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.     

肝X受体激动剂在肿瘤治疗中的研究进展北大核心

肝X受体(liver X receptors,LXRs)是孤儿核受体转录因子超家族成员,当LXRs被激活后,可调节靶基因的转录表达,不但参与胆固醇、脂肪、糖的代谢以及炎症等过程,并且在许多恶性肿瘤组织中均有表达。为全面了解肝X受体激动剂在治疗癌症中的研究现状,本文将从肝X受体激动剂与胃癌、肝癌、卵巢癌、乳腺癌、子宫内膜癌、肺癌以及结直肠癌的相关性方面进行综述。     

Time-varying characteristics of the induced membrane and its effects on bone defect repair

PurposeThis study intended to determine the properties of induced membranes after various periods of polymethyl methacrylate (PMMA) retention and the effect of different retention intervals on subsequent defect repair.MethodsModel of a critical bone defect in rabbits was prepared to obtain the induced membrane. For varying intervals of spacer insertion (2, 4, 6, 8, 12, 16, and 20 weeks postoperatively), angiogenesis, osteogenesis, and MSC-related properties were analyzed by immunohistochemistry and western-blot. Furthermore, 2, 4, 6, and 8 weeks after PMMA insertion, bone grafting was performed. Characteristics of defect repair were analyzed by X-ray and micro-CT analysis.ResultsThe induced membrane displayed angiogenesis, osteogenesis, and MSC-related properties from the 2- to 20-week intervals. Quantitation of protein expression (RUNX2, ALP, VEGF, TGF-beta, OCT4, and STRO1) revealed that selected proteins gradually rose to a high level at 4–8 weeks postoperatively and then decreased to a low level over a long time period. Following bone grafting, the most new bone formation was in the group when grafting was performed at 4 weeks, followed by the groups at 2 and 6 weeks, with the least in the group at 8 weeks.ConclusionThe induced membrane displays angiogenesis, osteogenesis, and MSC-related properties from the 2- to 20-week intervals. These were increased to a peak level at 4–8 weeks postoperatively and then gradually decreased. The optimal timing for bone grafting at the second stage in the presented model was 4 weeks after PMMA insertion.     

Derivation and Validation of a Model to Predict 30-Day Readmission in Surgical Patients Discharged to Skilled Nursing Facility

ObjectivesTo identify factors associated with 30-day all-cause readmission rates in surgical patients discharged to skilled nursing facilities (SNFs), and derive and validate a risk score.DesignRetrospective cohort.Setting and participantsPatients admitted to 1 tertiary hospital's surgical services between January 1, 2011, and December 31, 2014 and subsequently discharged to 110 SNFs within a 25-mile radius of the hospital. The first 2 years were used for the derivation set and the last 2 for validation.MethodsData were collected on 30-day all cause readmissions, patient demographics, procedure and surgical service, comorbidities, laboratory tests, and prior health care utilization. Multivariate regression was used to identify risk factors for readmission.ResultsDuring the study period, 2405 surgical patients were discharged to 110 SNFs, and 519 (21.6%) of these patients experienced readmission within 30 days. In a multivariable regression model, hospital length of stay [odds ratio (OR) per day: 1.03, 95% confidence interval (CI) 1.02-1.04], number of hospitalizations in past year (OR 1.24 per hospitalization, 95% CI 1.18-1.31), nonelective surgery (OR 1.33, 95% CI 1.18-1.65), low-risk service (orthopedic/spine service) (OR 0.32, 95% CI 0.25-0.42), and intermediate-risk service (cardiothoracic surgery/urology/gynecology/ear, nose, throat) (OR 0.69, 95% CI 0.53-0.88) were associated with all-cause readmissions. The model had a C index of 0.71 in the validation set. Using the following risk score [0.8 × (hospital length of stay) + 7 × (number of hospitalizations in past year) +10 for nonelective surgery, +36 for high-risk surgery, and +20 for intermediate-risk surgery], a score of >40 identified patients at high risk of 30-day readmission (35.8% vs 12.6%, P < .001).Conclusions/ImplicationsAmong surgical patients discharged to an SNF, a simple risk score with 4 parameters can accurately predict the risk of 30-day readmission.     

Improving Prenatal Diagnosis of Coarctation of the Aorta

Background

The purpose of the study was to evaluate the association between fetal echocardiographic measurements and the need for intervention (primary coarctation repair, staged coarctation repair, or catheter intervention) in prenatally diagnosed coarctation of the aorta.

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.     

Ethanol upregulates the P2X7 purinergic receptor in human macrophages

Alcohol consumption is considered to be the third leading cause of death in the United States. In addition to its direct toxicity, ethanol has two contrasting effects on the immune system: the nucleotide oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3) inflammasome is inhibited by acute ethanol exposure but activated by chronic ethanol exposure. Purinergic receptors (especially the P2X7 receptor) are able to activate the NLRP3 inflammasome and are involved in many ethanol‐related diseases (such as gout, pulmonary fibrosis, alcoholic steatohepatitis, and certain cancers). We hypothesized that ethanol regulates purinergic receptors and thus modulates the NLRP3 inflammasome's activity. In experiments with monocyte‐derived macrophages, we found that interleukin (IL)‐1β secretion was inhibited after 7 h of exposure (but not 48 h of exposure) to ethanol. The disappearance of ethanol's inhibitory effect on IL‐1β secretion after 48 h was not mediated by the upregulated production of IL‐1β, IL‐1α, IL‐6 or the inflammasome components NLRP3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain, and caspase 1. P2X7R expression was upregulated by ethanol, whereas expression of the P2X4 and P2X1 receptors was not. Taken as a whole, our results suggest that ethanol induces NLRP3 inflammasome activation by upregulating the P2X7 receptor. This observation might have revealed a new mechanism for inflammation in ethanol‐related diseases.     

Contemporary Outcomes and Factors Associated With Mortality After a Fetal or Postnatal Diagnosis of Common Arterial Trunk

Background

Common arterial trunk (CAT) is a rare anomaly with a spectrum of pathology. We sought to identify current trends and factors associated with postnatal outcomes.