Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

BackgroundHistone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.MethodsThis phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.ResultsIn total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.ConclusionThese findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting

A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer

BackgroundHistone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points.MethodsPatients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated.ResultsIn all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.ConclusionThe combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination

Comparisons of the factor structure and measurement invariance of the Spence children’s anxiety scale - parent version in children with autism spectrum disorder and typically developing anxious children

The Spence Children’s Anxiety Scale - Parent version (SCAS-P) is often used to assess anxiety in children with autism spectrum disorder (ASD), however, little is known about the validity of the tool in this population. The aim of this study was to determine whether the SCAS-P has the same factorial validity in a sample of young people with ASD (n=285), compared to a sample of typically developing young people with anxiety disorders (n=224). Poor model fit with all of the six hypothesised models precluded invariance testing. Exploratory factor analysis indicated that different anxiety phenomenology characterises the two samples. The findings suggest that cross-group comparisons between ASD and anxious samples based on the SCAS-P scores may not always be appropriat

More Stable Productivity of Semi Natural Grasslands than Sown Pastures in a Seasonally Dry Climate

In the Neotropics the predominant pathway to intensify productivity is generally thought to be to convert grasslands to sown pastures, mostly in monoculture. This article examines how above-ground net primary productivity (ANPP) in semi-natural grasslands and sown pastures in Central America respond to rainfall by: (i) assessing the relationships between ANPP and accumulated rainfall and indices of rainfall distribution, (ii) evaluating the variability of ANPP between and within seasons, and (iii) estimating the temporal stability of ANPP. We conducted sequential biomass harvests during 12 periods of 22 days and related those to rainfall. There were significant relationships between ANPP and cumulative rainfall in 22-day periods for both vegetation types and a model including a linear and quadratic term explained 74% of the variation in the data. There was also a significant correlation between ANPP and the number of rainfall events for both vegetation types. Sown pastures had higher ANPP increments per unit rainfall and higher ANPP at the peak of the rainy season than semi-natural grasslands. In contrast, semi-natural grasslands showed higher ANPP early in the dry season. The temporal stability of ANPP was higher in semi-natural grasslands than in the sown pastures in the dry season and over a whole annual cycle. Our results reveal that, contrary to conventional thinking amongst pasture scientists, there appears to be no increase in ANPP arising from replacing semi-natural grasslands with sown pastures under prevailing pasture management practices in seasonally dry climates, while the temporal distribution of ANPP is more even in semi-natural grasslands. Neither sown pastures nor semi-natural grasslands are productive towards the end of the dry season, indicating the potential importance of the widespread practice of retaining tree cover in pastures

Risk factors for unintentional poisoning in children aged 1–3 years in NSW Australia: a case–control study

BACKGROUND: Unintentional poisoning in young children is an important public health issue. Age pattern studies have demonstrated that children aged 1–3 years have the highest levels of poisoning risk among children aged 0–4 years, yet little research has been conducted regarding risk factors specific to this three-year age group and the methodologies employed varied greatly. The purpose of the current study is to investigate a broad range of potential risk factors for unintentional poisoning in children aged 1–3 years using appropriate methodologies. METHODS: Four groups of children, one case group (children who had experienced a poisoning event) and three control groups (children who had been ‘injured’, ‘sick’ or who were ‘healthy’), and their mothers (mother-child dyads) were enrolled into a case–control study. All mother-child dyads participated in a 1.5-hour child developmental screening and observation, with mothers responding to a series of questionnaires at home. Data were analysed as three case–control pairs with multivariate analyses used to control for age and sex differences between child cases and controls. RESULTS: Five risk factors were included in the final multivariate models for one or more case–control pairs. All three models found that children whose mothers used more positive control in their interactions during a structured task had higher odds of poisoning. Two models showed that maternal psychiatric distress increased poisoning risk (poisoning-injury and poisoning-healthy). Individual models identified the following variables as risk factors: less proximal maternal supervision during risk taking activities (poisoning-injury), medicinal substances stored in more accessible locations in bathrooms (poisoning-sick) and lower total parenting stress (poisoning-healthy). CONCLUSIONS: The findings of this study indicate that the nature of the caregiver-child relationship and caregiver attributes play an important role in influencing poisoning risk. Further research is warranted to explore the link between caregiver-child relationships and unintentional poisoning risk. Caregiver education should focus on the benefits of close interaction with their child as a prevention measure

Targeting histone deacetyalses in the treatment of B- and T-cell malignancies

HDAC inhibitors (HDACI) are now emerging as one of the most promising new classes of drugs for the treatment of select forms of non-Hodgkin’s lymphoma (NHL). They are particularly active in T-cell lymphomas, possibly hodgkin’s lymphoma and indolent B cell lymphomas. Presently, two of these agents, vorinostat and romidepsin, have been approved in the US for the treatment of relapsed and refractory cutaneous T cell lymphomas (CTCL). Initially, these agents were developed with the idea that they affected transcriptional activation and thus gene expression, by modulating chromatin condensation and decondensation. It is now clear that their effects go beyond chromatin and by affecting the acetylation status of histones and other intra-cellular proteins, they modify gene expression and cellular function via multiple pathways. Gene expression profiles and functional genetic analysis has led to further understanding of the various molecular pathways that are affected by these agents including cell cycle regulation, pathways of cellular proliferation, apoptosis and angiogenesis all important in lymphomagenesis. There is also increasing data to support the effects of these agents on T cell receptor and immune function which may explain the high level of activity of these agents in T cell lymphomas and hodgkin’s lymphoma. There is ample evidence of epigenetic dysregulation in lymphomas which may underlie the mechanisms of action of these agents but how these agents work is still not clear. Current HDAC inhibitors can be divided into at least four classes based on their chemical structure. At present several of these HDAC inhibitors are in clinical trials both as single agents and in combination with chemotherapy or other biological agents. They are easy to administer and are generally well tolerated with minimal side effects. Different dosing levels and schedules and the use of isospecific HDAC inhibitors are some of the strategies that are being employed to increase the therapeutic effect of these agents in the treatment of lymphomas. There may also be class differences that translate into specific activity against different lymphoma. HDAC inhibitors will likely be incorporated into combinations of targeted therapies both in the upfront and relapsed setting for lymphomas

Cognitive Behavior Therapy for Anxious Adolescents: Developmental Influences on Treatment Design and Delivery

Anxiety disorders in adolescence are common and disruptive, pointing to a need for effective treatments for this age group. Cognitive behavior therapy (CBT) is one of the most popular interventions for adolescent anxiety, and there is empirical support for its application. However, a significant proportion of adolescent clients continue to report anxiety symptoms post-treatment. This paper underscores the need to attend to the unique developmental characteristics of the adolescent period when designing and delivering treatment, in an effort to enhance treatment effectiveness. Informed by the literature from developmental psychology, developmental psychopathology, and clinical child and adolescent psychology, we review the ‘why’ and the ‘how’ of developmentally appropriate CBT for anxious adolescents. ‘Why’ it is important to consider developmental factors in designing and delivering CBT for anxious adolescents is addressed by examining the age-related findings of treatment outcome studies and exploring the influence of developmental factors, including cognitive capacities, on engagement in CBT. ‘How’ clinicians can developmentally tailor CBT for anxious adolescents in six key domains of treatment design and delivery is illustrated with suggestions drawn from both clinically and research-oriented literature. Finally, recommendations are made for research into developmentally appropriate CBT for anxious adolescents

Neurodegeneration of the retina in mouse models of Alzheimer’s disease: what can we learn from the retina?

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease commonly found among elderly. In addition to cognitive and behavioral deficits, vision abnormalities are prevalent in AD patients. Recent studies investigating retinal changes in AD double-transgenic mice have shown altered processing of amyloid precursor protein and accumulation of β-amyloid peptides in neurons of retinal ganglion cell layer (RGCL) and inner nuclear layer (INL). Apoptotic cells were also detected in the RGCL. Thus, the pathophysiological changes of retinas in AD patients are possibly resembled by AD transgenic models. The retina is a simple model of the brain in the sense that some pathological changes and therapeutic strategies from the retina may be observed or applicable to the brain. Furthermore, it is also possible to advance our understanding of pathological mechanisms in other retinal degenerative diseases. Therefore, studying AD-related retinal degeneration is a promising way for the investigation on (1) AD pathologies and therapies that would eventually benefit the brain and (2) cellular mechanisms in other retinal degenerations such as glaucoma and age-related macular degeneration. This review will highlight the efforts on retinal degenerative research using AD transgenic mouse models

Polo kinase recruitment via the constitutive centromere-associated network at the kinetochore elevates centromeric RNA

The kinetochore, a multi-protein complex assembled on centromeres, is essential to segregate chromosomes during cell division. Deficiencies in kinetochore function can lead to chromosomal instability and aneuploidy-a hallmark of cancer cells. Kinetochore function is controlled by recruitment of regulatory proteins, many of which have been documented, however their function often remains uncharacterized and many are yet to be identified. To identify candidates of kinetochore regulation we used a proteome-wide protein association strategy in budding yeast and detected many proteins that are involved in post-translational modifications such as kinases, phosphatases and histone modifiers. We focused on the Polo-like kinase, Cdc5, and interrogated which cellular components were sensitive to constitutive Cdc5 localization. The kinetochore is particularly sensitive to constitutive Cdc5 kinase activity. Targeting Cdc5 to different kinetochore subcomplexes produced diverse phenotypes, consistent with multiple distinct functions at the kinetochore. We show that targeting Cdc5 to the inner kinetochore, the constitutive centromere-associated network (CCAN), increases the levels of centromeric RNA via an SPT4 dependent mechanism

Protection from ultraviolet damage and photocarcinogenesis by vitamin d compounds

© Springer Nature Switzerland AG 2020. Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds