A prognostic six-gene expression risk-score derived from proteomic profiling of the metastatic colorectal cancer secretome.

The necessity to accurately predict recurrence and clinical outcome in early stage colorectal cancer (CRC) is critical to identify those patients who may benefit from adjuvant chemotherapy. Here, we developed and validated a gene-based risk-score algorithm for patient stratification and personalised treatment in early stage disease based on alterations in the secretion of metastasis-related proteins. A quantitative label-free proteomic analysis of the secretome of highly and poorly metastatic CRC cell lines with different genetic backgrounds revealed 153 differentially secreted proteins (fold-change >5). These changes in the secretome were validated at the transcriptomic level. Starting from 119 up-regulated proteins, a six-gene/protein-based prognostic signature composed of IGFBP3, CD109, LTBP1, PSAP, BMP1, and NPC2 was identified after sequential discovery, training, and validation in four different cohorts. This signature was used to develop a risk-score algorithm, named SEC6, for patient stratification. SEC6 risk-score components showed higher expression in the poor prognosis CRC subtypes: consensus molecular subtype 4 (CMS4), CRIS-B, and stem-like. High expression of the signature was also associated with patients showing dMMR, CIMP+ status, and BRAF mutations. In addition, the SEC6 signature was associated with lower overall survival, progression-free interval, and disease-specific survival in stage II and III patients. SEC6-based risk stratification indicated that 5-FU treatment was beneficial for low-risk patients, whereas only aggressive treatments (FOLFOX and FOLFIRI) provided benefits to high-risk patients in stages II and III. In summary, this novel risk-score demonstrates the value of the secretome compartment as a reliable source for the retrieval of biomarkers with high prognostic and chemotherapy-predictive capacity, providing a potential new tool for tailoring decision-making in patient care.

Integrative multi-omics approach to targeted therapy for glioblastoma.

This review describes recent technological advances applied to glioblastoma (GBM), a brain tumor with dismal prognosis. International consortial efforts suggest the presence of molecular subtypes within histologically identical GBM tumors. This emphasizes that future treatment decisions should no longer be made based solely on morphological analyses, but must now take into consideration such molecular and cellular heterogeneity. The use of single-cell technologies has advanced our understanding and assignation of functional subtypes revealing therapeutic vulnerabilities. Our team has developed stratification approaches in the past few years, and we have been able to identify patient cohorts enriched for various signaling pathways. Importantly, our Glioportal brain tumor resource has been established under the National Neuroscience Institute Tissue Bank in 2021. This resource offers preclinical capability to validate working hypotheses established from patient clinical datasets. This review highlights recent developments with the ultimate goal of assigning functional meaning to molecular subtypes, revealing therapeutic vulnerabilities.

Circulating proteins reveal prior use of menopausal hormonal therapy and increased risk of breast cancer.

Accessible risk predictors are crucial for improving the early detection and prognosis of breast cancer. Blood samples are widely available and contain proteins that provide important information about human health and disease, however, little is still known about the contribution of circulating proteins to breast cancer risk prediction. We profiled EDTA plasma samples collected before diagnosis from the Swedish KARMA breast cancer cohort to evaluate circulating proteins as molecular predictors. A data-driven analysis strategy was applied to the molecular phenotypes built on 700 circulating proteins to identify and annotate clusters of women. The unsupervised analysis of 183 future breast cancer cases and 366 age-matched controls revealed five stable clusters with distinct proteomic plasma profiles. Among these women, those in the most stable cluster (N = 19; mean Jaccard index: 0.70 ± 0.29) were significantly more likely to have used menopausal hormonal therapy (MHT), get a breast cancer diagnosis, and were older compared to the remaining clusters. The circulating proteins associated with this cluster (FDR < 0.001) represented physiological processes related to cell junctions (F11R, CLDN15, ITGAL), DNA repair (RBBP8), cell replication (TJP3), and included proteins found in female reproductive tissue (PTCH1, ZP4). Using a data-driven approach on plasma proteomics data revealed the potential long-lasting molecular effects of menopausal hormonal therapy (MHT) on the circulating proteome, even after women had ended their treatment. This provides valuable insights concerning proteomics efforts to identify molecular markers for breast cancer risk prediction.

Positive influence of gut microbiota on the effects of Korean red ginseng in metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Ginseng, a traditional herbal medicine, has been used for thousands of years to treat various diseases including metabolic syndrome (MS). However, the underlying mechanism(s) of such beneficial actions of ginseng against MS is poorly understood. Emerging evidence indicates a close association of the host gut microbiota with MS. The present study was conducted to examine, whether the beneficial effects of Korean red ginseng (KRG) against MS could be influenced by gut microbial population and whether gut microbial profile could be considered a valuable biomarker for targeted treatment strategy for MS in compliance with the predictive, preventive, and personalized medicine (PPPM / 3PM). METHODS: This clinical study was a randomized, double-blind, placebo-controlled trial evaluating the effects of KRG treatment for 8 weeks on patients with MS. The anthropometric parameters, vital signs, metabolic biomarkers, and gut microbial composition through 16S rRNA gene sequencing were assessed at the baseline and endpoint. The impact of KRG was also evaluated after categorizing the subjects into responders and non-responders, as well as enterotypes 1 and 2 based on their gut microbial profile at the baseline. RESULTS: Fifty out of 60 subjects who meet the MS criteria completed the trial without showing adverse reactions. The KRG treatment caused a significant decrease in systolic blood pressure (SBP). Microbial analysis revealed a decrease in Firmicutes, Proteobacteria, and an increase in Bacteroidetes in response to KRG. In patient stratification analysis, the responders showing marked improvement in the serum levels of lipid metabolic biomarkers TC and LDL due to the KRG treatment exhibited higher population of both the family Lachnospiraceae and order Clostridiales compared to the non-responders. The homeostasis model assessment-insulin resistance (HOMA-IR) and insulin level were decreased in enterotype 1 (Bacteroides-abundant group) and increased in enterotype 2 (prevotella-abundant group) following the KRG treatment. CONCLUSION: In this study, the effects of KRG on the glucose metabolism in MS patients were influenced by the relative abundances of gut microbial population and differed according to the individual enterotype. Therefore, the analysis of enterotype categories is considered to be helpful in predicting the effectiveness of KRG on glucose homeostasis of MS patients individually. This will further help to decide on the appropriate treatment strategy for MS, in compliance with the perspective of PPPM.

Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine.

Mitochondrial injury plays a key role in the aetiopathology of multifactorial diseases exhibiting a "vicious circle" characteristic for pathomechanisms of the mitochondrial and multi-organ damage frequently developed in a reciprocal manner. Although the origin of the damage is common (uncontrolled ROS release, diminished energy production and extensive oxidative stress to life-important biomolecules such as mtDNA and chrDNA), individual outcomes differ significantly representing a spectrum of associated pathologies including but not restricted to neurodegeneration, cardiovascular diseases and cancers. Contextually, the role of predictive, preventive and personalised (PPPM/3P) medicine is to introduce predictive analytical approaches which allow for distinguishing between individual outcomes under circumstance of mitochondrial impairments followed by cost-effective targeted prevention and personalisation of medical services. Current article considers innovative concepts and analytical instruments to advance management of mitochondriopathies and associated pathologies.

Carotenoids in Cancer Metastasis-Status Quo and Outlook.

Metastasis represents a major obstacle in cancer treatment and the leading cause of cancer-related deaths. Therefore, the identification of compounds targeting the multi-step and complex process of metastasis could improve outcomes in the management of cancer patients. Carotenoids are naturally occurring pigments with a plethora of biological activities. Carotenoids exert a potent anti-cancer capacity in various cancer models in vitro and in vivo, mediated by the modulation of signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of the epithelial-mesenchymal transition and regulatory molecules, such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), urokinase plasminogen activator (uPA) and its receptor (uPAR), hypoxia-inducible factor-1α (HIF-1α), and others. Moreover, carotenoids modulate the expression of genes associated with cancer progression and inflammatory processes as key mediators of the complex process involved in metastasis. Nevertheless, due to the predominantly preclinical nature of the known anti-tumor effects of carotenoids, and unclear results from certain carotenoids in specific cancer types and/or specific parts of the population, a precise analysis of the anti-cancer effects of carotenoids is essential. The identification of carotenoids as effective compounds targeting the complex process of cancer progression could improve the outcomes of advanced cancer patients.

Artificial Intelligence to Decode Cancer Mechanism: Beyond Patient Stratification for Precision Oncology.

The multitude of multi-omics data generated cost-effectively using advanced high-throughput technologies has imposed challenging domain for research in Artificial Intelligence (AI). Data curation poses a significant challenge as different parameters, instruments, and sample preparations approaches are employed for generating these big data sets. AI could reduce the fuzziness and randomness in data handling and build a platform for the data ecosystem, and thus serve as the primary choice for data mining and big data analysis to make informed decisions. However, AI implication remains intricate for researchers/clinicians lacking specific training in computational tools and informatics. Cancer is a major cause of death worldwide, accounting for an estimated 9.6 million deaths in 2018. Certain cancers, such as pancreatic and gastric cancers, are detected only after they have reached their advanced stages with frequent relapses. Cancer is one of the most complex diseases affecting a range of organs with diverse disease progression mechanisms and the effectors ranging from gene-epigenetics to a wide array of metabolites. Hence a comprehensive study, including genomics, epi-genomics, transcriptomics, proteomics, and metabolomics, along with the medical/mass-spectrometry imaging, patient clinical history, treatments provided, genetics, and disease endemicity, is essential. Cancer Moonshot℠ Research Initiatives by NIH National Cancer Institute aims to collect as much information as possible from different regions of the world and make a cancer data repository. AI could play an immense role in (a) analysis of complex and heterogeneous data sets (multi-omics and/or inter-omics), (b) data integration to provide a holistic disease molecular mechanism, (c) identification of diagnostic and prognostic markers, and (d) monitor patient's response to drugs/treatments and recovery. AI enables precision disease management well beyond the prevalent disease stratification patterns, such as differential expression and supervised classification. This review highlights critical advances and challenges in omics data analysis, dealing with data variability from lab-to-lab, and data integration. We also describe methods used in data mining and AI methods to obtain robust results for precision medicine from "big" data. In the future, AI could be expanded to achieve ground-breaking progress in disease management.

Carotenoids in Cancer Apoptosis-The Road from Bench to Bedside and Back.

An incidence and mortality of cancer are rapidly growing worldwide, especially due to heterogeneous character of the disease that is associated with irreversible impairment of cellular homeostasis and function. Targeting apoptosis, one of cancer hallmarks, represents a potent cancer treatment strategy. Carotenoids are phytochemicals represented by carotenes, xanthophylls, and derived compounds such as apocarotenoids that demonstrate a broad spectrum of anti-cancer effects involving pro-apoptotic signaling through extrinsic and intrinsic pathways. As demonstrated in preclinical oncology research, the apoptotic modulation is performed at post-genomic levels. Further, carotenoids demonstrate additive/synergistic action in combination with conventional oncostatic agents. In addition, a sensitization of tumor cells to anti-cancer conventional treatment can be achieved by carotenoids. The disadvantage of anti-cancer application of carotenoids is associated with their low solubility and, therefore, poor bioavailability. However, this deficiency can be improved by using nanotechnological approaches, solid dispersions, microemulsions or biofortification that significantly increase the anti-cancer and pro-apoptotic efficacy of carotenoids. Only limited number of studies dealing with apoptotic potential of carotenoids has been published in clinical sphere. Pro-apoptotic effects of carotenoids should be beneficial for individuals at high risk of cancer development. The article considers the utility of carotenoids in the framework of 3P medicine.

Interrelations of Sphingolipid and Lysophosphatidate Signaling with Immune System in Ovarian Cancer.

The sphingolipid and lysophosphatidate regulatory networks impact diverse mechanisms attributed to cancer cells and the tumor immune microenvironment. Deciphering the complexity demands implementation of a holistic approach combined with higher-resolution techniques. We implemented a multi-modular integrative approach consolidating the latest accomplishments in gene expression profiling, prognostic/predictive modeling, next generation digital pathology, and systems biology for epithelial ovarian cancer. We assessed patient-specific transcriptional profiles using the sphingolipid/lysophosphatidate/immune-associated signature. This revealed novel sphingolipid/lysophosphatidate-immune gene-gene associations and distinguished tumor subtypes with immune high/low context. These were characterized by robust differences in sphingolipid-/lysophosphatidate-related checkpoints and the drug response. The analysis also nominates novel survival models for stratification of patients with CD68, LPAR3, SMPD1, PPAP2B, and SMPD2 emerging as the most prognostically important genes. Alignment of proprietary data with curated transcriptomic data from public databases across a variety of malignancies (over 600 categories; over 21,000 arrays) showed specificity for ovarian carcinoma. Our systems approach identified novel sphingolipid-lysophosphatidate-immune checkpoints and networks underlying tumor immune heterogeneity and disease outcomes. This holds great promise for delivering novel stratifying and targeting strategies.

Are cold extremities an issue in women's health? Epidemiological evaluation of cold extremities among Japanese women.

BACKGROUND: Unlike traditional East Asian medicine, the necessity of health care services for cold extremities is yet to be acknowledged in Western medicine. In this study, we aimed to conduct an epidemiological evaluation of this unremarkable symptom among women in Japan. MATERIALS AND METHODS: A cross-sectional study was conducted from February 2016 to April 2017, and data of 238 women throughout Japan were analyzed. Questionnaires were used to examine participants' demographics, health-related behaviors, health status, and frequency of subjective symptoms over the past 1 year. The association between cold extremities and other subjective symptoms was examined by the multiple logistic regression analysis. RESULTS: The prevalences of mild and severe cold extremities were 49.6% and 35.3%, respectively. Temperature and utilization of health care services were not significantly different by the severity of cold extremities. The accompanying symptoms that were significantly associated with the cold extremities were shoulder stiffness, fatigue, low back pain, headache, nasal congestion, itching, injury, and difficulty hearing. After multiple logistic regression analysis, low back pain (OR: 4.91) and difficulty hearing (OR: 4.84) kept the significance. Factors related to cold extremities including mental quality of life, sleep quality, and habitual drinking were significantly associated with other accompanying symptoms. CONCLUSION: Women with cold extremities have various accompanying symptoms and health-risk behaviors. Symptomatic treatment for cold extremities may not be sufficient, and comprehensive care would be required.

Plant natural modulators in breast cancer prevention: status quo and future perspectives reinforced by predictive, preventive, and personalized medical approach.

In contrast to the genetic component in mammary carcinogenesis, epigenetic alterations are particularly important for the development of sporadic breast cancer (BC) comprising over 90% of all BC cases worldwide. Most of the DNA methylation processes are physiological and essential for human cellular and tissue homeostasis, playing an important role in a number of key mechanisms. However, if dysregulated, DNA methylation contributes to pathological processes such as cancer development and progression. A global hypomethylation of oncogenes and hypermethylation of tumor-suppressor genes are characteristic of most cancer types. Moreover, histone chemical modifications and non-coding RNA-associated multi-gene controls are considered as the key epigenetic mechanisms governing the cellular homeostasis and differentiation states. A number of studies demonstrate dietary plant products as actively affecting the development and progression of cancer. "Nutri-epigenetics" focuses on the influence of dietary agents on epigenetic mechanisms. This approach has gained considerable attention; since in contrast to genetic alterations, epigenetic modifications are reversible affect early carcinogenesis. Currently, there is an evident lack of papers dedicated to the phytochemicals/plant extracts as complex epigenetic modulators, specifically in BC. Our paper highlights the role of plant natural compounds in targeting epigenetic alterations associated with BC development, progression, as well as its potential chemoprevention in the context of preventive medicine. Comprehensive measures are stated with a great potential to advance the overall BC management in favor of predictive, preventive, and personalized medical services and can be considered as "proof-of principle" model, for their potential application to other multifactorial diseases.

"Dry mouth" and "Flammer" syndromes-neglected risks in adolescents and new concepts by predictive, preventive and personalised approach.

BACKGROUND: "Dry mouth" syndrome (chronic hyposalivation) can be caused by a number of pathophysiological conditions such as acute and chronic stress exposure, abnormal body weight (both too high and too low ones), eating disorders (such as anorexia nervosa), metabolic syndrome(s), Sjögren's and Sicca syndromes, drugs and head/neck radiotherapy application. In turn, the chronic hyposalivation as a suboptimal health condition significantly reduces quality of life, may indicate a systemic dehydration, provokes and contributes to a number of pathologies such as a strongly compromised protection of the oral cavity, chronic infections and inflammatory processes, periodontitis, voice and digestive disorders. Consequently, "dry mouth" syndrome might be extremely useful as an indicator for an in-depth diagnostics of both-co-existing and snowballing health-threating conditions. However, predictive diagnostics, targeted prevention and personalisation of treatments are evidently underdeveloped for individuals at high risk suffering from the "dry mouth" syndrome. WORKING HYPOTHESIS AND METHODOLOGY: In the current study, we have hypothesised that individuals demonstrating "Flammer syndrome" (FS) phenotype may suffer from the "dry mouth" syndrome more frequently, due to disturbed microcirculation, psychological factors (obsessional personality/perfectionism), and diminished feeling of thirst with consequently insufficient daily liquid intake potentially resulting in the systemic dehydration with individually pronounced level of severity. If confirmed, FS phenotyping linked to the chronic hyposalivation might be predictive for individuals at risk identified by innovative screening programmes. To verify the working hypothesis, healthy individuals (negative control group) versus individuals with evident hyposalivation as well as patients diagnosed with periodontitis (positive control group) observed and treated at the dental clinic were investigated. The degree to which an individual is affected by hyposalivation was determined by the Bother xerostomia Index utilising a questionnaire of 10 issue-specific items and monitoring of a typically matt roof of the mouth in dental practice. An extent to which individuals included in the study are the carriers of the FS phenotype was estimated by the specialised 15-item questionnaire. RESULTS AND CONCLUSIONS: For both-the target group (hyposalivation) and positive control group (periodontitis)-FS phenotype was demonstrated to be more specific compared to the disease-free (negative control) group. Moreover, self-reports provided by interviewed adolescents of the target group frequently recorded remarkable discomfort related to "dry mouth" syndrome, acute and chronic otorhinolaryngological infections and even delayed wound healing. Further, interviewed adolescents do worry about the symptoms which might be indicative for potential diseases; they are also amazed that too little attention is currently paid to the issue by caregivers. In conclusion, FS questionnaire linked to the "dry mouth" syndrome is strongly recommended for application in primary healthcare. Consequently, targeted preventive measures can be triggered early in life. For example, traditional, complementary and alternative medicine demonstrates positive therapeutic effects in individuals suffering from xerostomia. For in-depth diagnostics, epi/genetic regulations involved into pathophysiologic mechanisms of hyposalivation in FS-affected individuals should be thoroughly investigated at molecular level. Identified biomarker panels might be of great clinical utility for predictive diagnostics and patient stratification that, further, would sufficiently improve personalised care to the patient.

Proposals for enhanced health risk assessment and stratification in an integrated care scenario.

OBJECTIVES: Population-based health risk assessment and stratification are considered highly relevant for large-scale implementation of integrated care by facilitating services design and case identification. The principal objective of the study was to analyse five health-risk assessment strategies and health indicators used in the five regions participating in the Advancing Care Coordination and Telehealth Deployment (ACT) programme (http://www.act-programme.eu). The second purpose was to elaborate on strategies toward enhanced health risk predictive modelling in the clinical scenario. SETTINGS: The five ACT regions: Scotland (UK), Basque Country (ES), Catalonia (ES), Lombardy (I) and Groningen (NL). PARTICIPANTS: Responsible teams for regional data management in the five ACT regions. PRIMARY AND SECONDARY OUTCOME MEASURES: We characterised and compared risk assessment strategies among ACT regions by analysing operational health risk predictive modelling tools for population-based stratification, as well as available health indicators at regional level. The analysis of the risk assessment tool deployed in Catalonia in 2015 (GMAs, Adjusted Morbidity Groups) was used as a basis to propose how population-based analytics could contribute to clinical risk prediction. RESULTS: There was consensus on the need for a population health approach to generate health risk predictive modelling. However, this strategy was fully in place only in two ACT regions: Basque Country and Catalonia. We found marked differences among regions in health risk predictive modelling tools and health indicators, and identified key factors constraining their comparability. The research proposes means to overcome current limitations and the use of population-based health risk prediction for enhanced clinical risk assessment. CONCLUSIONS: The results indicate the need for further efforts to improve both comparability and flexibility of current population-based health risk predictive modelling approaches. Applicability and impact of the proposals for enhanced clinical risk assessment require prospective evaluation.

Systems biology and p4 medicine: past, present, and future.

Studying complex biological systems in a holistic rather than a "one gene or one protein" at a time approach requires the concerted effort of scientists from a wide variety of disciplines. The Institute for Systems Biology (ISB) has seamlessly integrated these disparate fields to create a cross-disciplinary platform and culture in which "biology drives technology drives computation." To achieve this platform/culture, it has been necessary for cross-disciplinary ISB scientists to learn one another's languages and work together effectively in teams. The focus of this "systems" approach on disease has led to a discipline denoted systems medicine. The advent of technological breakthroughs in the fields of genomics, proteomics, and, indeed, the other "omics" is catalyzing striking advances in systems medicine that have and are transforming diagnostic and therapeutic strategies. Systems medicine has united genomics and genetics through family genomics to more readily identify disease genes. It has made blood a window into health and disease. It is leading to the stratification of diseases (division into discrete subtypes) for proper impedance match against drugs and the stratification of patients into subgroups that respond to environmental challenges in a similar manner (e.g. response to drugs, response to toxins, etc.). The convergence of patient-activated social networks, big data and their analytics, and systems medicine has led to a P4 medicine that is predictive, preventive, personalized, and participatory. Medicine will focus on each individual. It will become proactive in nature. It will increasingly focus on wellness rather than disease. For example, in 10 years each patient will be surrounded by a virtual cloud of billions of data points, and we will have the tools to reduce this enormous data dimensionality into simple hypotheses about how to optimize wellness and avoid disease for each individual. P4 medicine will be able to detect and treat perturbations in healthy individuals long before disease symptoms appear, thus optimizing the wellness of individuals and avoiding disease. P4 medicine will 1) improve health care, 2) reduce the cost of health care, and 3) stimulate innovation and new company creation. Health care is not the only subject that can benefit from such integrative, cross-disciplinary, and systems-driven platforms and cultures. Many other challenges plaguing our planet, such as energy, environment, nutrition, and agriculture can be transformed by using such an integrated and systems-driven approach.