The search for novel diagnostic and prognostic biomarkers in cholangiocarcinoma

The poor prognosis of cholangiocarcinoma (CCA) is in part due to late diagnosis, which is currently achieved by a combination of clinical, radiological and histological approaches. Available biomarkers determined in serum and biopsy samples to assist in CCA diagnosis are not sufficiently sensitive and specific. Therefore, the identification of new biomarkers, preferably those obtained by minimally invasive methods, such as liquid biopsy, is important. The development of innovative technologies has permitted to identify a significant number of genetic, epigenetic, proteomic and metabolomic CCA features with potential clinical usefulness in early diagnosis, prognosis or prediction of treatment response. Potential new candidates must be rigorously evaluated prior to entering routine clinical application. Unfortunately, to date, no such biomarker has achieved validation for these purposes. This review is an up-to-date of currently used biomarkers and the candidates with promising characteristics that could be included in the clinical practice in the next future. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

MicroRNAs and extracellular vesicles in cholangiopathies

Cholangiopathies encompass a heterogeneous group of disorders affecting biliary epithelial cells (i.e. cholangiocytes). Early diagnosis, prognosis and treatment still remain clinically challenging for most of these diseases and are critical for adequate patient care. In the past decade, extensive research has emphasized microRNAs (miRs) as potential non-invasive biomarkers and tools to accurately identify, predict and treat cholangiopathies. MiRs can be released extracellularly conjugated with lipoproteins or encapsulated in extracellular vesicles (EVs). Research on EVs is also gaining attention since they are present in multiple biological fluids and may represent a relevant source of novel non-invasive biomarkers and be vehicles for new therapeutic approaches. This review highlights the most promising candidate miRs and EV-related biomarkers in cholangiopathies, as well as their relevant roles in biliary pathophysiology. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Optimising the clinical strategy for autoimmune liver diseases: Principles of value-based medicine

Background

Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis represent the three major autoimmune liver diseases (AILDs). Their management is highly specialized, requires a multidisciplinary approach and often relies on expensive, orphan drugs. Unfortunately, their treatment is often unsatisfactory, and the care pathway heterogeneous across different centers. Disease-specific clinical outcome indicators (COIs) able to evaluate the whole cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. Aim of our study was to generate a set of COIs for the three AILDs. We then prospectively validated these indicators based on a series of consecutive patients recruited at three tertiary clinical centers in Lombardy, Italy.

Cholemic nephropathy – Historical notes and novel perspectives

Acute kidney injury is common in patients with liver disease and associated with significant morbidity and mortality. Besides bacterial infections, fluid loss, and use of nephrotoxic drugs AKI in liver disease may be triggered by tubular toxicity of cholephiles. Cholemic nephropathy, also known as bile cast nephropathy, supposedly represents a widely underestimated but important cause of renal dysfunction in cholestasic or advanced liver diseases with jaundice. Cholemic nephropathy describes impaired renal function along with characteristic histomorphological changes consisting of intratubular cast formation and tubular epithelial cell injury directed towards distal nephron segments. The underlying pathophysiologic mechanisms are not entirely understood and clear defined diagnostic criteria are still missing.This review aims to summarize (i) the present knowledge on clinical and morphological characteristics of cholemic nephropathy, (ii) available preclinical models, (iii) potential pathomechanisms especially the potential role of bile acids, and (iv) future diagnostic and therapeutic strategies for cholemic nephropathy. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

人大隐静脉干细胞原代培养方法的改良

旨在探讨如何高效获取优质的人大隐静脉(Great saphenous vein)原代干细胞。大隐静脉剪碎后分别采用组织块贴壁法和Ⅱ型胶原酶消化法获取血管壁细胞。倒置显微镜下观察不同时间段两组血管壁细胞形态学变化,台盼蓝染色测定血管壁细胞存活率,流式分选CD34和CD117双阳性干细胞,免疫荧光进一步证实。细胞培养至第三代(P3)时组织块贴壁法提取的细胞出现纤维化老化,而酶消化法提取的细胞仍有集落样生长,细胞存活率分别为(91.7±1.2)%和(97.2±0.7)%(P=0.005)。流式分选结果显示:组织块法和酶消化法获得CD34和CD117双阳性细胞所占比例分别为(0.16±0.05)%和(0.44±0.07)%,差异有统计学意义(P=0.005)。免疫荧光染色显示,分选出的干细胞培养1周后组织块法获得双阳性干细胞的阳性率(89.41±2.06)%,酶消化法为(94.03±1.83)%,P0.05。流式细胞仪检测分选出的干细胞中CD31、VEGF2和SMA阳性率分别为(0.12±0.01)%、(0.19±0.02)%和(0.45±0.01)%,与阴性对照组差异无统计学意义(P0.05),排除成熟内皮细胞和平滑肌细胞存在的可能性。分选出的干细胞进行管腔形成实验进一步证实其具有向内皮分化的潜能。上述结果显示,采用酶消化法可以获得形态更好、数量更多、存活率相对更高的干细胞,可广泛用于临床和基础研究。     

Ethylene mediates dichromate‐induced inhibition of primary root growth by altering AUX1 expression and auxin accumulation in Arabidopsis thaliana

The hexavalent form of chromium [Cr(VI)] causes a major reduction in yield and quality of crops worldwide. The root is the first plant organ that interacts with Cr(VI) toxicity, which inhibits primary root elongation, but the underlying mechanisms of this inhibition remain elusive. In this study, we investigate the possibility that Cr(VI) reduces primary root growth of Arabidopsis by modulating the cell cycle‐related genes and that ethylene signalling contributes to this process. We show that Cr(VI)‐mediated inhibition of primary root elongation was alleviated by the ethylene perception and biosynthesis antagonists silver and cobalt, respectively. Furthermore, the ethylene signalling defective mutants (ein2‐1 and etr1‐3) were insensitive, whereas the overproducer mutant (eto1‐1) was hypersensitive to Cr(VI). We also report that high levels of Cr(VI) significantly induce the distribution and accumulation of auxin in the primary root tips, but this increase was significantly suppressed in seedlings exposed to silver or cobalt. In addition, genetic and physiological investigations show that AUXIN‐RESISTANT1 (AUX1) participates in Cr(VI)‐induced inhibition of primary root growth. Taken together, our results indicate that ethylene mediates Cr(VI)‐induced inhibition of primary root elongation by increasing auxin accumulation and polar transport by stimulating the expression of AUX1.     

Inhomogeneous Encoding of the Visual Field in the Mouse Retina

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2000—2015年秦巴山区植被净初级生产力时空变化及其驱动因子

基于2000—2015年MOD17A3数据及各驱动因素数据,辅以地统计学理论,利用趋势分析、Hurst指数及相关分析等方法,剖析秦巴山区近16年植被净初级生产力(NPP)时空变化特征,研究气候变化、土壤类型、地形因子、植被类型及人类活动等对植被NPP的影响.结果表明: 秦巴山区植被NPP空间上呈西南高、东北低的分布格局;时间上,近16年呈西北增、东北减的变化特征,在未来呈北部持续性、南部反持续性的发展态势.秦巴山区植被NPP与降雨量和气温呈正相关;暗棕壤、黄壤、紫色土和水稻土4种土壤类型的NPP均值明显高于其他土壤类型;不同植被类型的NPP存在空间分布和变化趋势的差异;NPP的高值主要分布在坡度25°～50°、海拔500～1000 m 以及大于2500 m的区域内;人类活动对NPP具有双重扰动性,表现为正向促进,反向抑制.     

富士苹果萌芽至新梢旺长期肥料氮去向和土壤氮库盈亏

运用¹⁵N同位素示踪技术,以5年生‘烟富3’/SH6/平邑甜茶苹果为试材,研究了萌芽至新梢旺长期不同施氮水平(0、50、100、150、200、250 kg·hm^-2)下肥料氮的吸收利用、土壤残留和土壤氮库盈亏特点.结果表明:早春施氮后,15N均优先分配到根系中,然后转运用于地上部新生器官(果实、新生枝叶)的形态建造.新梢旺长期结束后(施氮2个月后),5.9%~9.9%的肥料氮被树体吸收,29.8%~33.4%的肥料氮残留在0~60 cm土体中,56.7%~64.4%的肥料氮通过其他途径损失.随施氮水平的提高,树体吸收的肥料氮量和土壤残留氮量逐渐增加,但肥料氮利用率和土壤残留率却不断降低,同时损失量和损失率不断增加.随施氮水平的提高,土壤氮素总平衡由亏缺转为盈余,且盈余量随施氮水平的提高而显著提高.表明施氮不足将会造成土壤氮肥力的下降;而过量施氮则会加剧土壤氮素累积,增加氮素污染风险.施氮水平与土壤氮素总平衡呈显著线性相关关系,拟合方程为:y=0.3511x-20.808(R^2=0.9927),当施氮量为59.27 kg·hm^-2时,由萌芽至新梢旺长期的土壤氮库达到平衡.