Association of plasma neurofilament light chain with disease activity in chronic inflammatory demyelinating polyradiculoneuropathy

BACKGROUND AND PURPOSE: This study was undertaken to explore associations between plasma neurofilament light chain (pNfL) concentration (pg/ml) and disease activity in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and examine the usefulness of pNfL concentrations in determining disease remission. METHODS: We examined pNfL concentrations in treatment-naïve CIDP patients (n = 10) before and after intravenous immunoglobulin (IVIg) induction treatment, in pNfL concentrations in patients on maintenance IVIg treatment who had stable (n = 15) versus unstable disease (n = 9), and in clinically stable IVIg-treated patients (n = 10) in whom we suspended IVIg to determine disease activity and ongoing need for maintenance IVIg. pNfL concentrations in an age-matched healthy control group were measured for comparison. RESULTS: Among treatment-naïve patients, pNfL concentration was higher in patients before IVIg treatment than healthy controls and subsequently reduced to be comparable to control group values after IVIg induction. Among CIDP patients on IVIg treatment, pNfL concentration was significantly higher in unstable patients than stable patients. A pNFL concentration > 16.6 pg/ml distinguished unstable treated CIDP from stable treated CIDP (sensitivity = 86.7%, specificity = 66.7%, area under receiver operating characteristic curve = 0.73). Among the treatment withdrawal group, there was a statistically significant correlation between pNfL concentration at time of IVIg withdrawal and the likelihood of relapse (r = 0.72, p < 0.05), suggesting an association of higher pNfL concentration with active disease. CONCLUSIONS: pNfL concentrations may be a sensitive, clinically useful biomarker in assessing subclinical disease activity

Prognostic DNA methylation markers for sporadic colorectal cancer: a systematic review

Background Biomarkers that can predict the prognosis of colorectal cancer (CRC) patients and that can stratify high-risk early stage patients from low-risk early stage patients are urgently needed for better management of CRC. During the last decades, a large variety of prognostic DNA methylation markers has been published in the literature. However, to date, none of these markers are used in clinical practice. Methods To obtain an overview of the number of published prognostic methylation markers for CRC, the number of markers that was validated independently, and the current level of evidence (LoE), we conducted a systematic review of PubMed, EMBASE, and MEDLINE. In addition, we scored studies based on the REMARK guidelines that were established in order to attain more transparency and complete reporting of prognostic biomarker studies. Eighty-three studies reporting on 123 methylation markers fulfilled the study entry criteria and were scored according to REMARK. Results Sixty-three studies investigated single methylation markers, whereas 20 studies reported combinations of methylation markers. We observed substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology. The median (range) REMARK score for the studies was 10.7 points (4.5 to 17.5) out of a maximum of 20 possible points. The median REMARK score was lower in studies, which reported a p value below 0.05 versus those, which did not (p = 0.005). A borderline statistically significant association was observed between the reported p value of the survival analysis and the size of the study population (p = 0.051). Only 23 out of 123 markers (17%) were investigated in two or more study series. For 12 markers, and two multimarker panels, consistent results were reported in two or more study series. For four markers, the current LoE is level II, for all other markers, the LoE is lower. Conclusion This systematic review reflects that adequate reporting according to REMARK and validation of prognostic methylation markers is absent in the majority of CRC methylation marker studies. However, this systematic review provides a comprehensive overview of published prognostic methylation markers for CRC and highlights the most promising markers that have been published in the last two decades

Vasospasm in children with traumatic brain injury

To determine the incidence of vasospasm in children who have suffered moderate to severe traumatic brain injury. A prospective observational pilot study in a 24-bed pediatric intensive care unit was performed. Twenty-two children aged 7 months to 14 years with moderate to severe traumatic brain injury as indicated by Glasgow Coma Score ≤12 and abnormal head imaging were enrolled. Transcranial Doppler ultrasound was performed to identify and follow vasospasm. Patients with a flow velocity in the middle cerebral artery (MCA) &gt;120 cm/s were considered to have vasospasm by criterion A. If flow velocity in the MCA was &gt;120 cm/s and the Lindegaard ratio was &gt;3, vasospasm was considered to be present by criterion B. Patients with basilar artery (BA) flow velocity &gt;90 cm/s met criteria for vasospasm in the posterior circulation (criterion C). In the MCA, 45.5% of patients developed vasospasm based on criterion A and 36.3% developed vasospasm based on criterion B. A total of 18.2% of patients developed vasospasm in the BA by criterion C. Typical day of onset of vasospasm was hospital day 2–3. Duration of vasospasm in the anterior circulation was 4 ± 2 days based on criteria A and 3 ± 1 days based on criteria B. Vasospasm in the posterior circulation persisted for 2 ± 1 days. Using the adult criteria outlined above to diagnose vasospasm, a significant proportion of pediatric patients who have suffered moderate to severe traumatic brain injury develop vasospasm during the course of their treatment

Imaging in breast cancer: Diffuse optics in breast cancer: detecting tumors in pre-menopausal women and monitoring neoadjuvant chemotherapy

Diffuse optical spectroscopy (DOS) and diffuse optical imaging (DOI) are non-invasive diagnostic techniques that employ near-infrared (NIR) light to quantitatively characterize the optical properties of centimeter-thick, multiple-scattering tissues. Although NIR was first applied to breast diaphanography more than 70 years ago, quantitative optical methods employing time- or frequency-domain 'photon migration' technologies have only recently been used for breast imaging. Because their performance is not limited by mammographic density, optical methods can provide new insight regarding tissue functional changes associated with the appearance, progression, and treatment of breast cancer, particularly for younger women and high-risk subjects who may not benefit from conventional imaging methods. This paper reviews the principles of diffuse optics and describes the development of broadband DOS for quantitatively measuring the optical and physiological properties of thick tissues. Clinical results are shown highlighting the sensitivity of diffuse optics to malignant breast tumors in 12 pre-menopausal subjects ranging in age from 30 to 39 years and a patient undergoing neoadjuvant chemotherapy for locally advanced breast cancer. Significant contrast was observed between normal and tumor regions of tissue for deoxy-hemoglobin (p = 0.005), oxy-hemoglobin (p = 0.002), water (p = 0.014), and lipids (p = 0.0003). Tissue hemoglobin saturation was not found to be a reliable parameter for distinguishing between tumor and normal tissues. Optical data were converted into a tissue optical index that decreased 50% within 1 week in response to neoadjuvant chemotherapy. These results suggest a potential role for diffuse optics as a bedside monitoring tool that could aid the development of new strategies for individualized patient care

Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy

The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5–29.2%) and 49% (95% CI, 42.2–55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27–3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05–2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites ⩾2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients

Identifying and Prioritizing Greater Sage-Grouse Nesting and Brood-Rearing Habitat for Conservation in Human-Modified Landscapes

BACKGROUND: Balancing animal conservation and human use of the landscape is an ongoing scientific and practical challenge throughout the world. We investigated reproductive success in female greater sage-grouse (Centrocercus urophasianus) relative to seasonal patterns of resource selection, with the larger goal of developing a spatially-explicit framework for managing human activity and sage-grouse conservation at the landscape level. METHODOLOGY/PRINCIPAL FINDINGS: We integrated field-observation, Global Positioning Systems telemetry, and statistical modeling to quantify the spatial pattern of occurrence and risk during nesting and brood-rearing. We linked occurrence and risk models to provide spatially-explicit indices of habitat-performance relationships. As part of the analysis, we offer novel biological information on resource selection during egg-laying, incubation, and night. The spatial pattern of occurrence during all reproductive phases was driven largely by selection or avoidance of terrain features and vegetation, with little variation explained by anthropogenic features. Specifically, sage-grouse consistently avoided rough terrain, selected for moderate shrub cover at the patch level (within 90 m(2)), and selected for mesic habitat in mid and late brood-rearing phases. In contrast, risk of nest and brood failure was structured by proximity to anthropogenic features including natural gas wells and human-created mesic areas, as well as vegetation features such as shrub cover. CONCLUSIONS/SIGNIFICANCE: Risk in this and perhaps other human-modified landscapes is a top-down (i.e., human-mediated) process that would most effectively be minimized by developing a better understanding of specific mechanisms (e.g., predator subsidization) driving observed patterns, and using habitat-performance indices such as those developed herein for spatially-explicit guidance of conservation intervention. Working under the hypothesis that industrial activity structures risk by enhancing predator abundance or effectiveness, we offer specific recommendations for maintaining high-performance habitat and reducing low-performance habitat, particularly relative to the nesting phase, by managing key high-risk anthropogenic features such as industrial infrastructure and water developments

BST2/Tetherin Enhances Entry of Human Cytomegalovirus

Interferon-induced BST2/Tetherin prevents budding of vpu-deficient HIV-1 by tethering mature viral particles to the plasma membrane. BST2 also inhibits release of other enveloped viruses including Ebola virus and Kaposi's sarcoma associated herpesvirus (KSHV), indicating that BST2 is a broadly acting antiviral host protein. Unexpectedly however, recovery of human cytomegalovirus (HCMV) from supernatants of BST2-expressing human fibroblasts was increased rather than decreased. Furthermore, BST2 seemed to enhance viral entry into cells since more virion proteins were released into BST2-expressing cells and subsequent viral gene expression was elevated. A significant increase in viral entry was also observed upon induction of endogenous BST2 during differentiation of the pro-monocytic cell line THP-1. Moreover, treatment of primary human monocytes with siRNA to BST2 reduced HCMV infection, suggesting that BST2 facilitates entry of HCMV into cells expressing high levels of BST2 either constitutively or in response to exogenous stimuli. Since BST2 is present in HCMV particles we propose that HCMV entry is enhanced via a reverse-tethering mechanism with BST2 in the viral envelope interacting with BST2 in the target cell membrane. Our data suggest that HCMV not only counteracts the well-established function of BST2 as inhibitor of viral egress but also employs this anti-viral protein to gain entry into BST2-expressing hematopoietic cells, a process that might play a role in hematogenous dissemination of HCMV

Prognostic Significance and Gene Expression Profiles of p53 Mutations in Microsatellite-Stable Stage III Colorectal Adenocarcinomas

Although the prognostic value of p53 abnormalities in Stage III microsatellite stable (MSS) colorectal cancers (CRCs) is known, the gene expression profiles specific to the p53 status in the MSS background are not known. Therefore, the current investigation has focused on identification and validation of the gene expression profiles associated with p53 mutant phenotypes in MSS Stage III CRCs. Genomic DNA extracted from 135 formalin-fixed paraffin-embedded tissues, was analyzed for microsatellite instability (MSI) and p53 mutations. Further, mRNA samples extracted from five p53-mutant and five p53-wild-type MSS-CRC snap-frozen tissues were profiled for differential gene expression by Affymetrix Human Genome U133 Plus 2.0 arrays. Differentially expressed genes were further validated by the high-throughput quantitative nuclease protection assay (qNPA), and confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and by immunohistochemistry (IHC). Survival rates were estimated by Kaplan-Meier and Cox regression analyses. A higher incidence of p53 mutations was found in MSS (58%) than in MSI (30%) phenotypes. Both univariate (log-rank, P = 0.025) and multivariate (hazard ratio, 2.52; 95% confidence interval, 1.25–5.08) analyses have demonstrated that patients with MSS-p53 mutant phenotypes had poor CRC-specific survival when compared to MSS-p53 wild-type phenotypes. Gene expression analyses identified 84 differentially expressed genes. Of 49 down-regulated genes, LPAR6, PDLIM3, and PLAT, and, of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8 were confirmed by qNPA, qRT-PCR, and IHC platforms. p53 mutations are associated with poor survival of patients with Stage III MSS CRCs and p53-mutant and wild-type phenotypes have distinct gene expression profiles that might be helpful in identifying aggressive subsets