Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. FINDINGS: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR \u3c 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p \u3c 0·01) compared to controls. INTERPRETATION: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. FUNDING: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842

What Can Parents Do to Reduce Youth Obesity? An Initial Study With a Diverse Sample

The body mass index (BMI) of diverse, low-income fifth grade students (n = 36) was regressed on physical activity (Child Adolescent Activity Log), percentage dietary fat (Food Habits Questionnaire), and the Food/Activity Parenting Practices Questionnaire. The model explained 50% of the variance in student BMI, adjusted R2 = .50, F (4, 19) = 6.84, p = .001. Students accurately perceived their weight status. Students\u27 perception of parenting strategies, along with dietary fat, was significantly associated with their BMI. Parent\u27s (n = 14) BMI, not the child\u27s, was associated with the strategies they used. Three parents tested an online authoritative parenting program. Further research is needed

A Qualitative Assessment of Kansas Tracking and Reporting of Controlled Substances (K-TRACS)

Introduction. This study assessed the Kansas Tracking and Reporting of Controlled Substances system (K-TRACS), the online controlled prescription medication monitoring website in Kansas. The specific aims were to determine if and when pharmacists and physicians in Kansas were using K-TRACS and to identify any perceived benefits or barriers to using K-TRACS. Methods. A non-randomized, convenience sample of Kansas pharmacists and family physicians were interviewed face to face using a guided semi-structured questionnaire. NVivo 10 (QSR International Pty Ltd.) was used to analyze data. Results. Ten physicians and sixteen pharmacists were interviewed. All pharmacists and 70% of physicians were using K-TRACS. Usage was prompted by encounters with new patients or unease with the patient interaction. The perceived benefits included increased communication with the patient and all providers, increased provider comfort with treating chronic pain, and altered prescriber habits. Barriers to the use of K-TRACS were identified as login, password, and operating system problems. Conclusions. Among study participants, K-TRACS is used regularly, is perceived to be a benefit to providers, patients and communities, and has become a useful new tool in the treatment of chronic pain. K-TRACS is perceived to facilitate increased communication between providers and with patients

Simulated Winter Incubation of Soil With Swine Manure Differentially Affects Multiple Antimicrobial Resistance Elements

Gastrointestinal bacteria that harbor antibiotic resistance genes (ARG) become enriched with antibiotic use. Livestock manure application to cropland for soil fertility presents a concern that ARG and bacteria may proliferate and be transported in the environment. In the United States, manure applications typically occur during autumn with slow mineralization until spring planting season. A laboratory soil incubation study was conducted mimicking autumn swine manure application to soils with concentrations of selected ARG monitored during simulated 120-day winter incubation with multiple freeze-thaw events. Additionally, the effects of two soil moistures [10 and 30% water holding capacity (WHC)] and two manure treatments [raw versus hydrated lime alkaline stabilization (HLAS)] were assessed. Fourteen tetracycline resistance genes were evaluated; tet(D), tet(G), and tet(L) were detected in background soil while swine manure contained tet(A), tet(B), tet(C), tet(G), tet(M), tet(O), tet(Q), and tet(X). By day 120, the manure-borne tet(M) and tet(O) were still detected while tet(C), tet(D), tet(L), and tet(X) genes were detected less frequently. Other tet resistance genes were detected rarely, if at all. The sum of unique tet resistance genes among all treatments decreased during the incubation from an average of 8.9 to 3.8 unique tet resistance genes. Four resistance elements, intI1, blactx−m−32, sul(I), erm(B), and 16s rRNA genes were measured using quantitative PCR. ARG abundances relative to 16S abundance were initially greater in the raw manure compared to background soil (−1.53 to −3.92 log abundance in manure; −4.02 to \u3c−6.7 log abundance in soil). In the mixed manure/soil, relative abundance of the four resistance elements decreased (0.87 to 1.94 log abundance) during the incubation largely because 16S rRNA genes increased by 1.21 log abundance. Throughout the incubation, the abundance of intI1, blactx−m−32, sul(I), and erm(B) per gram in soil amended with HLAS-treated manure was lower than in soil amended with raw manure. Under low initial soil moisture conditions, HLAS treatment reduced the abundance of intI1 and resulted in loss of blactx−m−32, sul(I), and erm(B)] compared to other treatment-moisture combinations. Although one might expect antibiotic resistance to be relatively unchanged after simulated winter manure application to soil, a variety of changes in diversity and relative abundance can be expected

Dietary Impact on Antibiotic Resistance in Feedlot Manure

There is a growing public concern regarding antibiotic resistance and the use of antibiotics, including in livestock management. Understanding the ecology of antibiotic resistance among microbes, identifying resistance gene reservoirs, and implementing antibiotic resistance mitigation practices in livestock production are critical to protecting animal and human health while meeting increasing food demands. This research is one of several studies seeking to assess risk for livestock- to- human transfer of antibiotic resistance and to identify mechanisms for reducing that risk where possible. This study evaluated the impact of forage concentration and supplemental essential oil in beef cattle finishing diets on antibiotic resistance in freshly excreted and consolidated beef feedlot manure. Results indicate that antibiotic resistance in manure was not impacted by either of the two dietary treatments considered

Adverse Childhood Experiences, Interpersonal Violence, and Racial Disparities in Early Prenatal Care in North Dakota (ND PRAMS 2017–2019)

In North Dakota (ND), American Indian women are more likely to be exposed to adverse childhood experiences (ACEs) and interpersonal violence, and receive late prenatal care (PNC) compared to other racial groups. In a sample of 1,849 (weighted n = 26,348) women from the 2017 to 2019 North Dakota Pregnancy Risk Assessment Monitoring System, we performed a series of logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for AI and Other Racial Identity women compared to White women regarding risk of late PNC (initiated after week 13) and dissatisfaction of PNC timing. Models were adjusted for interpersonal violence (from husband/partner, family member, someone outside of family, ex-husband/partner, or any) to determine if violence accounts for racial/ethnic disparities in PNC. AI women experienced two-fold higher risk of late PNC (OR: 2.25, 95% CI: 1.55, 3.26) and dissatisfaction of PNC timing (OR: 2.34, 95% CI: 1.61, 3.40) than White women. In the analyses for the association between joint ACEs (Higher: ≥4; Lower: \u3c4)/Race and PNC outcomes, odds of late PNC were two-fold among AI women with Higher ACEs (OR: 2.35, 95% CI: 1.41, 3.94) and Lower ACEs (OR: 2.73, 95% CI: 1.69, 4.41), compared to White women with Lower ACEs. Results were similar for dissatisfaction of PNC timing. Accounting for violence did not significantly change odds ratios in any analyses. Thus, interpersonal violence surrounding pregnancy does not explain racial disparities in PNC in ND. To understand disparities in PNC among AI women, risk factors like historic trauma and systemic oppression should be examined

Promoting VCU Community Solutions

This promotional project focuses on VCU Community Solutions — the new interdisciplinary initiative for education, research, and service. Since this initiative demonstrates the synergy that students, faculty, and community members can create by working together, the promotional video captures their perspectives. Through interviews and footage of community programs, the video shows how VCU Community Solutions engages university and community partners in addressing critical social issues — creating more imovative approaches by working together

Effects of Lime Amendment on Antibiotic Resistance in Beef Cattle Manure of Open Feedlots

The objective of this study was to evaluate the effectiveness of lime amendment on the reduction of antimicrobial resistant bacteria and antimicrobial resistance genes in beef cattle manure in open feedlots. Hydrated lime was uniformly applied to the surface of feedlot pen floor 1 day prior to cattle harvest at a rate of 0.36 lb/ft2 and samples were collected over time. Collected samples were analyzed for change in pH and levels of antimicrobial resistant bacteria and antimicrobial resistance genes. Lime amendment elevated the pH of pen floor surface materials to pH \u3e 12 for 4 hours and then pH \u3e 11 for another 24 hours. Lime amendment reduced the concentration of generic and resistant Escherichia coli by 1–2 log for up to 4 hours. The abundance of antimicrobial resistance genes, such as tet(X) and tet(O), decreased by 1–2 order of magnitude with lime amendment. Results indicate that lime addition reduced the concentrations of antimicrobial resistant bacteria and antimicrobial resistance genes in pen surface materials from open beef feedlot pens

Retention of Swine Slurry Constituents in Soil and Crop Residue as Affected by Setback Distance

Setbacks are prescribed distances from surface waters within which manure application is not allowed. Little information is available concerning the retention of swine slurry constituents in soil and crop residue materials within setback areas. This study was conducted to measure the retention of selected constituents within a setback area following the upslope application of swine slurry and the introduction of simulated rainfall. The no-till cropland site had a slope gradient of 4.9% and a mean winter wheat residue cover of 7.73 Mg ha−1 . Soil and vegetative samples were collected on 3.7 m wide by 23.2 m long plots with and without the addition of slurry. Slurry was added at the 0–4.9 m distance on selected plots, and simulated rainfall was then applied to the entire plot area during two separate events. Soil cores and vegetative samples were collected from each plot at distances of 2.44, 5.18, 7.92, 11.0, 14.0, 17.1, and 20.1 m from the upper plot border. The soil cores were separated into 0–10, 10–20, and 20– 30 cm depth increments. Significant increases in soil concentrations of chloride, nitrate, phosphorus, and zinc were found both within and downslope from the slurry application area. Residue materials located both within and downslope from the slurry application area contained significantly increased concentrations of boron, calcium, copper, magnesium, sulfur, and zinc. When estimating the downslope transport of constituents contained in swine slurry, contributions from runoff, soil, and residue should all be considered

Setback Distance Requirements for Removal of Swine Slurry Constituents in Runoff

The use of setback distances for manure application on cropland areas adjacent to surface water bodies could serve a function similar to vegetative filter strips. However, little information currently exists to identify the setback distances necessary to effectively reduce the transport of contaminants in runoff. The objective of this study was to determine the effects of setback distance and runoff rate on concentrations of selected constituents in runoff following land application of swine slurry to a no-till cropland area in southeast Nebraska. The study site had a residue cover of 7.73 Mg ha-1 and a slope gradient of 4.9%. The twenty plots examined during the investigation were 3.7 m across the slope by 4.9, 7.9, 11.0, 17.1, or 23.2 m long. An initial set of rainfall simulation tests were completed to identify background concentrations of selected constituents. Swine slurry was then applied to the upper 4.9 m of each plot, and additional rainfall simulation tests were conducted on the same plots examined previously. A first-order exponential decay function was used to estimate the effects of setback distance on concentrations of selected constituents. A setback distance of 12.2 m reduced runoff concentrations of dissolved phosphorus (DP), NH4-N, total nitrogen (TN), boron, chloride, manganese, potassium, sulfate, zinc, electrical conductivity (EC), and pH to background values similar to those measured for the no-slurry condition. Runoff rate significantly influenced transport of several of the constituents, with concentrations generally decreasing as runoff rate increased. The transport of selected pollutants in runoff was significantly reduced when setback areas were employed