A Novel Combination of Serum Markers in a Multivariate Model to Help Triage Patients Into “Low-” and “High-Risk” Categories for Prostate Cancer

BACKGROUND: Almost 50,000 men in the United Kingdom (UK) are diagnosed each year with prostate cancer (PCa). Secondary referrals for investigations rely on serum prostate-specific antigen (PSA) levels and digital rectal examination. However, both tests lack sensitivity and specificity, resulting in unnecessary referrals to secondary care for costly and invasive biopsies. MATERIALS AND METHODS: Serum samples and clinical information were collected from N = 125 age-matched patients (n = 61 non-PCa and n = 64 PCa) and analyzed using Biochip Array Technology on high-sensitivity cytokine array I (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1α, IL-1β, TNFα, MCP-1, INFγ, EGF, and VEGF), cerebral array II (CRP, D-dimer, neuron-specific enolase, and sTNFR1), and tumor PSA oncology array (fPSA, tPSA, and CEA). RESULTS: The data showed that 11/19 (68.8%) markers were significantly different between the non-PCa and the PCa patients. A combination of EGF, log(10) IL-8, log(10) MCP-1, and log(10) tPSA significantly improved the predictive potential of tPSA alone to identify patients with PCa (DeLong, p < 0.001). This marker combination had an increased area under the receiver operator characteristic (0.860 vs. 0.700), sensitivity (78.7 vs. 68.9%), specificity (76.5 vs. 67.2%), PPV (76.2 vs. 66.7%), and NPV (79.0 vs. 69.4%) compared with tPSA. CONCLUSIONS: The novel combination of serum markers identified in this study could be employed to help triage patients into “low-” and “high-risk” categories, allowing general practitioners to improve the management of patients in primary care settings and potentially reducing the number of referrals for unnecessary, invasive, and costly treatments

Post-traumatic stress disorder: A biopsychosocial case-control study investigating peripheral blood protein biomarkers

Experiencing traumatic events is unfortunately commonplace and, in some cases, may lead to the onset of debilitating mental health disorders, such as post-traumatic stress disorder (PTSD). Current diagnostic criteria for PTSD results in high depression and anxiety comorbidity. Better understanding of biological mechanisms and pathways underlying PTSD could aid in more accurate case identification and stratification of treatments. Recent meta-analysis has identified chronic PTSD to be associated with increased expression of pro-inflammatory cytokines and alterations in neuronal structures which contribute to an overall reduction in brain volume. Despite this, there are currently no biological markers in clinical use to identify PTSD or monitor treatment. This case-control study (n = 40) aimed to identify differences in peripheral blood biomarkers, and biomarker combinations, able to distinguish PTSD participants from controls, and examine in a biopsychosocial framework. The levels of 5/37 biomarkers investigated were significantly altered in the serum of PTSD participants: HDL and LDL cholesterol, tPA, IL-8 and EGF. Biomarkers could be used in combination with psychological criteria, in a biopsychosocial model, to support clinical management decisions and ensure appropriate individual treatment pathways

Analysis of reactive aldehydes in urine and plasma of type-2 diabetes mellitus patients through liquid chromatography-mass spectrometry: Reactive aldehydes as potential markers of diabetic nephropathy

IntroductionDiabetes is a major public health issue that is approaching epidemic proportions globally. Diabetes mortality is increasing in all ethnic groups, irrespective of socio-economic class. Obesity is often seen as the main contributor to an increasing prevalence of diabetes. Oxidative stress has been shown to trigger obesity by stimulating the deposition of white adipose tissue. In this study, we measured reactive aldehydes by liquid chromatography-mass spectrometry (LC-MS), in the urine and plasma of type-2 diabetic mellitus (T2DM) patients, as potential surrogates of oxidative stress. Our hypothesis was that reactive aldehydes play a significant role in the pathophysiology of diabetes, and these reactive species, may present potential drug targets for patient treatment.Materials and methodsStudy participants [N = 86; control n = 26; T2DM n = 32, and diabetic nephropathy (DN) n = 28] were recruited between 2019 and 2020. Urine and blood samples were collected from all participants, including a detailed clinical history, to include patient behaviours, medications, and co-morbidities. Reactive aldehyde concentrations in urine and plasma were measured using pre-column derivatisation and LC-MS, for control, T2DM and DN patients.ResultsReactive aldehydes were measured in the urine and plasma of control subjects and patients with T2DM and DN. In all cases, the reactive aldehydes under investigation; 4-HNE, 4-ONE, 4-HHE, pentanal, methylglyoxal, and glyoxal, were significantly elevated in the urine and serum of the patients with T2DM and DN, compared to controls (p &lt; 0.001) (Kruskal–Wallis). Urine and serum reactive aldehydes were significantly correlated (≥0.7) (p &lt; 0.001) (Spearman rho). The concentrations of the reactive aldehydes were significantly higher in plasma samples, when compared to urine, suggesting that plasma is the optimal matrix for screening T2DM and DN patients for oxidative stress.ConclusionReactive aldehydes are elevated in the urine and plasma of T2DM and DN patients. Reactive aldehydes have been implicated in the pathobiology of T2DM. Therefore, if reactive aldehydes are surrogates of oxidative stress, these reactive aldehyde species could be therapeutic targets for potential drug development

Non-alcoholic fatty liver disease—A pilot study investigating early inflammatory and fibrotic biomarkers of NAFLD with alcoholic liver disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a condition where excess fat accumulates in the liver (hepatic steatosis) and there is no history of alcohol abuse or other secondary causes of chronic liver disease. NAFLD is a very common disorder, occurring in 25% of the global population. NAFLD is now the most common chronic liver disorder in Western countries. Liver biopsy is the gold standard for NAFLD diagnosis and staging; however, this is invasive, costly and not without risk. Biomarkers that could diagnose and stage disease would reduce the need for biopsy and allow stratification of patients at risk of progression to non-alcoholic steatohepatitis (NASH).Methods: One hundred and thirty-five patients were involved in the study [N = 135: n = 34 controls; n = 26 simple steatosis; n = 61 NAFLD/NASH, and n = 14 alcoholic liver disease (ALD)]. Clinically diagnosed (ICD-10) patient serum samples were obtained from Discovery Life Sciences (US) along with clinical history. Samples were run in duplicate using high-sensitivity cytokine array I, immunoassays and ELISAs. In total, n = 20 individual biomarkers were investigated in this pilot study.Results: Thirteen/20 (65%) biomarkers were identified as significantly different between groups; IFNγ, EGF, IL-1β, IL-6, IL-8, IL-10, TNFα, FABP-1, PIIINP, ST2/IL-33R, albumin, AST and ALT. Five/20 (25%) biomarker candidates were identified for further investigation; namely, three biomarkers of inflammation, IL-6, IL-8, and TNFα, and two biomarkers of fibrosis, PIIINP and ST2/IL-33R.Discussion: Single biomarkers are unlikely to be diagnostic or predictive at staging NAFLD due to the complex heterogeneity of the disease. However, biomarker combinations may help stratify risk and stage disease where patients are averse to biopsy. Further studies comparing the 5 biomarkers identified in this study with current diagnostic tests and fibrotic deposition in liver tissue are warranted

LYVE-1+ macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells that facilitate cancer progression. However, our knowledge of the niches of individual TAM subsets and their development and function remain incomplete. Here, we describe a population of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)-expressing TAMs, which form coordinated multi-cellular “nest” structures that are heterogeneously distributed proximal to vasculature in tumors of a spontaneous murine model of breast cancer. We demonstrate that LYVE-1+ TAMs develop in response to IL-6, which induces their expression of the immune-suppressive enzyme heme oxygenase-1 and promotes a CCR5-dependent signaling axis, which guides their nest formation. Blocking the development of LYVE-1+ TAMs or their nest structures, using gene-targeted mice, results in an increase in CD8+ T cell recruitment to the tumor and enhanced response to chemotherapy. This study highlights an unappreciated collaboration of a TAM subset to form a coordinated niche linked to immune exclusion and resistance to anti-cancer therapy

Lateral variability in strain along a mass-transport deposit (MTD) toewall: a case study from the Makassar Strait, offshore Indonesia

Contractional features characterise the toe domain of mass-transport deposits (MTDs). Their frontal geometry is typically classified as frontally-confined or frontally-emergent. However, it remains unclear how frontal emplacement style and contractional strain within an MTD can vary along strike. We use bathymetry and 3D seismic reflection data to investigate lateral variability of frontal emplacement and strain within the toe domain of the Haya Slide in the Makassar Strait. The slide originated from an anticline flank collapse, and the toe domain is characterised by a radial fold-and-thrust belt that reflects southwestwards emplacement. The frontal geometry of the slide changes laterally. In the S, it is frontally-confined, associated with a deep, c. 200 mbsf, and planar basal shear surface. The frontal geometry gradually changes to frontally-emergent in the W, associated with a shallow, c. 120 mbsf, and NE-dipping, c. 3o, basal shear surface. Strain analysis shows c. 8-14% shortening, with cumulative throw of the thrusts that increases along strike westwards from c. 20-40 to c. 40-80 m. We show that even minor horizontal translation of MTDs (c. 1 km) can result in marked lateral variability in frontal geometry and strain within the failed body, which may influence their seal potential in petroleum systems

LYVE-1+ macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer.

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells that facilitate cancer progression. However, our knowledge of the niches of individual TAM subsets and their development and function remain incomplete. Here, we describe a population of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)-expressing TAMs, which form coordinated multi-cellular "nest" structures that are heterogeneously distributed proximal to vasculature in tumors of a spontaneous murine model of breast cancer. We demonstrate that LYVE-1 + TAMs develop in response to IL-6, which induces their expression of the immune-suppressive enzyme heme oxygenase-1 and promotes a CCR5-dependent signaling axis, which guides their nest formation. Blocking the development of LYVE-1 + TAMs or their nest structures, using gene-targeted mice, results in an increase in CD8 + T cell recruitment to the tumor and enhanced response to chemotherapy. This study highlights an unappreciated collaboration of a TAM subset to form a coordinated niche linked to immune exclusion and resistance to anti-cancer therapy

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo