A novel framework for high-quality voice source analysis and synthesis

The analysis, parameterization and modeling of voice source estimates obtained via inverse filtering of recorded speech are some of the most challenging areas of speech processing owing to the fact humans produce a wide range of voice source realizations and that the voice source estimates commonly contain artifacts due to the non-linear time-varying source-filter coupling. Currently, the most widely adopted representation of voice source signal is Liljencrants-Fant's (LF) model which was developed in late 1985. Due to the overly simplistic interpretation of voice source dynamics, LF model can not represent the fine temporal structure of glottal flow derivative realizations nor can it carry the sufficient spectral richness to facilitate a truly natural sounding speech synthesis. In this thesis we have introduced Characteristic Glottal Pulse Waveform Parameterization and Modeling (CGPWPM) which constitutes an entirely novel framework for voice source analysis, parameterization and reconstruction. In comparative evaluation of CGPWPM and LF model we have demonstrated that the proposed method is able to preserve higher levels of speaker dependant information from the voice source estimates and realize a more natural sounding speech synthesis. In general, we have shown that CGPWPM-based speech synthesis rates highly on the scale of absolute perceptual acceptability and that speech signals are faithfully reconstructed on consistent basis, across speakers, gender. We have applied CGPWPM to voice quality profiling and text-independent voice quality conversion method. The proposed voice conversion method is able to achieve the desired perceptual effects and the modified speech remained as natural sounding and intelligible as natural speech. In this thesis, we have also developed an optimal wavelet thresholding strategy for voice source signals which is able to suppress aspiration noise and still retain both the slow and the rapid variations in the voice source estimate.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

cyTRON and cyTRON/JS: two Cytoscape-based applications for the inference of cancer evolution models

The increasing availability of sequencing data of cancer samples is fueling the development of algorithmic strategies to investigate tumor heterogeneity and infer reliable models of cancer evolution. We here build up on previous works on cancer progression inference from genomic alteration data, to deliver two distinct Cytoscape-based applications, which allow to produce, visualize and manipulate cancer evolution models, also by interacting with public genomic and proteomics databases. In particular, we here introduce cyTRON, a stand-alone Cytoscape app, and cyTRON/JS, a web application which employs the functionalities of Cytoscape/JS. cyTRON was developed in Java; the code is available at https://github.com/BIMIB-DISCo/cyTRON and on the Cytoscape App Store http://apps.cytoscape.org/apps/cytron. cyTRON/JS was developed in JavaScript and R; the source code of the tool is available at https://github.com/BIMIB-DISCo/cyTRON-js and the tool is accessible from https://bimib.disco.unimib.it/cytronjs/welcome

Kidney cancer: The next decade

Chris Boshoff, Senior Vice President of Immuno-Oncology, Translational and Early Development at Pfizer, and colleagues Samra Turajlic and Charles Swanton from the Francis Crick Institute and University College London give us their personal point of view on new insights and future therapeutic approaches for renal cancer

Resolving genetic heterogeneity in cancer

To a large extent, cancer conforms to evolutionary rules defined by the rates at which clones mutate, adapt and grow. Next-generation sequencing has provided a snapshot of the genetic landscape of most cancer types, and cancer genomics approaches are driving new insights into cancer evolutionary patterns in time and space. In contrast to species evolution, cancer is a particular case owing to the vast size of tumour cell populations, chromosomal instability and its potential for phenotypic plasticity. Nevertheless, an evolutionary framework is a powerful aid to understand cancer progression and therapy failure. Indeed, such a framework could be applied to predict individual tumour behaviour and support treatment strategies

Tracking Cancer Evolution through the Disease Course.

During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field. SIGNIFICANCE: Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non-small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials

An immunotherapy survivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune checkpoint inhibitors

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achievinghigh-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aimofthis study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-relatedadverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK.Methods We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durableresponse to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression.HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEsand survival. HRQoL data was compared with two norm-based datasets.Results Eighty-four metastatic melanoma survivors were eligible and 87% (N = 73) completed the SF-36. ICI-related toxicity ofany grade occurred in 92%of patients and 43%had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients requiredsteroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyondsteroids.Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical rolefunctioning and general health compared with the normative population. There was a trend towards inferior scores in patientswith previous exposure to ipilimumab compared with those never exposed to ipilimumab.Conclusions Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicityand experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population’sunique survivorship needs.Peer reviewe

Optimisation of b-values for the accurate estimation of the apparent diffusion coefficient (ADC) in whole-body diffusion-weighted MRI in patients with metastatic melanoma.

OBJECTIVE: To establish optimised diffusion weightings ('b-values') for acquisition of whole-body diffusion-weighted MRI (WB-DWI) for estimation of the apparent diffusion coefficient (ADC) in patients with metastatic melanoma (MM). Existing recommendations for WB-DWI have not been optimised for the tumour properties in MM; therefore, evaluation of acquisition parameters is essential before embarking on larger studies. METHODS: Retrospective clinical data and phantom experiments were used. Clinical data comprised 125 lesions from 14 examinations in 11 patients with multifocal MM, imaged before and/or after treatment with immunotherapy at a single institution. ADC estimates from these data were applied to a model to estimate the optimum b-value. A large non-diffusing phantom was used to assess eddy current-induced geometric distortion. RESULTS: Considering all tumour sites from pre- and post-treatment examinations together, metastases exhibited a large range of mean ADC values, [0.67-1.49] × 10-3 mm2/s, and the optimum high b-value (bhigh) for ADC estimation was 1100 (10th-90th percentile: 740-1790) s/mm2. At higher b-values, geometric distortion increased, and longer echo times were required, leading to reduced signal. CONCLUSIONS: Theoretical optimisation gave an optimum bhigh of 1100 (10th-90th percentile: 740-1790) s/mm2 for ADC estimation in MM, with the large range of optimum b-values reflecting the wide range of ADC values in these tumours. Geometric distortion and minimum echo time increase at higher b-values and are not included in the theoretical optimisation; bhigh in the range 750-1100 s/mm2 should be adopted to maintain acceptable image quality but performance should be evaluated for a specific scanner. KEY POINTS: • Theoretical optimisation gave an optimum high b-value of 1100 (10th-90th percentile: 740-1790) s/mm2 for ADC estimation in metastatic melanoma. • Considering geometric distortion and minimum echo time (TE), a b-value in the range 750-1100 s/mm2 is recommended. • Sites should evaluate the performance of specific scanners to assess the effect of geometric distortion and minimum TE

Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis.

INTRODUCTION: Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis. METHODS: We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment. RESULTS: Twenty-two patients (14 male) with a median age of 64 (range 45-84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD. CONCLUSIONS: Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen