Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Crowdsourced and crowdfunded: the future of forensic DNA?

ABSTRACT

Forensic DNA analysis is dependent on comparing the known and the unknown. Expand the number of known profiles, and the likelihood of a successful match increases. Forensic use of DNA is moving towards comparing samples of unknown origin with publicly available genetic data, such as the records held by genetic genealogy providers. Use of forensic genetic genealogy has yielded a number of recent high-profile successes but has raised ethical and privacy concerns. Navigating family trees is complex, even more so when combined with a comparison of genetic relationships. This intelligence-gathering process has led to occasional false leads, and its use also risks a public backlash, similar to concerns over Cambridge Analytica. A cautious approach to use of this technique is therefore warranted.     

Rescue of the Cold Preserved Rat Liver by Hypothermic Oxygenated Machine Perfusion

The aim of the study was to investigate whether hypothermic oxygenated liver perfusion after cold liver preservation resuscitated metabolic parameters and whether this treatment had a benefit for liver viability upon reperfusion.
We preserved rat livers either by cold storage (UW) for 10 h, or by perfusion for 3 h (oxygenated modified UW) after 10 h cold storage. We assessed viability of livers after preservation and after ischemic rewarming + normothermic reperfusion ex vivo . Ten hour cold storage reduced mitochondrial cytochrome oxidase and metabolically depleted the livers. Oxygenated perfusion after cold storage resulted in uploaded cellular energy charge and oxidized mitochondrial cytochrome oxidase. Reperfusion after 10 h cold storage increased formation of superoxid anions, release of cytosolic LDH, lipid peroxidation, caspase activities and led to disruption of sinusoidal endothelial cells. In contrast, reperfusion after 10 h cold storage + 3 h hypothermic oxygenated perfusion resulted in no changes of lipid peroxidation, bile flow, energy charge, total glutathione, LDH release and of caspase activation, as compared to fresh resected livers.
This study demonstrates, that a metabolically depleted liver due to cold storage can be energy recharged by short-termed cold machine perfusion. The machine perfused graft exhibited improved viability and functional integrity.     

人精子体外氧化损伤对线粒体tRNA~(LeuUUR)基因的影响

目的:探讨活性氧(ROS)对人类精子线粒体tRNALeuUUR基因的氧化损伤。方法:采用Percoll梯度离心法筛选具有正常生理功能的精子,作为正常精子模型,并分为损伤组20例和对照组20例,分别加入次黄嘌呤-黄嘌呤氧化酶体系或不予处理,37℃有氧环境中孵育60min。分别提取精子DNA,以Fpg酶切损伤碱基并采用接头介导PCR(LM-PCR)检测线粒体tRNALeuUUR基因的氧化损伤。采用Rhodamine(Rh123)荧光探针标记精子,通过流式细胞仪检测线粒体膜电位,观察精子的功能。结果:与对照组相比,损伤组精子孵育后线粒体膜电位明显降低[(116.27±11.72)%vs(64.00±4.88)%,P<0.05]。Fpg酶切和LM-PCR显示精子线粒体tRNALeuUUR基因损伤。结论:ROS可能通过对精子线粒体tRNALeuUUR基因氧化损伤而影响精子功能(线粒体膜电位明显降低),从而引起不育。     

X chromosome instability associated with familial Turner syndrome

A family with two members (two generations) exhibiting Turner syndrome is described. Cytogenetic studies on these individuals showed the presence of multiple X chromosome changes. Evidence is presented to show that the maternally inherited X chromosome is the chromosome involved in the structural alterations observed. The effect of a tendency of the maternal X chromosome to break at specific sites on the development of the Turner phenotype and abnormal karyology is discussed.     

Ocular findings in familial adenomatous polyposis

Background: Retinal pigment epithelium (RPE)lesions are predictive congenital phenotypic markersfor familial adenomatous polyposis (FAP). Thisprospective screening study aims at assessing theincidence and significance of these lesions in FAPpatients and their family members.Methods: Sixty-two members from three familiesincluding five patients with the diagnosis of FAP havebeen ophthalmologically surveyed. All RPE lesions weredocumented with fundus photography and fluoresceinangiography was performed in 13 subjects.Sigmoidoscopy and/or radiological examination wereperformed annually in 9 family members with typicalRPE lesions during 4 years to allow early diagnosis ofFAP.Results: Typical RPE lesions were present infive FAP patients and 15 family members.Telangiectatic dilatations in the retinal peripherywith small dot-like hemorrhages were detected in 6subjects from 3 families These lesions wereparticularly evident on fluorescein angiography.Annual colon analysis showed polyps in 3 out of 9subjects who were positive for RPE lesions.Conclusion: RPE lesions are valuable as aclinical marker in predicting FAP. The co-existingperipheral vascular alterations which have not beenreported before, are probably related to FAP.     

Significance of the hepatic mitochondrial redox state in the development of posttraumatic jaundice

The effect of the hepatic energy status on the development of posttraumatic jaundice (PTJ) was studied to clarify the mechanism of PTJ. Fifty-four patients with severe torso injury who were expected to develop PTJ on admission with an average Injury Severity Score of 27 were selected for this study. They were retrospectively divided into three groups according to their maximum bilirubin concentration by day 10: group H, 12 patients with marked elevation of serum bilirubin (>8 g/dl); group L, 23 with mild bilirubinemia (2–8 g/dl); and group N, 19 with no bilirubinemia (<2 g/dl). Group H patients, in whom trauma-related shock was severe and prolonged, developed severe hyperbilirubinemia, and their arterial ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state and is closely correlated to its energy production, was significantly lower throughout the first week. In contrast, the AKBR increased to an above normal level, indicating enhanced energy production in groups N and L. The serum direct/total bilirubin was also higher in group H. The abnormal hepatic energy metabolism is considered to have reduced the excretion of conjugated bilirubin from the hepatocytes into the bile canaliculi, which is a process that has to proceed against the bilirubin concentration gradient. The subsequent diffusion of the accumulated water-soluble conjugated bilirubin in hepatocytes into the blood is thus considered to be one of the causes of PTJ.     

PUVA治疗诱导皮肤线粒体DNA 4977 bp缺失突变累积的研究

为探讨线粒体DNA(mitochondrialDNA,mtDNA)4977bp缺失突变与皮肤光老化之间的关系,采用三条引物PCR的方法检测长波紫外线光化学疗法(PUVA)治疗的银屑病患者背部非皮损区皮肤mtDNA4977bp缺失突变的累积。结果发现,在PUVA治疗期间3～21天、治疗后1～6个月和治疗后6个月以上的各组活检标本中,发生4977bp缺失突变的mtDNA占总mtDNA比例分别为0.06,0.12和0.19,和未经PUVA治疗的对照组比较均有显著性差异(P<0.01)。表明线粒体DNA4977bp缺失突变累积与皮肤光老化密切相关,可能作为衡量皮肤紫外线损伤程度的分子生物学标志。