Designers manual for computer-aided design of control circuits Final technical report

Computer aided design of linear time invariant feedback control circuit

Utility of gross tumor palpability or tumor size as a measure of drug efficacy for cancer prevention

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Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3(-/-) mice, but not wildtype mice.

Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are 'direct' effects of light on affect, an 'indirect' pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3(-/-) mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3(-/-)) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3(-/-) mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3(-/-) nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3(-/-) phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light

Acquisition of a Unique Onshore/Offshore Geophysical and Geochemical Dataset in the Northern Malawi (Nyasa) Rift

The Study of Extension and maGmatism in Malawi aNd Tanzania (SEGMeNT) project acquired a comprehensive suite of geophysical and geochemical datasets across the northern Malawi (Nyasa) rift in the East Africa rift system. Onshore/offshore active and passive seismic data, long‐period and wideband magnetotelluric data, continuous Global Positioning System data, and geochemical samples were acquired between 2012 and 2016. This combination of data is intended to elucidate the sedimentary, crustal, and upper‐mantle architecture of the rift, patterns of active deformation, and the origin and age of rift‐related magmatism. A unique component of our program was the acquisition of seismic data in Lake Malawi, including seismic reflection, onshore/offshore wide‐angle seismic reflection/refraction, and broadband seismic data from lake‐bottom seismometers, a towed streamer, and a large towed air‐gun source

Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration

The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis

Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.

UNLABELLED: Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell-mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. SIGNIFICANCE: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer

Amplicon-Dependent CCNE1 Expression Is Critical for Clonogenic Survival after Cisplatin Treatment and Is Correlated with 20q11 Gain in Ovarian Cancer

Genomic amplification of 19q12 occurs in several cancer types including ovarian cancer where it is associated with primary treatment failure. We systematically attenuated expression of genes within the minimally defined 19q12 region in ovarian cell lines using short-interfering RNAs (siRNA) to identify driver oncogene(s) within the amplicon. Knockdown of CCNE1 resulted in G1/S phase arrest, reduced cell viability and apoptosis only in amplification-carrying cells. Although CCNE1 knockdown increased cisplatin resistance in short-term assays, clonogenic survival was inhibited after treatment. Gain of 20q11 was highly correlated with 19q12 amplification and spanned a 2.5 Mb region including TPX2, a centromeric protein required for mitotic spindle function. Expression of TPX2 was highly correlated with gene amplification and with CCNE1 expression in primary tumors. siRNA inhibition of TPX2 reduced cell viability but this effect was not amplicon-dependent. These findings demonstrate that CCNE1 is a key driver in the 19q12 amplicon required for survival and clonogenicity in cells with locus amplification. Co-amplification at 19q12 and 20q11 implies the presence of a cooperative mutational network. These observations have implications for the application of targeted therapies in CCNE1 dependent ovarian cancers

Planar Tc99m – sestamibi scintimammography should be considered cautiously in the axillary evaluation of breast cancer protocols: Results of an international multicenter trial

BACKGROUND: Lymph node status is the most important prognostic indicator in breast cancer in recently diagnosed primary lesion. As a part of an interregional protocol using scintimammography with Tc99m compounds, the value of planar Tc99m sestamibi scanning for axillary lymph node evaluation is presented. Since there is a wide range of reported values, a standardized protocol of planar imaging was performed. METHODS: One hundred and forty-nine female patients were included prospectively from different regions. Their mean age was 55.1 ± 11.9 years. Histological report was obtained from 2.987 excised lymph nodes from 150 axillas. An early planar chest image was obtained at 10 min in all patients and a delayed one in 95 patients, all images performed with 740–925 MBq dose of Tc99m sestamibi. Blind lecture of all axillary regions was interpreted by 2 independent observers considering any well defined focal area of increased uptake as an involved axilla. Diagnostic values, 95% confidence intervals [CI] and also likelihood ratios (LR) were calculated. RESULTS: Node histology demonstrated tumor involvement in 546 out of 2987 lymph nodes. Sestamibi was positive in 30 axillas (25 true-positive) and negative in 120 (only 55 true-negative). The sensitivity corresponded to 27.8% [CI = 18.9–38.2] and specificity to 91.7% [81.6–97.2]. The positive and negative LR were 3.33 and 0.79, respectively. There was no difference between early and delayed images. Sensitivity was higher in patients with palpable lesions. CONCLUSION: This work confirmed that non tomographic Tc99m sestamibi scintimammography had a very low detection rate for axillary lymph node involvement and it should not be applied for clinical assessment of breast cancer