed using linear regression, adjusting for potential confounders. MAIN RESULTS: Sixty-six infants were included; 18 had PH and 48 did not. Z-score values for functional residual capacity (FRC), residual volume (RV), FRC/total lung capacity (TLC), and RV/TLC were significantly higher in infants with CDH and PH compared to those without PH. Z-score values for forced flows including forced expiratory volume in the first 0.5 sec (FEV0.5) and FEV0.5/forced vital capacity were significantly lower in infants with CDH and PH compared to those without PH. For 29 infants studied on ≥2 occasions, the slopes of FRC, RV, and TLC versus length were significantly higher in those with persistent PH compared to those without. CONCLUSIONS: Infants with CDH and persistent PH demonstrate greater airspace overdistension with growth compared to those without. Therapies that modify disrupted pulmonary vascular and alveolar formation could potentially improve future care of these patients.

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. This finding was supported by histology, which showed that each family has a different type of ciliary defect; transposition defect (family A), nude epithelium (family B) and absence of inner and outer dynein arms (family C). Therefore, each family was analysed independently using homozygosity mapping and exome sequencing. The affected siblings in family A share a novel 1 bp duplication in RSPH4A (NM_001161664.1:c.166dup; p.Arg56Profs*11), a radial-spoke head protein involved in ciliary movement. In family B, we identified three candidate genes (CCNO, KCNN3 and CDKN1C), with a 5-bp duplication in CCNO (NM_021147.3:c.258_262dup; p.Gln88Argfs*8) being the most likely cause of ciliary aplasia. This is the first study to implicate CCNO, a DNA repair gene reported to be involved in multiciliogenesis, in PCD. In family C, we identified a ∼3.5-kb deletion in DYX1C1, a neuronal migration gene previously associated with PCD. This is the first report of a disorder in the relatively small Irish Traveller population to be caused by >1 disease gene. Our study identified at least three different PCD genes in the Irish Traveller population, highlighting that one cannot always assume genetic homogeneity, even in small consanguineous populations.

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. Electronic searches were performed in the following databases: PubMed, CENTRAL, and the US National Institutes of Health Clinical Trial database. Following selection according to clearly defined inclusion and exclusion criteria and in accordance with the PRISMA statement; 5 double-blind, randomized, placebo-controlled trials of montelukast as monotherapy or add-on therapy in childhood asthma and 2 review articles were analysed in this systematic review. Treatment with LTRAs provides protection from EIB, when used as both monotherapy and add-on therapy. However, disease variables and aetiological factors may impact on the extent of clinical improvement. Genetic variability may influence leukotriene production and subsequent response to LTRAs. This issue could be addressed in further studies.

Clinical practice. The impact of lung disease on the heart and cardiac disease on the lungs.

Pathologies in both the respiratory and cardiovascular systems frequently coexist and impact on each other. This manuscript introduces an approach to the interpretation of this complex relationship. Pulmonary hypertension can be a significant consequence of many respiratory diseases. This in turn can lead to right ventricular dysfunction and cor pulmonale. Many childhood illnesses can result in cor pulmonale and can be conveniently grouped into three categories: idiopathic pulmonary hypertension, neonatal lung diseases, and lung disease beyond the neonatal period. When considering the impact of cardiac disease on the lung, one must consider two main pathologies: compression of the pediatric airway and increased lung water. In conclusion, thorough attention must be given to the interpretation of the complex relationship between cardiac and respiratory diseases. Pulmonary hypertension is a complication to consider in respiratory illness at all ages. In addition, when dealing with the complexities of congenital heart disease, one must always be aware of the risks of pulmonary complications whether parenchymal or airway. Ongoing improvements in ventilation strategies, vasodilator therapy, and surgical interventions continue to improve the outlook for these complex cases.