NF-κB pathway as a molecular target for curcumin in diabetes mellitus treatment: Focusing on oxidative stress and inflammation.

Diabetes mellitus (DM) is a collection of metabolic disorder that is characterized by chronic hyperglycemia. Recent studies have demonstrated the crucial involvement of oxidative stress (OS) and inflammatory reactions in the development of DM. Curcumin (CUR), a natural compound derived from turmeric, exerts beneficial effects on diabetes mellitus through its interaction with the nuclear factor kappa B (NF-κB) pathway. Research indicates that CUR targets inflammatory mediators in diabetes, including tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), by modulating the NF-κB signaling pathway. By reducing the expression of these inflammatory factors, CUR demonstrates protective effects in DM by improving pancreatic ß-cells function, normalizing inflammatory cytokines, reducing OS and enhancing insulin sensitivity. The findings reveal that CUR administration effectively lowered blood glucose elevation, reinstated diminished serum insulin levels, and enhanced body weight in Streptozotocin -induced diabetic rats. CUR exerts its beneficial effects in management of diabetic complications through regulation of signaling pathways, such as calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII), peroxisome proliferator-activated receptor gamma (PPAR-γ), NF-κB, and transforming growth factor ß1 (TGFB1). Moreover, CUR reversed the heightened expression of inflammatory cytokines (TNF-α, Interleukin-1 beta (IL-1ß), IL-6) and chemokines like MCP-1 in diabetic specimens, vindicating its anti-inflammatory potency in counteracting hyperglycemia-induced alterations. CUR diminishes OS, avert structural kidney damage linked to diabetic nephropathy, and suppress NF-κB activity. Furthermore, CUR exhibited a protective effect against diabetic cardiomyopathy, lung injury, and diabetic gastroparesis. Conclusively, the study posits that CUR could potentially offer therapeutic benefits in relieving diabetic complications through its influence on the NF-κB pathway.

Neoadjuvant chemotherapy in breast cancer: a retrospective pathway assessment in a regional cancer centre.

BACKGROUND: The optimal care pathway (OCP) for people with breast cancer provides a framework for investigation and management of patients with breast cancer, with delays previously identified regionally. AIM: With emphasis on the neoadjuvant pathway, the primary aim of this study was to assess the practicality of implementing the breast cancer OCP timeframes regionally in comparison to nationally referenced standards. METHODS: A retrospective institutional audit was performed for patients undergoing neoadjuvant therapy for breast cancer. The time from referral to specialist review, completion of investigations, discussion at multidisciplinary team (MDT) meetings, initiation of neoadjuvant chemotherapy (NACT) and surgery were calculated and compared to OCP. RESULTS: Fifty-three patients were included, with 19 patients living rurally (36%). Twenty-four patients (45%) were seen by a specialist surgeon within 2 weeks of referral. Following surgical review, 44 patients (83%) completed investigations within 2 weeks, and 43 patient cases (81%) were discussed at MDT meetings within 2 weeks. Forty-eight patients (91%) were commenced on neoadjuvant treatment within 4 weeks of decision to treat, and 43 patients (81%) underwent surgery within 6 weeks of neoadjuvant treatment completion. Delays from initial referral to NACT were more frequent in rural patients compared to urban (79% vs 94%, P < 0.05). CONCLUSION: Adherence to OCP timeframes for patients undergoing neoadjuvant therapy in a regional centre was feasible and strategies are needed to bridge gaps identified for rural patients.

Neutrophil-Derived Protein S100A8/A9 Alters the Platelet Proteome in Acute Myocardial Infarction and Is Associated With Changes in Platelet Reactivity.

OBJECTIVE: Platelets are central to acute myocardial infarction (MI). How the platelet proteome is altered during MI is unknown. We sought to describe changes in the platelet proteome during MI and identify corresponding functional consequences. Approach and Results: Platelets from patients experiencing ST-segment-elevation MI (STEMI) before and 3 days after treatment (n=30) and matched patients with severe stable coronary artery disease before and 3 days after coronary artery bypass grafting (n=25) underwent quantitative proteomic analysis. Elevations in the proteins S100A8 and S100A9 were detected at the time of STEMI compared with stable coronary artery disease (S100A8: FC, 2.00; false discovery rate, 0.05; S100A9: FC, 2.28; false discovery rate, 0.005). During STEMI, only S100A8 mRNA and protein levels were correlated in platelets (R=0.46, P=0.012). To determine whether de novo protein synthesis occurs, activated platelets were incubated with 13C-labeled amino acids for 24 hours and analyzed by mass spectrometry. No incorporation was confidently detected. Platelet S100A8 and S100A9 was strongly correlated with neutrophil abundance at the time of STEMI. When isolated platelets and neutrophils were coincubated under quiescent and activated conditions, release of S100A8 from neutrophils resulted in uptake of S100A8 by platelets. Neutrophils released S100A8/A9 as free heterodimer, rather than in vesicles or extracellular traps. In the community-based Bruneck study (n=338), plasma S100A8/A9 was inversely associated with platelet reactivity-an effect abrogated by aspirin. CONCLUSIONS: Leukocyte-to-platelet protein transfer may occur in a thromboinflammatory environment such as STEMI. Plasma S100A8/A9 was negatively associated with platelet reactivity. These findings highlight neutrophils as potential modifiers for thrombotic therapies in coronary artery disease.

Measurement of radon concentration in soil gas and radon exhalation rate from soil samples along and across the Main Central Thrust of Garhwal Himalaya, India.

The present study focuses on measuring radon concentrations in soil gas at various depths, radon exhalation rate (surface and mass) from soil samples, and gamma dose rate along and across the Main Central Thrust of Garhwal Himalaya, India. Radon concentration in soil gas, surface, and mass exhalation rates was measured using a portable SMART radon monitor (RnDuo). Furthermore, the gamma dose rate was measured using a pocket radiation monitor. The soil gas radon concentration varied from 15 ± 4 to 579 ± 82 Bq m-3 at a depth of 25 cm, 10 ± 2 to 533 ± 75 Bq m-3 at a depth of 30 cm, and 9 ± 1 to 680 ± 95 Bq m-3 at a depth of 35 cm. The surface and mass exhalation rates were found 3 ± 0.7 to 98 ± 3 Bq m-2 h-1 (with AM ± SD = 36 ± 28 Bq m-2 h-1) and 1 ± 0.2 to 95 ± 2 mBq kg-1 h-1 (with AM ± SD = 30 ± 22 mBq kg-1 h-1), respectively. The gamma dose rate for the present study area varies from 0.11 ± 0.05 to 0.28 ± 0.05 µSv h-1 with a mean value of 0.17 ± 0.05 µSv h-1. The correlation analysis between the exhalation rates (mass and surface) and radon concentration of soil gas at various depths was carried out in the current study.

Administration of immune checkpoint inhibitors at rural towns using the Teleoncology model of care-A North Queensland perspective.

OBJECTIVE: This study aimed at evaluating the safety of administering immune checkpoint inhibitors (ICIs) and monitoring for immune-related adverse events (irAEs) using the Teleoncology model of care. DESIGN: A retrospective cohort study comparing two patient groups. SETTING: The North Queensland Teleoncology Network (NQTN) operated by the Townsville (THHS) and Cairns Hospital Health Services (CHHS) with the Townsville Cancer Centre (TCC) acting as the control group setting. PARTICIPANTS: Patients who received ICI treatment via the NQTN between January 2015 and April 2019. Patients who received ICI at the TCC over the same time period were used for comparison. MAIN OUTCOME MEASURES: Rates of high-grade irAEs and irAE-related deaths. RESULTS: Fifty-two patients received a total of 822 cycles of ICIs via the Teleoncology model through NQTN. Over the same time period, 142 patients received a total of 1521 cycles at the TCC. There were no significant differences in all demographic characteristics between either group, including tumour profile and Indigenous status. There were no statistically significant differences between the rates of high-grade irAE across multiple body organ systems (p = 0.151) and rate of hospital admissions (13.5% (NQTN) vs 5.6% (TCC), p = 0.702). There were no irAE-related deaths in either group. CONCLUSIONS: The results suggest that with adequate governance and clinical resources, ICIs can be administered safely using Teleoncology models to rural and remote towns.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

OBJECTIVE: To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. PATIENTS AND METHODS: We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. RESULTS: The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. CONCLUSION: This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

Comparative Analysis of Circulating Noncoding RNAs Versus Protein Biomarkers in the Detection of Myocardial Injury.

RATIONALE: Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs), are proposed novel biomarkers of myocardial injury. Their release kinetics have not been explored without confounding by heparin nor has their relationship to myocardial protein biomarkers. OBJECTIVE: To compare ncRNA types in heparinase-treated samples with established and emerging protein biomarkers for myocardial injury. METHODS AND RESULTS: Screening of 158 circRNAs and 21 lncRNAs in human cardiac tissue identified 12 circRNAs and 11 lncRNAs as potential biomarkers with cardiac origin. Eleven miRNAs were included. At low spike-in concentrations of myocardial tissue, significantly higher regression coefficients were observed across ncRNA types compared with cardiac troponins and cMyBP-C (cardiac myosin-binding protein C). Heparinase treatment of serial plasma and serum samples of patients undergoing transcoronary ablation of septal hypertrophy removed spurious correlations between miRNAs in non-heparinase-treated samples. After transcoronary ablation of septal hypertrophy, muscle-enriched miRNAs (miR-1 and miR-133a) showed a steeper and earlier increase than cardiac-enriched miRNAs (miR-499 and miR-208b). Putative cardiac lncRNAs, including LIPCAR (long intergenic noncoding RNA predicting cardiac remodeling and survival), did not rise, refuting a predominant cardiac origin. Cardiac circRNAs remained largely undetectable. In a validation cohort of acute myocardial infarction, receiver operating characteristic curve analysis revealed noninferiority of cardiac-enriched miRNAs, but miRNAs failed to identify cases presenting with low troponin values. cMyBP-C was validated as a biomarker with highly sensitive properties, and the combination of muscle-enriched miRNAs with high-sensitive cardiac troponin T and cMyBP-C returned the highest area under the curve values. CONCLUSIONS: In a comparative assessment of ncRNAs and protein biomarkers for myocardial injury, cMyBP-C showed properties as the most sensitive cardiac biomarker while miRNAs emerged as promising candidates to integrate ncRNAs with protein biomarkers. Sensitivity of current miRNA detection is inferior to cardiac proteins but a multibiomarker combination of muscle-enriched miRNAs with cMyBP-C and cardiac troponins could open a new path of integrating complementary characteristics of different biomarker types.

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition.

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y12 inhibition. While P2Y12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.

MicroRNA Biomarkers and Platelet Reactivity: The Clot Thickens.

Over the last few years, several groups have evaluated the potential of microRNAs (miRNAs) as biomarkers for cardiometabolic disease. In this review, we discuss the emerging literature on the role of miRNAs and other small noncoding RNAs in platelets and in the circulation, and the potential use of miRNAs as biomarkers for platelet activation. Platelets are a major source of miRNAs, YRNAs, and circular RNAs. By harnessing multiomics approaches, we may gain valuable insights into their potential function. Because not all miRNAs are detectable in the circulation, we also created a gene ontology annotation for circulating miRNAs using the gene ontology term extracellular space as part of blood plasma. Finally, we share key insights for measuring circulating miRNAs. We propose ways to standardize miRNA measurements, in particular by using platelet-poor plasma to avoid confounding caused by residual platelets in plasma or by adding RNase inhibitors to serum to reduce degradation. This should enhance comparability of miRNA measurements across different cohorts. We provide recommendations for future miRNA biomarker studies, emphasizing the need for accurate interpretation within a biological and methodological context.

Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling.

OBJECTIVE: Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic ECM (extracellular matrix). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteases has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development. APPROACH AND RESULTS: A model of aortic dilatation by AngII (angiotensin II) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat). Adamts5Δcat mice showed an attenuated rise in blood pressure while displaying increased dilatation of the ascending aorta (AsAo). Interestingly, a proteomic comparison of the aortic ECM from AngII-treated wild-type and Adamts5Δcat mice revealed versican as the most upregulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of LRP1 (low-density lipoprotein-related protein 1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine, but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice but was not sufficient to maintain versican processing and prevent aortic dilatation. CONCLUSIONS: Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation.

Doppler echocardiography underestimates the prevalence and magnitude of mid-cavity obstruction in patients with symptomatic hypertrophic cardiomyopathy.

OBJECTIVES: To evaluate utility of Doppler echocardiography in the assessment of left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy (HCM). BACKGROUND: LVMCO is a relatively under-diagnosed complication of HCM and may occur alone or in combination with LV outflow tract obstruction (LVOTO). Identifying and quantifying LVMCO and differentiating it from LVOTO has important implications for patient management. We aimed to assess diagnostic performance of Doppler echocardiography in the assessment of suspected LV obstruction. METHODS: Forty symptomatic HCM patients with suspected obstruction underwent cardiac catheterization, and comparison of location and magnitude of Doppler derived gradients with synchronous invasive measurements (reference standard), at rest and isoprenaline stress (IS). RESULTS: Doppler's diagnostic accuracy for any obstruction (≥30 mmHg) in this cohort was 75% with false positive and false negative rates of 2.5 and 22.5%, respectively. During subanalysis, Doppler's diagnostic accuracy for isolated LVOTO in this selected cohort is 83% with false positive and false negative rates of 4 and 12.5%, respectively. For LVMCO, the accuracy is only 50%, with false positive and false negative rates of 10 and 40%, respectively. Doppler gradients for isolated LVOTO were similar to invasive: 85 ± 51 and 87 ± 35 mmHg, respectively (P = 0.77). Doppler gradients in LVMCO were consistently lower than invasive: 45 ± 38 and 81 ± 31 mmHg, respectively (P = 0.0002). Mid-systolic flow cessation and/or contamination of spectral signals were identified as causes of Doppler-derived inaccuracies. CONCLUSIONS: Doppler echocardiography under-diagnoses and underestimates severity of LVMCO in symptomatic HCM patients. Recognition of abrupt mid-systolic flow cessation and invasive measurements may improve detection of LVMCO in HCM.

High-density lipoproteins in high resolution: Will proteomics solve the paradox for cardiovascular risk?

While lipid abnormalities continue to account for over 60% of the population attributable risk for myocardial infarction, the well-known inverse correlation between plasma high-density lipoprotein (HDL) cholesterol and cardiovascular risk has failed to deliver clinically useful therapeutic interventions. Thus, there is an unmet need to better understand the function of different HDL particles. Targeted, high-resolution lipoproteomics provides an innovative approach to studying the kinetics of HDL particles. In this commentary, we discuss the development of an informatics platform for increased throughput and highlight how this approach delivers the potential for novel, hybrid instrument technologies to inform clinical dyslipidemia studies.

Clinical profile and treatment outcomes of advanced neuroendocrine tumours in rural and regional patients: a retrospective study from a regional cancer centre in North Queensland, Australia.

BACKGROUND: Neuroendocrine tumours (NET) arise from neuroendocrine cells, which are widely distributed throughout the body. However, diagnosing NET is difficult due to nonspecific symptoms and the paucity of experience among health professionals. This retrospective study was carried out to improve our understanding about NET. This knowledge can be used for optimal utilisation and distribution of limited resources. AIM: To study the clinical profile, treatment and survival outcomes for advanced NET patients in Australian regional and remote settings. METHODS: We reviewed all adult patients who were diagnosed with NET between 1994 and 2012. Patients' data were extracted from electronic databases of The Townsville Cancer Centre. Remoteness was based on postcodes, with patients stratified as regional or rural North Queensland according to Australian Standard Geographical Classification (ASGC). Overall survival was studied using survival analysis. RESULTS: Data from 79 patients were included in the study. The median age at diagnosis was 60 years. A total of 48 patients (60.8%) was male and 31 (39.2%) female. The majority of the patients lived in rural areas (51, 64%) as compared to residing in regional areas (28, 36%). There were 34 deaths at the study cut-off point. Median overall survival of NET patients in rural areas is significantly less than those living in regional areas (1613 days vs. 2935 days, respectively), P = 0.03. CONCLUSION: Remoteness has an adverse impact on overall survival of NET patients. This outcome may be because of varied access to health services and/or lack of access to specialised scans and medical and surgical expertise.

Timely access to specialist medical oncology services closer to home for rural patients: experience from the Townsville Teleoncology Model.

PROBLEM: Prior to 2009, the teleoncology model of the Townsville Cancer Centre (TCC) did not achieve its aims of equal waiting times for rural and urban patients and the provision of reliable, local acute cancer care. From 2007-2009, 60 new patients from Mt Isa travelled to TCC for their first consultation and their first dose of chemotherapy. Six of these patients required inter-hospital transfers and eight required urgent flights to attend outpatient clinics. Only 50% these rural patients (n = 30) were reviewed within one week of their referral, compared with 90% of Townsville patients. DESIGN: A descriptive study. SETTING: TCC provides teleoncology services to 21 rural towns; the largest is Mt Isa, Qld. KEY MEASURES FOR IMPROVEMENT: Specialist review of 90% of urgent cases within 24 hours, and 90% of non-urgent cases within one week of referral via videoconferencing. A 50% reduction in inpatient inter-hospital transfers from Mt Isa to Townsville. STRATEGIES FOR CHANGE: Employment of a half-time medical officer and a half-time cancer care coordinator, and implementation of new policies. EFFECTS OF CHANGE: Between 2009 and 2011, TCC provided cancer care to 70 new patients from Mt Isa. Of these new patients, 93% (65/70) were seen within one week of referral. All 17 patients requiring urgent reviews were seen within 24 hours of referral and managed locally thus eliminating the need for inpatient inter-hospital transfers. LESSONS LEARNT: Provision of timely acute cancer care closer to home requires an increase in the rural case complexity and human resources.

Diagnostic accuracy of mean corpuscular volume in detecting coexisting iron deficiency in patients of sickle cell disorders: A hospital-based study.

Background: Co-existing iron deficiency in patients of sickle cell disease (SCD) and trait may worsen anemia, and adversely affect neuro-cognitive development and growth. Determining a cut-off below which Mean corpuscular Volume (MCV) can predict iron deficiency in SCD patients can preclude use of more expensive test serum ferritin. Aims: This study was conducted to determine the diagnostic accuracy of low MCV in detecting iron deficiency compared to serum ferritin levels in patients with SCD. Methods: 60 consecutive patients with SS or AS pattern on hemoglobin electrophoresis were enrolled. The index test (MCV) and the reference standard test (serum ferritin) were performed in a blind and independent manner. The measures of diagnostic accuracy were calculated and the precision of the point estimates were expressed by 95% confidence intervals. As MCV is a continuous variable, we also used multi-level likelihood ratios to compute diagnostic accuracy of MCV at several cut-points. Results: The sensitivity of low MCV in detecting iron deficiency was 40.0% (95% CI-20.0-63.6), the specificity was 78.4% (95% CI-61.3-89.6) using serum ferritin as a reference standard. The sensitivity and specificity of predicting coexisting iron deficiency at this point was 60.9% (CI-38.6-80.3%) and 75.7% (CI-58.8-88.2%) respectively. Conclusions: The low sensitivity (40%) of microcytosis in detecting iron deficiency indicates that many cases will be missed if MCV alone is used to detect co-existing iron deficiency anemia in SCD patients. No single test is good enough to detect co-existing iron deficiency and a combination of tests might be useful.