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Purpose: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M.Experimental Design: In this multicohort, phase I study (NCT02113813), escalating doses of ASP8273 (25–500 mg) were administered once daily to non–small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint.Results: A total of 110 patients were treated with ASP8273 across dose escalation (n = 36), response–expansion (n = 36), RP2D (300 mg; n = 19) and food–effect (n = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n = 27/88; 95% CI, 19.5%–44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5–10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression.Conclusions: ASP8273 was well tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy. Clin Cancer Res; 23(24); 7467–73. ©2017 AACR.

Supplementary Table 1. Pharmacokinetic Parameters of ASP8273 from Patients in Dose-Escalation Cohort (PKAS) ; Supplementary Figure 1. Study design; Supplementary Figure 2. Quantitative change in EGFR cfDNA from baseline to Cycle 2 in escalating dose levels of ASP8273; Supplementary Figure 3. Changes in Levels of Mutant EGFR cfDNA (Activating or T790M) in Patients after One Cycle of Treatment with ASP8273 by Best Overall Response; Supplementary Figure 4. Identification of EGFR activating mutations, EGFR T790M and EGFR C797S in cfDNA from patients with Emergence of acquired resistance to ASP8273.

Identify predictors of maternal bonding and responsiveness for mothers of very preterm infants ( 32 weeks gestational age) at 6 weeks and 12 months corrected-age (CA). Cross-sectional and longitudinal study containing 39 mothers of very preterm infants. At 6 weeks CA maternal self-efficacy made a significant unique contribution to the variance in self-reported maternal bonding and responsiveness (21% and 26%, respectively). At 12 months CA maternal trauma symptoms, depressive symptoms and self-efficacy made a significant unique contribution to the variance in bonding (14%, 9% and 9%, respectively). Maternal self-efficacy made a significant 31% unique contribution to the variance in responsiveness. The combined effects of maternal trauma symptoms, depressive symptoms and self-efficacy at 6 weeks CA predicted maternal responsiveness at 12 months CA (p = .042). Supporting maternal self-efficacy is key to facilitating bonding and responsiveness up to 12 months CA following a very preterm birth.Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12612000194864.

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin (HTT) protein. Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. Here we show that the levels of Bim, a BH3-only protein, are significantly increased in HD human post-mortem and HD mouse striata, correlating with neuronal death. Bim reduction ameliorates mHTT neurotoxicity in HD cells. In the HD mouse model, heterozygous Bim knockout significantly mitigates mHTT accumulation and neuronal death, ameliorating disease-associated phenotypes and lifespan. Therefore, Bim could contribute to the progression of HD.

It is crucial to spare lung when treating early stage lung carcinoma with stereotactic body radiotherapy (SBRT) for minimizing the radiation induced toxicities, such as radiation pneumonitis and late fibrosis. A retrospective study was performed with a combination of approaches to determine the optimal range of prescription isodose line (P-IDL) within which lung tissue was best spared in SBRT plans with Volumetric-Modulated Arc Therapy (VMAT) and Monte-Carlo-like dose calculation algorithm. Twenty clinically-delivered SBRT lung plans were optimized using traditional LINAC MLC based approaches: an average P-IDL of (88.8 ± 0.5)% (the error bar of all the data is the 95% confidence interval (CI)). The plans were then re-optimized using a new combination of approaches with variation of P-IDL from 60% to 90% for each case. The combination of approaches included finding and utilizing an optimal P-IDL, implementing tuning ring structures internal and external to the target, as well as normal tissue objective and equivalent. The plans were evaluated with the following indexes: 1. R(50%), the ratio of 50% prescription isodose volume to the plan target volume (PTV); 2. V(20) and V(5), the volume of lung within 20Gy and 5Gy, respectively; 3. PCI, the Paddick comformity index; 4. D(2cm), the maximum dose at 2 cm from PTV in any direction; 5. MLD, the mean dose in total lung volume; 6. Focal Index (FI), an indicator of dose in the core of the target. The optimal P-IDL was found to be in the range of 75-80%. The average optimal P-IDL for the 20 cases was (77.9 ± 0.9)%. With the optimization strategies the average PCI was increased by (10.3 ± 2.1)%; the average R(50%), V(20), V(5), D(2cm) and MLD were decreased by (29.1 ± 4.1)%, (26.9 ± 5.4)%, (13.9 ± 3.5)%, (13.4 ± 4.3)% and (16.7 ± 2.3)%, respectively. The FI was increased by (23.7 ± 1.3)%. The optimal P-IDL range was 75-80% for SBRT VMAT lung treatment plans. The application of the set of optimization approaches can significantly improve the lung sparing in SBRT VMAT plans with AXB dose calculation algorithm and makes treatment plans more conformal in high, intermediate and low dose regions, while higher dose is delivered to the target.

This article examines the evolution of advance care planning (ACP) in Singapore through the development of a less-formal, communications-based model - the Living Matters program - and its experience with local cultural and community responses to the process and its outcomes. Living Matters is, in practice, arguably a communitarian approach to ACP. The article then examines the challenges Living Matters poses to the overarching legal framework for ACP and suggests improvements to the proxy decision-making framework under the Mental Capacity Act (Singapore, cap 177A, 2010 rev ed), offering more flexible legal tools for ACP, and more regulatory support for the means to implement ACP outcomes effectively.

Objective International appeals call for interventions to prevent aggression and other behavioral problems in individuals with dementia (IWD). Aggression Prevention Training (APT), based on intervening in three contributors to development of aggression (IWD pain, IWD depression, and caregiver–IWD relationship problems) aims to reduce incidence of aggression in IWD over 1 year. Design Randomized, controlled trial. Setting Three clinics that assess, diagnose, and treat dementia. Participants Two hundred twenty-eight caregiver–IWD dyads who screened positive for IWD pain, IWD depression, or caregiver–IWD relationship problems randomized to APT or Enhanced Usual Primary Care (EU-PC). Intervention APT, a skills-based intervention delivered over 3 months to address pain/depression/caregiver–IWD relationship issues. EU-PC included printed material on dementia and community resources; and eight brief, weekly support calls. Measurements The primary outcome was incidence of aggression over 1 year, determined by the Cohen Mansfield Agitation Inventory-Aggression Subscale. Secondary outcomes included pain, depression, caregiver–IWD relationship, caregiver burden, positive caregiving, behavior problems, and anxiety. Results Aggression incidence and secondary outcomes did not differ between groups. However, in those screening positive for IWD depression or caregiver–IWD relationship problems, those receiving EU-PC had significant increases in depression and significant decreases in quality of the caregiver–IWD relationship, whereas those receiving APT showed no changes in these outcomes over time. Conclusion The cost to patients, family, and society of behavioral problems in IWD, along with modest efficacy of most pharmacologic and nonpharmacologic interventions, calls for more study of novel preventive approaches.

The objective was to examine one family’s experience with the parenting intervention Baby Triple P for parents of a very preterm infant. The family was in the intervention group of a large randomized controlled trial. At baseline, 6-weeks corrected-age and 12-months corrected-age, both parents were assessed for depression as measured by the Edinburgh Postnatal Depression Scale and subjective stress as measured by the Impact of Event Scale. At 6-weeks corrected-age and 12-months corrected-age, the mother was assessed for maternal self-efficacy as measured by the Maternal Self-Efficacy Scale, attachment as measured by the Maternal Postnatal Attachment Scale, responsiveness as measured by the Maternal Infant Responsiveness Instrument, and the quality of the mother-infant relationship as measured by the Emotional Availability Scales. Results at baseline showed the mother was at risk for depression and was experiencing a moderate level of subjective stress, while the father was experiencing a mild level of subjective stress. After the Baby Triple P intervention, the mother’s Edinburgh Postnatal Depression Scale and Impact of Event Scale scores and the father’s Impact of Event Scale score had dropped to within the normal range at 6-weeks corrected-age, and were maintained at 12-months corrected-age. The mother also indicated she experienced greater levels of self-efficacy, attachment, responsiveness, and the quality of the relationship with her infant. Both parents rated that they were very satisfied with the Baby Triple P program on the Client Satisfaction Questionnaire. This study indicated that the Baby Triple P intervention may be beneficial for some families with a very preterm infant.

This study examined intervention outcomes for mothers and their preterm infants. The objective was to evaluate the effects of the parenting intervention Baby Triple P ( BTP ) for parents’ of very preterm infants ( < 32-weeks gestational age ), on the quality of the mother–infant relationship and a mother’s attachment and responsiveness to her infant at 6-weeks and 12-months corrected-age. A randomized controlled trial was conducted with 120 families being randomly assigned to the BTP or Care as Usual groups. The primary outcome was the quality of the mother-very preterm infant relationship which was evaluated in a mother-infant observation and measured by the Emotional Availability Scales. Secondary outcomes were maternal attachment as measured by the Maternal Postnatal Attachment Scale and maternal responsiveness as measured by the Maternal Infant Responsiveness Instrument. The results showed that at 6-weeks corrected-age, no significant differences were found between groups on the outcome measures. At 12-months corrected-age, the Care as Usual mothers scored significantly higher for self-reported maternal attachment compared to the BTP mothers. This study found no evidence that BTP improved the quality of the mother-very preterm infant relationship, maternal attachment or responsiveness at 6-weeks corrected-age or 12-months corrected-age. Results will be examined at 24-months corrected-age to determine if BTP impacts on child behavior, emotional problems, cognitive development, language and motor abilities.

Autophagy is an intracellular degradation process that mediates the clearance of cytoplasmic components. As well as being an important function for cellular homeostasis, autophagy also promotes the removal of aberrant protein accumulations, such as those seen in conditions like neurodegeneration. The dynamic nature of autophagy requires precise methods to examine the process at multiple stages. The protocols described herein enable the dissection of the complete autophagy process (the "autophagy flux"). These allow for the elucidation of which stages of autophagy may be altered in response to various diseases and treatments.

Autophagy cargo recognition and clearance are essential for intracellular protein quality control. SQSTM1/p62 sequesters intracellular aberrant proteins and mediates cargo delivery for their selective autophagic degradation. The formation of p62 non-membrane-bound liquid compartments is critical for its function as a cargo receptor. The regulation of p62 phase separation/condensation has yet been poorly characterised. Using an unbiased yeast two-hybrid screening and complementary approaches, we found that DAXX physically interacts with p62. Cytoplasmic DAXX promotes p62 puncta formation. We further elucidate that DAXX drives p62 liquid phase condensation by inducing p62 oligomerisation. This effect promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated stress response. The present study suggests a mechanism of p62 phase condensation by a protein interaction, and indicates that DAXX regulates redox homoeostasis, providing a mechanistic insight into the prosurvival function of DAXX., The autophagy protein p62 undergoes liquid-liquid phase separation but how this is regulated is unclear. Here, the authors report that the histone chaperone DAXX interacts with p62 in the cytoplasm to drive its phase separation.

Autophagy is an intracellular degradation process that mediates the clearance of cytoplasmic components. As well as being an important function for cellular homeostasis, autophagy also promotes the removal of aberrant protein accumulations, such as those seen in conditions like neurodegeneration. The dynamic nature of autophagy requires precise methods to examine the process at multiple stages. The protocols described herein enable the dissection of the complete autophagy process (the "autophagy flux"). These allow for the elucidation of which stages of autophagy may be altered in response to various diseases and treatments.

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia, where an accumulation of aggregated fibrillar alpha-synuclein in neurons of limbic and forebrain regions of the brain leads to visual hallucination, cognitive impairment of a fluctuating nature and extrapyramidal motor disturbances. Beta-synuclein counteracts aggregation of alpha-synuclein in vitro and in animal models, however it is not clear whether this effect occurs in human Lewy body dementia (LBD) diseases. Here we examine expression of alpha-, beta-synuclein and autophagy markers in the frontal cortex (BA9) and occipital cortex (BA18-19) of patients with neuropathologically confirmed DLB/LBD and age-matched controls. We provide evidence for neuronal upregulation of beta-synuclein within the frontal cortex and its decrease in occipital cortex of DLB patients. While beta-synuclein-containing neurons were consistently devoid of oligomeric alpha-synuclein in the frontal cortex, we did not observe an overall correlation between total beta-synuclein and 5G4 levels (marker of oligomeric alpha-synuclein). The autophagy markers LC3-II and p62 were increased in the areas of beta-synuclein upregulation in DLB brains, and we show attenuation of autophagy flux when beta-synuclein is overexpressed in vitro. Altogether, this data suggests that beta-synuclein changes in DLB may exacerbate neuronal dysfunction caused by accumulation of alpha-synuclein by influencing protein degradation pathways; this should be taken into consideration when designing therapeutic strategies aimed to decrease alpha-synuclein burden in Lewy body diseases.

Aim To systematically review the efficacy of parenting interventions in improving the quality of the relationship between mothers and preterm infants. Method Randomized or quasi-randomized controlled trials (RCT) of parenting interventions for mothers of preterm infants where mother–infant relationship quality outcomes were reported. Databases searched: The Cochrane Library, PubMed, CINAHL, PsycINFO and Web of Science. Results Seventeen studies met the inclusion criteria, 14 with strong methodological quality. Eight parenting interventions were found to improve the quality of the mother–preterm infant relationship. Conclusions Heterogeneity of the interventions calls for an integrated new parenting program focusing on cue-based, responsive care from the mother to her preterm infant to improve the quality of the relationship for these mother–preterm infant dyads.

Healthcare decision-making has traditionally focused on individual autonomy, but there is now a change occurring in which the involvement of families is gaining prominence. This appears to stem from an increasing emphasis on relational aspects of autonomy which recognises the individual's connectedness to their family, and also state reliance upon families to share the burdens and costs of caring for elderly and disabled dependents. Such a reorientation calls for similar legal emphasis on patient autonomy as understood in relational terms, and one that offers more adequate conceptions of independence, confidentiality and decision-making authority in the light of this change. This paper outlines how two common law jurisdictions, New Zealand and Singapore, have accommodated, or are responding to, these changes.

Transplant tourism is spurred by the global shortage of organs and the potential for regulatory arbitrage in purchasing an organ in jurisdictions that do not prohibit sale or lack effective regulatory mechanisms to enforce prohibition. Various nations once identified as transplant tourism hotspots have since enacted legislation prohibiting organ sales and emplaced regulatory oversight. However, concerns persist that the legitimization of altruistic unrelated living donor transplants conceals underlying commercialism and unethical practices. These concerns are heightened when transplant candidates travel across borders in search of international transplant medicine. This article examines the regulatory challenges associated with differentiating international transplant medicine from transplant tourism, and various regulatory mechanisms that have been developed to address them from the domestic perspective – in particular, those recently implemented in the Singapore. It seeks to identify the strengths and weaknesses of the Singapore system and what lessons this has for international standards and practices.

Developments in medical technology, healthcare delivery, and commercial interests in medicine have increased both the potential for conflicts of interest on the part of physicians, and doubts over the sufficiency of patient autonomy as a justification for administering innovative therapy. The legal and regulatory treatment of innovative therapy is therefore an important question, on which there is a current lack of consensus on a number of issues. This paper discusses recent developments in Singapore and uses them as a springboard to flesh out basic regulatory issues that arise from the deployment of innovative treatment: the distinction between innovative treatment and clinical research, the adequacy of the current post hoc scrutiny of innovative therapy under existing legal principles and the need for further specialised regulatory oversight.

This paper reviews the use of schemes of arrangement (SOA) in Singapore as a corporate rescue mechanism, and argues that a number of features have contributed to its emergence as a de facto debtor-in-possession regime. It also offers some suggestions on how this organic process can be further enhanced without unduly prejudicing the interests of stakeholders. Copyright © 2009 John Wiley & Sons, Ltd.

This paper examines the challenges of enrolling minors in biomedical research that does not offer participants any prospect of direct benefit. It does so in the context of the current Singapore regime for the protection of research subjects, and seeks to evaluate if this is adequate for the task. In the process, it reviews appropriate Commonwealth and US precedents, regulatory instruments and guidelines that bear on three main issues raised by such research, and makes some recommendations on how they might be better addressed: first, the protective ceilings of risk prescribed beyond which minors may not be exposed to. Secondly, the allocation of decision-making authority and processes employed before a minor is permitted to enrol in such research. Finally, the particular regulatory oversight mechanisms that are needed to improve ethical and legal compliance.

Background Scant information exists about the epidemiological characteristics and outcome of patients in the intensive care unit (ICU) at risk of acute respiratory distress syndrome (ARDS) and how ventilation is managed in these individuals. We aimed to establish the epidemiological characteristics of patients at risk of ARDS, describe ventilation management in this population, and assess outcomes compared with people at no risk of ARDS. Methods PRoVENT (PRactice of VENTilation in critically ill patients without ARDS at onset of ventilation) is an international, multicentre, prospective study undertaken at 119 ICUs in 16 countries worldwide. All patients aged 18 years or older who were receiving mechanical ventilation in participating ICUs during a 1-week period between January, 2014, and January, 2015, were enrolled into the study. The Lung Injury Prediction Score (LIPS) was used to stratify risk of ARDS, with a score of 4 or higher defining those at risk of ARDS. The primary outcome was the proportion of patients at risk of ARDS. Secondary outcomes included ventilatory management (including tidal volume [VT] expressed as mL/kg predicted bodyweight [PBW], and positive end-expiratory pressure [PEEP] expressed as cm H2O), development of pulmonary complications, and clinical outcomes. The PRoVENT study is registered at ClinicalTrials.gov, NCT01868321. The study has been completed. Findings Of 3023 patients screened for the study, 935 individuals fulfilled the inclusion criteria. Of these critically ill patients, 282 were at risk of ARDS (30%, 95% CI 27–33), representing 0·14 cases per ICU bed over a 1-week period. VTwas similar for patients at risk and not at risk of ARDS (median 7·6 mL/kg PBW [IQR 6·7–9·1] vs 7·9 mL/kg PBW [6·8–9·1]; p=0·346). PEEP was higher in patients at risk of ARDS compared with those not at risk (median 6·0 cm H2O [IQR 5·0–8·0] vs 5·0 cm H2O [5·0–7·0]; p

Recent research and ethical analysis have forced a clinical and ethical reappraisal of the utility of placebos in medical practice. The main concern of ethics and law is that using placebos in health care involves deception, which is antithetical to patient autonomy and trust in the physician-patient relationship. This article reviews the various, more nuanced scientific conceptions of the placebo effect, and evaluates the ethical and legal objections to deploying placebos in clinical practice. It argues that the placebo effect may be legitimately accommodated on the basis that it does not engage the requirement for material or quasi-fiduciary disclosures of information, and may also be justified by therapeutic privilege. In addition, this reconceptualisation of the placebo effect offers a new justification for therapeutic privilege in these contexts. Notwithstanding this, using the placebo effect in clinical practice raises regulatory issues that will require special regulatory supervision.

Background: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are a major factor in nursing home placement and a primary cause of stress for caregivers. Elevated cholesterol has been linked to psychiatric disorders and has been shown to be a risk factor for AD and to impact disease progression. The present study investigated the relationship between cholesterol and NPS in AD. Methods: Data on cholesterol and NPS from 220 individuals (144 females, 76 males) with mild-to-moderate AD from the Texas Alzheimer's Research and Care Consortium (TARCC) cohort were analyzed. The total number of NPS and symptoms of hyperactivity, psychosis, affect and apathy were evaluated. Groups based on total cholesterol (TC; ≥200 vs. Results: Individuals with high TC had lower MMSE scores as well as significantly more NPS and more symptoms of psychosis. When stratified by gender, males with high TC had significantly more NPS than females with high TC or than males or females with low TC. Conclusion: The role of elevated cholesterol in the occurrence of NPS in AD appears to be gender and symptom specific. A cross-validation of these findings will have implications for possible treatment interventions, especially for males with high TC.

Background: Health professional students from high-income countries increasingly participate in short-term experiences in global health (STEGH) conducted abroad. One common criticism of STEGH is the inherent power differential that exists between visiting learners and the local community. To highlight this power differential, this paper explores perceived benefits as described by volunteer and community respondents and applies Maslow's hierarchy of needs to commonly identified themes in each respondent group. Methods: A semistructured survey was used to collect qualitative responses from both volunteers and community members located in a Dominican Republic community, that is, a hotspot for traditionally conducted STEGH. Thematic analysis identified themes of perceived benefits from both respondent groups; each group's common themes were then classified and compared within Maslow's hierarchy of needs. Results: Each respondent group identified resource provision as a perceived benefit of STEGH, but volunteer respondents primarily focused on the provision of highly-skilled, complex resources while community respondents focused on basic necessities (food, water, etc.) Volunteer respondents were also the only group to also mention spiritual/religious/life experiences, personal skills development, and relationships as perceived benefits. Applying Maslow's hierarchy thus demonstrates a difference in needs: community respondents focused on benefits that address deficiency needs at the bottom of the hierarchy while volunteers focused on benefits addressing self-transcendence/actualization needs at the top of the hierarchy. Conclusions: The perceived difference in needs met by STEGH between volunteers and the host community within Maslow's hierarchy may drive an inherent power differential. Refocusing STEGH on the relationship level of the hierarchy (i.e., focusing on partnerships) might help mitigate this imbalance and empower host communities.

A plateau has been reached in the efficacy of cytotoxic chemotherapy for non-small cell lung cancer (NSCLC), highlighting the need for novel treatments for this poor-prognosis malignancy. Antiangiogenic agents, including the approved vascular endothelial growth factor (VEGF)-targeted monoclonal antibody, bevacizumab, as well as a number of investigational tyrosine kinase inhibitors (TKIs) that simultaneously target multiple angiogenic pathways, have demonstrated activity in patients with NSCLC. However, unlike the epidermal growth factor receptor (EGFR) TKIs erlotinib and gefitinib, for which the presence of EGFR-activating mutations are now known to predict response, no validated markers currently exist for the efficacy of antiangiogenic agents. Hypertension has been associated with antiangiogenic therapy and has also been evaluated as a surrogate marker for efficacy with this class of agents, although analyses, to date, have yielded conflicting results. This review provides a summary of currently available, clinically relevant data on the incidence of hypertension with VEGF-targeted antibodies and multitargeted antiangiogenic TKIs in advanced NSCLC and discusses the potential predictive role of hypertension on antiangiogenic therapy in such patients.

a b s t r a c t Objective: To investigate the relationship between the predictor variables of experiential avoidance, relationship satisfaction, prenatal expectations (compared to postnatal experi- ence) and postpartum support, and the criterion variables of maternal attachment, maternal psychological symptoms and maternal responsiveness, after controlling for birth weight. Design: A quantitative survey study. Method: The participants were 127 mothers of preterm infants (delivery prior to 37 weeks gestation

Surveys the provision of selected sources of European business information in 11 libraries with business collections