Judicial punishtecture and mercying in Cyprus

The thesis unveils how judges decide sentences in Cyprus and how they employ mercy to contour their judgments by determining at the same time whether these decisions are reached within or on the basis of a consistent legitimising framework founded in or derived from moral legal theory. The study professes a degree of originality in that it deals with the academically unexplored ground of the Cypriot sentencing reality and investigates the role of mercy not only as a component (or not) element of justice but, additionally, as a purposive ingredient of judicial discretion in the determination of sentence. It emphasises positive rather than normative analysis. It concentrates on how Cypriot judges sentence, and not on how they should or ought to sentence, by depicting and explaining the judges’ method of reaching their sentencing decisions in substance and in form (or their punishtecture as it will be characterised), including the demonstration on their part of mercy to certain defendants at the sentencing stage (or mercying as it will similarly be referred to). Following a discussion of relevant conceptual and empirical literature the thesis present and analyses a substantial body of data generated from a series of tête-à-tête semi-structured interviews conducted by the researcher with the majority of the Cypriot judiciary between 2007 and 2008. The research yields the judges’ views on the nature of the sentencing process and the conceptions, design, structuring, and utterance of their resultant judgments within the criminal justice context in which they find themselves acting. It presents what they have said about the choice of punishment and mercy and reconstructs what they may be taken to have meant by saying it; their aims and purposes in sentencing; the constraints under which they operate; the way they exercise their penal choices; and the use (or dismissal) of mercy as an etiological foundation of sentencing rationales

Sub-kHz Quantum Linewidth Semiconductor Laser On Silicon Chip

We report on a semiconductor laser on silicon platform with record-low sub-kHz quantum noise-limited linewidth, based on spontaneous emission control and optical loss reduction

Quantum control of phase fluctuations in semiconductor lasers

Few laser systems allow access to the light–emitter interaction as versatile and direct as that afforded by semiconductor lasers. Such a level of access can be exploited for the control of the coherence and dynamic properties of the laser. Here, we demonstrate, theoretically and experimentally, the reduction of the quantum phase noise of a semiconductor laser through the direct control of the spontaneous emission into the laser mode, exercised via the precise and deterministic manipulation of the optical mode’s spatial field distribution. Central to the approach is the recognition of the intimate interplay between spontaneous emission and optical loss. A method of leveraging and “walking” this fine balance to its limit is described. As a result, some two orders of magnitude reduction in quantum noise over the state of the art in semiconductor lasers, corresponding to a minimum linewidth of 1 kHz, is demonstrated. Further implications, including an additional order-of-magnitude enhancement in effective coherence by way of control of the relaxation oscillation resonance frequency and enhancement of the intrinsic immunity to optical feedback, highlight the potential of the proposed concept for next-generation, integrated coherent systems

Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease

Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial

Kicking the habit/semiconductor lasers without isolators

In this paper, we propose and demonstrate a solution to the problem of coherence degradation and collapse caused by the back reflection of laser power into the laser resonator. The problem is most onerous in semiconductor lasers (SCLs), which are normally coupled to optical fibers, and results in the fact that practically every commercial SCL has appended to it a Faraday-effect isolator that blocks most of the reflected optical power preventing it from entering the laser resonator. The isolator assembly is many times greater in volume and cost than the SCL itself. This problem has resisted a practical and economic solution despite decades of effort and remains the main obstacle to the emergence of a CMOS-compatible photonic integrated circuit technology. A simple solution to the problem is thus of major economic and technological importance. We propose a strategy aimed at weaning semiconductor lasers from their dependence on external isolators. Lasers with large internal Q-factors can tolerate large reflections, limited only by the achievable Q values, without coherence collapse. A laser design is demonstrated on the heterogeneous Si/III-V platform that can withstand 25 dB higher reflected power compared to commercial DFB lasers. Larger values of internal Qs, achievable by employing resonator material of lower losses and improved optical design, should further increase the isolation margin and thus obviate the need for isolators altogether

Quantum control of phase fluctuations in semiconductor lasers

Few laser systems allow access to the light–emitter interaction as versatile and direct as that afforded by semiconductor lasers. Such a level of access can be exploited for the control of the coherence and dynamic properties of the laser. Here, we demonstrate, theoretically and experimentally, the reduction of the quantum phase noise of a semiconductor laser through the direct control of the spontaneous emission into the laser mode, exercised via the precise and deterministic manipulation of the optical mode’s spatial field distribution. Central to the approach is the recognition of the intimate interplay between spontaneous emission and optical loss. A method of leveraging and “walking” this fine balance to its limit is described. As a result, some two orders of magnitude reduction in quantum noise over the state of the art in semiconductor lasers, corresponding to a minimum linewidth of 1 kHz, is demonstrated. Further implications, including an additional order-of-magnitude enhancement in effective coherence by way of control of the relaxation oscillation resonance frequency and enhancement of the intrinsic immunity to optical feedback, highlight the potential of the proposed concept for next-generation, integrated coherent systems

In vitro and preclinical systematic dose-effect studies of Auger electron- and beta particle-emitting radionuclides and external beam radiation for cancer treatment:Dose-effect relationship for Auger electrons and beta particles

Purpose. Despite a rise in clinical use of radiopharmaceutical therapies, the biological effects of radionuclides and their relationship with absorbed radiation dose are poorly understood. Here, we set out to define this relationship for Auger electron-emitters [99mTc]TcO4─ and [123I]I─, and β--particle-emitter [188Re]ReO4─. Studies were carried out using genetically-modified cells that permitted direct radionuclide comparisons. Methods and Materials. Triple-negative MDA-MB-231 breast cancer cells, expressing the human sodium/iodide symporter (hNIS) and green fluorescent protein (GFP; MDA-MB-231.hNIS-GFP) were used. In vitro radiotoxicity of [99mTc]TcO4─, [123I]I─ and [188Re]ReO4─ was determined using clonogenic assays. Radionuclide uptake, efflux, and subcellular location were used to calculate nuclear-absorbed doses using the Medical Internal Radiation Dose formalism. In vivo studies were performed using female NSG mice bearing orthotopic MDA-MB-231.hNIS-GFP tumors and compared to X-ray-treated (12.6-15 Gy) and untreated cohorts. Absorbed dose per unit activity in tumors and NIS-expressing organs were extrapolated to reference human adult models using OLINDA/EXM®. Results. [99mTc]TcO4− and [123I]I─ reduced the survival fraction only in hNIS-expressing cells, whereas [188Re]ReO4─ reduced survival fraction in hNIS-expressing and parental cells. [123I]I─ required 2.4-fold and 1.5-fold lower decays/cell to achieve 37% survival compared to [99mTc]TcO4− and [188Re]ReO4─, respectively, following 72 hours incubation. Additionally, [99mTc]TcO4−, [123I]I─ and [188Re]ReO4─ had superior cell killing effectiveness in vitro compared to X-rays. In vivo, X-ray led to a greater median survival compared to [188Re]ReO4─ and [123I]I─ (54 days versus 45 and 43 days, respectively). Unlike the X-ray cohort, no metastases were visualized in the radionuclide-treated cohorts. Extrapolated human absorbed doses of [188Re]ReO4─ to a 1 g tumor were 13.8-fold and 11.2-fold greater than for [123I]I─ in female and male models, respectively. Conclusions. This work reports reference dose-effect data using cell and tumor models for [99mTc]TcO4─, [123I]I─, and [188Re]ReO4─, for the first time. We further demonstrate the tumor controlling effects of [123I]I─, and [188Re]ReO4─ in comparison to EBRT

MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition.

Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resistant); H1975L858R (sensitized) and H1975WT (wild-type). We assessed cell proliferation in vitro and tumor growth/stroma formation in derived xenograft models in response to a MET TKI (SGX523) and correlated with EGFR-MET dimerization assessed by Förster Resonance Energy Transfer (FRET). SGX523 significantly reduced H1975L858R/T790M cell proliferation, xenograft tumor growth and decreased ERK phosphorylation. The same was not seen in H1975L858R or H1975WT cells. SGX523 only reduced stroma formation in H1975L858R. SGX523 reduced EGFR-MET dimerization in H1975L858R/T790M but induced dimer formation in H1975L858R with no effect in H1975WT. Our data suggests that MET inhibition by SGX523 and EGFR-MET heterodimerisation are determined by EGFR genotype. As tumor behaviour is modulated by this interaction, this could determine treatment efficacy