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Abstract Background Accurate preoperative risk assessment for major colorectal cancer (CRC) surgery remains challenging. Body composition (BC) and cardiopulmonary exercise testing (CPET) can be used to evaluate risk. The relationship between BC and CPET in patients undergoing curative CRC surgery is unclear. Methods Consecutive patients undergoing CPET prior to CRC surgery between 2010 and 2020 were identified between two different UK hospitals. Body composition phenotypes such as sarcopenia, myosteatosis, and visceral obesity were defined using widely accepted thresholds using preoperative single axial slice CT image at L3 vertebrae. Relationships between clinicopathological, BC, and CPET variables were investigated using linear regression analysis. Results Two hundred eighteen patients with stage I–III CRC were included. The prevalence of sarcopenia, myosteatosis, and visceral obesity was 62%, 33%, and 64%, respectively. The median oxygen uptake at anaerobic threshold (VO2 at AT) was 12.2 mL/kg/min (IQR 10.6–14.2), and oxygen uptake at peak exercise (VO2 peak) was 18.8 mL/kg/min (IQR 15.4–23). On univariate linear regression analysis, male sex (P

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.

CD28 costimulatory signalling can be suppressed by immune checkpoints, such as CTLA-4 and PD-1. Here the authors describe the design of the fusion therapeutic davoceticept (ALPN-202), based on a variant CD80 extracellular domain engineered to bind PD-L1 as well as CD28 and CTLA-4, providing direct T cell costimulation and dual checkpoint inhibition to enable anti-tumor immune responses.

Purpose: The incidence of oral cavity and pharynx cancer is rising in the United States and South Dakota (SD) (2009-2018). In 2018, it was estimated that 396,937 of Americans were living with oral cavity and pharynx cancer. The 5-year relative survival rate for oral cancer is 66.2%, which is less than the survival rates for breast, colorectum, and prostate cancers. Tobacco and alcohol use and human papillomavirus (HPV16) exposure are some of the risk factors for oral cancer. Overall rural populations have higher cancer mortality than no rural population due to higher poverty, lower access to health services, and cigarette use. The purpose of this study is to investigate the prevalence of the oral cancer risk factors (e.g., cigarette smoking), HPV vaccination rates, and to identify the spatial distribution of social and environmental factors (e.g., social vulnerability, dental care access) in SD. Finally, this article discusses how nurses can contribute to oral cancer prevention and early detection. Methods: This descriptive study used data from multiple data sources (e.g., SD Department of Health, HRSA, County Health Rankings). Maps were created using ArcGIS. Findings: From the 66 SD counties, nearly 17% presented high-level shortage scores and were also highly socially vulnerable. HPV vaccination among youth was higher than the national average. Studies showed that improving nurse’s knowledge by training on oral cancer is needed and this may increase nurses’ practice in oral cancer prevention and control. Conclusions: Primary care professionals like nurse practitioners can assist in early detection of oral cancer and promote awareness of signs and main risk factors in rural areas. As part of the total patient care, nurses hold a vital role in prevention and early detection of oral cancer. These efforts with referral to oral cancer screening are vital for decreasing oral cancers morbidity and mortality rates primarily. Keywords: Rural health, Nurses, oral cancer, dentalcare access, Geographic Information Systems DOI: https://doi.org/10.14574/ojrnhc.v21i2.692

Macrophage scavenger receptor 1 (MSR1), also named CD204, holds key inflammatory roles in multiple pathophysiologic processes. Present primarily on the surface of various types of macrophage, this receptor variably affects processes such as atherosclerosis, innate and adaptive immunity, lung and liver disease, and more recently, cancer. As highlighted throughout this review, the role of MSR1 is often dichotomous, being either host protective or detrimental to the pathogenesis of disease. We will discuss the role of MSR1 in health and disease with a focus on the molecular mechanisms influencing MSR1 expression, how altered expression affects disease process and macrophage function, the limited cell signalling pathways discovered thus far, the emerging role of MSR1 in tumour associated macrophages as well as the therapeutic potential of targeting MSR1.

A reduction in FADD levels has been reported in precursor T-cell neoplasms and other tumor types. Such reduction would impact on the ability of tumor cells to undergo apoptosis and has been associated with poor clinical outcomes. However, FADD is also known to participate in non-apoptotic functions, but these mechanisms are not well-understood. Linking FADD expression to the severity of precursor T-cell neoplasms could indicate its use as a prognostic marker and may open new avenues for targeted therapeutic strategies. Using transcriptomic and clinical data from patients with precursor T-cell neoplasms, complemented by in vitro analysis of cellular functions and by high-throughput interactomics, our results allow us to propose a dual role for FADD in precursor T-cell neoplasms, whereby resisting cell death and chemotherapy would be a canonical consequence of FADD deficiency in these tumors, whereas deregulation of the cellular metabolism would be a relevant non-canonical function in patients expressing FADD. These results reveal that evaluation of FADD expression in precursor T-cell neoplasms may aid in the understanding of the biological processes that are affected in the tumor cells. The altered biological processes can be of different natures depending on the availability of FADD influencing its ability to exert its canonical or non-canonical functions. Accordingly, specific therapeutic interventions would be needed in each case.

Abstract This study characterized the effect of moderate‐ or vigorous‐intensity exercise on leukocyte counts, using fingertip sampling, and mitogen‐stimulated oxidative burst, measured in whole blood with a point‐of‐care test. In a randomized crossover design, 13 healthy adults (mean ± SD age: 22 ± 2 years; seven male, six female) cycled for 30‐min, once at 52 ± 5% V˙O2peak and on another occasion at 74 ± 9% V˙O2peak. Blood was sampled at baseline, immediately post‐exercise, and 15‐ and 60‐min post‐exercise. The leukocyte differential and mitogen‐stimulated Reactive Oxygen Species (ROS) production were assessed. Lymphocytes increased immediately post‐exercise and decreased below pre‐exercise levels 15‐ and 60‐min later. Lymphocyte mobilization immediately post‐exercise was 59 ± 36% greater with vigorous‐ compared to moderate‐intensity exercise (p

Dynamic, coordinated changes in metabolic pathway activity underpin the protective and inflammatory activity of T cells, through provision of energy and biosynthetic precursors for effector functions, as well as direct effects of metabolic enzymes, intermediates and end-products on signaling pathways and transcriptional mechanisms. Consequently, it has become increasingly clear that the metabolic status of the tissue microenvironment directly influences T cell activity, with changes in nutrient and/or metabolite abundance leading to dysfunctional T cell metabolism and interlinked immune function. Emerging evidence now indicates that additional signals are integrated by T cells to determine their overall metabolic phenotype, including those arising from interaction with cytokines and hormones in their environment. The impact of these on T cell metabolism, the mechanisms involved and the pathological implications are discussed in this review article.

Abstract Background Systematic screening of all colorectal tumors for Lynch Syndrome (LS) has been recommended since 2009. Currently, implementation of LS screening in healthcare systems remains variable, likely because LS screening involves the complex coordination of multiple departments and individuals across the healthcare system. Our specific aims are to (1) describe variation in LS screening implementation across multiple healthcare systems; (2) identify conditions associated with both practice variation and optimal implementation; (3) determine the relative effectiveness, efficiency, and costs of different LS screening protocols by healthcare system; and (4) develop and test in a real-world setting an organizational toolkit for LS screening program implementation and improvement. This toolkit will promote effective implementation of LS screening in various complex health systems. Methods This study includes eight healthcare systems with 22 clinical sites at varied stages of implementing LS screening programs. Guided by the Consolidated Framework for Implementation Research (CFIR), we will conduct in-depth semi-structured interviews with patients and organizational stakeholders and perform economic evaluation of site-specific implementation costs. These processes will result in a comprehensive cross-case analysis of different organizational contexts. We will utilize qualitative data analysis and configurational comparative methodology to identify facilitators and barriers at the organizational level that are minimally sufficient and necessary for optimal LS screening implementation. Discussion The overarching goal of this project is to combine our data with theories and tools from implementation science to create an organizational toolkit to facilitate implementation of LS screening in various real-world settings. Our organizational toolkit will account for issues of complex coordination of care involving multiple stakeholders to enhance implementation, sustainability, and ongoing improvement of evidence-based LS screening programs. Successful implementation of such programs will ultimately reduce suffering of patients and their family members from preventable cancers, decrease waste in healthcare system costs, and inform strategies to facilitate the promise of precision medicine. Trial registration N/A

Abstract Background Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the effectiveness of targeted gene panels for these purposes remains unknown. Methods RapSeq, a newly developed panel targeting 4,503 disease‐causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences. Results A diagnosis was made in 10/20 neonates (50%); eight had de novo variants (ASXL1, CHD, FBN1, KMT2D, FANCB, FLNA, PAX3), one was a compound heterozygote for CHAT, and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control. Conclusions This study shows that a gene panel that includes the majority of known disease‐causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.

The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics. AMG 330 caused modest cytotoxicity that was correlated with the amount of autologous T-cells (P = 0.0001) but not CD33 expression, as AMG 330 exerted marked cytotoxic effects in several specimens with minimal CD33 expression. With healthy donor T-cells added, AMG 330 cytotoxicity depended on the drug dose and effector:target (E:T) cell ratio. High cytotoxic activity was observed even with minimal CD33 expression, and AMG 330 cytotoxicity and CD33 expression correlated only at high E:T cell ratio and high AMG 330 doses (P

Introduction: Breast cancer is the most common cancer among women and early detection is critical to improve breast cancer survival. The All Women Count! (AWC!) Program, part of the National Breast and Cervical Cancer Early Detection Program, provides breast and cervical screening services at no cost to underserved women in South Dakota. Aiming to investigate program participation, we examined trends in the number of women eligible for breast cancer screening services through the AWC! Program along with mammography screening participation by county. Methods: Using the State-level Small Area Health Insurances Estimates data and the AWC! data, we calculated the proportion of South Dakotan women eligible for mammography screening under the AWC! Program from 2016 to 2019, and calculated the standardized participation ratio and 95 percent confidence interval by county (2019). To investigate differences in screening participation over time and by counties, analysis of variance (ANOVA) and Tukey statistical test were conducted, respectively. Results: From 2016 to 2019, the number of women eligible for breast cancer screening services declined by 12 percent. Differences in screening participation were not statistically significant over the four-year period. Conversely, county-level variations in screening participation were found. In 2019, among the 59 counties with screening data, 15 percent presented statistically higher participation in screening. Conclusion: A decrease in the number of women eligible for breast cancer services provided by AWC! was observed. Additionally, screening participation varied by county. A more comprehensive investigation is needed to explain these geographic disparities so prevention strategies can reduce the burden of breast cancer among South Dakota underserved women. [ABSTRACT FROM AUTHOR]

Gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a calicheamicin-γ(1) derivative, induces remissions and improves survival in a subset of patients with acute myeloid leukemia (AML). As the mechanisms underlying GO and calicheamicin-γ(1) resistance are incompletely understood, we herein used flow cytometry-based single cell network profiling (SCNP) assays to study cellular responses of primary human AML cells to GO. Our data indicate that the extent of DNA damage is quantitatively impacted by CD33 expression and drug efflux activity. However, although DNA damage is required for GO-induced cytotoxicity, it is not sufficient for effective cell kill, suggesting that downstream anti-apoptotic pathways may function as relevant resistance mechanisms. Supporting this notion, we found activated PI3K/AKT signaling to be associated with GO resistance in vitro in primary AML cells. Consistently, the investigational AKT inhibitor MK-2206 significantly sensitized various human AML cells to GO or free calicheamicin-γ(1) with particularly pronounced effects in otherwise GO or free calicheamicin-γ(1)-resistant cells. Likewise, MK-2206 also sensitized primary AML cells to calicheamicin-γ(1). Together, our findings illustrate the capacity of SCNP assays to discover chemotherapy-related biological pathways and signaling networks relevant to GO-induced genotoxic stress. The identification of AKT signaling as being associated with GO resistance in vitro may provide a novel approach to improve the in vivo efficacy of GO/calicheamicin-γ(1) and, by extrapolation, other DNA damage-based therapeutics.

Objective: To examine the impact of The National Training Program for Lapco on the rate of laparoscopic surgery and clinical outcomes of cases performed by Lapco surgeons after completion of training. Summary of Background Data: Lapco provided competency-based supervised clinical training for specialist colorectal surgeons in England. Methods: We compared the rate of laparoscopic surgery, mortality, and morbidity for colorectal cancer resections by Lapco delegates and non-Lapco surgeons in 3-year periods preceding and following Lapco using difference in differences analysis. The changes in the rate of post-Lapco laparoscopic surgery with the Lapco sign-off competency assessment and in-training global assessment scores were examined using risk-adjusted cumulative sum to determine their predictive clinical validity with predefined competent scores of 3 and 5 respectively. Results: One hundred eight Lapco delegates performed 4586 elective colo-rectal resections pre-Lapco and 5115 post-Lapco while non-Lapco surgeons performed 72,930 matched cases. Lapco delegates had a 37.8% increase in laparoscopic surgery which was greater than non-Lapco surgeons by 20.9% [95% confidence interval (CI), 18.5–23.3, P < 0.001) with a relative decrease in 30-day mortality by -1.6% (95% CI, -3.4 to -0.2, P = 0.039) and 90-day mortality by -2.3% (95% CI, -4.3 to -0.4, P = 0.018). The change point of risk-adjusted cumulative sum was 3.12 for competency assessment tool and 4.74 for global assessment score whereas laparoscopic rate increased from 44% to 66% and 40% to 56%, respectively. Conclusions: Lapco increased the rate of laparoscopic colorectal cancer surgery and reduced mortality and morbidity in England. In-training competency assessment tools predicted clinical performance after training. [ABSTRACT FROM AUTHOR]

The present report describes a case involving a 57-year-old HIV-positive man who presented with acute retrosternal chest pain accompanied by 24 h of fever. Septic arthritis of the manubriosternal joint was diagnosed based on magnetic resonance imaging findings in addition to Staphylococcus aureus bacteremia. To the authors’ knowledge, the present case is only the 12th reported case of manubriosternal septic arthritis, and the first in an HIV-positive patient. Early diagnosis and treatment can circumvent the need for surgical intervention. Based on the present case report and review of the literature, the authors summarize the epidemiology, appropriate imaging and suggestions for antibiotic therapy for this rare presentation.

Purpose: The incidence of oral cavity and pharynx cancer is rising in the United States and South Dakota (SD) (2009-2018). In 2018, it was estimated that 396,937 of Americans were living with oral cavity and pharynx cancer. The 5-year relative survival rate for oral cancer is 66.2%, which is less than the survival rates for breast, colorectum, and prostate cancers. Tobacco and alcohol use and human papillomavirus (HPV16) exposure are some of the risk factors for oral cancer. Overall rural populations have higher cancer mortality than no rural population due to higher poverty, lower access to health services, and cigarette use. The purpose of this study is to investigate the prevalence of the oral cancer risk factors (e.g., cigarette smoking), HPV vaccination rates, and to identify the spatial distribution of social and environmental factors (e.g., social vulnerability, dental care access) in SD. Finally, this article discusses how nurses can contribute to oral cancer prevention and early detection. Methods: This descriptive study used data from multiple data sources (e.g., SD Department of Health, HRSA, County Health Rankings). Maps were created using ArcGIS. Findings: From the 66 SD counties, nearly 17% presented high-level shortage scores and were also highly socially vulnerable. HPV vaccination among youth was higher than the national average. Studies showed that improving nurse's knowledge by training on oral cancer is needed and this may increase nurses' practice in oral cancer prevention and control. Conclusions: Primary care professionals like nurse practitioners can assist in early detection of oral cancer and promote awareness of signs and main risk factors in rural areas. As part of the total patient care, nurses hold a vital role in prevention and early detection of oral cancer. These efforts with referral to oral cancer screening are vital for decreasing oral cancers morbidity and mortality rates primarily. [ABSTRACT FROM AUTHOR]

The article presents an editorial focuses on lung cancer statistics in South Dakota, highlighting the annual average of 124,127 deaths in the United States and the creation of a new interactive Lung Cancer Dashboard. Topics include disparities by gender and race, modifiable risk factors like smoking and radon exposure, and the importance of early detection through screening efforts, particularly with low-dose computed tomography (LDCT).

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity. [Display omitted] • Canagliflozin (cana) inhibits human T cell effector function • Cana compromises T cell receptor signaling • Cana impairs the activity of ERK, mTORC, and Myc, preventing metabolic rewiring • Cana impairs the effector function of T cells derived from patients with autoimmunity Jenkins et al. report that the SGLT2 inhibitor, canagliflozin, compromises human T cell effector function. Canagliflozin prevents T cell activation and proliferation by antagonizing TCR signaling, impairing the activity of c-Myc, leading to a failure to engage in metabolic rewiring. In vitro , canagliflozin impairs T cell function in patients with autoimmunity. [ABSTRACT FROM AUTHOR]