Immunohistochemistry in Irradiated Skin Tissue

Currently there is no effective treatment for radiation dermatitis that results from clinical or accidental radiation exposures. Radiation exposure can cause severe burns and sloughing of the skin and damage muscle and bone layers underneath the skin. Radiation exposure in cells results in several types of cell death, such as necrosis, apoptosis, or autophagy, or accelerated senescence. Preliminary experiments demonstrated that accelerated senescence is a primary response to radiation in normal skin cells in culture and skin tissue in vivo in mice. We wanted to use immunohistochemistry to identify the skin cells that undergo senescence in tissues obtained from 4 mice over a time course from 1-30 days following exposure to 17.9 Gy (0.6 Gy/min) irradiation. The different stains that are going to be used are hematoxylin and eosin stain which shows the morphology of the whole tissue, K15 which marks adult skin epidermal stem cells, p21/waf1 which is a marker for senescence, DCT which marks melanocyte stem cells, and c-kit which marks melanocytes and basal epithelial cells. The results from these experiments will help us to determine which cells to protect in order to treat severe radiation exposure

A Dynamic Query-Rewriting Mechanism for Role-Based Access Control in Databases

Although Role-Based Access Control (RBAC) is a common security model currently, it has not been systematically applied in databases. In this paper, we propose a framework that enforces RBAC based on dynamic query rewriting. This framework grants privileges to data based on an intersection of roles, database structures, content, and privileges. All of this is implemented at the database level, which also offers a centralized location for administering security policies. We have implemented the framework within a healthcare setting

Goal Attainment on Long Tail Websites: An Information Foraging Approach

Information foraging theory (IFT) has emerged within the previous decade as a way of explaining the behavior of individuals as they hunt for information (Pirolli, 2007). In IFT, users forage for information using their metaphorical sense of smell which helps guides them through patchy areas of their environment. This preliminary research leverages IFT to build two versions of a clickstream model of information foraging that uses clickstream data to explain goal achievement. The goal being examined is the purchase of a product or submission of a contact form at long tail websites (i.e., sites with limited traffic). The first version of the model uses session-level panel data to examine across-website goal-seeking browsing patterns. Page-level data is used in the second version of the model to reason about browsing patterns within a website. The hypotheses and their related measures are presented for each version of the model

Association of Sperm-Associated Antigen 5 and Treatment Response in Patients With Estrogen Receptor-Positive Breast Cancer

There is no proven test that can guide the optimal treatment, either endocrine therapy or chemotherapy, for estrogen receptor-positive breast cancer. Objective: To investigate the associations of sperm-associated antigen 5 (SPAG5) transcript and SPAG5 protein expressions with treatment response in systemic therapy for estrogen receptor-positive breast cancer. Design, Settings, and Participants: This retrospective cohort study included patients with estrogen receptor-positive breast cancer who received 5 years of adjuvant endocrine therapy with or without neoadjuvant anthracycline-based combination chemotherapy (NACT) derived from 11 cohorts from December 1, 1986, to November 28, 2019. The associations of SPAG5 transcript and SPAG5 protein expression with pathological complete response to NACT were evaluated, as was the association of SPAG5 mRNA expression with response to neoadjuvant endocrine therapy. The associations of distal relapse-free survival with SPAG5 transcript or SPAG5 protein expressions were analyzed. Data were analyzed from September 9, 2015, to November 28, 2019. Main Outcomes and Measures: The primary outcomes were breast cancer-specific survival, distal relapse-free survival, pathological complete response, and clinical response. Outcomes were examined using Kaplan-Meier, multivariable logistic, and Cox regression models. Results: This study included 12 720 women aged 24 to 78 years (mean [SD] age, 58.46 [12.45] years) with estrogen receptor-positive breast cancer, including 1073 women with SPAG5 transcript expression and 361 women with SPAG5 protein expression of locally advanced disease stage IIA through IIIC. Women with SPAG5 transcript and SPAG5 protein expressions achieved higher pathological complete response compared with those without SPAG5 transcript or SPAG5 protein expressions (transcript: odds ratio, 2.45 [95% CI, 1.71-3.51]; P < .001; protein: odds ratio, 7.32 [95% CI, 3.33-16.22]; P < .001). Adding adjuvant anthracycline chemotherapy to adjuvant endocrine therapy for SPAG5 mRNA expression in estrogen receptor-positive breast cancer was associated with prolonged 5-year distal relapse-free survival in patients without lymph node involvement (hazard ratio, 0.34 [95% CI, 0.14-0.87]; P = .03) and patients with lymph node involvement (hazard ratio, 0.35 [95% CI, 0.18-0.68]; P = .002) compared with receiving 5-year endocrine therapy alone. Mean (SD) SPAG5 transcript was found to be downregulated after 2 weeks of neoadjuvant endocrine therapy compared with pretreatment levels in 68 of 92 patients (74%) (0.23 [0.18] vs 0.34 [0.24]; P < .001). Conclusions and Relevance: These findings suggest that SPAG5 transcript and SPAG5 protein expressions could be used to guide the optimal therapies for estrogen receptor-positive breast cancer. Retrospective and prospective clinical trials are warranted

Reducing substance use risk and mental health problems among sexually assaulted adolescents: A pilot randomized controlled trial.

The current study reports results from a pilot randomized controlled trial evaluating the feasibility and efficacy of Risk Reduction through Family Therapy (RRFT) for reducing substance use risk and trauma-related mental health problems among sexually assaulted adolescents. Thirty adolescents (aged 13–17 years; M=14.80; SD=1.51) who had experienced at least one sexual assault and their caregivers were randomized to RRFT or treatment as usual (TAU) conditions. Participants completed measures of substance use, substance use risk factors (e.g., family functioning), mental health problems (i.e., posttraumatic stress disorder, depression, and general internalizing/externalizing symptoms) and risky sexual behavior at four time points (baseline, post-treatment, and 3- and 6-month follow-up). Mixed-effects regression models yielded significantly greater reductions in substance use, specific substance use risk factors, and (parent-reported) PTSD, depression, and general internalizing symptoms among youth in the RRFT condition relative to youth in the TAU condition. However, significant baseline differences in functioning between the two conditions warrant caution in interpreting between-group findings. Instead, emphasis is placed on replication of feasibility findings and within-group improvements over time among the RRFT youth

Hydrothermal scavenging of ^(230)Th on the Southern East Pacific Rise during the last deglaciation

Thorium-230 (^(230)Th) is a fundamental tool for estimating sediment fluxes in the open ocean. Because ^(230)Th is rapidly scavenged by particles falling through the water column, the flux of ^(230)Th to underlying sediments is typically equal to its water column production rate. However, recent surveys suggest hydrothermal plumes are unusually efficient scavengers of ^(230)Th. Here we show that hydrothermal scavenging on the Southern East Pacific Rise (SEPR) resulted in ^(230)Th fluxes several times higher than the water column production rate during the last deglaciation. Elevated fluxes likely require diffusive transport of dissolved ^(230)Th from the ridge flanks towards the ridge crest. Depending on the length-scale of ^(230)Th transport, the resulting deficits in ^(230)Th may yield overestimates of sediment flux to ridge flank sediments. We also show that Fe fluxes at 19°S on the SEPR lag those at 11°S and 6°S by several thousand years, inconsistent with a signal driven by changes in deep water pH and oxygen levels. Instead, variable hydrothermal activity is the simplest explanation of the observed signals in the Pacific, Indian, and Atlantic basins

Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer

In vitro studies have suggested proteasome inhibitors could be effective in triple-negative breast cancer (TNBC). We found that bortezomib and carfilzomib induce proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cell lines, with sensitivity correlated with expression of immuno-(PSMB8/9/10) but not constitutive-(PSMB5/6/7) proteasome subunits. Equally, the transcriptomes of i-proteasome-high human TNBCs are enriched with UPR gene sets, and the genomic copy number landscape reflects positive selection pressure favoring i-proteasome activity, but in the setting of adjuvant treatment, this is actually associated with favorable prognosis. Tumor expression of PSMB8 protein (β5i) is associated with levels of MHC-I, interferon-γ-inducible proteasome activator PA28β, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high β5i but did not stratify survival amongst β5i-low TNBCs. Moreover, β5i expression was lower in brain metastases than in patient-matched primary breast tumors (n = 34; P = 0.007), suggesting that suppression contributes to immune evasion and metastatic progression. Hence, inhibiting proteasome activity could be counterproductive in the adjuvant treatment setting because it potentiates anti-TNBC immunity.Alaknanda Adwal, Priyakshi Kalita-de Croft, Reshma Shakya, Malcolm Lim, Emarene Kalaw, Lucinda D Taege, Amy E McCart Reed, Sunil R Lakhani, David F Callen, Jodi M Saunu

Quantifying the habitat and zoogeomorphic capabilities of spawning European barbel Barbus barbus, a lithophilous cyprinid

Suitable gravel availability is critical for the spawning success of lithophilous fishes, including redd builders. Redd construction during spawning can alter substrate characteristics, thereby influencing hydraulic conditions and sediment transport, highlighting the importance of spawning as a zoogeomorphic activity. Here, interactions between redd‐building fish and their spawning environment were investigated for European barbel Barbus barbus with a comparative approach across three English rivers: Teme (western), Great Ouse (eastern) and Idle (central). Sediment characteristics of spawning habitats were similar across the rivers, including subsurface fine sediment (<2 mm) content (≈20% dry weight), but elevated subsurface silt content and coarser surface sediments were found in the river Teme. Water velocities were similar at spawning sites despite differences in channel width and depth. Redds were characterized by a pit and tailspill, with no differences in surface grain‐size characteristics between these and the surrounding riverbed, but with topographic alteration (dimensions and tailspill amplitude) in line with those of salmonids. Estimates of the fraction of the bed that spawning barbel were capable of moving exceeded 97% in all rivers. Estimated reproductive potential varied significantly between the rivers Idle and Teme (3,098 to 9,715 eggs/m2), which was largely due to differences in barbel lengths affecting fecundity. Larger barbel, capable of producing and depositing more eggs, but in more spatially extensive redds, meaning fewer redds per given surface area of riverbed. Predictions of barbel egg mortality based on sand content were low across both rivers. The effects of silt on barbel egg and larvae development are unknown, but the levels detected here would significantly impact salmon egg mortality. Similarities in fish length to redd area and the size of moveable grains by spawning barbel and salmon suggest they have similar geomorphic effects on sediments, although fine sediment tolerance is highly divergent

Efficacy and Safety/Toxicity Study of Recombinant Vaccinia Virus JX-594 in Two Immunocompetent Animal Models of Glioma

The purpose of this study was to investigate the oncolytic potential of the recombinant, granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing vaccinia virus (VV) JX-594 in experimental malignant glioma (MGs) in vitro and in immunocompetent rodent models. We have found that JX-594 killed all MG cell lines tested in vitro. Intratumoral (i.t.) administration of JX-594 significantly inhibited tumor growth and prolonged survival in rats-bearing RG2 intracranial (i.c.) tumors and mice-bearing GL261 brain tumors. Combination therapy with JX-594 and rapamycin significantly increased viral replication and further prolonged survival in both immunocompetent i.c. MG models with several animals considered “cured” (three out of seven rats >120 days, terminated experiment). JX-594 infected and killed brain tumor-initiating cells (BTICs) from patient samples grown ex vivo, and did so more efficiently than other oncolytic viruses MYXV, Reovirus type-3, and VSVΔM51. Additional safety/toxicity studies in nontumor-bearing rodents treated with a supratherapeutic dose of JX-594 demonstrated GM-CSF-dependent inflammation and necrosis. These results suggest that i.c. administered JX-594 triggers a predictable GM-CSF-mediated inflammation in murine models. Before proceeding to clinical trials, JX-594 should be evaluated in the brains of nonhuman primates and optimized for the viral doses, delivery routes as well as the combination agents (e.g., mTOR inhibitors)

Cross-Sectional Study into the Costs and Impact on Family Functioning of 4-Year-Old Children with Aggressive Behavior

Early-onset aggressive behavior is known for its negative developmental consequences, and the associated high costs for families, the health care system and wider society. Although the origins of aggressive behavior are to be found in early childhood, the costs incurred by aggressive behavior of young children have not been studied extensively. The present study aimed to investigate whether preschool children with a high level of aggressive behavior already differ in the generated amount of costs and impact on family functioning from children with lower levels of aggressive behavior. A population-based sample of 317 preschool children was divided into four groups with different levels of aggression (moderate, borderline, clinical). Parents filled out questionnaires to assess service use (lifetime and past 3 months) and impact on family functioning. Over the past 3 months as well as over the first 4 years of life, children with a clinical level of aggression were more costly than children with a low level of aggression (mean total costs over the past 3 months: low = €167,05 versus clinical € = 1034,83 and mean lifetime costs: low € = 817,37 versus clinical € = 1433,04), due to higher costs of services used by the child. In addition, families of children with a borderline or clinical level of aggressive behavior reported more impairment in their daily functioning than families of children with lower levels of aggression. The findings demonstrate that a high level of aggressive behavior results in high costs and impaired family functioning in the preschool years already