Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR

Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform ( https://oncotools.elixir.no ), and can also be accessed as a stand-alone R package ( https://github.com/sigven/oncoEnrichR ).     

The biological basis of the experience and categorization of colour

We used the Land Colour Mondrian experiments in a Bayesian context to test the degree to which subjects vary in categorizing the colour of different patches, when each patch is made to reflect light of the identical wavelength‐energy composition. The brain uses a ratio‐taking mechanism to determine the ratio of light of every waveband reflected from a surface and from its surrounds. Our (Bayesian) hypothesis was that this ratio‐taking mechanism is similar in all humans and therefore leads to a constant categorization of colours that differs little between them. The similarly categorized colours are the initial priors, with initial hues attached to them. Twenty subjects of different ethnic and cultural backgrounds, for all but one of whom English was not the primary language, viewed eight patches of different colour in two Mondrian displays; each patch, when viewed, was made to reflect identical ratios of long‐, middle‐ and short‐wave light. Subjects were asked to match the colour of the viewed patch with that of the Munsell chip coming closest in colour to that of the viewed patch, without using language. In terms of hue, there was less variability in matching warm hues than cool ones. In terms of colour categorization, there was little variability overall. We take the lack of significant variability between subjects in the matches made as a pointer to similar computational mechanisms being employed in different subjects to perceive colours, thus permitting them to assume that their categorization of colours has universal agreement and assent.     

Impact of increased venous pressure on kidney function and mortality in cardiovascular patients with preserved ejection fraction

Abstract

Background: Right but not left ventricular hemodynamic parameters have been found to be independently associated with adverse renal outcomes in patients with acute decompensated heart failure (HF).

Aim: To investigate the hemodynamic profile of patients without acute decompensated heart failure and left ventricular ejection fraction >50% referred for elective left and right heart catheterization and to correlate left and right filling pressures, stroke volume and arterial blood pressure to renal function parameters. Subsequently, we tested the hypothesis that right ventricle and left ventricle hemodynamic parameters can predict all-cause mortality in our non-HF subjects.

Methods: Between October 2009 and November 2010, 151 consecutive patients referred for elective left and right heart catheterization were studied and consequently followed up for a mean period of 8?years in order to identify all-cause mortality. Patient’s initial cohort was subdivided in two groups according to right atrial pressure. The RAPR_LOW group (Right Atrium Pressure ≤ 9?mmHg) and the RAPR_HIGH group (Right Atrium Pressure > 9mmHg)

Results: No correlation between blood pressure, pulmonary capillary wedges pressure, cardiac index, stroke volume and stroke volume index (SVI), and parameters of kidney function was observed. However, a weak, although, significant correlation between right atrial pressure (RAP) and modification of diet in renal disease (MDRD) (r = –0.202; p?=?.014) could be detected. RAPR_LOW patients had a statistically significant lower MDRD value of 16.6?mL/min/1.73 m² than RAPR_HIGH patients. Increased RAP (HR = 2.03; 95% [CI]: 1.05 to 3.9; p?=?.025) and age (HR = 1.08, 95% [CI] 1.04–1.12, p?<?.001) independently predicted all-cause mortality during follow up.

Conclusions: Our study demonstrates that right ventricular preload affects renal function in patients with preserved systolic function and that neither aortic systolic pressure nor left ventricle pressure indices were related to estimated glomerular filtration rate. Furthermore, we demonstrate for the first time that an increased RAP is able to predict a worse prognosis in patients with preserved ejection fraction independently of well-established risk factors, such as blood pressure and SVI.     

Nanomagnetic Modulation of Tumor Redox State

Modulation of reactive oxygen and nitrogen species in a tumor could be exploited for nanotherapeutic benefits. We investigate the antitumor effect in Walker-256 carcinosarcoma of magnetic nanodots composed of doxorubicin-loaded Fe₃O₄ nanoparticles combined with electromagnetic fields. Treatment using the magnetic nanodot with the largest hysteresis loop area (3402 erg/g) had the greatest antitumor effect with the minimum growth factor 0.49 ± 0.02 day^–1 (compared to 0.58 ± 0.02 day^–1 for conventional doxorubicin). Electron spin resonance spectra of Walker-256 carcinosarcoma treated with the nanodots, indicate an increase of 2.7 times of free iron (that promotes the formation of highly reactive oxygen species), using the nanodot with the largest hysteresis loop area, compared to conventional doxorubicin treatment as well as increases in ubisemiquinone, lactoferrin, NO-FeS-proteins. Hence, we provide evidence that the designed magnetic nanodots can modulate the tumor redox state. We discuss the implications of these results for cancer nanotherapy.     

Light-cured or chemically cured orthodontic adhesive resins? A selection based on the degree of cure,monomer leaching,and cytotoxicity

PURPOSE: The purpose of this study was to estimate the degree of cure and monomer leaching of a light-cured and a chemically cured (no-mix) adhesive and to assess their biologic properties. MATERIAL: The degree of cure of adhesive specimens prepared with a procedure identical to the clinical bonding process was assessed by infrared spectroscopy. The adhesives were then immersed in normal saline solution for 2 months, and the residual monomer leached from the adhesives was quantitatively and qualitatively analyzed by liquid chromatography. The effect of the immersion media on human gingival fibroblasts' viability and proliferation was also evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and deoxyribonucleic acid (DNA) synthesis assays, respectively. The results were analyzed by analysis of variance and Tukey test (alpha = .05). RESULTS: No difference was found between the 2 adhesives with respect to their degree of cure and the amount of triethylene glycol dimethacrylate released; no diglycidyl dimethacrylate monomer was detected in the eluent. However, significant qualitative changes in the composition of the substances eluted from the 2 adhesives were observed. CONCLUSIONS: Whereas no cytotoxic effect was shown for either immersion media, a moderate reduction in the DNA synthesis was obtained by both adhesives, implying a minor cytostatic effect. Further research is required to assess the long-term biologic properties of adhesives, including potential estrogenic action.     

Early soft tissue healing around one-stage dental implants: clinical and microbiologic parameters

BACKGROUND: Despite the potential significance of early soft tissue healing to long-term outcomes, this aspect of one-stage dental implants has not been investigated. The purpose of this prospective study was to characterize clinical and microbiologic parameters of early soft tissue healing around dental implants placed following a one-stage protocol. METHODS: Twenty-one patients (11 females and 10 males, aged 18 to 78 years; two smokers) needing a single implant were included. Clinical parameters included probing depth, buccal flap thickness, papilla height, and bleeding on probing. Subgingival plaque samples were obtained pre- and postoperatively and analyzed using molecular techniques. RESULTS: The newly formed peri-implant sulcus probing depth remained fairly stable from 4 to 12 weeks (P > 0.05). There was no statistically significant association between flap thickness or papillary height and number of implant bleeding sites at 12 weeks (P > 0.05). Detection of known periodontal pathogens was rare. Fusobacterium nucleatum was present in 17 patients prior to surgery, and 71% of them became carriers of this bacterium at the implant site by the second postoperative week. The number of F. nucleatum-positive subjects around the implant was significantly lower than the number of F. nucleatum-positive subjects around teeth (P < 0.05). CONCLUSIONS: Peri-implant soft tissue clinical maturity may be established as early as 4 weeks following implant placement by a one-stage surgical protocol; neither preexisting flap thickness nor papillary height seemed to influence newly forming peri-implant sulcus depth or bleeding on probing prevalence. For the most part, the newly created peri-implant crevices were colonized by specific bacteria within 2 weeks.     

Coronally positioned flap with subepithelial connective tissue graft for root coverage: various indications and flap designs

Aesthetic concerns and functional abnormalities, such as dentin hypersensitivity, are often associated with gingival recession defects. Root coverage procedures aim to restore both gingival aesthetics and function in recession defects. The coronally positioned flap combined with the subepithelial connective tissue graft is one of the most widely used root coverage procedures. The present report illustrates four different indications where this procedure has been successfully employed. An isolated Miller class II recession defect associated with frenum pull, multiple adjacent Miller class I defects in the aesthetic zone, an isolated Miller class I defect associated with dentin hypersensitivity, and an isolated Miller class II defect on a retained deciduous tooth are the four diverse conditions treated by periodontal plastic surgery. Different approaches were used to create the coronally positioned flap. Treatment resulted in complete root coverage, resolution of hypersensitivity, and satisfaction of the patients' aesthetic concerns. An effective and predictable treatment modality, such as the coronally positioned flap combined with the subepithelial connective tissue graft, should be considered when treatment planning for gingival recession defects.     

Modulation of clinical expression of plaque-induced gingivitis: response in aggressive periodontitis subjects

AIM: The aim of this study was to characterize the gingival inflammatory response to de novo plaque accumulation in subjects treated for aggressive periodontitis (AP). The gingival inflammatory response of the AP subjects was retrospectively compared with that of periodontally healthy individuals (PH) matched for exposure to plaque and of periodontally healthy subjects previously identified as "high responders" (HR) and "low responders" (LR). MATERIALS AND METHODS: 13 AP subjects and 26 matched PH subjects participated in a 21-day experimental gingivitis trial. Plaque index (PlI), Gingival index (GI), gingival crevicular fluid volume (GCF) and angulated bleeding score (AngBS) were recorded at days 0, 7, 14 and 21. Cumulative plaque exposure (CPE), i.e. PlI over time, was also calculated. RESULTS: GCF was significantly higher in AP compared with PH group at each observation interval (p< or =0.001). In addition, GCF was significantly higher in AP group compared with either LR or HR groups at each observation interval (p<0.001). CONCLUSIONS: These results suggest that susceptibility to gingival inflammation in response to de novo plaque accumulation may be related to susceptibility to periodontitis.     

Effect of platelet-rich plasma on the healing of intrabony defects treated with an enamel matrix protein derivative and a natural bone mineral

Background: Regenerative periodontal surgery utilizing a combination of an enamel matrix protein derivative (EMD) and a natural bone mineral (NBM) and platelet‐rich plasma (PRP) has been shown to enhance the outcomes of regenerative surgery significantly. At present, it is unknown whether root conditioning with EMD, followed by defect fill with a combination of NBM+PRP may additionally enhance the clinical results obtained with EMD+NBM. Aim: To compare clinically the treatment of deep intrabony defects with either EMD+NBM+PRP or EMD+NBM. Material and Methods: Twenty‐six patients suffering from advanced chronic periodontitis, and each of whom displayed one advanced intrabony defect were randomly treated with either EMD+NBM+PRP (test) or EMD+NBM (control). The following clinical parameters were evaluated at baseline and at 1 year after treatment: plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing depth (PD), gingival recession (GR) and clinical attachment level (CAL). The primary outcome variable was CAL. Results: Healing was uneventful in all patients. At 1 year after therapy, the test sites showed a reduction in mean PD from 8.8±1.9 mm to 3.1±0.9 mm ( p<0.001) and a change in mean CAL from 10.8±2.0 mm to 6.0±1.5 mm ( p<0.001). In the control group the mean PD was reduced from 8.8±2.0 mm to 2.8±1.6 mm ( p<0.001) and the mean CAL changed from 10.5±1.6 mm to 5.5±1.4 mm ( p<0.001). CAL gains of 4 mm were measured in 77% (i.e. in 10 out of 13 defects) of the cases treated with EMD+NBM+PRP and in 100% (i.e. in all 13 defects) treated with EMD+NBM. No statistically significant differences in any of the investigated parameters were observed between the two groups. Conclusions: Within its limits, the present study has shown that (i) 1 year after regenerative surgery, both treatments resulted in statistically significant PD reductions and CAL gains and (ii) the use of PRP failed to enhance the results obtained with EMD+NBM.