Role and regulation of the forkhead transcription factors FOXO3a and FOXM1 in carcinogenesis and drug resistance

The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream effector of the PI3K-AKT-FOXO signaling cascade.In addition,FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes,which are involved in chemotherapeutic drug sensitivity and resistance.Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients,and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.

Sox2, a key factor in the regulation of pluripotency and neural differentiation

Sex determining region Y-box 2(Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells(PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. Furthermore, Sox2 plays an essential role in somatic cell reprogram-ming, reversing the epigenetic configuration of differ-entiated cells back to a pluripotent embryonic state. In addition to its role in regulation of pluripotency, Sox2 is also a critical factor for directing the differentiation of PSCs to neural progenitors and for maintaining the properties of neural progenitor stem cells. Here, we review recent findings concerning the involvement of Sox2 in pluripotency, somatic cell reprogramming and neural differentiation as well as the molecular mecha-nisms underlying these roles.

Non-invasive means of measuring hepatic fat content

Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, it is an invasive procedure and its use is limited, particularly in children. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Ultrasound is widely used to detect hepatic steatosis, but its sensitivity is reduced in the morbidly obese and also in those with small amounts of fatty infiltration. It has been used to grade hepatic fat content, but this is subjective. CT can detect hepatic steatosis, but exposes subjects to ionising radiation, thus limiting its use in longitudinal studies and in children. Recently, magnetic resonance (MR) techniques using chemical shift imaging have provided a quantitative assessment of the degree of hepatic fatty infiltration, which correlates well with liver biopsy results in the same patients. Similarly, in vivo 1H MRS is a fast, safe, non-invasive method forthe quantification of intrahepatocellular lipid (IHCL) levels. Both techniques will be useful tools in future longitudinal clinical studies, either in examining the natural history of conditions causing hepatic steatosis (e.g. non-alcoholic fatty liver disease), or in testing new treatments for these conditions.

Surgical treatment for liver cancer

Primary liver cancer is amongst the commonest tumors worldwide,particularly in parts of the developing world,and is increasing in incidence. Over the past three decades,surgical hepatic resection has evolved from a high risk,resource intensive procedure with limited application,to a safe and commonly performed operation with a range of indications. This article reviews the approach to surgical resection for malignancies such as hepatocellular cancer,metastatic liver de-posits and neuroendocrine tumors. Survival data after resection is also reviewed,as well as indications for curative resection.

Diagnosis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the diagnosis of HCC, including serum markers, radiological techniques and histological evaluation, and summarises international guidelines for the diagnostic approach to HCC.

Use of second generation contrast-enhanced ultrasound in the assessment of focal liver lesions

Ultrasound (US) is often the first imaging modality employed in patients with suspected focal liver lesions. The role of US in the characterisation of focal liver lesions has been transformed with the introduction of specific contrast media and the development of specialized imaging techniques. Ultrasound now can fully characterise the enhancement pattern of hepatic lesions, similar to that achieved with contrast enhanced multiphasic computed tomography (CT) and magnetic resonance imaging (MRI). US contrast agents are safe, well-tolerated and have very few contraindications. Furthermore, real-time evaluation of the vascularity of focal liver lesions has become possible with the use of the newer microbubble contrast agents. This article reviews the enhancement pattern of the most frequent liver lesions seen, using the second generation US contrast media. The common pitfalls for each type of lesion are discussed. The recent developments in US contrast media and specific imaging techniques have been a major advance and this technique, in view of the intrinsic advantages of US, will undoubtedly gain popularity in the years to come.

Current and future applications of in vitro magnetic resonance spectroscopy in hepatobiliary disease

原子磁性的回声光谱学允许细胞的生物化学和新陈代谢的学习，在整个身体在活体内并且在更高的磁场力量在试管内。因为这种技术非侵略、非选择，磁性的回声光谱学方法论广泛地在生物化学和药被使用了。房间，身体液体和纸巾的在试管内磁性的回声光谱学研究在医药生物化学被使用了调查 pathophysiological 过程，更最近，这种技术被医生使用了决定疾病畸形在活体内。这个加亮的话题说明在试管内的潜力在学习肝胆管系统的磁性的回声光谱学。在恶意、非恶意的肝疾病和胆汁作文的学习的磁性的回声光谱学学习的在试管内质子和磷的角色被讨论，特别地与关联词在活体内的参考整个身体的磁性的回声光谱学应用。在摘要，磁性的回声光谱学技术能在到内在的 pathophysiological 过程的疾病严厉和指针上提供非侵略的生物化学的信息。磁性的回声光谱学为疾病简历标记，以及估计的治疗学的反应作为一个屏蔽工具保持潜在的诺言。

3.0 T运动校正多参数肾动脉自旋标记成像:可重复性及血管扩张剂效应

目的本文旨在探究自由呼吸下运动校正的多反转时间脉冲肾动脉自旋标记(PASL)的可行性和可重复性,通过一般动力学参数图同时定量分析肾灌注(RBF)、团注达到时间(BAT)及组织T1值。

有 laparoscopic Habib 4 × radiofrequency 设备的巨大的 exophytic 肝 haemangioma 的 Laparoscopic 切除术

Haemangiomas are the most common solitary benign neoplasm of the liver with an incidence ranging from 5% to 20%. Although usually small and asymptomatic, they may reach considerable proportions and rarely give rise to life-threatening complications. Surgical intervention is required for incapacitating symptoms, established complications, and diagnostic uncertainty. The resection of haemangiomas demands meticulous surgical technique, owing to their high vascularity and the concomitant risk of intra-operative haemorrhage. Laparoscopic resection of giant haemangiomas is even more challenging, and has only been reported twice. We here report the case of a giant 10 cm liver haemangioma which was successfully resected laparoscopically using the laparoscopic HabibTM 4×, a bipolar radiofrequency device, without clamping major vessels and with minimal blood loss. Transfusion of blood or blood products was not required. The patient had an uneventful recovery and was asymptomatic at 7-mo follow-up.

Role of microbubble ultrasound contrast agents in the non-invasive assessment of chronic hepatitis C-related liver disease

长期地感染丙肝病毒的病人经常得长期的肝疾病，对肝损伤的严厉的评价在认为病毒的根除是治疗以前被要求。这篇文章检验从标准答案肝活体检视当前可得到的各种各样的评价方法到血清学的标记和成像。超声是在临床的实践的最广泛地使用的成像形式之一并且已经是为肝疾病的一个首要的诊断工具。Microbubble 超声对比代理人允许更高的分辨率要获得的图象和对要执行的微脉管的变化的功能的评价。在确定的这些代理人的角色肝的损害的状态作为与丙肝在病人决定肝疾病的阶段和等级的一个可行方法被讨论。尽管当前限制了到专家中心，提高对比的超声将不可避免地在临床的背景增加的微水泡的可获得性。

Costs of laparoscopic and open liver and pancreatic resection:A systematic review

AIM:To study costs of laparoscopic and open liver and pancreatic resections,all the compiled data from available observational studies were systematically reviewed.METHODS:A systematic review of the literature was performed using the Medline,Embase,Pub Med,and Cochrane databases to identify all studies published up to 2013 that compared laparoscopic and open liver[laparoscopic hepatic resection(LLR)vs open liver resection(OLR)]and pancreatic[laparoscopic pancreatic resection(LPR)vs open pancreatic resection]resection.The last search was conducted on October 30,2013.RESULTS:Four studies reported that LLR was associated with lower ward stay cost than OLR(2972 USD vs 5291 USD).The costs related to equipment(3345USD vs 2207 USD)and theatre(14538 vs 11406)were reported higher for LLR.The total cost was lower in patients managed by LLR(19269 USD)compared to OLR(23419 USD).Four studies reported that LPR was associated with lower ward stay cost than OLR(6755vs 9826 USD).The costs related to equipment(2496USD vs 1630 USD)and theatre(5563 vs 4444)were reported higher for LPR.The total cost was lower in the LPR(8825 USD)compared to OLR(13380 USD).CONCLUSION:This systematic review support the economic advantage of laparoscopic over open approach to liver and pancreatic resection.

Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells

Mitochondrial dysfunction and endoplasmic reticulum stress(ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide(NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca^(2+) flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstratedthe need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.

先天性肌营养不良和FKRP基因突变患者的脑部变化谱

Objectives: To report the spectrum of brain magnetic resonance imaging findings in 13 patients with congenital muscular dystrophy and FKRP gene mutations and to explore possible genotype-phenotype correlations. Design: We retrospectively reviewed brain magnetic resonance imaging in patients with congenital muscular dystrophy and FKRP gene mutations. Patients: Thirteen patients with congenital muscular dystrophy and mutations in the FKRP gene. Results: Five of the 13 patients had the typical phenotype originally described for congenital muscular dystrophy (MDC1C) with normal intelligence and normal brain magnetic resonance imaging while 3 other patients had isolated cerebellar cysts and mental retardation without any other sign of posterior fossa of supratentorial abnormalities. In the remaining 5 patients cerebellar cysts were associated with structural brain changes involving the posterior fossa and the cortex, ranging from focal unilateral periventricular nodular heterotopia to marked cerebellar dysplasia and pontine hypoplasia. In 2 of these 5 patients the severity and distribution of changes resembled muscle-eye-brain disease in 1 patient who had mild Walker-Warburg syndr ome. The distribution of FKRP gene mutations identified in this group of patients did not reveal any obvious association with the severity of central nervous system involvement. Conclusions: The severity of central nervous system involvement observed in our patients in contrast broadly reflected the severity of the disruption of α-dystroglycan glycosylation. In particular, dystroglycan expression was almost absent in the patients with muscle-eye-brain diseaselike phenotype and less severely reduced in the patients with congenital muscular dystrophy (MDC1C) with or without cerebellar cysts. This study further highlights the central role that dystroglycan has in neuronal migration.

Evaluation of the Hypothalamic Kisspeptin System during the Attainment of Puberty in Gilts

Background: Kisspeptin has been demonstrated to affect the attainment of puberty in multiple species, presumably through its actions on GnRH and LH. It has previously been found there is an increase in expression of hypothalamic in the rat and the monkey coincident with puberty. Whether a similar phenomenon occurs in the pig remains to be determined. The objectives of the current experiments were to determine 1) Plasma concentrations of estradiol-17β;2) Anterior pituitary gland concentrations of LH, IGF-I, kisspeptin, and anterior pituitary gland expression of LH-β and GnRH receptor;3) Mediobasal hypothalamus expression of Kiss1 and concentrations of kisspeptin during the peripubertal period in the gilt. Methods: Two experiments were performed, each with 25 crossbred gilts (151 d, 105 kg). Gilts were relocated and exposed to a mature boar beginning on d 1 and continuing throughout the experiments to naturally induce puberty. Gilts that stood immobile within 24 hours of slaughter were considered to have attained puberty. Plasma samples were collected on d 1, 3, and 7 of the first experiment and d 2, 4, 6, and 8 of the second experiment. Gilts were slaughtered on d 7 (experiment 1) or d 8 (experiment 2), when mediobasal hypothalamus (MBH), anterior pituitary glands (AP), and blood were collected. Relative expression of MBH Kiss1 and β-actin and AP GnRH receptor, LH-β, was determined using real-time reverse transcriptase PCR. Fold changes in relative expression were determined using the Relative Expression Software Tool. Hypothalamic and AP content of kisspeptin were determined by RIA and differences were determined using the GLIMMIX procedure of SAS. Results: Relative expression of Kiss1 was increased (P = 0.005) 2.2 fold in the gilts that had attained puberty in the first experiment, however, those that had attained puberty in the second were not different (P > 0.05) from gilts that had not. Relative expression of GnRH receptor was not different (P > 0.05) between treatments in both experiments. Relative expression of LH-β tended to be decreased (P = 0.09) 0.80 fold in gilts that attained puberty in the first experiment but was not different (P > 0.05) in gilts that attained puberty in the second experiment. AP concentrations of LH were not different (P > 0.05) between treatments in the first experiment and were decreased (P = 0.01) in gilts that attained puberty in the second experiment. AP concentrations of kisspeptin were not different (P > 0.05) in the first experiment but were increased (P = 0.04) in gilts that had attained puberty in the second experiment. MBH concentrations of kisspeptin were increased (P = 0.03) in gilts that had attained puberty in the first experiment but were not different (P > 0.05) between treatments in the second experiment. Conclusions: These data further support the role that MBH expression of Kiss1 and concentrations of kisspeptin and AP concentrations of kisspeptin fluctuate during the peripubertal period and may play a role in the attainment of puberty in the gilt.

Evaluation of the Hypothalamic Kisspeptin System throughout the Estrous Cycle in Gilts

Kisspeptin has been demonstrated to affect reproductive cyclicity and the attainment of puberty in multiple species, presumably through its actions on gonadotropin releasing hormone and luteinizing hormone. Kisspeptin administration causes increased plasma concentrations of LH in pigs, sheep, and rats. The objective of this experiment was to evaluate changes in the hypothalamic kisspeptin system throughout the estrous cycle in gilts. Estrus was synchronized in forty crossbred gilts (191 d, 121 kg) and estrus detection was performed by exposing gilts to a mature boar. The first day gilts stood immobile was denoted d 1 of the estrous cycle. Blood samples were collected via jugular venipuncture on d 1, 4, 7, 9, 14, 16, and 19 of the estrous cycle. Ten animals were slaughtered on d 1, 9, 14, and 21 of the estrous cycle when medial basal hypothalami, anterior pituitary glands, and blood were collected. Relative expression of hypothalamic kisspeptin (KISS1), kisspeptin receptor (KISS1R), estrogen receptors-a, anterior pituitary gland GnRH receptor, β-actin, and GAPDH was determined using real-time reverse transcriptase PCR. Fold changes in relative expression were determined using the Relative Expression Software Tool. Relative expression of KISS1 was increased (P = 0.006) 3.2 fold on d 1 versus d 21 and 2.3 fold (P = 0.003) on d 9 versus d 21 of the estrous cycle, but was not different (P > 0.05) among the remaining days of the estrous cycle. Relative expression of estrogen receptor-b was decreased (P = 0.05) 0.8 fold on d 9 versus d 21 and (P = 0.005) 0.7 fold on d 14 versus d 21, but was not different (P > 0.05) among the remaining days. Relative expression of anterior pituitary gland GnRH receptor was increased (P < 0.01) on d 1 and 21 versus d 9 and 14. These data support the notion that medial basal hypothalamic expression of KISS1 changes throughout the estrous cycle and may influence reproductive cyclicity in the gilt.

Current situation of Giardia infection in Spain: Implications for public health

Giardia is an enteric protozoan that infects a wide range of vertebrate hosts, being considered a major causative agent of gastrointestinal disease in humans in both developing and developed countries. Giardia infection has also a significant impact on livestock health, causing diarrhoea and resulting in significant economic lost. Transmission is either direct, through the faecal-oral route, or indirect, through ingestion of contaminated water or food. In this article, we review current knowledge about the epidemiology of giardiasis in different populations in Spain, including humans, livestock, companion animals, and wildlife. Environmental contamination of surface waters and raw foods by Giardia cysts is also addressed. Special relevance has been given to the data available on the molecular characterization of the Giardia isolates obtained from clinical and environmental samples, as determining thespecies/assemblages and subassemblages involved is essential for accurately identifying the parasite and assessing zoonotic transmission. The public health significance of these findings has also been thoroughly discussed.

Roux-en-Y gastric bypass or sleeve gastrectomy for obstructive sleep apnea:A systematic review and meta-analysis

Objective:Bariatric surgery has been shown to be an effective method of treatment for obstructive sleep apnea(OSA)with long-term benefits,however,the mechanisms of action and the optimum operative procedure remains unclear.The aim of this systemic review was to compare the efficacy of laparoscopic sleeve gastrectomy(LSG)and Roux-en-Y gastric bypass(RYGB)in resolving OSA.Methods:A comprehensive search of MEDLINE,Pubmed,Embase,and OVID was performed.Studies that reported OSA resolution in obese patients with BMI>30 kg/m2 were included in the study.RCTs,comparative prospective and matched cohort studies comparing RYGB with LSG were considered for this study.Results:Five studies(309 participants)were included:4 cohort studies and 1 RCT;all with low risk of bias.At 12 months follow-up,there was a trend towards improved resolution of OSA with LSG(OR 0.47,95%CI[0.20 to 1.06];p=0.07)when compared to RYGB.In contrast,there was a trend to poorer weight loss in the LSG group(SMD 3.83,95%CI[-1.82 to 9.48];p=0.18).Similarly,at 36 months follow-up,there was a trend towards better resolution of OSA with LSG(OR 0.52,95%CI[0.16 to 1.71];p=0.28)and a significantly poorer weight loss in LSG when compared to RYGB(SMD 8.25,95%CI[2.91 to 13.58];p=0.002).Conclusion:Despite poorer weight loss following LSG,there is a trend towards increased resolution of sleep apnea post-LSG.These findings suggest the possibility of weight loss independent factors causing OSA resolution,which should be further investigated.Registration:PROSPERO:CRD42018090367.

NOD2相关性克罗恩病患者胞壁酰二肽和Toll样受体的敏感性

Both NOD2 (CARD15) alleles aremutated in roughly 15%of patients with Crohn’s disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFαor interleukin 1β, but strong interleukin-8 secretion. MDP also substantially upregulated sec retion of TNFαand interleukin 1βinduced by toll-like receptor ligands. These effects were abolished by the most common Crohn’s NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. In Crohn’s disease, there are defects in neutrophil recruitment driven by NOD2 and interleukin 8 and in cross talk between the NO D2 and toll-like receptor pathways, which suggests that the immune system fails to receive an early priming signal.

英国妇女妊娠期肝内胆汁淤积病例发生的ATP8B1突变

Background: Intrahepatic cholestasis of pregnancy (ICP) affects approximately 0.7%of pregnancies in the UK and is associated with prematurity, fetal distress, and intrauterine death. Homozygous mutations in the ATP8B1 gene cause cholestasis with a normal serum gamma-glutamyl transpeptidase (γ-GT), and have been reported in two forms of cholestasis: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). Aims: To establish whether mutations in ATP8B1 are associated with ICP in British cases. Patients: Sixteen well phenotyped women with ICP without raised γ-GT were selected for sequence analysis. Subsequently, 182 patients and 120 controls were examined for the presence of the variants detected. Methods: All coding exons were sequenced in 16 cases. Eight ICP cases, including two women carrying a mutation, were investigated using in vivo hepatic 31P magnetic resonance spectroscopy (MRS). Results: Two heterozygous ATP8B1 transitions (208G >A and 2599C >T) that resulted in amino acid substitutions were identified; 208G >A was identified in three cases. MRS revealed an increased phosphodiester signal (Mann-Whitney U test, p = 0.03) and a decreased phosphomonoester/phosphodiester ratio (p = 0.04) in ICP cases compared with controls. Conclusions: We were able to demonstrate ATP8B1 mutations in ICP. MRS studies suggest that susceptibility to ICP is associated with a relative rise in biliary phospholipid. These data also suggest that MRS may be used for non-invasive assessment of the liver and biliary constituents in cholestasis.

脊髓多发性硬化斑块周围组织的重塑

关于多发性硬化(multiple sclerosis,MS)斑块的病理以及MS患者灰白质的弥散性改变,目前已有相当多的深入研究报道。但对于脱髓鞘斑块周围组织的改变,尤其对是脊髓MS斑块周围组织的病理研究,目前几乎没有报道。本研究即对进展性脊髓MS患者的脊髓脱髓鞘病灶周围组织(periplaque demyelinated lesions,PDLs)进行分子免疫病理方面的研究。纳入初发或复发进展型脊髓MS患者21例,尸检得到其颈髓组织,对其PDLs的神经病理特征进行分析。结果显示,PDLs存在大面积的不完全性脱髓鞘现象,而且存在促炎症和抗炎症的叠加分子反应。巨噬细胞和小胶质细胞聚集在PDLs,但对脱髓鞘碎片的吞噬作用很弱。下调PDLs的少突胶质细胞基因,胶质细胞相关的分子标志物,如水通道蛋白(aquaporin)-4、缝隙连接蛋白(connexin)-43及谷氨酸转运子(glutamate transporter)EAAT1的mRNA及蛋白表达水平均明显下调。本研究还显示,在进展型脊髓MS患者的脊髓组织中,伴随脱髓鞘斑块的形成,PDLs内的组织重塑早已开始并一直伴随着斑块的形成。笔者推测脊髓病灶PDLs内,组织重塑的过程一定伴随着星形胶质细胞功能的改变、较轻的炎症反应,共同促进了脱髓鞘的发生和进展。