An artificial intelligence-powered, patient-centric digital tool for self-management of chronic pain: a prospective, multicenter clinical trial.

OBJECTIVE: To investigate how a behavioral health, artificial intelligence (AI)-powered, digital self-management tool affects the daily functions in adults with chronic back and neck pain. DESIGN: Eligible subjects were enrolled in a 12-week prospective, multicenter, single-arm, open-label study and instructed to use the digital coach daily. Primary outcome was a change in Patient-Reported Outcomes Measurement Information Systems (PROMIS) scores for pain interference. Secondary outcomes were changes in PROMIS physical function, anxiety, depression, pain intensity scores and pain catastrophizing scale (PCS) scores. METHODS: Subjects logged daily activities, using PainDrainerTM, and data analyzed by the AI engine. Questionnaire and web-based data were collected at 6 and 12 weeks and compared to subjects' baseline. RESULTS: Subjects completed the 6- (n = 41) and 12-week (n = 34) questionnaires. A statistically significant Minimal Important Difference (MID) for pain interference was demonstrated in 57.5% of the subjects. Similarly, MID for physical function was demonstrated in 72.5% of the subjects. A pre- to post-intervention improvement in depression score was also statistically significant, observed in 100% of subjects, as was the improvement in anxiety scores, evident in 81.3% of the subjects. PCS mean scores was also significantly decreased at 12 weeks. CONCLUSION: Chronic pain self-management, using an AI-powered, digital coach anchored in behavioral health principles significantly improved subjects' pain interference, physical function, depression, anxiety, and pain catastrophizing over the 12-week study period.

Analysis of the Human Protein Atlas Weakly Supervised Single-Cell Classification competition.

While spatial proteomics by fluorescence imaging has quickly become an essential discovery tool for researchers, fast and scalable methods to classify and embed single-cell protein distributions in such images are lacking. Here, we present the design and analysis of the results from the competition Human Protein Atlas - Single-Cell Classification hosted on the Kaggle platform. This represents a crowd-sourced competition to develop machine learning models trained on limited annotations to label single-cell protein patterns in fluorescent images. The particular challenges of this competition include class imbalance, weak labels and multi-label classification, prompting competitors to apply a wide range of approaches in their solutions. The winning models serve as the first subcellular omics tools that can annotate single-cell locations, extract single-cell features and capture cellular dynamics.

Spatiotemporal dissection of the cell cycle with single-cell proteogenomics.

The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer1-3. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.

Identification of a serum biomarker signature associated with metastatic prostate cancer.

PURPOSE: Improved early diagnosis and determination of aggressiveness of prostate cancer (PC) is important to select suitable treatment options and to decrease over-treatment. The conventional marker is total prostate specific antigen (PSA) levels in blood, but lacks specificity and ability to accurately discriminate indolent from aggressive disease. EXPERIMENTAL DESIGN: In this study, we sought to identify a serum biomarker signature associated with metastatic PC. We measured 157 analytes in 363 serum samples from healthy subjects, patients with non-metastatic PC and patients with metastatic PC, using a recombinant antibody microarray. RESULTS: A signature consisting of 69 proteins differentiating metastatic PC patients from healthy controls was identified. CONCLUSIONS AND CLINICAL RELEVANCE: The clinical value of this biomarker signature requires validation in larger independent patient cohorts before providing a new prospect for detection of metastatic PC.

Fluorescence Signal Enhancement in Antibody Microarrays Using Lightguiding Nanowires.

Fluorescence-based detection assays play an essential role in the life sciences and medicine. To offer better detection sensitivity and lower limits of detection (LOD), there is a growing need for novel platforms with an improved readout capacity. In this context, substrates containing semiconductor nanowires may offer significant advantages, due to their proven light-emission enhancing, waveguiding properties, and increased surface area. To demonstrate and evaluate the potential of such nanowires in the context of diagnostic assays, we have in this work adopted a well-established single-chain fragment antibody-based assay, based on a protocol previously designed for biomarker detection using planar microarrays, to freestanding, SiO2-coated gallium phosphide nanowires. The assay was used for the detection of protein biomarkers in highly complex human serum at high dilution. The signal quality was quantified and compared with results obtained on conventional flat silicon and plastic substrates used in the established microarray applications. Our results show that using the nanowire-sensor platform in combination with conventional readout methods, improves the signal intensity, contrast, and signal-to-noise by more than one order of magnitude compared to flat surfaces. The results confirm the potential of lightguiding nanowires for signal enhancement and their capacity to improve the LOD of standard diagnostic assays.

The Value of a New Diagnostic Test for Prostate Cancer: A Cost-Utility Analysis in Early Stage of Development.

BACKGROUND: Standard biopsy for prostate cancer diagnosis is an unpleasant and sometimes painful procedure with a detection rate as low as around 50%. Consequently, an accurate blood-based test would be highly desirable to improve the predictive accuracy. However, the clinical value of a new blood test for diagnosing prostate cancer depends on its sensitivity and specificity, in relation to the selected target population. OBJECTIVE: The aim of this analysis was to investigate the health-economic value of introducing a new and more accurate diagnostic blood-based test to identify men in need of a biopsy to diagnose prostate cancer. METHOD: We developed a Discrete Event Simulation Model with outputs including number of biopsies, cancer diagnosis, treatments and prostate cancer deaths. The analysis was performed from a health care perspective. It used epidemiologic data, treatment patterns, and health care costs from the Swedish region Skåne (population of 1.3 million). A 90% sensitivity and specificity of the new test was assumed. RESULTS: Among 31,250 men, age 50-69 years, 16.4% had a PSA between 3.0 and 9.9 µg/L and 28.9% a PSA of 2.0-9.9 µg/L. Testing men with PSA 3.0-9.9 µg/L, as in current clinical practice, decreased the number of biopsies by 3595, detected 61 more cancers, resulting in and two more fatalities and subsequently a loss of 14 QALYs. Cost offsets could justify a test value of SEK 4996. Testing a larger population, PSA 2.0-9.9 µg/L prevented 6 deaths, added 50 QALYs, and could justify a value of the test of SEK 5165, given a value of health of SEK 500,000 per QALY. CONCLUSION: A new blood-based test for prostate cancer has a significant potential to reduce the number of biopsies needed, resulting in reduced health care costs and improve patient care.

Psychological Resilience and Health-Related Quality of Life in Swedish Women with Newly Diagnosed Breast Cancer.

PURPOSE: Psychological resilience appears to be an important influencing factor in various aspects of health-related quality of life (HRQoL) in a context of adversity, eg, being informed of a cancer diagnosis. The purpose was to investigate psychological resilience and HRQoL in Swedish women with newly diagnosed breast cancer in relation to demographic and clinicopathological characteristics. METHODS: A population-based cross-sectional study was conducted including 517 women with breast cancer in the South Swedish Health Care Region. Participants were enrolled at the time of consultation for the diagnosis. Psychological resilience was assessed with the Connor-Davidson Resilience Scale 25 (CD-RISC25), and HRQoL was assessed with the Short Form Health Survey. The participants responded to questions regarding demographic variables. Clinicopathological data were collected from the Swedish National Quality Register for Breast Cancer. RESULTS: The mean score for psychological resilience was 70.6, identifying 15% of included patients with a score lower than 58 (-1 standard deviation). The study cohort had significantly lower mean scores for several aspects of HRQoL compared with Swedish normative data. Regression analyses demonstrated that psychological resilience was significantly associated with all domains of HRQoL after adjustment for demographic and clinicopathological factors. CONCLUSION: Higher levels of psychological resilience were significantly related to higher levels of HRQoL in Swedish women with newly diagnosed breast cancer and no modifying factor was identified. The assessment of psychological resilience at the time of breast cancer diagnosis might allow for early identification of women in need of more intense psychosocial support. Future studies are needed to identify a clinically relevant threshold of the CD-RISC25.

Multiplex profiling of serum proteins in solution using barcoded antibody fragments and next generation sequencing.

The composition of serum proteins is reflecting the current health status and can, with the right tools, be used to detect early signs of disease, such as an emerging cancer. An earlier diagnosis of cancer would greatly increase the chance of an improved outcome for the patients. However, there is still an unmet need for proficient tools to decipher the information in the blood proteome, which calls for further technological development. Here, we present a proof-of-concept study that demonstrates an alternative approach for multiplexed protein profiling of serum samples in solution, using DNA barcoded scFv antibody fragments and next generation sequencing. The outcome shows high accuracy when discriminating samples derived from pancreatic cancer patients and healthy controls and represents a scalable alternative for serum analysis.

Spatial Characterization of the Human Centrosome Proteome Opens Up New Horizons for a Small but Versatile Organelle.

After a century of research, the human centrosome continues to fascinate. Based on immunofluorescence and confocal microscopy, an extensive inventory of the protein components of the human centrosome, and the centriolar satellites, with the important contribution of over 300 novel proteins localizing to these compartments is presented. A network of candidate centrosome proteins involved in ubiquitination, including six interaction partners of the Kelch-like protein 21, and an additional network of protein phosphatases, together supporting the suggested role of the centrosome as an interactive hub for cell signaling, is identified. Analysis of multi-localization across cellular organelles analyzed within the Human Protein Atlas (HPA) project shows how multi-localizing proteins are particularly overrepresented in centriolar satellites, supporting the dynamic nature and wide range of functions for this compartment. In summary, the spatial dissection of the human centrosome and centriolar satellites described here provides a comprehensive knowledgebase for further exploration of their proteomes.

Psychometric properties of the Connor-Davidson Resilience Scale (CD-RISC) in a non-clinical population in Sweden.

BACKGROUND: The Connor-Davidson Resilience Scale (CD-RISC) is the most widely used scale which assesses psychological resilience. Although it is recommended to be applied as a unidimensional scale, its factor structure, reliability, as well as discriminant and predictive validity need to be assessed when used in a new context. Moreover, the original five-factor structure has not been replicated in previous investigations. This study aimed to explore psychometric properties of the scale in a Swedish context. METHODS: Construct validity of the five-factor model of CD-RISC was assessed using Exploratory and Confirmatory Factor Analyses. Its discriminant validity was assessed in relation to a measure of emotion regulation (Brief Version of the Difficulties in Emotion Regulation Scale) using a Confirmatory Factor Analysis. Predictive validity of CD-RISC was assessed in relation to measures of physical and mental health-related quality of life (The 12-Item Short Form Survey) using hierarchical multiple regression analyses. A population based sample cohort was employed (N = 2599). RESULTS: Exploratory and Confirmatory Factor Analyses suggested a 22-item unidimensional model of CD-RISC. Psychological resilience was found to be independent from the measure of emotion regulation. It was shown to predict both physical and mental health-related quality of life, being especially strongly associated with mental health aspects. CONCLUSIONS: The study showed that the Swedish version of CD-RISC is an instrument with high discriminant and predictive validity, although the original factor structure does not apply in this context. CD-RISC can thus be used to identify individuals with a higher need of psychosocial support, especially relating to mental health needs.

A multicenter study investigating the molecular fingerprint of psychological resilience in breast cancer patients: study protocol of the SCAN-B resilience study.

BACKGROUND: Individual patients differ in their psychological response when receiving a cancer diagnosis, in this case breast cancer. Given the same disease burden, some patients master the situation well, while others experience a great deal of stress, depression and lowered quality of life. Patients with high psychological resilience are likely to experience fewer stress reactions and better adapt to and manage the life threat and the demanding treatment that follows the diagnosis. If this phenomenon of mastering difficult situations is reflected also in biomolecular processes is not much studied, nor has its capacity for impacting the cancer prognosis been addressed. This project specifically aims, for the first time, to investigate how a breast cancer patient's psychological resilience is coupled to biomolecular parameters using advanced "omics" and, as a secondary aim, whether it relates to prognosis and quality of life one year after diagnosis. METHOD: The study population consists of newly diagnosed breast cancer patients enrolled in the Sweden Cancerome Analysis Network - Breast (SCAN-B) at four hospitals in Sweden. At the time of cancer diagnosis, the patient fills out the standardized method to measure psychological resilience, the "Connor-Davidson Resilience scale" (CD-RISC), the quality of life measure SF-36, as well as providing social and socioeconomic variables. In addition, one blood sample is collected. At the one-year follow-up, the patient will be subjected to the same assessments, and we also collect information regarding smoking, exercise habits, and BMI, as well as patients' trust in the treatment and their satisfaction with the care and treatment. DISCUSSION: This explorative hypothesis-generating project will pave the way for larger validation studies, potentially leading to a standardized method of measuring psychological resilience as an important parameter in cancer care. Revealing the body-mind interaction, in terms of psychological resilience and quality of life, will herald the development of truly personalized psychosocial care and cancer intervention treatment strategies. TRIAL REGISTRATION: This is a retrospectively registered trial at ClinicalTrials.gov, ID: NCT03430492 on February 6, 2018.

A nucleosome turnover map reveals that the stability of histone H4 Lys20 methylation depends on histone recycling in transcribed chromatin.

Nucleosome composition actively contributes to chromatin structure and accessibility. Cells have developed mechanisms to remove or recycle histones, generating a landscape of differentially aged nucleosomes. This study aimed to create a high-resolution, genome-wide map of nucleosome turnover in Schizosaccharomyces pombe. The recombination-induced tag exchange (RITE) method was used to study replication-independent nucleosome turnover through the appearance of new histone H3 and the disappearance or preservation of old histone H3. The genome-wide location of histones was determined by chromatin immunoprecipitation-exonuclease methodology (ChIP-exo). The findings were compared with diverse chromatin marks, including histone variant H2A.Z, post-translational histone modifications, and Pol II binding. Finally, genome-wide mapping of the methylation states of H4K20 was performed to determine the relationship between methylation (mono, di, and tri) of this residue and nucleosome turnover. Our analysis showed that histone recycling resulted in low nucleosome turnover in the coding regions of active genes, stably expressed at intermediate levels. High levels of transcription resulted in the incorporation of new histones primarily at the end of transcribed units. H4K20 was methylated in low-turnover nucleosomes in euchromatic regions, notably in the coding regions of long genes that were expressed at low levels. This transcription-dependent accumulation of histone methylation was dependent on the histone chaperone complex FACT. Our data showed that nucleosome turnover is highly dynamic in the genome and that several mechanisms are at play to either maintain or suppress stability. In particular, we found that FACT-associated transcription conserves histones by recycling them and is required for progressive H4K20 methylation.

DNA topoisomerase III localizes to centromeres and affects centromeric CENP-A levels in fission yeast.

Centromeres are specialized chromatin regions marked by the presence of nucleosomes containing the centromere-specific histone H3 variant CENP-A, which is essential for chromosome segregation. Assembly and disassembly of nucleosomes is intimately linked to DNA topology, and DNA topoisomerases have previously been implicated in the dynamics of canonical H3 nucleosomes. Here we show that Schizosaccharomyces pombe Top3 and its partner Rqh1 are involved in controlling the levels of CENP-A(Cnp1) at centromeres. Both top3 and rqh1 mutants display defects in chromosome segregation. Using chromatin immunoprecipitation and tiling microarrays, we show that Top3, unlike Top1 and Top2, is highly enriched at centromeric central domains, demonstrating that Top3 is the major topoisomerase in this region. Moreover, centromeric Top3 occupancy positively correlates with CENP-A(Cnp1) occupancy. Intriguingly, both top3 and rqh1 mutants display increased relative enrichment of CENP-A(Cnp1) at centromeric central domains. Thus, Top3 and Rqh1 normally limit the levels of CENP-A(Cnp1) in this region. This new role is independent of the established function of Top3 and Rqh1 in homologous recombination downstream of Rad51. Therefore, we hypothesize that the Top3-Rqh1 complex has an important role in controlling centromere DNA topology, which in turn affects the dynamics of CENP-A(Cnp1) nucleosomes.

CHD1 remodelers regulate nucleosome spacing in vitro and align nucleosomal arrays over gene coding regions in S. pombe.

Nucleosome positioning governs access to eukaryotic genomes. Many genes show a stereotypic organisation at their 5'end: a nucleosome free region just upstream of the transcription start site (TSS) followed by a regular nucleosomal array over the coding region. The determinants for this pattern are unclear, but nucleosome remodelers are likely critical. Here we study the role of remodelers in global nucleosome positioning in S. pombe and the corresponding changes in expression. We find a striking evolutionary shift in remodeler usage between budding and fission yeast. The S. pombe RSC complex does not seem to be involved in nucleosome positioning, despite its prominent role in S. cerevisiae. While S. pombe lacks ISWI-type remodelers, it has two CHD1-type ATPases, Hrp1 and Hrp3. We demonstrate nucleosome spacing activity for Hrp1 and Hrp3 in vitro, and that together they are essential for linking regular genic arrays to most TSSs in vivo. Impaired arrays in the absence of either or both remodelers may lead to increased cryptic antisense transcription, but overall gene expression levels are only mildly affected.