Current diagnostic techniques used for the early detection of cancers are successful but subject to detection bias. A recent focus lies in the development of more accurate diagnostic tools. An ...increase in serologic autoantibody levels has been shown to precede the development of cancer disease symptoms. Therefore, autoantibody levels in patient blood serum have been proposed as diagnostic biomarkers for early-stage diagnosis of cancers. Their clinical application has, however, been hindered by low sensitivity, specificity, and low predictive value scores. These scores have been shown to improve when panels of multiple diagnostic autoantibody biomarkers are used. A five-marker biomarker panel has been shown to increase the sensitivity of prostate cancer diagnosis to 95% as compared with 12.2% for prostate-specific antigen alone. New potential biomarker panels were also discovered for lung, colon, and stomach cancer diagnosis with sensitivity of 76%, 65.4%, and 50.8%, respectively. Studies in breast and liver cancer, however, seem to favor single markers, namely α-2-HS-glycoprotein and des-γ-carboxyprothrombin with sensitivities of 79% and 89% for the early detection of the cancers. The aim of this review is to discuss the relevance of autoantibodies in cancer diagnosis and to outline the current methodologies used in the detection of autoantibodies. The review concludes with a discussion of the autoantibodies currently used in the diagnosis of cancers of the prostate, breast, lung, colon, stomach, and liver. A discussion of the potential future use of autoantibodies as diagnostic cancer biomarkers is also included in this review.
The use of immune checkpoint inhibitors (ICIs) has evolved rapidly with unprecedented treatment benefits being obtained for cancer patients, including improved patient survival. However, over half of ...the patients experience immune related adverse events (irAEs) or toxicities, which can be fatal, affect the quality of life of patients and potentially cause treatment interruption or cessation. Complications from these toxicities can also cause long term irreversible organ damage and other chronic health conditions. Toxicities can occur in various organ systems, with common observations in the skin, rheumatologic, gastrointestinal, hepatic, endocrine system and the lungs. These are not only challenging to manage but also difficult to detect during the early stages of treatment. Currently, no biomarker exists to predict which patients are likely to develop toxicities from ICI therapy and efforts to identify robust biomarkers are ongoing. B cells and antibodies against autologous antigens (autoantibodies) have shown promise and are emerging as markers to predict the development of irAEs in cancer patients. In this review, we discuss the interplay between ICIs and toxicities in cancer patients, insights into the underlying mechanisms of irAEs, and the involvement of the humoral immune response, particularly by B cells and autoantibodies in irAE development. We also provide an appraisal of the progress, key empirical results and advances in B cell and autoantibody research as biomarkers for predicting irAEs. We conclude the review by outlining the challenges and steps required for their potential clinical application in the future.
This brief report details the measurement and identification of IgA antibodies to tropomyosin in a case of presumed ocular myositis with paraspinal myositis in a patient with metastatic uveal ...melanoma treated with checkpoint inhibitors. High-throughput functional protein microarray analysis and pathway analysis was conducted to identify IgG and IgA antibodies of interest. Antibody levels were compared to generic antibody screening results and levels of the antibodies in a cohort of melanoma patients without myositis (n = 100) at baseline prior to undergoing immunotherapy. The finding of specific muscle antibodies in this clinical case indicates the pathogenic potential of anti-tropomyosin IgA in the development of checkpoint inhibitor associated myositis and requires further investigation.
Cutaneous melanoma circulating tumour cells (CTCs) are phenotypically and molecularly heterogeneous. We profiled the gene expression of CTC subpopulations immunomagnetic-captured by targeting either ...the melanoma-associated marker, MCSP, or the melanoma-initiating marker, ABCB5. Firstly, the expression of a subset of melanoma genes was investigated by RT-PCR in MCSP-enriched and ABCB5-enriched CTCs isolated from a total of 59 blood draws from 39 melanoma cases. Of these, 6 MCSP- and 6 ABCB5-enriched CTC fractions were further analysed using a genome-wide gene expression microarray. The transcriptional programs of both CTC subtypes included cell survival maintenance, cell proliferation, and migration pathways. ABCB5-enriched CTCs were specifically characterised by up-regulation of genes involved in epithelial to mesenchymal transition (EMT), suggesting an invasive phenotype. These findings underscore the presence of at least two distinct melanoma CTC subpopulations with distinct transcriptional programs, which may have distinct roles in disease progression and response to therapy.
Pathological changes within the hypothalamus have been proposed to mediate circadian rhythm and habitual sleep disturbances in individuals with Huntington's disease (HD). However, investigations ...examining the relationships between hypothalamic volume and circadian rhythm and habitual sleep in individuals with HD are sparse. This study aimed to comprehensively evaluate the relationships between hypothalamic pathology and circadian rhythm and habitual sleep disturbances in individuals with premanifest HD.
Thirty-two individuals with premanifest HD and twenty-nine healthy age- and gender-matched controls participated in this dual-site, cross-sectional study. Magnetic resonance imaging scans were performed to evaluate hypothalamic volume. Circadian rhythm and habitual sleep were assessed via measurement of morning and evening cortisol and melatonin levels, wrist-worn actigraphy, the Consensus Sleep Diary and sleep questionnaires. Information on mood, physical activity levels and body composition were also collected.
Compared to healthy controls, individuals with premanifest HD displayed significantly reduced grey matter volume in the hypothalamus, decreased habitual sleep efficiency and increased awakenings; however, no alterations in morning cortisol or evening melatonin release were noted in individuals with premanifest HD. While differences in the associations between hypothalamic volume and cortisol and melatonin output existed in individuals with premanifest HD compared to healthy controls, no consistent associations were observed between hypothalamic volume and circadian rhythm or habitual sleep outcomes.
While significant differences in associations between hypothalamic volume and cortisol and melatonin existed between individuals with premanifest HD and healthy controls, no differences in circadian markers were observed between the groups. This suggests that circadian regulation is maintained despite hypothalamic pathology, perhaps via neural compensation. Longitudinal studies are required to further understand the relationships between the hypothalamus and circadian rhythm and habitual sleep disturbances in HD as the disease course lengthens.
Background
Recent findings suggest that individuals with Huntington’s disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens ...as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear.
Objectives
To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments.
Methods
Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment.
Results
Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test–retest reliability ICC: 0.61‐0.99 for individuals with presymptomatic and prodromal HD and healthy controls.
Conclusions
Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls.
Throughout the process of carcinogenesis, autologous cells are transformed into cancer cells, leading to changes in their protein expression profiles. It has been suggested that mutations, protein ...misfolding, overexpression and aberrant post-translational modifications, changes in protein abundance or location can render tumour-associated antigens immunogenic. Subsequent changes in the tumour microenvironment may lead to humoral immune responses and therefore the production of tumour-associated autoantibodies. Hence, autoantibodies are suggested to be immunological biomarkers of aberrant cellular mechanisms occurring throughout tumourigenesis. Since autoantibodies represent a stable and amplified signature of the anti-tumour immune response that may be generated prior to the clinical detection of other tumour proteins and prior to the first clinically detectable signs of the cancer or its recurrence, there is great interest in using autoantibodies as diagnostic and prognostic blood-based biomarkers. In this review, we discuss the current evidence supporting the prognostic value of autoantibodies in a highly immunogenic cancer such as melanoma as well as breast, lung, colon, prostate and stomach cancer, the most commonly diagnosed cancers globally in 2020.
Melanoma is an aggressive form of skin cancer that is curable by surgical excision in the majority of cases, if detected at an early stage. To improve early stage melanoma detection, the development ...of a highly sensitive diagnostic test is of utmost importance. Here we aimed to identify antibodies to a panel of tumour associated antigens that can differentiate primary melanoma patients and healthy individuals. A total of 245 sera from primary melanoma patients and healthy volunteers were screened against a high-throughput microarray platform containing 1627 functional proteins. Following rigorous statistical analysis, we identified a combination of 10 autoantibody biomarkers that, as a panel, displays a sensitivity of 79%, specificity of 84% and an AUC of 0.828 for primary melanoma detection. This melanoma autoantibody signature may prove valuable for the development of a diagnostic blood test for routine population screening that, when used in conjunction with current melanoma diagnostic techniques, could improve the early diagnosis of this malignancy and ultimately decrease the mortality rate of patients.
Abstract Objectives To evaluate the associations between sleep quality and serum levels of neurofilament light (NfL) protein in individuals with premanifest Huntington disease (HD). Materials and ...Methods We recruited 28 individuals with premanifest HD from a pre-existing database (of the Huntington's Environmental Research Optimisation Scheme, HEROs). The participants filled out the Pittsburgh Sleep Quality Index (PSQI), a subjective measure of sleep quality, and blood was collected via routine venepuncture to measure peripheral NfL levels. Results The PSQI scores (median: 5.0; interquartile range: 4.0–7.5) indicated poor sleep quality. General linear modelling revealed no significant (p = 0.242) association between PSQI scores and NfL levels. No significant differences were found between individuals with good and poor sleep quality for any demographic variable collected. Discussion Contrary to studies on other neurological conditions, there was no association between sleep quality and NfL levels in individuals with premanifest HD. This was unexpected, given the influence of environmental factors (such as social network size) on neurodegeneration in individuals with premanifest HD.
Abstract As the rise in cancer cases, there is an increasing demand to develop accurate and rapid diagnostic tools for early intervention. Pathologists are looking to augment manual analysis with ...computer-based evaluation to develop more efficient cancer diagnostics reports. The processing of these reports from manual evaluation is time-consuming, where the pathologists focus on accurately segmenting individual cancer cells, a vital step in analysis. This paper describes the design and validation of an application which has been developed based on deep learning networks. The application includes a workflow of image pre-processing followed by synthetic image generation, which is crucial due to the lack of training data in pathology settings. The next steps are the segmentation of nuclei regions and overlapping nuclei splitting. An improved approach has been considered based on a cycle-consistent GAN network for synthetic image generation. The synthetic images were utilized in a modified U-net network. Accurately outlining the individual nucleus border assisted an automated system that split the nuclei cluster into the individual nucleus. The SSIM and PSNR values of synthetic images corresponding to original were 0.204 and 10.610. The DSC value of the network trained by the synthetic data was 0.984 which was higher than the network trained by original images (0.805). The developed application provided better individual nuclei segmentation performance, where the average accuracy of different group images was 0.97. This higher accuracy suggests the benefit of using synthetic images in a situation to avoid the scarcity of labeled histopathology images in deep networks.
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