The kinase polypharmacology landscape of clinical PARP inhibitors.

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles

To Cycle or Fight-CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity.

Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anticancer drug development. Three selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are FDA and European Medicines Agency (EMA) approved for hormone receptor-positive/HER2-negative advanced breast cancer. A major emerging appreciation is that these inhibitors not only are cytostatic, but also play critical roles in the interaction between tumor cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell-cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anticancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anticancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immunotherapy

Hand-held internet tablets for school-based data collection

<p>Abstract</p> <p>Background</p> <p>In the last 20 years, researchers have been using computer self-administered questionnaires to gather data on a wide range of adolescent health related behaviours. More recently, researchers collecting data in schools have started to use smaller hand-held computers for their ease of use and portability. The aim of this study is to describe a new technology with wi-fi enabled hand-held internet tablets and to compare adolescent preferences of laptop computers or hand-held internet tablets in administering a youth health and well-being questionnaire in a school setting.</p> <p>Methods</p> <p>A total of 177 students took part in a pilot study of a national youth health and wellbeing survey. Students were randomly assigned to internet tablets or laptops at the start of the survey and were changed to the alternate mode of administration about half-way through the questionnaire. Students at the end of the questionnaire were asked which of the two modes of administration (1) they preferred, (2) was easier to use, (3) was more private and confidential, and (4) was easier to answer truthfully.</p> <p>Results</p> <p>Many students expressed no preference between laptop computers or internet tablets. However, among the students who expressed a preference between laptop computers or internet tablets, the majority of students found the internet tablets more private and confidential (p < 0.001) and easier to answer questions truthfully (p < 0.001) compared to laptop computers.</p> <p>Conclusion</p> <p>This study demonstrates that using wi-fi enabled hand-held internet tablets is a feasible methodology for school-based surveys especially when asking about sensitive information.</p

Parent and teacher-reported child outcomes seven years after mild traumatic brain Injury: A nested case control study

Background: Increasing evidence suggests potential lifetime effects following mild traumatic brain injury (TBI) in childhood. Few studies have examined medium-term outcomes among hospitalized and non-hospitalized samples. Study aims were to describe children's behavioral and emotional adjustment, executive function (EF), quality of life, and participation at 7-years following mild TBI using parents' and teachers' reports. Methods: Nested case control study of 86 children (68% male, mean age at assessment = 11.27 years; range 7–17 years) who sustained a mild TBI 7-years previously, identified from a prospective, population-based study. They were compared to 69 children free from TBI (61% male, mean age at assessment = 11.12 years; range 5–17 years). In addition to parent-reported socio-demographic details, parents (mild TBI n = 86, non-TBI n = 69) completed age-appropriate standardized questionnaires about children's health-related quality of life, behavioral and emotional adjustment, EF, and social participation. Parents own mood was assessed using the Hospital Anxiety and Depression Scale. Teachers (mild TBI n = 53, non-TBI n = 42) completed questionnaires about children's behavioral and emotional adjustment, and EF. Results: Parent reports showed median group-level scores for cases were statistically significantly greater than controls for emotional symptoms, conduct problems, hyperactivity/inattention, total behavioral difficulties, inhibitory control, shifting, planning/organizing, and Global Executive Composite (total) EF difficulties (p-values 0.001–0.029). Parent reports of child quality of life and social participation were similar, as were teacher reports of child behavioral and emotional adjustment, and EF (p > 0.05). When examining clinical cut-offs, compared to controls, cases had a higher risk of parent-reported total EF difficulties (odds ratio = 3.00) and, to a lesser extent, total behavior problems (odds ratio = 2.51). Conclusions: As a group, children with a history of mild TBI may be at elevated risk for clinically significant everyday EF difficulties in the medium-term compared to non-TBI controls, as judged by their parents. Further multi-informant longitudinal research is required, following larger samples. Aspects requiring particular attention include pre-injury characteristics, such as sleep disturbances and comorbidities (e.g., headaches), that may act as potential confounders influencing the association between mild TBI and child behavioral problems

CNS cancer immunity cycle and strategies to target this for glioblastoma.

Immunotherapeutics have revolutionized the management of solid malignancies over the last few years. Nevertheless, despite relative successes of checkpoint inhibitors in numerous solid tumour types, success in tumours of the central nervous system (CNS) has been lacking. There are several possible reasons for the relative lack of success of immunotherapeutics in this setting, including the immune microenvironment of glioblastoma, lymphocyte tracking through the blood-brain barrier (BBB) into the central nervous system and impairment of drug delivery into the CNS through the BBB. This review utilizes the cancer-immunity cycle as a conceptual framework through which the specific challenges associated with the development of immunotherapeutics for CNS malignancies can be viewed

Computational repurposing of oncology drugs through off‐target drug binding interactions from pharmacological databases

PurposeSystematic repurposing of approved medicines for another indication may accelerate drug development in oncology. We present a strategy combining biomarker testing with drug repurposing to identify new treatments for patients with advanced cancer.MethodsTumours were sequenced with the Illumina TruSight Oncology 500 (TSO-500) platform or the FoundationOne CDx panel. Mutations were screened by two medical oncologists and pathogenic mutations were categorised referencing literature. Variants of unknown significance were classified as potentially pathogenic using plausible mechanisms and computational prediction of pathogenicity. Gain of function (GOF) mutations were evaluated through repurposing databases Probe Miner (PM), Broad Institute Drug Repurposing Hub (Broad Institute DRH) and TOPOGRAPH. GOF mutations were repurposing events if identified in PM, not indexed in TOPOGRAPH and excluding mutations with a known Food and Drug Administration (FDA)-approved biomarker. The computational repurposing approach was validated by evaluating its ability to identify FDA-approved biomarkers. The total repurposable genome was identified by evaluating all possible gene-FDA drug-approved combinations in the PM dataset.ResultsThe computational repurposing approach was accurate at identifying FDA therapies with known biomarkers (94%). Using next-generation sequencing molecular reports (n = 94), a meaningful percentage of patients (14%) could have an off-label therapeutic identified. The frequency of theoretical drug repurposing events in The Cancer Genome Atlas pan-cancer dataset was 73% of the samples in the cohort.ConclusionA computational drug repurposing approach may assist in identifying novel repurposing events in cancer patients with no access to standard therapies. Further validation is needed to confirm a precision oncology approach using drug repurposing. Repurposing identified Food and Drug Administration-approved drug-biomarker combinations with high sensitivity and specificity. In a real-world dataset, repurposing identified novel drug-biomarker combinations in patients who were ineligible for standard therapies or biomarker-matched trials. Preliminary functional validation was demonstrated for two drug-biomarker combinations. Using The Cancer Genome Atlas data, the potential scope of repurposing was identified. imag

The clinical utility of molecular diagnostic testing for primary immune deficiency disorders: a case based review

Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic predisposition to recurrent infections, malignancy, autoimmunity and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. Identifying the underlying genetic defect plays a critical role in patient management including diagnosis, family studies, prognostic information, prenatal diagnosis and is useful in defining new diseases. In this review we outline the clinical utility of molecular testing for these disorders using clinical cases referred to Auckland Hospital. It is written from the perspective of a laboratory offering a wide range of tests for a small developed country

Anaphylaxis to hyperallergenic functional foods

<p>Abstract</p> <p>Background</p> <p>Food allergy can cause life threatening reactions. Currently, patients with severe food allergy are advised to avoid foods which provoke allergic reactions. This has become increasingly difficult as food proteins are being added to a broader range of consumer products.</p> <p>Patients and methods</p> <p>Here we describe our investigations into the allergenicity of a new drink when two cow's milk allergic children suffered anaphylaxis after consuming <it>Wh</it>_<it>2</it><it>ole</it>^®.</p> <p>Results</p> <p>Our studies have shown that in comparison with cow's milk, <it>Wh</it>_<it>2</it><it>ole</it>^®contains at least three times the concentration of β-lactoglobulin. β-lactoglobulin is one of the dominant allergens in bovine milk.</p> <p>Conclusions</p> <p>These studies have shown that modern technology allows the creation of "hyperallergenic" foods. These products have the potential to cause severe reactions in milk allergic persons. Avoiding inadvertent exposure is the shared responsibility of allergic consumers, regulatory authorities and the food industry.</p

The Importance of Poisoning vs. Road Traffic Injuries as a Cause of Death in Rural Sri Lanka

Road traffic crashes are considered by the WHO to be the most important global cause of death from injury. However, this may not be true for large areas of rural Asia where road vehicles are uncommon. The issue is important, since emphasising the importance of road traffic crashes risks switching resources to urban areas, away from already underfunded rural regions. In this study, we compared the importance of road traffic crashes with other forms of injury in a poor rural region of South Asia.We collected data on all deaths from injury in the North Central Province of Sri Lanka (NCP; population 1,105,198 at 2001 census) over 18 months using coronial, hospital, and police data. We calculated the incidence of death from all forms of intentional and unintentional injury in the province. The annual incidence of death from injury in the province was high: 84.2 per 100,000 population. Half of the deaths were from self-harm (41.3/100,000). Poisoning (35.7/100,000)-in particular, pesticide self-poisoning (23.7/100,000)-was the most common cause of death, being 3.9-fold more common than road traffic crashes (9.1/100,000).In poor rural regions of South Asia, fatal self-harm and pesticide self-poisoning in particular are significantly more important than road traffic injuries as a cause of death. It is possible that the data used by the WHO to calculate global injury estimates are biased towards urban areas with better data collection but little pesticide poisoning. More studies are required to inform a debate about the importance of different forms of injury and how avoidable deaths from any cause can be prevented. In the meantime, marked improvements in the effectiveness of therapy for pesticide poisoning, safer storage, reduced pesticide use, or reductions in pesticide toxicity are required urgently to reduce the number of deaths from self-poisoning in rural Asia

Impact of an injury hospital admission on childhood academic performance: a Welsh population-based data linkage study

Background While injuries can impact on children’s educational achievements (with threats to their development and employment prospects), these risks are poorly quantified. This population-based longitudinal study investigated the impact of an injury-related hospital admission on Welsh children’s academic performance. Methods The Secure Anonymised Information Linkage databank, 55 587 children residing in Wales from 2006 to 2016 who had an injury hospital admission (58.2% males; 16.8% born in most deprived Wales area; 80.1% one injury hospital admission) were linked to data from the Wales Electronic Cohort for Children. The primary outcome was the Core Subject Indicator reflecting educational achievement at key stages 2 (school years 3–6), 3 (school years 7–9) and 4 (school years 10–11). Covariates in models included demographic, birth, injury and school characteristics. Results Educational achievement of children was negatively associated with: pedestrian injuries (adjusted risk ratio, (95% CIs)) (0.87, (0.83 to 0.92)), cyclist (0.96, (0.94 to 0.99)), high fall (0.96, (0.94 to 0.97)), fire/flames/smoke (0.85, (0.73 to 0.99)), cutting/piercing object (0.96, (0.93 to 0.99)), intentional self-harm (0.86, (0.82 to 0.91)), minor traumatic brain injury (0.92, (0.86 to 0.99)), contusion/open wound (0.93, (0.91 to 0.95)), fracture of vertebral column (0.78, (0.64 to 0.95)), fracture of femur (0.88, (0.84 to 0.93)), internal abdomen/pelvic haemorrhage (0.82, (0.69 to 0.97)), superficial injury (0.94, (0.92 to 0.97)), young maternal age (<18 years: 0.91, (0.88 to 0.94); 19–24 years: 0.94, (0.93 to 0.96)); area based socioeconomic status (0.98, (0.97 to 0.98)); moving to a more deprived area (0.95, (0.93 to 0.97)); requiring special educational needs (0.46, (0.44 to 0.47)). Positive associations were: being female (1.04, (1.03 to 1.06)); larger pupil school sizes and maternal age 30+ years. Conclusion This study highlights the importance on a child’s education of preventing injuries and implementing intervention programmes that support injured children. Greater attention is needed on equity-focused educational support and social policies addressing needs of children at risk of underachievement, including those from families experiencing poverty