The extracellular matrix fibulin 7 maintains epidermal stem cell heterogeneity during skin aging.

Tissue stem cells (SCs) divide infrequently as a protective mechanism against internal and external stresses associated with aging. Here, we demonstrate that slow- and fast-cycling SCs in the mouse skin epidermis undergo distinct aging processes. Two years of lineage tracing reveals that Dlx1+ slow-cycling clones expand into the fast-cycling SC territory, while the number of Slc1a3+ fast-cycling clones gradually declines. Transcriptome analysis further indicate that the molecular properties of each SC population are altered with age. Mice lacking fibulin 7, an extracellular matrix (ECM) protein, show early impairments resembling epidermal SC aging, such as the loss of fast-cycling clones, delayed wound healing, and increased expression of inflammation- and differentiation-related genes. Fibulin 7 interacts with structural ECM and matricellular proteins, and the overexpression of fibulin 7 in primary keratinocytes results in slower proliferation and suppresses differentiation. These results suggest that fibulin 7 plays a crucial role in maintaining tissue resilience and epidermal SC heterogeneity during skin aging.

Validation of the Performance of A1HPV6, a Triage Blood Test for the Early Diagnosis and Prognosis of SARS-CoV-2 Infection.

BACKGROUND AND AIMS: Apolipoprotein A1 (A1) and haptoglobin (HP) serum levels are associated with the spread and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We have constructed and validated a multivariable risk calculator (A1HPV6) integrating A1, HP, alpha2-macroglobulin, and gamma glutamyl transferase to improve the performances of virological biomarkers. METHODS: In a prospective observational study of hospitalized patients with nonsevere SARS-CoV-2 infection, A1HPV6 was constructed in 127 patients and validated in 116. The specificity was assessed in 7482 controls representing the general population. The primary diagnostic endpoint was the area under the receiver operating characteristic curve in patients with positive SARS-CoV-2 PCR. The primary prognostic endpoint was the age-and sex-adjusted risk of A1HPV6 to predict patients with WHO-stage > 4 (W > 4) severity. We assessed the kinetics of the A1HPV6 components in a nonhuman primate model (NHP), from baseline to 7 days (D7) after SARS-CoV-2 infection. RESULTS: The area under the receiver operating characteristic curve for A1HPV6 was 0.99 (95% CI 0.97-0.99) in the validation subset, which was not significantly different from that in the construction subset, 0.99 (0.99-0.99; P = .80), like for sensitivity 92% (85-96) vs 94% (88-97; P = .29). A1HPV6 was associated with W > 4, with a significant odds ratio of 1.3 (1.1-1.5; 0.002). In NHP, A1 levels decreased (P < .01) at D2 and normalized at D4; HP levels increased at D2 and peaked at D4. In patients, A1 concentration was very low at D2 vs controls (P < .01) and increased at D14 (P < .01) but was still lower than controls; HP increased at D2 and remained elevated at D14. CONCLUSION: These results validate the diagnostic and prognostic performances of A1HPV6. Similar kinetics of apolipoprotein A1, HP, and alpha-2-macroglobulin were observed in the NHP model. ClinicalTrials.gov number, NCT01927133.

Baveno VI criteria as a prognostic factor for clinical complications in patients with compensated cirrhosis.

BACKGROUND: Combination of liver stiffness measurement and platelets count is a tool to safely rule out varices needing treatment (VNT) in patients with compensated advanced chronic liver disease (cACLD). AIMS: to evaluate 4-year liver-related complications and survival in low-risk patients according to Baveno VI criteria. METHODS: we conducted a monocentric retrospective analysis of prospectively collected data of all consecutive patients, with cirrhosis (LSM≥12.5 kPa) and without previous complication, evaluated between 2012 and 2015. Liver-related complications and survival were compared between 2 groups of patients: favourable (LSM< 20 kPa and platelet count>150.000/mm3) and unfavourable Baveno VI status patients (LSM ≥ 20 kPa or platelet count ≤150.000/mm3). RESULTS: 455 patients with cACLD were analysed. Two hundred patients had favourable Baveno VI criteria, 3.6% with VNT. The 4-year probability of being free of acute decompensation was higher in low-risk patients (94.4 ± 1.8% vs. 85.7%±2.6%, p = 0.018). Unfavourable Baveno status was independently associated with acute decompensation. The probability of being free of HCC was significantly higher in low-risk patients (94.2 ± 1.8% vs. 87.6 ± 2.4%, p = 0.048). Liver-related mortality was not different between the 2 groups (p = 0.56). CONCLUSION: The Baveno VI criteria could predict clinical outcome in cACLD.

Isolation and Culture of Primary Oral Keratinocytes from the Adult Mouse Palate.

For years, most studies involving keratinocytes have been conducted using human and mouse skin epidermal keratinocytes. Recently, oral keratinocytes have attracted attention because of their unique function and characteristics. They maintain the homeostasis of the oral epithelium and serve as resources for applications in regenerative therapies. However, in vitro studies that use oral primary keratinocytes from adult mice have been limited due to the lack of an efficient and well-established culture protocol. Here, oral primary keratinocytes were isolated from the palate tissues of adult mice and cultured in a commercial low-calcium medium supplemented with a chelexed-serum. Under these conditions, keratinocytes were maintained in a proliferative or stem cell-like state, and their differentiation was inhibited even after increased passages. Marker expression analysis showed that the cultured oral keratinocytes expressed the basal cell markers p63, K14, and α6-integrin and were negative for the differentiation marker K13 and the fibroblast marker PDGFRα. This method produced viable and culturable cells suitable for downstream applications in the study of oral epithelial stem cell functions in vitro.

Simple paper-based colorimetric and fluorescent glucose sensor using N-doped carbon dots and metal oxide hybrid structures.

A new strategy for the fluorescent and colorimetric sensing of hydrogen peroxide (H2O2) and glucose based on the metal oxide - carbon-dot hybrid structure was investigated. The sensing system is related to the catalytic oxidation reaction of glucose-by-glucose oxidase (GOx) to H2O2. In this study, a metal oxide hybrid with nitrogen-doped carbon dots (MFNCDs) that showed intrinsic peroxidase-like activity was synthesized and used as a catalyst instead of GOx to oxidize 3,3',5,5'-tetramethylbenzidine (TMB) to blue-emitting oxidized TMB (oxTMB) in the presence of hydrogen peroxide (H2O2). The fluorescence of MFNCDs/TMB at 405 nm was quenched in the presence of H2O2 through the inner filter effect (IFE) and electron transfer within MFNCDs, oxTMB, and glucose system. Therefore, the fluorescence and absorbance intensity can be applied to the quantitative determination of the concentration of H2O2 and glucose with a wide linear range. The detection limit for H2O2 and glucose based on the colorimetric method were as low as 84 nM and 0.41 µM, respectively. In contrast, the detection limit for H2O2 and glucose based on the fluorescent method were as low as 97 nM and 0.85 µM, respectively. Furthermore, the colorimetric readout on the paper device based on the changing color of the solution could also be integrated with a smartphone platform to conduct the on-site analysis of glucose without the use of the spectrometer. In addition, this dual sensor can be applied to detect glucose in real serum with highly accurate results, making it a good candidate for biosensor applications.

Performance of serum apolipoprotein-A1 as a sentinel of Covid-19.

BACKGROUND: Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19. METHODS: We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population. RESULTS: The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04). CONCLUSION: Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14.

Palmitoyl Protein Thioesterase 1 Is Essential for Myogenic Autophagy of C2C12 Skeletal Myoblast.

Skeletal muscle differentiation is an essential process for the maintenance of muscle development and homeostasis. Reactive oxygen species (ROS) are critical signaling molecules involved in muscle differentiation. Palmitoyl protein thioesterase 1 (PPT1), a lysosomal enzyme, is involved in removing thioester-linked fatty acid groups from modified cysteine residues in proteins. However, the role of PPT1 in muscle differentiation remains to be elucidated. Here, we found that PPT1 plays a critical role in the differentiation of C2C12 skeletal myoblasts. The expression of PPT1 gradually increased in response to mitochondrial ROS (mtROS) during muscle differentiation, which was attenuated by treatment with antioxidants. Moreover, we revealed that PPT1 transactivation occurs through nuclear factor erythroid 2-regulated factor 2 (Nrf2) binding the antioxidant response element (ARE) in its promoter region. Knockdown of PPT1 with specific small interference RNA (siRNA) disrupted lysosomal function by increasing its pH. Subsequently, it caused excessive accumulation of autophagy flux, thereby impairing muscle fiber formation. In conclusion, we suggest that PPT1 is factor a responsible for myogenic autophagy in differentiating C2C12 myoblasts.

A 70-Gene Signature for Predicting Treatment Outcome in Advanced-Stage Cervical Cancer.

Cervical cancer is the fourth most common cancer in women worldwide. The current approaches still have limitations in predicting the therapy outcome of each individual because of cancer heterogeneity. The goal of this study was to establish a gene expression signature that could help when choosing the right therapeutic method for the treatment of advanced-stage cervical cancer. The 666 patients were collected from four independent datasets. The 70-gene expression signature was established using univariate Cox proportional hazard regression analysis. The 70-gene signature was significantly different between low- and high-risk groups in the training dataset (p = 4.24e-6) and in the combined three validation datasets (p = 4.37e-3). Treatment of advanced-stage cancer patients in the high-risk group with molecular-targeted therapy combined with chemoradiotherapy yielded a better survival rate than with only chemoradiotherapy (p = 0.0746). However, treatment of the patients in the low-risk group with the combined therapy resulted in significantly lower survival (p = 0.00283). Functional classification of 70 genes revealed involvement of the angiogenesis pathway, specifically phosphatidylinositol 3-kinase signaling (p = 0.040), extracellular matrix organization (p = 0.0452), and cell adhesion (p = 0.011). The 70-gene signature could predict the prognosis and indicate an optimal therapeutic modality in molecular-targeted therapy or chemotherapy for advanced-stage cervical cancer.

Glycome profiling by lectin microarray reveals dynamic glycan alterations during epidermal stem cell aging.

Aging in the epidermis is marked by a gradual decline in barrier function, impaired wound healing, hair loss, and an increased risk of cancer. This could be due to age-related changes in the properties of epidermal stem cells and defective interactions with their microenvironment. Currently, no biochemical tools are available to detect and evaluate the aging of epidermal stem cells. The cellular glycosylation is involved in cell-cell communications and cell-matrix adhesions in various physiological and pathological conditions. Here, we explored the changes of glycans in epidermal stem cells as a potential biomarker of aging. Using lectin microarray, we performed a comprehensive glycan profiling of freshly isolated epidermal stem cells from young and old mouse skin. Epidermal stem cells exhibited a significant difference in glycan profiles between young and old mice. In particular, the binding of a mannose-binder rHeltuba was decreased in old epidermal stem cells, whereas that of an α2-3Sia-binder rGal8N increased. These glycan changes were accompanied by upregulation of sialyltransferase, St3gal2 and St6gal1 and mannosidase Man1a genes in old epidermal stem cells. The modification of cell surface glycans by overexpressing these glycogenes leads to a defect in the regenerative ability of epidermal stem cells in culture. Hence, our study suggests the age-related global alterations in cellular glycosylation patterns and its potential contribution to the stem cell function. These glycan modifications detected by lectins may serve as molecular markers for aging, and further functional studies will lead us to a better understanding of the process of skin aging.

Input of serum haptoglobin fucosylation profile in the diagnosis of hepatocellular carcinoma in patients with non-cirrhotic liver disease.

BACKGROUND: Haptoglobin bifucosylated tetra-antennary glycan have been identified in patients with early stage hepatocellular carcinoma, but its specificity according to the presence or not of cirrhosis has never been assessed. The aims of this study were to determine if haptoglobin bifucosylated tetra-antennary glycan (1) could be a marker of HCC in patients without cirrhosis; (2) could increase the performance of standard alpha-fetoprotein (AFP) or recent blood tests for HCC detection, i.e., lectin-reactive alpha-fetoprotein (AFP-L3), des-gamma-carboxy prothrombin (DCP) and Liver-Cancer-Risk-test (LCR1-test). METHODS: We retrospectively selected patients, 102 with HCC (21 without cirrhosis), matched by stages with 140 controls without HCC (81 without cirrhosis). Haptoglobin fucosylation was assessed by MALDI-TOF. LCR-glycan algorithm was constructed combining components of the LCR-1 test (haptoglobin, gammaglutamyl-transpeptidase, apolipoproteinA1, alpha-2-macroglobulin) with AFP, AFP-L3, DCP and haptoglobin bifucosylated tetra-antennary glycan. RESULTS: In 102 patients without cirrhosis (21 HCC and 81 controls), the intention-to-diagnose analyses showed that haptoglobin bifucosylated tetra-antennary glycan alone had a sensitivity of 71% (15/21;95%CI 50-86), significantly better (P=0.02) than standard AFP (43%;9/21;95%CI 24-63), and a specificity of 96% (78/81;95% 90-99). The sensitivity of LCR-glycan, in patients without cirrhosis, was 86% (18/21; 95%CI 63-95) significantly better (P=0.001) than standard AFP (43%; 9/21; 95%CI 24-63), with an AUROC of 0.943 (95%CI 0.806-0.98) compared to 0.811 (95%CI 0.630-0.908) for AFP (P=0.06). CONCLUSION: Haptoglobin bifucosylated tetra-antennary glycan is associated with the presence of HCC in patients with chronic liver disease including those without cirrhosis. Its combination with existing HCC biomarkers could improve the performance of standard AFP for HCC detection.

Deregulated Mitochondrial DNA in Diseases.

Mitochondria play various important roles in energy production, metabolism, and apoptosis. Mitochondrial dysfunction caused by alterations in mitochondrial DNA (mtDNA) can lead to the initiation and progression of cancers and other diseases. These alterations include mutations and copy number variations. Especially, the mutations in D-loop, MT-ND1, and MT-ND5 affect mitochondrial functions and are widely detected in various cancers. Meanwhile, several other mutations have been correlated with muscular and neuronal diseases, especially MT-TL1 is deeply related. These pieces of evidence indicated mtDNA alterations in diseases show potential as a novel therapeutic target. mtDNA repair enzymes are the target for delaying or stalling the mtDNA damage-induced cancer progression and metastasis. Moreover, some mutations reveal a prognosis ability of the drug resistance. Current efforts aim to develop mitochondrial transplantation technique as a direct cure for deregulated mitochondria-associated diseases. This review summarizes the implications of mitochondrial dysfunction in cancers and other pathologies; and discusses the relevance of mitochondria-targeted therapies, along with their contribution as potential biomarkers.

Performance of liver biomarkers, in patients at risk of nonalcoholic steato-hepatitis, according to presence of type-2 diabetes.

OBJECTIVE: There is a controversy about the performance of blood tests for the diagnostic of metabolic liver disease in patients with type-2-diabetes in comparison with patients without type-2-diabetes. These indirect comparisons assumed that the gold-standard is binary, whereas fibrosis stages, steatosis and nonalcoholic-steato-hepatitis (NASH) grades use an ordinal scale. The primary aim was to compare the diagnostic performances of FibroTest in type-2-diabetes vs. controls matched on gender, age, fibrosis stages and obesity, and taking into account the spectrum effect by Obuchowski measure. METHODS: Data were retrospectively compared among patients prospectively included, with simultaneous biopsy and blindly assessed FibroTest, SteatoTest-2 and NashTest-2. The secondary aim was to construct an index (SpectrumF3F4-Index) to predict an adjusted-area under the receiver operating curve (AUROC) for F3F4 diagnosis from the prevalences of fibrosis stages, permitting to reduce the spectrum effect when performances of FibroTest, transient elastography and magnetic resonance elastography are indirectly compared. RESULTS: In 505 patients at risk of NASH, the Obuchowski measures [95% confidence interval (CI)] of FibroTest, SteatoTest-2 and NashTest-2 were all equivalent in 136 type-2-diabetes cases vs. 369 matched controls: 0.871 (0.837-0.905), vs. 0.880 (0.879-0.881), 0.835 (0.797-0.873) vs. 0.806 (0.780-0.832) and 0.829 (0.793-0.865) vs. 0.855 (0.829-0.869), respectively. Standard-AUROCs (95% CI) were 0.932 (0.898-0.965), 0.872 (0.837-0.907) and 0.834 (0.699-0.969) and reduced after adjustment by SpectrumF3F4-Index to 0.794 (0.749-0.838), 0.767 (0.750-0.783) and 0.773 (0.725-0.822) for transient, magnetic resonance elastography and FibroTest, respectively. CONCLUSIONS: When compared by Obuchowski measures, the performances of tests were not different in patients with T2-diabetes vs. patients without T2-diabetes. When individual data are not available, adjusted-AUROCs reduced the spectrum effect.

PAC-5 Gene Expression Signature for Predicting Prognosis of Patients with Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAC) is one of the most aggressive malignancies. Intratumoural molecular heterogeneity impedes improvement of the overall survival rate. Current pathological staging system is not sufficient to accurately predict prognostic outcomes. Thus, accurate prognostic model for patient survival and treatment decision is demanded. Using differentially expressed gene analysis between normal pancreas and PAC tissues, the cancer-specific genes were identified. A prognostic gene expression model was computed by LASSO regression analysis. The PAC-5 signature (LAMA3, E2F7, IFI44, SLC12A2, and LRIG1) that had significant prognostic value in the overall dataset was established, independently of the pathological stage. We provided evidence that the PAC-5 signature further refined the selection of the PAC patients who might benefit from postoperative therapies. SLC12A2 and LRIG1 interacted with the proteins that were implicated in resistance of EGFR kinase inhibitor. DNA methylation was significantly involved in the gene regulations of the PAC-5 signature. The PAC-5 signature provides new possibilities for improving the personalised therapeutic strategies. We suggest that the PAC-5 genes might be potential drug targets for PAC.

Effect of GO Additive in ZnO/rGO Nanocomposites with Enhanced Photosensitivity and Photocatalytic Activity.

Zinc oxide/reduced graphene oxide nanocomposites (ZnO/rGO) are synthesized via a simple one-pot solvothermal technique. The nanoparticle-nanorod turnability was achieved with the increase in GO additive, which was necessary to control the defect formation. The optimal defect in ZnO/rGO not only increased ZnO/rGO surface and carrier concentration, but also provided the alternative carrier pathway assisted with rGO sheet for electron-hole separation and prolonging carrier recombination. These properties are ideal for photodetection and photocatalytic applications. For photosensing properties, ZnO/rGO shows the improvement of photosensitivity compared with pristine ZnO from 1.51 (ZnO) to 3.94 (ZnO/rGO (20%)). Additionally, applying bending strain on ZnO/rGO enhances its photosensitivity even further, as high as 124% at r = 12.5 mm, due to improved surface area and induced negative piezoelectric charge from piezoelectric effect. Moreover, the photocatalytic activity with methylene blue (MB) was studied. It was observed that the rate of MB degradation was higher in presence of ZnO/rGO than pristine ZnO. Therefore, ZnO/rGO became a promising materials for different applications.

In Operando Observation of Neuropeptide Capture and Release on Graphene Field-Effect Transistor Biosensors with Picomolar Sensitivity.

Transmission electron microscopy (TEM) is being pushed to new capabilities which enable studies on systems that were previously out of reach. Among recent innovations, TEM through liquid cells (LC-TEM) enables in operando observation of biological phenomena. This work applies LC-TEM to the study of biological components as they interact on an abiotic surface. Specifically, analytes or target molecules like neuropeptide Y (NPY) are observed in operando on functional graphene field-effect transistor (GFET) biosensors. Biological recognition elements (BREs) identified using biopanning with affinity to NPY are used to functionalize graphene to obtain selectivity. On working devices capable of achieving picomolar responsivity to neuropeptide Y, LC-TEM reveals translational motion, stochastic positional fluctuations due to constrained Brownian motion, and rotational dynamics of captured analyte. Coupling these observations with the electrical responses of the GFET biosensors in response to analyte capture and/or release will potentially enable new insights leading to more advanced and capable biosensor designs.

The diagnostic performance of a simplified blood test (SteatoTest-2) for the prediction of liver steatosis.

BACKGROUND: Serum biomarkers of steatosis such as the SteatoTest are recommended for large-scale screening studies, because imaging is less accessible and more expensive. AIMS: The primary aim of this retrospective analysis of prospective studies was to construct a new SteatoTest-2 that was not inferior to the reference first-generation SteatoTest, but that did not include BMI or bilirubin, as these two components can increase test variability because of the assessment of weight and height and in case of Gilbert syndrome or hemolysis, respectively. PATIENTS AND METHODS: Five different subsets of 2997 patients with biopsies were evaluated for test construction and validation, and four to assess the prevalence of steatosis in target populations with increasing risks of steatosis. The performance of the SteatoTest-2 was compared with the reference test, using the noninferiority test (0.10 margin) and the Lin concordance coefficient. RESULTS: Areas under the receiver operating characteristic curve of the SteatoTest-2 were noninferior to the reference test (P<0.001). Areas under the receiver operating characteristic curve varied in the SteatoTest-2 and the reference test according to subsets and the prevalence of steatosis, with 0.772 [95% confidence interval (CI): 0.713-0.820] versus 0.786 (95% CI: 0.729-0.832) in the 2997 cases with biopsy and 0.822 (95% CI: 0.810-0.834) versus 0.868 (95% CI: 0.858-0.878) in the 5776 cases including healthy individuals without risk factors of steatosis as controls, respectively. The Lin coefficient was highly concordant (P<0.001), from 0.74 (95% CI: 0.74-0.74) in presumed NAFLD to 0.91 (95% CI: 0.89-0.93) in the construction subset. CONCLUSION: The SteatoTest-2 is simpler and noninferior to the first-generation SteatoTest for the diagnosis of steatosis, without the limitations of BMI and bilirubin.

LCR1 and LCR2, two multi-analyte blood tests to assess liver cancer risk in patients without or with cirrhosis.

BACKGROUND: No blood test has been shown to be effective in the prediction of primary liver cancer in patients without cirrhosis. AIM: To construct and internally validate two sequential tests for early prediction of liver cancer. These tests enable an algorithm which could improve the performance of the standard surveillance protocol recommended (imaging with or without AFP), limited to patients with cirrhosis. METHODS: We performed a retrospective analysis in prospectively collected specimens from an ongoing cohort. We designed an early sensitive high-risk test (LCR1) that combined (using Cox model) hepatoprotective proteins (apolipoproteinA1, haptoglobin) with known risk factors (gender, age, gammaglutamyltranspeptidase), and a marker of fibrosis (alpha2-macroglobulin). To increase the specificity, we then combined (LCR2) these components with alpha-fetoprotein. RESULTS: A total of 9892 patients, 85.9% without cirrhosis, were followed up for 5.9 years [IQR: 4.3-9.4]. LCR1 and LCR2 time-dependent AUROCs were not different in construction and validation randomised subsets. Among 2027 patients with high-LCR1 then high-LCR2, 167 cancers (113 with cirrhosis, 54 without cirrhosis) were detected, that is 12 patients needed to screen one cancer. The negative predictive value was 99.5% (95% CI 99.0-99.7) in the 2026 not screened patients (11 cancers without cirrhosis) higher than the standard surveillance, which detected 113 cancers in 755 patients screened, that is seven patients needed to screen one cancer, but with a lower negative predictive value 98.0% (97.5-98.5; Z = 4.3; P < 0.001) in 3298 not screened patients (42 cancers without cirrhosis). CONCLUSIONS: In patients with chronic liver disease the LCR1 and LCR2 tests identify those with a high risk of liver cancer, including in those without cirrhosis. NCT01927133.

Palliative Radiotherapy as a Treatment for Carcinoma Invasion of the Sacrum: An Observational Case Series Study.

BACKGROUND/AIM: Radiotherapy for carcinoma invasion of the sacrum (CIS) is an alternative treatment to surgery in patients with advanced, inoperable tumors or those not medically eligible for resection of the neoplasm. Herein we present an observational study of patients with imaging-confirmed CIS who were treated non-operatively with radiation. PATIENTS AND METHODS: A retrospective chart review of CIS patients treated with palliative radiotherapy (PR) during a 9-year period (2004-2013) was performed. RESULTS: Six women and 13 men with an average age of 60 years took part in this study. Most patients (84%) exhibited extrasacral metastases. Primary tumors included lung (n=6), colorectal (n=6), breast (n=3), bladder or kidney (n=2), and liver carcinoma or a tumor in an unknown primary site (n=2). The mean follow-up time was 10 months with a 2-year survival rate of 9%. The majority (71%) of symptomatic patients obtained relief from pain following PR. Half of those individuals who were non-ambulatory prior to therapy regained mobility. There were no acute ill-effects or later complications after irradiation. CONCLUSION: Despite the small cohort and poor overall survival rate, non-operative radiation treatment is a beneficial method of palliative care in patients with CIS.

Long-term prognostic value of the FibroTest in patients with non-alcoholic fatty liver disease, compared to chronic hepatitis C, B, and alcoholic liver disease.

BACKGROUND: Although the FibroTest has been validated as a biomarker to determine the stage of fibrosis in non-alcoholic fatty liver disease (NAFLD) with results similar to those in chronic hepatitis C (CHC), B (CHB), and alcoholic liver disease (ALD), it has not yet been confirmed for the prediction of liver-related death. AIM: To validate the 10-year prognostic value of FibroTest in NAFLD for the prediction of liver-related death. METHOD: Patients in the prospective FibroFrance cohort who underwent a FibroTest between 1997 and 2012 were pre-included. Mortality status was obtained from physicians, hospitals or the national register. Survival analyses were based on univariate (Kaplan-Meier, log rank, AUROC) and multivariate Cox risk ratio taking into account age, sex and response to anti-viral treatment as covariates. The comparator was the performance of the FibroTest in CHC, the most validated population. RESULTS: 7082 patients were included; 1079, 3449, 2051, and 503 with NAFLD, CHC, CHB, and ALD, respectively. Median (range) follow-up was 6.0 years (0.1-19.3). Ten year survival (95% CI) without liver-related death in patients with NAFLD was 0.956 (0.940-0.971; 38 events) and 0.832 (0.818-0.847; 226 events; P = 0.004) in CHC. The prognostic value (AUROC / Cox risk ratio) of FibroTest in patients with NAFLD was 0.941 (0.905-0.978)/1638 (342-7839) and even higher than in patients with CHC 0.875 (0.849-0.901; P = 0.01)/2657 (993-6586). CONCLUSIONS: The FibroTest has a high prognostic value in NAFLD for the prediction of liver-related death. (ClinicalTrials.gov number, NCT01927133).