Protein biomarkers for cardiorenal syndrome

Introduction: The term cardiorenal syndrome (CRS) describes the progressive pathology and interactions that develop upon heart and kidney failure. The definition of CRS is not firmly established and has evolved gradually during the last decade. The main clinical challenges associated with CRS are the lack of tools for early disease diagnosis and the inability to predict the development of cardiorenal pathophysiology. Currently several biomarkers have been proposed for improving CRS patient management. However, validation studies are needed to implement these initial findings to the clinical setting.

Areas covered: In this review the database PubMed was used for a literature search on the definition and classification of CRS as well as biomarkers for CRS diagnosis and prognosis.

Expert opinion: A universally acceptable classification system for CRS is not available. Thus, acquiring mechanistic insights relative to the pathophysiology of the disease is challenging. Reported biomarkers include well-established markers for heart/renal dysfunction and inflammation. Some proteins expressed in both organs have also been associated with CRS, yet their link to disease pathophysiology and organ cross-talk is missing. Establishing the link between deregulated molecular pathways and CRS phenotypes is required to define biological relevance of existing findings and ultimately biology-driven markers and targets.     

Multiparametric magnetic resonance imaging-guided salvage radiotherapy in prostate cancer

AimTo analyse the efficacy and toxicity of postprostatectomy SRT in patients with a BCR evaluated with mpMRI.BackgroundMultiparametric magnetic resonance imaging (mpMRI) has the ability to detect the site of pelvic recurrence in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). However, we do not know the oncological outcomes of mpMRI-guided savage radiotherapy (SRT).ResultsLocal, lymph node, and pelvic bone recurrence was observed in 13, 4 and 2 patients, respectively. PSA levels were significantly lower in patients with negative mpMRI (0.4 ng/mL [0.4]) vs. positive mpMRI (2.2 ng/mL [4.1], p = 0.003). Median planning target volume doses in patients with visible vs. non-visible recurrences were 76 Gy vs. 70 Gy. Overall, mean follow-up was 41 months (6–81). Biochemical relapse-free survival (bRFS) at 3 years was 82.3% and 82.5%, respectively, for the negative and positive mpMRI groups (p = 0.800). Three-year rates of late grade ≥2 urinary and rectal toxicity were 14.8% and 1.9%, respectively; all but one patient recovered without sequelae.ConclusionSRT to the macroscopic recurrence identified by mpMRI is a feasible and well-tolerated option. In this study, there were no differences in bRFS between MRI-positive and MRI-negative patients, indicating effective targeting of MRI-positive lesions.     

The roles of Groucho/Tle in left-right asymmetry and Kupffer's vesicle organogenesis

The heart is the first organ to form and function in the vertebrate embryo. Furthermore, differences between the left and right sides of the embryo become first detectable during cardiac development. We observed strong cardiac laterality phenotypes in medaka embryos by manipulating Groucho protein activity. The phenotypes produced by misexpressing Tle4 and the dominant-negative Aes reveal a general effect of these corepressor proteins on left-right (LR) development. With the help of an inducible expression system, we were able to define temporally different phases for these effects. In an early phase during gastrulation, Groucho proteins regulate Brachyury expression in the dorsal forerunner cells, which later gives rise to the Kupffer's vesicle (KV). The interference of endogenous Groucho proteins by misexpression of Aes leads to KVs of reduced size, whereas overexpression of Tle4 results in enlarged KVs. The expression level of the cilia marker Lrd was also affected both positively and negatively from these treatments. In the late phase during somitogenesis, Groucho proteins regulate the asymmetric activities of Nodal and Lefty genes. Altering canonical Wnt signaling produced similar results in late embryos, however, this did not affect KV morphogenesis or Lrd expression in early embryos. Therefore, changes in Kupffer's vesicle morphogenesis and the laterality of visceral organs following alterations in Groucho corepressor levels demonstrate two distinct phases in which Groucho proteins help establish LR asymmetry in medaka fish.     

虫草多糖治疗家犬夹闭肾动脉引起的急性肾衰

探讨了虫草多糖对家犬夹闭肾动脉造成的急性肾衰的治疗作用。将实验动物家犬分为假手术组、阴性模型组、阳性组、虫草多糖高、中、低三个剂量组,观察治疗后犬的肾功能、血液生化指标、尿常规、肾脏病理的变化。发现虫草多糖组肾功能受损程度明显轻于阴性模型组（P〈0．01）,肾脏病理损伤明显减轻。实验证明虫草多糖能够治疗肾缺血诱发的急性肾功能衰竭,其机理可能与改善肾功能、增加肾血流量、纠正代谢紊乱、促进肾小管的修复与再生等作用有关。     

Zonula occludens-1 and connexin 43 expression in the failing human heart

Focal disorganization of gap junctional distribution and down-regulation of the major gap junctional protein connexin 43 are typical features of myocardial remodelling in the failing human heart. Increasing evidence indicates that connexin 43 interacts with zonula-occludens-1 (ZO-1), and it has recently been shown that ZO-1 promotes the formation and growth of gap junctional plaques. In the present study, distribution patterns of ZO-1 and connexin 43 were studied in normal and in heart failure patients using double-label immunohistochemistry and confocal microscopy. ZO-1 was found to be co-localized with connexin 43 at intercalated disks. Importantly, in patients with heart failure due to dilated or ischaemic cardiomyopathy, areas of diminished connexin 43 expression were characterized by a markedly reduced ZO-1 staining. Based on these data it is concluded that in patients with heart failure, down-regulation of ZO-1 matches the diminished expression levels of connexin 43, suggesting that ZO-1 plays an important role in gap junction formation and gap junction plaque stability.     

Investigation of left heart flow using a numerical correlation to model heart wall motion

A three-dimensional computational fluid dynamics (CFD) method has been developed to model the flow in the left heart including atrium and ventricle. Since time resolution of the medical scans does not fit the requirements of the CFD calculations, the main challenge in a numerical simulation of heart chambers is wall motion modeling. This study employs a novel three-dimensional approximation scheme to correlate the wall boundary and grid movement in systole and diastole. It uses a geometry extracted from medical images in the literature and deformed based on the reported flow rates. The opening and closing of the mitral (MV) and the aortic valve (AV) considered as simultaneous events. Unstructured tetragonal grids were used for the meshing of the domain. The calculation was performed by a Navier–Stokes solver using the arbitrary Lagrange–Euler (ALE) formulation. Results show that the proposed correlation for the wall motion could predict the main features of heart flows.     

Extracellular micro/nanovesicles rescue kidney from ischemia-reperfusion injury

Acute renal failure (ARF) is a clinical challenge that is highly resistant to treatment, and its high rate of mortality is alarming. Ischemia–reperfusion injury (IRI) is the most common cause of ARF. Especially IRI is implicated in kidney transplantation and can determine graft survival. Although the exact pathophysiology of renal IRI is unknown, the role of inflammatory responses has been elucidated. Because mesenchymal stromal cells (MSCs) have strong immunomodulatory properties, they are under extensive investigation as a therapeutic modality for renal IRI. Extracellular vesicles (EVs) play an integral role in cell-to-cell communication. Because the regenerative potential of the MSCs can be recapitulated by their EVs, the therapeutic appeal of MSC-derived EVs has dramatically increased in the past decade. Higher safety profile and ease of preservation without losing function are other advantages of EVs compared with their producing cells. In the current review, the preliminary results and potential of MSC-derived EVs to alleviate kidney IRI are summarized. We might be heading toward a cell-free approach to treat renal IRI.     

HER2+ mCRC patients with exon 20 R784G substitution mutation do not respond to the cetuximab therapy

The human epidermal growth factor 2 (HER2) gene undergoes various mutations that could alter its activity or respond to the antibody therapies. Cetuximab, a known anti-EGFR monoclonal antibody (mAB), is widely administered in metastatic colorectal cancer (mCRC) cases. Here we identified mCRC patients who did not respond to cetuximab (500 mg/m², q2w) after fluoropyrimidine/oxaliplatin regimen failure. Tumor samples were examined with immunohistochemistry for protein distribution, polymerase chain reaction (PCR) sequencing for mutation detection and real-time PCR for mRNA expression pattern analysis between cetuximab sensitive and resistance patients. The conformational differences of normal and mutated protein structures were predicted by bioinformatics analysis. The 5-year survival rates of target groups were estimated using the Kaplan–Meier method. Immunohistochemistry showed that all cases had high level of HER2 protein. No K-Ras or B-Raf mutation was observed among the study population; however, cetuximab resistance patients harbored a somatic mutation R784G at the exon 20 region of HER2 coding sequence. According to bioinformatics analysis, this mutation caused a notable misfold in protein conformation. Meanwhile, survival analysis showed R784G mutated mCRC patients had shortened survival rate compared with the mCRC cases with wild-type HER2. Collectively, these data report a new mechanism of resistance to cetuximab and might be applicable in modifying new therapeutic strategies for HER2 involved cancers.     

The role of mitochondria in sepsis-induced cardiomyopathy

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Myocardial dysfunction, often termed sepsis-induced cardiomyopathy, is a frequent complication and is associated with worse outcomes. Numerous mechanisms contribute to sepsis-induced cardiomyopathy and a growing body of evidence suggests that bioenergetic and metabolic derangements play a central role in its development; however, there are significant discrepancies in the literature, perhaps reflecting variability in the experimental models employed or in the host response to sepsis. The condition is characterised by lack of significant cell death, normal tissue oxygen levels and, in survivors, reversibility of organ dysfunction. The functional changes observed in cardiac tissue may represent an adaptive response to prolonged stress that limits cell death, improving the potential for recovery. In this review, we describe our current understanding of the pathophysiology underlying myocardial dysfunction in sepsis, with a focus on disrupted mitochondrial processes.