Renal transplants increase in size and function in keeping with compensatory renal hypertrophy.

AIM: To evaluate changes in allograft kidney length in renal transplant recipients and the relationship with estimated glomerular filtration rate (eGFR). METHODS: This single-centre retrospective study of renal transplant recipients was conducted at Flinders Medical Centre (FMC) from January 2007 to June 2020. Donor and recipient details, renal allograft length from transplant ultrasounds at 0, 1, 3, 6 and 12 months were collected. The association between compensatory renal hypertrophy (CRH) and eGFR and its magnitude was analysed using multivariate multilevel mixed-effects linear regression models. RESULTS: A total of 183 renal transplant recipients were studied. 100 of 175 recipients (62.9%) demonstrated an increase in renal length defined as any increase in maximal longitudinal diameter on serial ultrasounds. Twenty-three recipients (13.1%) had no change in transplant length and 42 recipients (24%) had a decrease in length. The mean increase in kidney length over the first 12 months was 0.57 cm. Ninety of 156 (57.7%) recipients with a renal ultrasound within a month post-transplant demonstrated a mean increase kidney length of 0.3 cm. Multivariate analysis demonstrated that eGFR increased by 2.5 mL/min/1.73 m2 (95% CI 0.72- 4.4; p = .006) with every 1 cm increase in kidney length. Absolute changes in kidney length did not demonstrate any statistically significant correlation with eGFR in both complete case and multiple imputation analysis. CONCLUSION: An increase in transplant kidney length is common in renal transplant recipients and is associated with enhanced eGFR. However, further studies need to be performed to study the association of absolute change in kidney length and eGFR.

Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as "long COVID", post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects. METHODS: We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and > 50% reported ongoing symptoms more than 6 months post-infection. RESULTS: Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not. CONCLUSIONS: Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.

Protocol for the Flinders Kidney Health Registry: patient outcomes of kidney cancers and nephrectomies.

BACKGROUND: Kidney cancer accounts for 2% of new cancers diagnosed in Australia annually. Partial and radical nephrectomy are the treatment of choice for kidney cancer. Nephrectomy is also performed for living donor kidney transplantation. Nephrectomy is a risk factor for new-onset chronic kidney disease (CKD) or deterioration of pre-existing CKD. Understanding the risk factors for new-onset or deterioration of existing CKD after nephrectomy is important in developing preventive measures to provide better care for these patients. There is also a need to understand the incidence, natural history, management trends, and sequelae of radiofrequency ablation as well as surveillance of small renal cancers or small renal masses (SRMs). Clinical registries are critical in providing excellent patient-centre care and clinical research as well as basic science research. Registries evaluate current practice and guide future practice. The Flinders Kidney Health Registry will provide the key information needed to assess various treatment outcomes of patients with kidney cancer and patients who underwent nephrectomy for other reasons. The registry aims to provide clinical decision makers with longitudinal data on patient outcomes, health systems performance, and the effect of evolving clinical practice. The registry will also provide a platform for large-scale prospective clinical studies and research. METHODS: Patients above the age of 18 undergoing nephrectomy or radiofrequency ablation for any indication and patients with SRMs will be included in the registry. Demographic, clinical and quality of life data will be collected from hospital information systems and directly from the patient and/or caregiver. DISCUSSION: The Registry will report a summary of patient characteristics including indication for treatment, clinical risk profiles, surgical and oncological outcomes, the proportion of patients who progress to CKD and end stage kidney disease, quality of life post treatment as well as other relevant outcomes for all patients who have undergone nephrectomy for any indication, ablation or surveillance for SRMs. The registry will record the follow-up practice after nephrectomy and patient on active surveillance, which will help to develop and enhance a best practice protocol. The collected prospective data will provide a platform for ongoing patient-orientated research and improve patient-centred healthcare delivery.

In order for the light to shine so brightly, the darkness must be present-why do cancers fluoresce with 5-aminolaevulinic acid?

Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.

Compensatory renal hypertrophy following nephrectomy: When and how?

Following surgical removal of one kidney, the other enlarges and increases its function. The mechanism for the sensing of this change and the growth is incompletely understood but begins within days and compensatory renal hypertrophy (CRH) is the dominant contributor to the growth. In many individuals undergoing nephrectomy for cancer or kidney donation this produces a substantial and helpful increase in renal function. Two main mechanisms have been proposed, one in which increased activity by the remaining kidney leads to hypertrophy, the second in which there is release of a kidney specific factor in response to a unilateral nephrectomy that initiates CRH. Whilst multiple growth factors and pathways such as the mTORC pathway have been implicated in experimental studies, their roles and the precise mechanism of CRH are not defined. Unrestrained hypoxia inducible factor activation in renal cancer promotes growth and may play an important role in driving CRH.

Ankyrin Repeat Proteins of Orf Virus Influence the Cellular Hypoxia Response Pathway.

Hypoxia-inducible factor (HIF) is a transcriptional activator with a central role in regulating cellular responses to hypoxia. It is also emerging as a major target for viral manipulation of the cellular environment. Under normoxic conditions, HIF is tightly suppressed by the activity of oxygen-dependent prolyl and asparaginyl hydroxylases. The asparaginyl hydroxylase active against HIF, factor inhibiting HIF (FIH), has also been shown to hydroxylate some ankyrin repeat (ANK) proteins. Using bioinformatic analysis, we identified the five ANK proteins of the parapoxvirus orf virus (ORFV) as potential substrates of FIH. Consistent with this prediction, coimmunoprecipitation of FIH was detected with each of the ORFV ANK proteins, and for one representative ORFV ANK protein, the interaction was shown to be dependent on the ANK domain. Immunofluorescence studies revealed colocalization of FIH and the viral ANK proteins. In addition, mass spectrometry confirmed that three of the five ORFV ANK proteins are efficiently hydroxylated by FIH in vitro While FIH levels were unaffected by ORFV infection, transient expression of each of the ORFV ANK proteins resulted in derepression of HIF-1α activity in reporter gene assays. Furthermore, ORFV-infected cells showed upregulated HIF target gene expression. Our data suggest that sequestration of FIH by ORFV ANK proteins leads to derepression of HIF activity. These findings reveal a previously unknown mechanism of viral activation of HIF that may extend to other members of the poxvirus family. IMPORTANCE: The protein-protein binding motif formed from multiple repeats of the ankyrin motif is common among chordopoxviruses. However, information on the roles of these poxviral ankyrin repeat (ANK) proteins remains limited. Our data indicate that the parapoxvirus orf virus (ORFV) is able to upregulate hypoxia-inducible factor (HIF) target gene expression. This response is mediated by the viral ANK proteins, which sequester the HIF regulator FIH (factor inhibiting HIF). This is the first demonstration of any viral protein interacting directly with FIH. Our data reveal a new mechanism by which viruses reprogram HIF, a master regulator of cellular metabolism, and also show a new role for the ANK family of poxvirus proteins.

Circulating and Urinary miR-210 and miR-16 Increase during Cardiac Surgery Using Cardiopulmonary Bypass - A Pilot Study.

A pilot study to measure and compare blood and urine microRNAs miR-210 and miR-16 in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and off-pump coronary artery bypass grafting surgery. Frequent serial blood and urine samples were taken from patients undergoing cardiac surgery with CPB (n = 10) and undergoing off-pump cardiac surgery (n = 5) before, during, and after surgery. Circulating miR-210 and miR-16 levels were determined by relative quantification real-time polymerase chain reaction. Levels of plasma-free haemoglobin (fHb), troponin-T, creatine kinase, and creatinine were measured. Perioperative serum miR-210 and miR-16 were elevated significantly compared to preoperative levels in patients undergoing cardiac surgery with CPB (CPB vs. Pre Op and Rewarm vs. Pre Op; p < .05 for both). There were increases of greater than 200% in miR-210 levels during rewarming and immediately postoperatively and a 3,000% increase in miR-16 levels immediately postoperatively in urine normalized to urinary creatinine concentration. Serum levels of miR-16 were relatively constant during off-pump surgery. miR-210 levels increased significantly in off-pump patients perioperatively (p < .05 Octopus on vs. Pre Op); however, the release was less marked when compared to cardiac surgery with CPB. A significant association was observed between both miR-16 and miR-210 and plasma fHb when CPB was used (r = -.549, p < .0001 and r = -.463, p < .0001 respectively). Serum and urine concentrations of hypoxically regulated miR-210 and hemolysis-associated miR-16 increased in cardiac surgery using CPB compared to off-pump surgery. These molecules may have utility in indicating severity of cardiac, red cell, and renal injury during cardiac surgery.

Oxygen-dependent hydroxylation by FIH regulates the TRPV3 ion channel.

Factor inhibiting HIF (FIH, also known as HIF1AN) is an oxygen-dependent asparaginyl hydroxylase that regulates the hypoxia-inducible factors (HIFs). Several proteins containing ankyrin repeat domains (ARDs) have been characterised as substrates of FIH, although there is little evidence for a functional consequence of hydroxylation on these substrates. This study demonstrates that the transient receptor potential vanilloid 3 (TRPV3) channel is hydroxylated by FIH on asparagine 242 within the cytoplasmic ARD. Hypoxia, FIH inhibitors and mutation of asparagine 242 all potentiated TRPV3-mediated current, without altering TRPV3 protein levels, indicating that oxygen-dependent hydroxylation inhibits TRPV3 activity. This novel mechanism of channel regulation by oxygen-dependent asparaginyl hydroxylation is likely to extend to other ion channels.

Lack of appropriate investigations in making a diagnosis of syndrome of inappropriate antidiuretic hormone.

The syndrome of inappropriate antidiuretic hormone (SIADH) is reported as the most common cause of hyponatraemia. This retrospective cross-sectional study evaluated the diagnosis of SIADH in 110 hospitalised patients in an Australian tertiary hospital with reference to recently published clinical guidelines. Investigation of SIADH was incomplete in all but 20% of cases. Adrenal insufficiency and hypothyroidism were not excluded in a significant number of cases.

Albuminuria is not associated with elevated urinary vesicle concentration but can confound nanoparticle tracking analysis.

AIM: Extracellular vesicles, such as exosomes, are present in urine with reports of roles in intercellular signalling and diagnostic utility. However, the extent to which the concentration and characteristics of urinary vesicles are altered in albuminuric renal disease has not been well characterized. In this study, we examined the number and characteristics of extracellular vesicles in albuminuric urine. METHODS: Vesicles were isolated from the urine of 32 patients with varying levels of albuminuria using ultracentrifugation and density gradient purification and were examined using nanoparticle tracking analysis, immunoblotting and transmission electron microscopy. The size profile of particles in these urine preparations was compared with albumin-containing solutions. RESULTS: Overall, there were no substantial differences in the number, or characteristics, of vesicles released into proteinuric urine. Analysis of albumin-containing solutions showed particles of exosome-like size, suggesting that such particles can mimic exosomes in standard nanoparticle tracking analysis. Albumin and IgG depletion of proteinuric urine resulted in a substantial reduction in the concentration of particles detected by nanoparticle tracking analysis. CONCLUSION: There was no increase in urinary vesicle concentration in patients with albuminuria. Furthermore, these results demonstrate the need for cautious interpretation of nanoparticle tracking analysis of vesicle concentration in biological fluids containing protein and for sophisticated preparative methods in vesicle purification from urine.

Mending a broken heart but breaking the kidney.

The incidence of acute kidney injury (AKI) is a frequent and serious complication of cardiac surgery. In 2013, 95% of cardiac surgical procedures performed in Australia and New Zealand used cardiopulmonary bypass (CPB). AKI following CPB is well known, yet the perioperative factors contributing to its development are incompletely understood. AKI following CPB has significant implications on both short-term and long-term outcomes. The techniques for conducting CPB have evolved, moving towards evidence-based practice; however, there is still no generally accepted definition of optimal perfusion and its conduct. This review examines the current incidence of AKI following cardiac surgery and the short-term and longer-term effects of AKI on morbidity and mortality. The purpose of this review is to discuss the perioperative risk factors related to CPB and their contribution to the development of AKI. This review will also discuss outcomes in regard to off-pump cardiac surgery, the role of remote ischaemic preconditioning on AKI and outcomes in patients with chronic renal failure undergoing cardiac surgery.

Common Sequence Variation in the VEGFC Gene Is Associated with Diabetic Retinopathy and Diabetic Macular Edema.

PURPOSE: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional, case control study. PARTICIPANTS: White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. METHODS: Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. MAIN OUTCOME MEASURES: Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, individually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. RESULTS: Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001; OR, 0.67; confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001; OR, 0.62; CI, 0.47-0.81), and rs2333526 (P = 0.005; OR, 0.69; CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004; OR, 0.53; CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. CONCLUSIONS: Significant associations were found between VEGFC tag SNPs (individually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.

Myocardial perfusion is impaired in asymptomatic renal and liver transplant recipients: a cardiovascular magnetic resonance study.

BACKGROUND: Myocardial ischemia is a major cause of death in chronic kidney disease (CKD) patients, which can be caused by either epicardial or microvascular coronary artery disease (CAD). Although renal transplantation improves survival, cardiovascular disease remains a major cause of mortality in post renal transplant recipients, including those with no significant epicardial CAD pre-transplant. We aim to utilize stress cardiovascular magnetic resonance (CMR) and MR coronary angiography (MRCA) to assess silent myocardial ischemia and epicardial CAD in renal transplant recipients. METHODS: Forty-five subjects: twenty renal transplant (RT) with no known CAD, fifteen liver transplant (LT) controls without prior CKD and no known CAD, and ten hypertensive (HT) controls underwent stress perfusion CMR and MRCA. RESULTS: A total of 1308 myocardial segments (576 of RT, 468 of LT, and 264 of HT) were compared using mixed linear modeling. Left ventricular mass index, septal diameter and presence of diabetes mellitus were similar between the groups. The mean transmural MPRI was significantly lower in the RT and LT groups compared to HT controls (1.19 ± 0.50 in RT versus 1.23 ± 0.36 in LT versus 2.04 ± 0.32 in HT controls, p < 0.0001), in the subepicardium (1.33 ± 0.57 in RT versus 1.30 ± 0.33 in LT versus 2.01 ± 0.30 in HT controls, p < 0.001), and in the subendocardium (1.19 ± 0.54 in RT versus 1.11 ± 0.31 in LT versus 1.85 ± 0.34 in HT controls, p < 0.0001). Seven (35%) RT and five (33%) LT had significant epicardial CAD compared to none in HT controls, p = 0.12. One RT and one LT had LGE suggesting sub-endocardial infarction. CONCLUSIONS: RT recipients have impaired myocardial perfusion independent of LVH or diabetes mellitus. The impaired myocardial perfusion in RT is similar to LT without prior renal disease, thus unlikely related to previous CKD. It is not fully explained by the presence of significant epicardial CAD, and therefore most likely represents microvascular CAD.

The social determinants of health for people with type 1 diabetes that progress to end-stage renal disease.

OBJECTIVE: Self-management of type 1 diabetes over a lifetime is complex and challenging even in the best of circumstances, and the social environment can be a powerful determinant of health behaviours and outcomes. The aim of this study was to identify how social determinants of health can impact on the capacity of young people to manage their glycaemic control. METHODS: The findings emerged from a constructivist grounded theory approach through an in-depth examination of life course events that were recounted through qualitative interviews. The rich descriptive detail obtained from this enquiry locates common experiences and the context in which concordance with therapies occurs and health behaviours develop. RESULTS: This qualitative study of young people with type 1 diabetes who have developed end-stage renal disease demonstrates that there are many factors beyond individual control that can contribute to health outcomes. The social determinants of childhood environment, education, socio-economic status, gender and the culture of public health can contribute to disengagement from treatment regimens and the health-care system and to the development of microvascular complications at a comparatively young age. CONCLUSION: These findings challenge the assumptions of health-care practitioners about individual responsibility and highlight the importance of considering how social determinants can shape lives, behaviours and health.

Hypoxia represses microRNA biogenesis proteins in breast cancer cells.

BACKGROUND: Cancers are commonly characterised by hypoxia and also by global reductions in the levels of mature microRNAs. We have examined the hypothesis that hypoxia might mediate this reduction through repressive effects on microRNA biogenesis proteins. METHODS: Breast cancer cell lines were exposed to hypoxia and manipulations of hypoxia inducible factor (HIF) and HIF hydroxylase activity. The effects of hypoxia on the mRNA and protein levels of enzymes involved in microRNA biogenesis (Dicer, Drosha, TARPB2, DCGR8, XPO5) was determined by RT PCR and immunoblotting. The effect of hypoxia on microRNAs was determined with microarray studies, RT PCR and reporter assays. RESULTS: In breast cancer lines there was significant reduction of Dicer mRNA and protein levels in cells exposed to hypoxia. This effect was independent of HIF but dependent on the HIF hydroxylase PHD2 and was partly mediated by feedback effects via microRNAs. Furthermore, several other proteins with critical roles in microRNA biogenesis (Drosha, TARBP2 and DCGR8) also showed significant and co-ordinated repression under hypoxic conditions. Despite these substantial alterations no, or modest, changes were observed in mature microRNA production. CONCLUSION: These observations provide further and important interfaces between oxygen availability and gene expression and a potential mechanistic explanation for the reduced levels of microRNAs observed in some cancers. They provide further support for the existence of feedback mechanisms in the regulation of the microRNA biogenesis pathway and the relative stability of microRNAs.

SARS-CoV-2 produces a microRNA CoV2-miR-O8 in patients with COVID-19 infection.

Many viruses produce microRNAs (miRNAs), termed viral miRNAs (v-miRNAs), with the capacity to target host gene expression. Bioinformatic and cell culture studies suggest that SARS-CoV-2 can also generate v-miRNAs. This patient-based study defines the SARS-CoV-2 encoded small RNAs present in nasopharyngeal swabs of patients with COVID-19 infection using small RNA-seq. A specific conserved sequence (CoV2-miR-O8) is defined that is not expressed in other coronaviruses but is preserved in all SARS-CoV-2 variants. CoV2-miR-O8 is highly represented in nasopharyngeal samples from patients with COVID-19 infection, is detected by RT-PCR assays in patients, has features consistent with Dicer and Drosha generation as well as interaction with Argonaute and targets specific human microRNAs.

Exosomes and the kidney: blaming the messenger.

Exosomes are membrane-bound vesicles of endosomal origin, present in a wide range of biological fluids, including blood and urine. They range between 30 and 100 nm in diameter, and consist of a limiting lipid bilayer, transmembrane proteins and a hydrophilic core containing proteins, mRNAs and microRNAs (miRNA). Exosomes can act as extracellular vehicles by which cells communicate, through the delivery of their functional cargo to recipient cells, with many important biological, physiological and pathological implications. The exosome release pathway contributes towards protein secretion, antigen presentation, pathogen transfer and cancer progression. Exosomes and exosome-mediated signalling have been implicated in disease processes such as atherosclerosis, calcification and kidney diseases. Circulating levels of exosomes and extracellular vesicles can be influenced by the progression of renal disease. Advances in methods for purification and analysis of exosomes are leading to potential diagnostic and therapeutic avenues for kidney diseases. This review will focus on biophysical properties and biogenesis of exosomes, their pathophysiological roles and their potential as biomarkers and therapeutics in kidney diseases.

Hypoxic enhancement of exosome release by breast cancer cells.

BACKGROUND: Exosomes are nanovesicles secreted by tumour cells which have roles in paracrine signalling during tumour progression, including tumour-stromal interactions, activation of proliferative pathways and bestowing immunosuppression. Hypoxia is an important feature of solid tumours which promotes tumour progression, angiogenesis and metastasis, potentially through exosome-mediated signalling. METHODS: Breast cancer cell lines were cultured under either moderate (1% O2) or severe (0.1% O2) hypoxia. Exosomes were isolated from conditioned media and quantitated by nanoparticle tracking analysis (NTA) and immunoblotting for the exosomal protein CD63 in order to assess the impact of hypoxia on exosome release. Hypoxic exosome fractions were assayed for miR-210 by real-time reverse transcription polymerase chain reaction and normalised to exogenous and endogenous control genes. Statistical significance was determined using the Student T test with a P value of < 0.05 considered significant. RESULTS: Exposure of three different breast cancer cell lines to moderate (1% O2) and severe (0.1% O2) hypoxia resulted in significant increases in the number of exosomes present in the conditioned media as determined by NTA and CD63 immunoblotting. Activation of hypoxic signalling by dimethyloxalylglycine, a hypoxia-inducible factor (HIF) hydroxylase inhibitor, resulted in significant increase in exosome release. Transfection of cells with HIF-1α siRNA prior to hypoxic exposure prevented the enhancement of exosome release by hypoxia. The hypoxically regulated miR-210 was identified to be present at elevated levels in hypoxic exosome fractions. CONCLUSIONS: These data provide evidence that hypoxia promotes the release of exosomes by breast cancer cells, and that this hypoxic response may be mediated by HIF-1α. Given an emerging role for tumour cell-derived exosomes in tumour progression, this has significant implications for understanding the hypoxic tumour phenotype, whereby hypoxic cancer cells may release more exosomes into their microenvironment to promote their own survival and invasion.

Prostate cancer detection: a systematic review of urinary biosensors.

BACKGROUND: Current diagnostic methods for prostate cancer are invasive and lack specificity towards aggressive forms of the disease, which can lead to overtreatment. A new class of non-invasive alternatives is under development, in which urinary biomarkers are detected using biosensing devices to offer rapid and accurate prostate cancer diagnosis. These different approaches are systematically reviewed and their potential for translation to clinical practice is evaluated. METHODS: A systematic review of the literature was performed in May 2021 using PubMed Medline database, Embase, and Web of Science. The objective was to review the structural designs and performance of biosensors tested on urine samples from patients with prostate cancer. RESULTS: A total of 76 records were identified. After screening and eligibility, 14 articles were included and are discussed in this paper. The biosensors were discussed based on the target biomarkers and detection technologies used, as well as the results of the clinical studies. Most of the works reported good discrimination between patients with prostate cancer and controls. CONCLUSIONS: This review highlights the potential of urinary biosensors for non-invasive prostate cancer detection. However, clinical studies have so far only been conducted on small cohorts of patient, with large scale trials still needed to validate the proposed approaches. Overall, the consensus arising from the proof of concepts studies reviewed here, is that an adequate combination of biomarkers into multiplex biosensor platforms is required to achieve accurate diagnostic tests. Furthermore, whether such devices can discriminate between aggressive and indolent cancer has not yet been addressed, because it entails optimized biomarkers panels and long-term clinical trials.

Circulating microRNA expression is reduced in chronic kidney disease.

BACKGROUND: MicroRNAs (miRNAs) are important regulators of gene expression, which have roles in renal development and disease. They exist in biological fluids including blood and urine and may have signalling roles and potential as disease biomarkers. METHODS: We measured the levels of miRNAs in patients with different stages of chronic kidney failure including those receiving maintenance haemodialysis treatment. RESULTS: In patients with severe chronic renal failure, circulating levels of total and specific miRNAs are reduced in comparison to patients with mild renal impairment or normal renal function. A strong correlation exists between detected circulating miRNAs and estimated glomerular filtration rate, and less strong correlations with other features of chronic kidney disease, such as anaemia and hyperparathyroidism. CONCLUSION: These findings have important implications for the use of circulating miRNAs as biomarkers in individuals with renal impairment and for the pathogenesis of uraemia.