Characterization of Liposomes for Cancer Cell Transfection

We have characterized a broad range of liposome formulations with varying DcChol:DOPE ratio. Subsequent addition of DcChol to liposomes increases its positive surface charge. However, loading the nuclear acids did not neutralize the overall negative surface potential to a similar extent. The liposomes were tested by transfection of DNA in living cancer cells

Towards ultrasound-guided adaptive radiotherapy for cervical cancer: Evaluation of Elekta's semiautomated uterine segmentation method on 3D ultrasound images.

Purpose 3D ultrasound (US) images of the uterus may be used to adapt radiotherapy (RT) for cervical cancer patients based on changes in daily anatomy. This requires accurate on-line segmentation of the uterus. The aim of this work was to assess the accuracy of Elekta's "Assisted Gyne Segmentation" (AGS) algorithm in semi-automatically segmenting the uterus on 3D transabdominal ultrasound images by comparison with manual contours.Materials & methods Nine patients receiving RT for cervical cancer were imaged with the 3D Clarity® transabdominal probe at RT planning, and 1 to 7 times during treatment. Image quality was rated from unusable (0)-excellent (3). Four experts segmented the uterus (defined as the uterine body and cervix) manually and using AGS on images with a ranking > 0. Pairwise analysis between manual contours was evaluated to determine interobserver variability. The accuracy of the AGS method was assessed by measuring its agreement with manual contours via pairwise analysis.Results 35/44 images acquired (79.5%) received a ranking > 0. For the manual contour variation, the median [interquartile range (IQR)] distance between centroids (DC) was 5.41 [5.0] mm, the Dice similarity coefficient (DSC) was 0.78 [0.11], the mean surface-to-surface distance (MSSD) was 3.20 [1.8] mm, and the uniform margin of 95% (UM95) was 4.04 [5.8] mm. There was no correlation between image quality and manual contour agreement. AGS failed to give a result in 19.3% of cases. For the remaining cases, the level of agreement between AGS contours and manual contours depended on image quality. There were no significant differences between the AGS segmentations and the manual segmentations on the images that received a quality rating of 3. However, the AGS algorithm had significantly worse agreement with manual contours on images with quality ratings of 1 and 2 compared with the corresponding interobserver manual variation. The overall median [IQR] DC, DSC, MSSD, and UM95 between AGS and manual contours was 5.48 [5.45] mm, 0.77 [0.14], 3.62 [2.7] mm, and 5.19 [8.1] mm, respectively.Conclusions The AGS tool was able to represent uterine shape of cervical cancer patients in agreement with manual contouring in cases where the image quality was excellent, but not in cases where image quality was degraded by common artifacts such as shadowing and signal attenuation. The AGS tool should be used with caution for adaptive RT purposes, as it is not reliable in accurately segmenting the uterus on 'good' or 'poor' quality images. The interobserver agreement between manual contours of the uterus drawn on 3D US was consistent with results of similar studies performed on CT and MRI images

Combined Ultrasound and Cone Beam CT Improves Target Segmentation for Image Guided Radiation Therapy in Uterine Cervix Cancer.

Purpose Adaptive radiation therapy strategies could account for interfractional uterine motion observed in patients with cervix cancer, but the current cone beam computed tomography (CBCT)-based treatment workflow is limited by poor soft-tissue contrast. The goal of the present study was to determine if ultrasound (US) could be used to improve visualization of the uterus, either as a single modality or in combination with CBCT.Methods and materials Interobserver uterine contour agreement and confidence were compared on 40 corresponding CBCT, US, and CBCT-US-fused images from 11 patients with cervix cancer. Contour agreement was measured using the Dice similarity coefficient (DSC) and mean contour-to-contour distance (MCCD). Observers rated their contour confidence on a scale from 1 to 10. Pairwise Wilcoxon signed-rank tests were used to measure differences in contour agreement and confidence.Results CBCT-US fused images had significantly better contour agreement and confidence than either individual modality (P < .05), with median (interquartile range [IQR]) values of 0.84 (0.11), 1.26 (0.23) mm, and 7 (2) for the DSC, MCCD, and observer confidence ratings, respectively. Contour agreement was similar between US and CBCT, with median (IQR) DSCs of 0.81 (0.17) and 0.82 (0.14) and MCCDs of 1.75 (1.15) mm and 1.62 (0.74) mm. Observers were significantly more confident in their US-based contours than in their CBCT-based contours (P < .05), with median (IQR) confidence ratings of 7 (2.75) versus 5 (4).Conclusions CBCT and US are complementary and improve uterine segmentation precision when combined. Observers could localize the uterus with a similar precision on independent US and CBCT images

Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma

The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and copy number alterations. Three subgroups, with “low”, “intermediate”, and “high” immune signals, were identified in primary tumors and replicated in metastatic tumors. Genes in the low subgroup were enriched for cell-cycle and metabolic pathways, whereas genes in the high subgroup were enriched for IFN and NF-κB signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFNγ and NF-κB pathway genes as the regulators of immune suppression. Furthermore, we showed that cigarette smoking, a globally detrimental environmental factor, modulates immunity, reducing the survival primarily in patients with a strong immune response. Together, these analyses identify a set of factors that can be easily assessed that may serve as predictors of response to immunotherapy in patients with melanoma. Significance: These findings identify novel genetic and environmental modulators of the immune response against primary cutaneous melanoma and predict their impact on patient survival

Body dysmorphic disorder in patients undergoing septorhinoplasty surgery: should we be performing routine screening?

Objective: Body dysmorphic disorder (BDD) is defined as having a preoccupation with a perceived flaw in one's appearance, which appears slight to others and significantly interferes with a person's functioning. When undetected in septorhinoplasty patients, it will often lead to poor outcomes. // Design: We performed a prospective cohort study to determine the prevalence of BDD in our patients and whether surgical correction could be considered. // Setting and participants: We recruited 34 patients being considered for septorhinoplasty in a tertiary referral rhinology clinic and a control group of 50 from the otology clinic giving a total of 84. // Main outcome measures: Participants completed the Body Dysmorphic Disorder Questionnaire (BDDQ), the sino‐nasal outcome test‐23 (SNOT‐23) and underwent nasal inspiratory peak flow (NIPF). Those found to be at high risk for BDD were referred to a clinical psychologist. // Results: Of the septorhinoplasty patients, 11 (32%) were high risk for BDD. Following psychological assessment, 7 (63%) patients were felt to be unsuitable for surgery and were offered psychological therapy. SNOT‐23 scores were significantly higher in the BDD group indicating a negative impact on quality of life. NIPF readings were not significantly different in the BDD group compared to the control group. // Conclusions: The BDDQ is a valid tool for identifying patients at risk of BDD. A close working relationship with clinical psychology has been advantageous to help the selection process of candidates for surgery when there is a high risk of BDD

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies

A multicentre evaluation and expert recommendations of use of the newly developed BioFire Joint Infection polymerase chain reaction panel.

Septic arthritis is a serious condition with significant morbidity and mortality, routinely diagnosed using culture. The FDA has recently approved the rapid molecular BioFire® Joint Infection Panel (BJIP) for synovial fluid. We aimed to evaluate the BJIP compared to culture and its potential use in patient management. A multicentre retrospective evaluation of BJIP was conducted in the UK and Ireland. Positive percent agreement (PPA) and negative percent agreement (NPA) were calculated between the BJIP and routine culture. A multidisciplinary team (MDT) discussion addressing the optimal or potential case use of the assay practice was facilitated. Three hundred ninety-nine surplus synovial fluid samples (~ 70% from native joints) from eight centres were processed using BJIP in addition to routine culture. An increased yield of positive results was detected using BJIP compared to routine culture (98 vs 83), giving an overall PPA of 91.6% and overall NPA of 93% for the BJIP compared to culture results. The BJIP detected resistant markers and additional organisms that could influence antibiotic choices including Neisseria gonorrhoeae and Kingella kingae. The MDT agreed that the assay could be used, in addition to standard methods, in adult and children patients with specialist advice use based on local needs. Rapid results from BJIP were assessed as having potential clinical impact on patient management. Organisms not included in the panel may be clinically significant and may limit the value of this test for PJI

On the Role of Attention in Binocular Rivalry: Electrophysiological Evidence

During binocular rivalry visual consciousness fluctuates between two dissimilar monocular images. We investigated the role of attention in this phenomenon by comparing event-related potentials (ERPs) when binocular-rivalry stimuli were attended with when they were unattended. Stimuli were dichoptic, orthogonal gratings that yielded binocular rivalry and dioptic, identically oriented gratings that yielded binocular fusion. Events were all possible orthogonal changes in orientation of one or both gratings. We had two attention conditions: In the attend-to-grating condition, participants had to report changes in perceived orientation, focussing their attention on the gratings. In the attend-to-fixation condition participants had to report changes in a central fixation target, taking attention away from the gratings. We found, surprisingly, that attending to rival gratings yielded a smaller ERP component (the N1, from 160–210 ms) than attending to the fixation target. To explain this paradoxical effect of attention, we propose that rivalry occurs in the attend-to-fixation condition (we found an ERP signature of rivalry in the form of a sustained negativity from 210–300 ms) but that the mechanism processing the stimulus changes is more adapted in the attend-to-grating condition than in the attend-to-fixation condition. This is consistent with the theory that adaptation gives rise to changes of visual consciousness during binocular rivalry

Groundwater Chemistry and Blood Pressure: A Cross-Sectional Study in Bangladesh

Background: We assessed the association of groundwater chemicals with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Methods: Blood pressure data for ≥35-year-olds were from the Bangladesh Demographic and Health Survey in 2011. Groundwater chemicals in 3534 well water samples from Bangladesh were measured by the British Geological Survey (BGS) in 1998–1999. Participants who reported groundwater as their primary source of drinking water were assigned chemical measures from the nearest BGS well. Survey-adjusted linear regression methods were used to assess the association of each groundwater chemical with the log-transformed blood pressure of the participants. Models were adjusted for age, sex, body mass index, smoking status, geographical region, household wealth, rural or urban residence, and educational attainment, and further adjusted for all other groundwater chemicals. Results: One standard deviation (SD) increase in groundwater magnesium was associated with a 0.992 (95% confidence interval (CI): 0.986, 0.998) geometric mean ratio (GMR) of SBP and a 0.991 (95% CI: 0.985, 0.996) GMR of DBP when adjusted for covariates except groundwater chemicals. When additionally adjusted for groundwater chemicals, one SD increase in groundwater magnesium was associated with a 0.984 (95% CI: 0.972, 0.997) GMR of SBP and a 0.990 (95% CI: 0.979, 1.000) GMR of DBP. However, associations were attenuated following Bonferroni-correction for multiple chemical comparisons in the full-adjusted model. Groundwater concentrations of calcium, potassium, silicon, sulfate, barium, zinc, manganese, and iron were not associated with SBP or DBP in the full-adjusted models. Conclusions: Groundwater magnesium had a weak association with lower SBP and DBP of the participants

Neural Correlate of Filtering of Irrelevant Information from Visual Working Memory

In a dynamic environment stimulus task relevancy could be altered through time and it is not always possible to dissociate relevant and irrelevant objects from the very first moment they come to our sight. In such conditions, subjects need to retain maximum possible information in their WM until it is clear which items should be eliminated from WM to free attention and memory resources. Here, we examined the neural basis of irrelevant information filtering from WM by recording human ERP during a visual change detection task in which the stimulus irrelevancy was revealed in a later stage of the task forcing the subjects to keep all of the information in WM until test object set was presented. Assessing subjects' behaviour we found that subjects' RT was highly correlated with the number of irrelevant objects and not the relevant one, pointing to the notion that filtering, and not selection, process was used to handle the distracting effect of irrelevant objects. In addition we found that frontal N150 and parietal N200 peak latencies increased systematically as the amount of irrelevancy load increased. Interestingly, the peak latency of parietal N200, and not frontal N150, better correlated with subjects' RT. The difference between frontal N150 and parietal N200 peak latencies varied with the amount of irrelevancy load suggesting that functional connectivity between modules underlying fronto-parietal potentials vary concomitant with the irrelevancy load. These findings suggest the existence of two neural modules, responsible for irrelevant objects elimination, whose activity latency and functional connectivity depend on the number of irrelevant object