4,246 research outputs found

    T-cell receptor determinants of response to chemoradiation in locally-advanced HPV16-driven malignancies

    Get PDF
    BackgroundThe effect of chemoradiation on the anti-cancer immune response is being increasingly acknowledged; however, its clinical implications in treatment responses are yet to be fully understood. Human papillomavirus (HPV)-driven malignancies express viral oncogenic proteins which may serve as tumor-specific antigens and represent ideal candidates for monitoring the peripheral T-cell receptor (TCR) changes secondary to chemoradiotherapy (CRT).MethodsWe performed intra-tumoral and pre- and post-treatment peripheral TCR sequencing in a cohort of patients with locally-advanced HPV16-positive cancers treated with CRT. An in silico computational pipeline was used to cluster TCR repertoire based on epitope-specificity and to predict affinity between these clusters and HPV16-derived epitopes.ResultsIntra-tumoral repertoire diversity, intra-tumoral and post-treatment peripheral CDR3β similarity clustering were predictive of response. In responders, CRT triggered an increase peripheral TCR clonality and clonal relatedness. Post-treatment expansion of baseline peripheral dominant TCRs was associated with response. Responders showed more baseline clustered structures of TCRs maintained post-treatment and displayed significantly more maintained clustered structures. When applying clustering by TCR-specificity methods, responders displayed a higher proportion of intra-tumoral TCRs predicted to recognise HPV16 peptides.ConclusionsBaseline TCR characteristics and changes in the peripheral T-cell clones triggered by CRT are associated with treatment outcome. Maintenance and boosting of pre-existing clonotypes are key elements of an effective anti-cancer immune response driven by CRT, supporting a paradigm in which the immune system plays a central role in the success of CRT in current standard-of-care protocols

    Clinical Applications of Anterior Segment Optical Coherence Tomography:An Updated Review

    Get PDF
    Since its introduction, optical coherence tomography (OCT) has revolutionized the field of ophthalmology and has now become an indispensable, noninvasive tool in daily practice. Most ophthalmologists are familiar with its use in the assessment and monitoring of retinal and optic nerve diseases. However, it also has important applications in the assessment of anterior segment structures, including the cornea, conjunctiva, sclera, anterior chamber, and iris, and has the potential to transform the clinical examination of these structures. In this review, we aim to provide a comprehensive overview of the potential clinical utility of anterior segment OCT (AS-OCT) for a wide range of anterior segment pathologies, such as conjunctival neoplasia, pterygium, scleritis, keratoconus, corneal dystrophies, and infectious/noninfectious keratitis. In addition, the clinical applications of AS-OCT (including epithelial mapping) in preoperative planning and postoperative monitoring for corneal and refractive surgeries are discussed

    Cyclic proof systems for modal fixpoint logics

    Get PDF
    This thesis is about cyclic and ill-founded proof systems for modal fixpoint logics, with and without explicit fixpoint quantifiers.Cyclic and ill-founded proof-theory allow proofs with infinite branches or paths, as long as they satisfy some correctness conditions ensuring the validity of the conclusion. In this dissertation we design a few cyclic and ill-founded systems: a cyclic one for the weak Grzegorczyk modal logic K4Grz, based on our explanation of the phenomenon of cyclic companionship; and ill-founded and cyclic ones for the full computation tree logic CTL* and the intuitionistic linear-time temporal logic iLTL. All systems are cut-free, and the cyclic ones for K4Grz and iLTL have fully finitary correctness conditions.Lastly, we use a cyclic system for the modal mu-calculus to obtain a proof of the uniform interpolation property for the logic which differs from the original, automata-based one

    Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review

    Get PDF
    Background: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. Materials and methods: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. Results: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. Conclusion: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice

    Targeting immune and desmoplastic tumor microenvironment to sensitize gynecological cancer cells to therapy

    Get PDF
    Cancer is a pervasive global threat that manifests with diverse clinical attributes and notable mortality rates, particularly attributable to its metastatic potential in solid cancers. These tumours encompass various types including epithelial cancers like high-grade serous ovarian cancer (HGSC) and mesenchymal cancers like uterine sarcomas (USs). Despite the differing origins of USs and HGSCs, the pivotal concept of the transition between epithelial and mesenchymal states remains remarkably plastic, occurring frequently in these cancers. This plasticity holds immense significance in understanding tumour invasiveness and metastasis. The TME emerges as a crucial influencer as exerting its impact on cancer progression, epithelial-mesenchymal transition (EMT), metastasis, and even chemoresistance. The TME comprises various elements, with the extracellular matrix (ECM) containing structural proteins like collagens, standing out as a key constituent. Moreover, immune cells within the TME, such as lymphocytes and macrophages, actively engage in interactions with both the ECM and cancer cells shaping local responses to kill the cancer cells or support their growth. Understanding the intricate tumour-TME interactions become imperative in formulating effective strategies aimed at modulating the immune response and halting cancer progression. Therefore, a nuanced comprehension of these complexities is crucial in developing strategies to combat cancer effectively. This thesis focuses on identifying TME factors, including ECM components and immune cell interactions in gynaecological cancers for improved precision medicine including immunotherapies and other novel treatments. In Paper I, Uterine sarcomas present distinct immune signatures with prognostic value, independent of tumour type. FOXP3+ cell density and CD8+/FOXP3+ ratio (CFR) correlated with favourable survival in endometrial stromal sarcomas (ESS) and undifferentiated uterine sarcomas (USS). The CFR also highlighted the correlation between CFR high and upregulation of ECM organization pathways. In Paper II conversely, uterine leiomyosarcomas (uLMS) showed distinct behaviours, with lower collagen density and upregulated ECM remodelling enzymes correlating with aggressiveness. MMP-14 and yes-associated protein 1 (YAP) were required for uLMS growth and invasion. In Paper Ⅲ, shifting to HGSC, matrisome, a group of proteins encoded by genes for core ECM proteins 4 (collagens, proteoglycans, and ECM glycoproteins) and ECM-associated proteins (proteins structurally resembling ECM proteins, ECM remodelling enzymes, and secreted factors) in the ECM, showed changes in expression depending on the type of tumour host tissues and after chemotherapy. Collagen VI, among scrutinized proteins, exhibited elevated expression linked to shortened survival in ovarian cancer patients. Mechanistically, collagen VI promoted platinum resistance via the stiffness-dependent β1 integrin-pMLC and YAP/TAZ pathways in HGSC cell lines In summary, this integrated exploration of uterine sarcomas and ovarian cancer provides a comprehensive understating of their TME. The study elucidates diverse immune and molecular features, offering potential prognostic markers and therapeutic targets. The findings underscore the complexity of these gynaecological malignancies, emphasizing the need for tailored approaches in understanding and combating these diseases

    Stage 3 N2 lung cancer: A multidisciplinary therapeutic conundrum

    Get PDF
    The treatment of stage III N2 non-small cell lung cancer (NSCLC) remains debated. There is an absence of a universally agreed definition of resectability for this heterogeneous group and a lack of trial data. We reviewed and compared current international guidelines and evidence surrounding management of stage III N2 NSCLC. The Irish and Australian guidelines advise subcategorising N2 disease into N2a (may be resectable) and N2b (never resectable). On the contrary, American and British guidelines avoid subcategorising N2 disease, emphasising importance of local MDT decisions. It is suggested that evidence for resection of stage III tumours is relatively weak, but that stage IIIA should generally be considered for resection, and stage IIIB is not recommended for resection. For resectable disease, surgery may be combined with neoadjuvant chemoimmunotherapy, or adjuvant chemotherapy followed by immunotherapy and radiotherapy in selected patients. There is some evidence that technically resectable disease can be treated solely with radiotherapy with similar outcomes to resection. In the event of unresectable disease, chemoradiotherapy has been the traditional management option. However, recent studies with chemoradiotherapy alongside immunotherapy appear promising. There are many factors that influence the treatment pathway offered to patients with stage III N2 NSCLC, including patient factors, team expertise, and local resources. Therefore, the role of MDTs in defining resectability and formulating an individualised treatment plan is crucial. [Abstract copyright: © 2024. Crown.

    Fragments and frame classes:Towards a uniform proof theory for modal fixed point logics

    Get PDF
    This thesis studies the proof theory of modal fixed point logics. In particular, we construct proof systems for various fragments of the modal mu-calculus, interpreted over various classes of frames. With an emphasis on uniform constructions and general results, we aim to bring the relatively underdeveloped proof theory of modal fixed point logics closer to the well-established proof theory of basic modal logic. We employ two main approaches. First, we seek to generalise existing methods for basic modal logic to accommodate fragments of the modal mu-calculus. We use this approach for obtaining Hilbert-style proof systems. Secondly, we adapt existing proof systems for the modal mu-calculus to various classes of frames. This approach yields proof systems which are non-well-founded, or cyclic.The thesis starts with an introduction and some mathematical preliminaries. In Chapter 3 we give hypersequent calculi for modal logic with the master modality, building on work by Ori Lahav. This is followed by an Intermezzo, where we present an abstract framework for cyclic proofs, in which we give sufficient conditions for establishing the bounded proof property. In Chapter 4 we generalise existing work on Hilbert-style proof systems for PDL to the level of the continuous modal mu-calculus. Chapter 5 contains a novel cyclic proof system for the alternation-free two-way modal mu-calculus. Finally, in Chapter 6, we present a cyclic proof system for Guarded Kleene Algebra with Tests and take a first step towards using it to establish the completeness of an algebraic counterpart

    Comparative analysis of energy transfer mechanisms for neural implants

    Get PDF
    As neural implant technologies advance rapidly, a nuanced understanding of their powering mechanisms becomes indispensable, especially given the long-term biocompatibility risks like oxidative stress and inflammation, which can be aggravated by recurrent surgeries, including battery replacements. This review delves into a comprehensive analysis, starting with biocompatibility considerations for both energy storage units and transfer methods. The review focuses on four main mechanisms for powering neural implants: Electromagnetic, Acoustic, Optical, and Direct Connection to the Body. Among these, Electromagnetic Methods include techniques such as Near-Field Communication (RF). Acoustic methods using high-frequency ultrasound offer advantages in power transmission efficiency and multi-node interrogation capabilities. Optical methods, although still in early development, show promising energy transmission efficiencies using Near-Infrared (NIR) light while avoiding electromagnetic interference. Direct connections, while efficient, pose substantial safety risks, including infection and micromotion disturbances within neural tissue. The review employs key metrics such as specific absorption rate (SAR) and energy transfer efficiency for a nuanced evaluation of these methods. It also discusses recent innovations like the Sectored-Multi Ring Ultrasonic Transducer (S-MRUT), Stentrode, and Neural Dust. Ultimately, this review aims to help researchers, clinicians, and engineers better understand the challenges of and potentially create new solutions for powering neural implants
    • …
    corecore