Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials

Notes

Notes by Richard A. Molique, F. Louis Fautsch, John A. Berry, Joseph A. McCabe, Stephen P. Banas, Robert Devine, John J. Locher, and J. S. Montedonico

Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials

Targeting sexual health services in primary care: a systematic review of the psychosocial correlates of adverse sexual health outcomes reported in probability surveys of women of reproductive age

BACKGROUND: Women using primary care vary in need for sexually transmitted infections (STIs) testing and contraception. Psychosocial correlates of these needs may be useful for targeting services. We undertook a systematic review to identify psychosocial correlates of STI acquisition, unplanned pregnancy (UP), abortion and risky sexual behaviours in general population samples of women of reproductive age. METHODS: We searched bibliographic databases for probability surveys of women aged 16-44years in the European Union, USA, Canada, Australia, UK or New Zealand undertaken January 1994-January 2014. RESULTS: Eleven papers were included. Unplanned pregnancy was associated with smoking, depression, being single and sexual debut <16years. Abortion was associated with lack of closeness to parents, leaving home at an early age, and relationship break-up. Multiple partnerships were associated with intensity of marijuana and alcohol use, and smoking. STI diagnosis was associated with relationship break-up and younger partners. Non-use of contraception was associated with smoking, obesity, relationship status, sedentary lifestyles, fatalistic pregnancy attitudes and lower alcohol use. Condom non-use was higher (at first sex) with partners 5+years older and lower (at last sex) in less stable partnerships. CONCLUSION: Psychosocial variables, particularly relationship status and smoking, may help identify women in primary care for STI testing and contraception advice and supply

Changing Climate and Overgrazing Are Decimating Mongolian Steppes

Satellite observations identify the Mongolian steppes as a hotspot of global biomass reduction, the extent of which is comparable with tropical rainforest deforestation. To conserve or restore these grasslands, the relative contributions of climate and human activities to degradation need to be understood. Here we use a recently developed 21-year (1988-2008) record of satellite based vegetation optical depth (VOD, a proxy for vegetation water content and aboveground biomass), to show that nearly all steppe grasslands in Mongolia experienced significant decreases in VOD. Approximately 60% of the VOD declines can be directly explained by variations in rainfall and surface temperature. After removing these climate induced influences, a significant decreasing trend still persists in the VOD residuals across regions of Mongolia. Correlations in spatial patterns and temporal trends suggest that a marked increase in goat density with associated grazing pressures and wild fires are the most likely non-climatic factors behind grassland degradation.Funding for this research was through a University of New South Wales International Postgraduate Award and CSIRO Water for a Healthy Country Flagship Program scholarship. The data used in Figure 3b were supported through the Research Institute for Humanity and Nature (project number D-04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A common neural scale for the subjective pleasantness of different primary rewards.

When an economic decision is taken, it is between goals with different values, and the values must be on the same scale. Here, we used functional MRI to search for a brain region that represents the subjective pleasantness of two different rewards on the same neural scale. We found activity in the ventral prefrontal cortex that correlated with the subjective pleasantness of two fundamentally different rewards, taste in the mouth and warmth on the hand. The evidence came from two different investigations, a between-group comparison of two independent fMRI studies, and from a within-subject study. In the latter, we showed that neural activity in the same voxels in the ventral prefrontal cortex correlated with the subjective pleasantness of the different rewards. Moreover, the slope and intercept for the regression lines describing the relationship between activations and subjective pleasantness were highly similar for the different rewards. We also provide evidence that the activations did not simply represent multisensory integration or the salience of the rewards. The findings demonstrate the existence of a specific region in the human brain where neural activity scales with the subjective pleasantness of qualitatively different primary rewards. This suggests a principle of brain processing of importance in reward valuation and decision-making

Unimodality Problems in Ehrhart Theory

Ehrhart theory is the study of sequences recording the number of integer points in non-negative integral dilates of rational polytopes. For a given lattice polytope, this sequence is encoded in a finite vector called the Ehrhart $h^*$-vector. Ehrhart $h^*$-vectors have connections to many areas of mathematics, including commutative algebra and enumerative combinatorics. In this survey we discuss what is known about unimodality for Ehrhart $h^*$-vectors and highlight open questions and problems.Comment: Published in Recent Trends in Combinatorics, Beveridge, A., et al. (eds), Springer, 2016, pp 687-711, doi 10.1007/978-3-319-24298-9_27. This version updated October 2017 to correct an error in the original versio

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

Background: Previously we identified a DNA damage response–deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. Methods: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. Results: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher’s exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response–proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response–proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle–specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. Conclusions: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint–based therapies

New software for statistical analysis of Cambridge Structural Database data

A new piece of software for statistical analysis of geometrical, chemical and crystallographic data within the Cambridge Structural Database System is described. This software has been written specifically to deal with chemical structure data and crucially provides simultaneous visualization of the three-dimensional structural information

Emerging pharmacotherapy of tinnitus

Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin