Biomarkers Of Risk Research Articles

Broader Perspective on Atherosclerosis—Selected Risk Factors, Biomarkers, and Therapeutic Approach

Broader Perspective on Atherosclerosis—Selected Risk Factors, Biomarkers, and Therapeutic Approach

CLINICAL RELEVANCE OF HIGH SENSITIVITY C-REACTIVE PROTEIN IN ACUTE MYOCARDIAL INFARCTION PATIENTS

Objectives: Poor cardiovascular outcomes have been linked to high-sensitivity C-reaction protein (hs-CRP), a biomarker of residual inflammatory risk. Whether or not a patient has diabetes mellitus, evaluate the relationship among hs-CRP levels estimated at hospital admission and in-hospital consequences and death. Methods: This prospective cohort study included 100 acute myocardial infarction (AMI) patients with both non-ST elevation myocardial infarction (STEMI) and STEMI who were admitted to the cardiac care critical care unit intensive therapy unit. Results: Diabetics had a considerably higher incidence of hypertension (p=0.001) and dyslipidemia (p=0.001) compared to non-diabetics. Diabetics exhibited a significantly higher mean hs-CRP level (6.76±1.12 vs. 3.65±0.98 mg/dL; p=0.01) than non-diabetics. Meanwhile, compared to non-diabetics, diabetics utilized significantly more aspirin (p=0.001), beta-blockers (p=0.001), angiotensin receptor blockers (ARBs) (p=0.01), and statins (p=0.001). Furthermore, compared to those with hs-CRP <3 mg/L, those with hs-CRP ≥3 mg/dL had a significantly higher incidence of dyslipidemia (p=0.001) and hypertension (p=0.001). Conclusion: The results of the current study demonstrated that hs-CRP upon admission is a valid predictor of hospital morbidity and death in patients with AMI who are diabetic or non-diabetic. Individuals with diabetes showed greater CRP levels than non-diabetic AMI patients did.

Association of Rest-Activity Rhythm and Risk of Developing Dementia or Mild Cognitive Impairment in the Middle-Aged and Older Population: Prospective Cohort Study.

The relationship between 24-hour rest-activity rhythms (RARs) and risk for dementia or mild cognitive impairment (MCI) remains an area of growing interest. Previous studies were often limited by small sample sizes, short follow-ups, and older participants. More studies are required to fully explore the link between disrupted RARs and dementia or MCI in middle-aged and older adults. We leveraged the UK Biobank data to examine how RAR disturbances correlate with the risk of developing dementia and MCI in middle-aged and older adults. We analyzed the data of 91,517 UK Biobank participants aged between 43 and 79 years. Wrist actigraphy recordings were used to derive nonparametric RAR metrics, including the activity level of the most active 10-hour period (M10) and its midpoint, the activity level of the least active 5-hour period (L5) and its midpoint, relative amplitude (RA) of the 24-hour cycle [RA=(M10-L5)/(M10+L5)], interdaily stability, and intradaily variability, as well as the amplitude and acrophase of 24-hour rhythms (cosinor analysis). We used Cox proportional hazards models to examine the associations between baseline RAR and subsequent incidence of dementia or MCI, adjusting for demographic characteristics, comorbidities, lifestyle factors, shiftwork status, and genetic risk for Alzheimer's disease. During the follow-up of up to 7.5 years, 555 participants developed MCI or dementia. The dementia or MCI risk increased for those with lower M10 activity (hazard ratio [HR] 1.28, 95% CI 1.14-1.44, per 1-SD decrease), higher L5 activity (HR 1.15, 95% CI 1.10-1.21, per 1-SD increase), lower RA (HR 1.23, 95% CI 1.16-1.29, per 1-SD decrease), lower amplitude (HR 1.32, 95% CI 1.17-1.49, per 1-SD decrease), and higher intradaily variability (HR 1.14, 95% CI 1.05-1.24, per 1-SD increase) as well as advanced L5 midpoint (HR 0.92, 95% CI 0.85-0.99, per 1-SD advance). These associations were similar in people aged <70 and >70 years, and in non-shift workers, and they were independent of genetic and cardiovascular risk factors. No significant associations were observed for M10 midpoint, interdaily stability, or acrophase. Based on findings from a large sample of middle-to-older adults with objective RAR assessment and almost 8-years of follow-up, we suggest that suppressed and fragmented daily activity rhythms precede the onset of dementia or MCI and may serve as risk biomarkers for preclinical dementia in middle-aged and older adults.

Putative Risk Biomarkers of Bipolar Disorder in At-risk Youth.

Bipolar disorder is a highly heritable and functionally impairing disease. The recognition and intervention of BD especially that characterized by early onset remains challenging. Risk biomarkers for predicting BD transition among at-risk youth may improve disease prognosis. We reviewed the more recent clinical studies to find possible pre-diagnostic biomarkers in youth at familial or (and) clinical risk of BD. Here we found that putative biomarkers for predicting conversion to BD include findings from multiple sample sources based on different hypotheses. Putative risk biomarkers shown by perspective studies are higher bipolar polygenetic risk scores, epigenetic alterations, elevated immune parameters, front-limbic system deficits, and brain circuit dysfunction associated with emotion and reward processing. Future studies need to enhance machine learning integration, make clinical detection methods more objective, and improve the quality of cohort studies.

Agnostic identification of plasma biomarkers for postpartum hemorrhage risk.

Postpartum hemorrhage (PPH) is difficult to predict, is associated with significant maternal morbidity, and is the leading cause of maternal mortality worldwide. The identification of maternal biomarkers that can predict increased PPH risk would enhance clinical care and may uncover mechanisms that lead to PPH. This retrospective case-control study employed agnostic proteomic profiling of maternal plasma samples to identify differentially abundant proteins in controls and PPH cases. Maternal plasma samples were procured from a cohort of >60,000 participants in a single institution's perinatal repository. PPH was defined as a decrease in hematocrit of ≥10% or receipt of transfusion within 24 hours of delivery. PPH cases (N=30) were matched by maternal age and delivery mode (vaginal or cesarean) with controls (N=56). Mass spectrometry was used to identify differentially abundant proteins using integrated peptide peak areas. Statistically significant differences between groups were defined by a p-value of <0.05 after controlling for multiple comparisons. By study design, cases and controls did not differ in race, ethnicity, gestational age at delivery, blood type, or pre-delivery platelet count. Cases had slightly, but significantly lower pre- and post-delivery hematocrit and hemoglobin. Mass spectrometry detected 1140 proteins, including 77 proteins for which relative abundance differed significantly between cases and controls (fold change >1.15, P<0.05). Of these differentially abundant plasma proteins, most had likely liver or placental origins. Gene ontology term analysis mapped to protein clusters involved in responses to wound healing, stress response, and host immune defense. Significantly differentially abundant proteins with the highest fold change (prostaglandin D2 synthase, periostin, and several serine protease inhibitors) did not correlate with pre-delivery hematocrit or hemoglobin, but identified PPH cases with logistic regression modeling revealing good-to-excellent area under the operator receiver characteristic curves (AUROC 0.802-0.874). Incorporating pre-delivery hemoglobin with these candidate proteins further improved identification of PPH cases. Agnostic analysis of maternal plasma samples identified differentially abundant proteins in controls and PPH cases. Several of these proteins are known to participate in biologically plausible pathways for PPH risk and have potential value for predicting PPH. These findings identify candidate protein biomarkers for future validation and mechanistic studies.

Medical comorbidities in bipolar disorder (BIPCOM): clinical validation of risk factors and biomarkers to improve prevention and treatment. Study protocol

BackgroundBIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities.MethodsThe BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology.DiscussionBIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases.Trial registration: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602. Registration date: 18/04/2023.

Abstract PO4-08-07: Background parenchymal enhancement (BPE) on breast magnetic resonance imaging as a biomarker of breast cancer risk among BRCA1/2 carriers

Abstract Introduction: BRCA1/2 carriers are recommended to undergo dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) screening of the breasts annually. Fibroglandular tissue (FGT) may enhance with MRI contrast agent termed background parenchymal enhancement (BPE). BPE is believed to be a marker of hormonally responsive breast tissue, as BPE is impacted by aromatase inhibition and by oophorectomy. BPE has been shown to be more strongly associated with breast cancer risk than breast density. We hypothesize that BPE may serve as a useful dynamic marker of breast cancer risk among BRCA1/2 mutation carriers, given their frequent MRI screening. Methods: We identified female BRCA1/2 carriers from the University of Pennsylvania Cancer Risk Evaluation Program with no personal history of breast or ovarian cancer at the time of breast MRI. Patients diagnosed within 6 months were excluded to remove prevalent cancer cases at MRI. Among 421 eligible patients, 42 were diagnosed with breast cancer. BPE was quantified from all available breast MRIs using a validated, fully automated method to segment fibroglandular tissue (FGT) and quantify BPE. For preprocessing, the N4ITK algorithm was used for bias-field artifact correction and FGT was segmented using a soft-margin support vector machine classifier using the T1-weighted nonfat-saturated breast MRI. FGT was segmented and quantified in 3D. For BPE quantification, the T1-weighted nonfat-saturated image and the derived FGT mask were registered to the pre-contrast DCE-MRI. The first post contrast DCE-MRI and FGT mask were used to compute the relative enhancement map compared to the pre-contrast image. We calculated BPE metrics in two ways. First, the median BPE enhancement was calculated as the median enhancement of all voxels within the FGT mask. Second the BPE enhancement ratio was calculated as the proportion of voxels enhancing at ≥20%. We performed Cox proportional hazards regression to estimate the hazard ratios for breast cancer per standard deviation unit increase in each BPE metric, with first MRI as the time origin and censoring upon bilateral mastectomy, ovarian cancer diagnosis, death, or loss to follow-up and adjustment for age at MRI, menopause status, volumetric breast density (VBD), body mass index (BMI), and BRCA1 vs. BRCA2 mutation. BPE, VBD, BMI, and menstrual status were included as time varying covariates, enabling inclusion of multiple BPE measurements per woman. Results: The mean age at first MRI was 39 for cases and 41 for non-cases, and the mean number of MRIs was 4. There were no significant differences in median BPE (14% vs. 14%, p=0.965) or BPE ratio (34% vs. 36%, p=0.769) between cases and non-cases. In regression analyses adjusted for age and menstrual status, median BPE was significantly associated with breast cancer risk (HR=1.12, p=0.025). The HR was similar in the fully adjusted model, though did not reach statistical significance (HR=1.11, p=0.055). Higher BPE ratio was significantly associated with increased breast cancer risk in both minimally (HR=1.21, p=0.005) and fully adjusted models (HR=1.21, p=0.012). Conclusions: Our results suggest that BPE is significantly associated with breast cancer diagnosis among BRCA1/2 carriers undergoing breast MRI screening. Both median BPE and BPE ratio metrics were associated with breast cancer risk, even after adjusting for breast density and when accounting for multiple measurements of BPE over time, suggesting that BPE may provide additional risk information for BRCA1/2 carriers. Table 1: Results of Cox proportional hazards regression with time varying covariates Citation Format: Anne Marie McCarthy, Alex Anh-Tu Nguyen, Walter Mankowski, Eric Cohen, Sarah Ehsan, Rhonda Gillette, Lauren Pantalone, Susan Weinstein, Emily Conant, Susan Domchek, Despina Kontos. Background parenchymal enhancement (BPE) on breast magnetic resonance imaging as a biomarker of breast cancer risk among BRCA1/2 carriers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-07.

Abstract PO4-13-10: The anti-metastatic role of BMP4 through cholesterol biosynthesis inhibition and consequent interaction with statin benefit in breast cancer

Abstract We have previously identified a role for bone morphogenic protein 4 (BMP4) in reducing distant relapse risk after early breast cancer (BrCa) (1). We therefore set out to identify mechanisms underlying the protective effect of BMP4, looking to translate this finding for patient benefit. A highly metastatic variant of the triple negative MDA-MB-231 human BrCa line (231-HM-turboGFP) was transduced with BMP4, leading to sustained BMP4 secretion. These modified tumours were established in NSG mice, resected at a given size and turboGFP-positive cancer cells were recovered from primary tumours for RNA sequencing analysis. Gene set enrichment analysis (GSEA) was completed to identify signalling pathways that were significantly modulated by BMP4. The four most significantly downregulated gene sets were associated with cholesterol synthesis, with the overwhelming majority of genes in this pathway being downregulated. BMP4 downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1, involved in cholesterol biosynthesis) was confirmed at the protein level by western blotting on whole tumour lysates. Forced expression of BMP4 also led to a significant reduction in the levels of free and total cholesterol. In a confirmatory analysis of the METABRIC human BrCa dataset, the expression of cholesterol biosynthesis-related genes inversely correlated with the expression of BMP4. Further, for the majority of these genes, expression was elevated in high-grade breast tumours, and predicted worse overall survival of patients. Finally, we tested the effect of a lipophilic statin, lovastatin, on the growth and metastasis of 231-HM-turboGFP tumours. Treatment did not affect the growth of primary tumours but significantly less metastases were observed in the lungs of treated mice, at least partially replicating the anti-metastatic effect of BMP4. Having identified inhibition of cholesterol biosynthesis as a potential mechanism of protective BMP4 action we then asked if BMP4 status interacted with any protective effect of co-administered statins. We therefore returned to the cohort initially employed to demonstrate BMP4 benefit (1) and looked at the interaction between BMP4 protein levels and statin usage with regards to recurrence. BMP4 protein and statin usage data were available on a cohort of 417 patients with early BrCa. Statin use compared to none led to a reduced risk of distant relapse (8 v 22%, 0.0029) at 15 years. BMP4 led to borderline reduction in distant relapse (16 v 24%, p=0.052). In BMP4 negative tumours, statin protected against any relapse (p=0.0025) whereas in BMP4 positive disease no significant risk reduction was not significant (p=0.074). Absence of BMP4 expression may be a biomarker of both higher relapse risk and statin benefit in early BrCa. 1. Eckhardt et al, Cancer Res. 2020;80(6):1304-1315 Citation Format: Lap Hing Chi, Andrew Redfern, Allan Burrows, Suraya Roslan, Leone Oh, Lisa Spalding, Robin Anderson. The anti-metastatic role of BMP4 through cholesterol biosynthesis inhibition and consequent interaction with statin benefit in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-10.

Abstract PO1-09-01: Patient Advocates, Oncologists &amp; Research Scientists Collaborate to Address PostPartum Breast Cancer

Abstract The incidence of young women (YW=&amp;lt; 45) with aggressive breast cancer (BC) has been increasing and BC in younger women tends to be diagnosed in more advanced stages1. A group of advocates, oncologists and scientists have established an advocate-researcher dialogue to address this. A key finding we are highlighting and sharing with the community is that postpartum BC (PPBC) is a "free biomarker" for increased risk of metastatic disease. We report our efforts to understand the biologic underpinnings of PPBC, strategize to disseminate information, and accomplish our longterm goals to reduce BC incidence and mortality in YW. Interactions Between Childbirth &amp; BC The interactions between the reproductive life phases and BC are complex. We are taught that having children and nursing them is protective against BC. What is complicated is the fact that after childbirth, women overall are at a 10-30% increased risk for getting early onset BC. For women &amp;lt; 30 at the time of their last baby, this increased risk converts to a protective effect about 10 years after childbirth, such that in later life they have a lower risk of getting BC in comparison to women who have not given birth. However for women who have children after 30, the risk remains increased for many decades. The peak window of time for YW to get BC is within 10 years after childbirth and diagnoses during this window are PPBC. The global trend of women delaying childbirth until they are older is one factor contributing to increased PPBC2. While lactation can be protective, this protection is seen most robustly against triple negative BC (TNBC). This protective effect is seen most strongly in women who nurse for about 6 months. In some who do not nurse, especially black women, risk for TNBC can be increased3. When women get diagnosed with PPBC several things are known4: The frequency of the different subtypes of BC (ER+,PR+,Her2+) is similar to BC diagnosed in YW overall, so most PPBC is ER+ Her2- While there is no difference in the % of women who will have Her2+ or TNBC among PPBC cases, more women with PPBC will have + lymph nodes at diagnosis Of women who get diagnosed with BC &amp;lt; 45, about half will occur in this PP window accounting for about 50% of all early onset BC Studies have shown that PPBC has a higher tendency towards developing metastatic disease in comparison to BC in women without children or in women diagnosed more than 10 years since last childbirth4. Research is ongoing to identify why this increased risk is occurring and how treatment can be tailored to eliminate this risk. Adherence to therapy and participation in clinical trials is crucial. Clinical trials should capture when a woman had her last child as a routine datapoint so PPBC can be researched more broadly. This datapoint - age of her youngest child when she was diagnosed - is essentially a "free biomarker" indicating risk for metastasis. Advocate-Researcher Outreach Efforts Production of a podcast episode "Rising Rates of BC &amp; MBC in YW" on www.OurMBCLife.org produced by SHARE Cancer Support Discussion with other advocates and organizations to raise awareness Approach donors to increase funding for research in PPBC Summary BC in YW is increasing and YW with recent childbirth are at increased risk. Raising health awareness in a proactive, non-alarming manner is an important advocacy goal YW diagnosed within 10 years of a recent childbirth represent a unique subset of BC called PPBC Age of youngest child at time of diagnosis is an important free biomarker for risk and should be added to medical histories Increase funding is essential to determine why PPBC has different outcomes and how treatments can be tailored to ensure the wellness of our young mothers

Inflammation, Immunonutritive, and Cardiovascular Risk Biomarkers in Men With Alcohol Use Disorder

Inflammation, Immunonutritive, and Cardiovascular Risk Biomarkers in Men With Alcohol Use Disorder

A Human-Centered AI Framework for Efficient Labelling of ECGs From Drug Safety Trials.

Drug safety trials require substantial ECG labelling like, in thorough QT studies, measurements of the QT interval, whose prolongation is a biomarker of proarrhythmic risk. The traditional method of manually measuring the QT interval is time-consuming and error-prone. Studies have demonstrated the potential of deep learning (DL)-based methods to automate this task but expert validation of these computerized measurements remains of paramount importance, particularly for abnormal ECG recordings. In this paper, we propose a highly automated framework that combines such a DL-based QT estimator with human expertise. The framework consists of 3 key components: (1) automated QT measurement with uncertainty quantification (2) expert review of a few DL-based measurements, mostly those with high model uncertainty and (3) recalibration of the unreviewed measurements based on the expert-validated data. We assess its effectiveness on 3 drug safety trials and show that it can significantly reduce effort required for ECG labelling-in our experiments only 10% of the data were reviewed per trial-while maintaining high levels of QT accuracy. Our study thus demonstrates the possibility of productive human-machine collaboration in ECG analysis without any compromise on the reliability of subsequent clinical interpretations.

421. Associated Impairments in Neurocognition and Psychophysiological Biomarkers for Psychosis Risk in Individuals With 22q11.2 Deletion Syndrome

421. Associated Impairments in Neurocognition and Psychophysiological Biomarkers for Psychosis Risk in Individuals With 22q11.2 Deletion Syndrome

Electrocortical Reactivity during Self-Referential Processing Predicts the Development of Depression across Adolescence

BackgroundNegative attentional biases and self-schemas have been implicated in the development of depression. Research has indicated that a larger late positive potential (LPP) to negative self-referential words is associated with depression—as well as a maternal history of depression, an indicator of risk. However, it is unclear whether the LPP to self-referential words predicts the actual development of depression. The present study examined whether electrocortical reactivity during self-referential processing predicts the development of depression across adolescence. MethodsThe sample consisted of 165 8 to 14-year-old girls with no lifetime history of a depressive disorder who completed the self-referential encoding task (SRET) while electroencephalography was recorded at a baseline assessment. Participants and their parent completed the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children at the baseline, 2-year, 4-year, and 6-year follow-up assessments. ResultsResults indicated that a larger LPP to negative self-referential words at baseline predicted an increased likelihood of developing chronic-intermittent depression (i.e., persistent and/or recurrent), but not non-chronic, single episode depression, across adolescence. In contrast, neither SRET recall biases nor the LPP to positive self-referential words predicted the development of either type of depression. ConclusionsThe present study suggests that electrocortical reactivity associated with a negative self-schema in late childhood predicts the development of a more pernicious subtype of depression across adolescence. Moreover, the present study highlights the importance of considering clinical course in the examination of biomarkers of risk for depression.

Comparative assessment of hsCRP and apolipoprotein B as ASCVD risk biomarkers

Comparative assessment of hsCRP and apolipoprotein B as ASCVD risk biomarkers

Erythrocyte Membrane Fatty Acid Concentrations and Myelin Integrity in Young People at Ultra-High Risk of Psychosis

Decreased white matter (WM) integrity and disturbance in fatty acid composition have been reported in individuals at ultra-high risk of psychosis (UHR). The current study is the first to investigate both WM integrity and erythrocyte membrane polyunsaturated fatty acid (PUFA) levels as potential risk biomarkers for persistent UHR status, and global functioning in UHR individuals. Forty UHR individuals were analysed at baseline for erythrocyte membrane PUFA concentrates. Tract-based spatial statistics (TBSS) was used to analyse fractional anisotropy (FA) and diffusivity measures. Measures of global functioning and psychiatric symptoms were evaluated at baseline and at 12-months. Fatty acids and WM indices did not predict functional outcomes at baseline or 12-months. Significant differences were found in FA between UHR remitters and non-remitters (individuals who no longer met UHR criteria versus those who continued to meet criteria at 12-months). Docosahexaenoic acid (DHA) was found to be a significant predictor of UHR status at 12-months, as was the interaction between the sum of ώ-3 and whole brain FA, and the interaction between the right anterior limb of the internal capsule and the sum of ώ-3. The results confirm that certain fatty acids have a unique relationship with WM integrity in UHR individuals.

DHEA-S, Androstenedione, 17-β-estradiol signature as novel biomarkers for early prediction of risk of malignant pleural mesothelioma linked to asbestos-exposure: A preliminary investigation

17-β-estradiol, involved in mesothelioma pathogenesis, and its precursors were explored as potential biomarkers for the early diagnosis of mesothelioma. Using enzyme-linked immunosorbent assay(ELISA) for 17-β-estradiol and ultra-high performance liquid chromatography/tandem mass spectrometry(UHPLC-MS/MS) for 19 17-β-estradiol precursors, a comprehensive analysis of 20steroid hormones was conducted in the serum of mesothelioma patients(n=67), asbestos-exposed healthy subjects(n=39), and non-asbestos-exposed healthy subjects(n=35). Bioinformatics analysis explored three potential serum biomarkers: 17-β-estradiol, DHEA-S, and androstenedione. The results revealed significant differences in 17-β-estradiol levels between mesothelioma patients and both non-asbestos-exposed and asbestos-exposed healthy subjects. No significant variations in serum 17-β-estradiol levels were observed among mesothelioma patients at different stages, suggesting its potential as an early diagnostic marker. 17-β-estradiol levels were similar in mesothelioma patients with environmental and occupational asbestos exposure, while males with occupational asbestos exposure exhibited significantly higher levels of 17-β-estradiol compared to females. Significant reduction in androstenedione and an increase in DHEA-S were observed in asbestos-exposed individuals compared to non-asbestos-exposed individuals. The analysis of DHEA-S-androstenedione-17-β-estradiol signature score showed an increase in asbestos-exposed individuals and mesothelioma patients compared to non-asbestos-exposed individuals, and this score effectively distinguished between the groups. The Cancer Genome Atlas data was utilized to analyze the expression of 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 genes. The findings indicated that mesothelioma patients with elevated gene values for 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 have a worse or better prognosis on overall survival, respectively. In conclusion, this study suggests 17-β-estradiol, DHEA-S, and androstenedione as biomarkers for mesothelioma risk and early diagnosis of mesothelioma in asbestos-exposed individuals, aiding timely intervention and improved care.

The ketogenic diet and MetSyn in Parkinson’s disease – Symptoms, biomarkers, depression and anxiety: A case study

The use of therapeutic carbohydrate restriction (TCR) in the form of a ketogenic diet (KD) in neurodegenerative disorders such as Parkinson’s disease (PD) is increasing as an alternative treatment for primary and secondary symptoms. There exists a gap in the literature on symptoms of PD in the setting of metabolic syndrome (MetSyn) and possible comorbid impact on symptoms, biomarkers of health, cardiac risk, depression and anxiety. This case report documents a 24-week KD intervention for a 53-year-old man with multiple comorbid diagnoses, PD (Hoehn-Yahr stage IIa) with a history of morbid obesity with increased waist circumference, prediabetes, hyperinsulinaemia and significantly impaired mobility with chronic back pain, anxiety disorder and depression. Baseline cardiac risk ratios (CRR = triglycerides/HDL) were calculated and compared. The KD approach involved a well-formulated, ketogenic diet (fats 70%; protein 25%; carbohydrates 5% according to total daily energy intake for 24 weeks). Baseline, 12-week and 24-week biomarkers and scores on scales were compared. Clinically significant results were found when baseline biomarker results and scales were compared with 12-week results. Positive trends were seen for all variables at 24 weeks. Improvements in health biomarkers, including HbA1C, high sensitivity C-reactive protein (hs-CRP), triglycerides, fasting insulin, weight loss, waist circumference and cardiac risk were observed at 12 and 24 weeks. Some improvements in scores on an anxiety scale were seen. Based on our findings, KD is safe and effective for improving health biomarkers and symptoms of MetSyn, depression, anxiety and symptoms of PD. Future clinical trial studies for more generalisable results are needed.

Thrombin generation profile using ST-Genesia after PEG-asparaginase in pediatric patients with acute lymphoblastic leukemia.

Venous thromboembolism (VTE) etiology in children with acute lymphoblastic leukemia (ALL) is multifactorial. The use of global assays of hemostasis as thrombin generation test (TGT) is useful to individualize VTE risk in adult patients. The aim of this prospective cohort study was to evaluate the usefulness of an automated TGT to evaluate VTE risk during ALL treatment in children. TGT (automated analyzer ST Genesia; ThromboScreen) and pro and anticoagulant plasma proteins were analyzed during ALL treatment in pediatric patients following LAL-SEHOP-PETHEMA-2013 guidelines. Results were compared with a series of pediatric normal controls and evaluated according to pegylated asparaginase PEG-ASP administration and to VTE risk factors. The study included 67 patients: males n=35, B-ALL (n=60). None had a VTE during the evaluated period. Compared to healthy controls, normalized endogenous thrombin potential (N-ETP) ratio in patients was higher and ETP inhibition (ETP-inh) was lower, especially after PEG-ASP administration. Plasmatic protein C and protein S levels decreased after PEG-ASP administration, but antithrombin mean level did not. A bivariant analysis showed that ETP-inh was lower in patients >10-year-old (p=0.05) and in those with non-O blood type (p=0.005). A linear mixed model also showed a higher TGT prothrombotic profile in patients with inherited thrombophilia. TGT could be a biomarker of a high VTE risk in ALL pediatric patients. Patients > 10 years, of non-O blood group and with inherited thrombophilia were associated with a significantly higher thrombotic profile, and an increased profile was also observed after administration of PEG-ASP.

Shedding Light on the Effects of Blood Pressure on Cognitive Decline and Dementia Risk by Way of Neurobiological Evidence.

Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer's disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer's disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits.

Higher peripheral blood mitochondrial DNA copy number and relative telomere length in under 48 years Indonesian breast cancer patients

ObjectiveBreast cancer is the leading cause of cancer incidence and mortality among Indonesian women. A comprehensive investigation is required to enhance the early detection of this disease. Mitochondrial DNA copy number (mtDNA-CN) and relative telomere length (RTL) have been proposed as potential biomarkers for several cancer risks, as they are linked through oxidative stress mechanisms. We conducted a case–control study to examine peripheral blood mtDNA-CN and RTL patterns in Indonesian breast cancer patients (n = 175) and healthy individuals (n = 181). The relative ratios of mtDNA-CN and RTL were determined using quantitative real-time PCR (qPCR).ResultsMedian values of mtDNA-CN and RTL were 1.62 and 0.70 in healthy subjects and 1.79 and 0.73 in breast cancer patients, respectively. We found a positive association between peripheral blood mtDNA-CN and RTL (p < 0.001). In under 48 years old breast cancer patients, higher peripheral blood mtDNA-CN (mtDNA-CN ≥ 1.73 (median), p = 0.009) and RTL (continuous variable, p = 0.010) were observed, compared to the corresponding healthy subjects. We also found a significantly higher ‘High-High’ pattern of mtDNA-CN and RTL in breast cancer patients under 48 years old (p = 0.011). Our findings suggest that peripheral blood mtDNA-CN and RTL could serve as additional minimally invasive biomarkers for breast cancer risk evaluation.