Corrigendum: Adenosine kinase on deoxyribonucleic acid methylation: Adenosine receptor-independent pathway in cancer therapy.

[This corrects the article DOI: 10.3389/fphar.2022.908882.].

Adenosine Kinase on Deoxyribonucleic Acid Methylation: Adenosine Receptor-Independent Pathway in Cancer Therapy.

Methylation is an important mechanism contributing to cancer pathology. Methylation of tumor suppressor genes and oncogenes has been closely associated with tumor occurrence and development. New insights regarding the potential role of the adenosine receptor-independent pathway in the epigenetic modulation of DNA methylation offer the possibility of new interventional strategies for cancer therapy. Targeting DNA methylation of cancer-related genes is a promising therapeutic strategy; drugs like 5-Aza-2'-deoxycytidine (5-AZA-CdR, decitabine) effectively reverse DNA methylation and cancer cell growth. However, current anti-methylation (or methylation modifiers) are associated with severe side effects; thus, there is an urgent need for safer and more specific inhibitors of DNA methylation (or DNA methylation modifiers). The adenosine signaling pathway is reported to be involved in cancer pathology and participates in the development of tumors by altering DNA methylation. Most recently, an adenosine metabolic clearance enzyme, adenosine kinase (ADK), has been shown to influence methylation on tumor suppressor genes and tumor development and progression. This review article focuses on recent updates on ADK and its two isoforms, and its actions in adenosine receptor-independent pathways, including methylation modification and epigenetic changes in cancer pathology.

Comprehensive analysis of the correlation between GSTM1 and tumor immunity in colon cancer.

Background: Glutathione S-transferase mu 1 (GSTM1) is one of the major glutathione conjugation enzymes. Its expression and activity have been suggested to correlate with the occurrence of colon cancer; however, the role of GSTM1 in tumor immunity remains unclear. Methods: Relevant data downloaded from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) was used to perform a multi-dimensional expression analysis of GSTM1 in colon adenocarcinoma (COAD). The correlation between GSTM1 and tumor immunity was analyzed with multiple online tools. Then protein-protein interaction (PPI) network and functional enrichment analyses of GSTM1-associated immunomodulators were performed. Further, we developed the Cox regression model based on the GSTM1-related immunomodulators. Finally, a GSTM1-based clinical nomogram and a calibration curve was established to predict the probability and accuracy of long-term survival. Result: GSTM1 was significantly downregulated in COAD versus normal tissues. Infiltration levels of B cells, CD8+ T cells, and dendritic cells were closely correlated to GSTM1 gene copy number deletion, and GSTM1 expression levels in COAD positively correlated with dendritic cell, B cell, neutrophil, and macrophage infiltration. Functional enrichment analysis indicated 36 GSTM1-related immunomodulators are involved in immune-related pathways of regulating T cell activation and lymphocytic activation. A 2-gene prognostic risk signature based on the 36 GSTM1-related immunomodulators was built using the Cox regression model, and the risk signature in combination with stage had an area under the curve (AUC) value of 0.747 by the receiver operating characteristic method. patients with higher risk scores-calculated based on 2 gene prognostic risk characteristics and further identified as an independent prognostic factor-were associated with worse survival using the Kaplan-Meier analysis. Together, the clinical nomogram and calibration curve based on GSTM1 suggested a good prediction accuracy for long-term survival probability. Conclusions: Our study provided evidence supporting the significant role of GSTM1 in COAD immunity and suggests GSTM1 as a potential novel target for COAD immunotherapy.

ICU Patient Family Stress Recovery During Breaks in a Hospital Garden and Indoor Environments.

OBJECTIVES: Measure the immediate change in intensive care unit (ICU) family members' state stress levels from the beginning to the end of a person's visit to a hospital garden and compare the changes produced by the garden with those associated with spending time in indoor hospital environments intended for respite and relaxation. BACKGROUND: No previous research has compared the efficacy of different physical environments as interventions to foster stress reduction in family members of ICU patients, a group of hospital visitors known to experience high levels of distress. METHOD: A convenience sample of 42 ICU patient family (from 42 different families) completed the Present Functioning Visual Analogue Scales (PFVAS) before and after each visit (128 total visits) to a garden, an atrium/café, or ICU waiting room. RESULTS: Stress scores significantly declined (i.e., improved) from the start to the end of a break on all PFVAS subscales (p < .0001) in both the garden and indoors locations. However, it is noteworthy that garden breaks resulted in significantly greater improvement in the "sadness" scale than breaks in indoor locations (p = .03), and changes in all five other PFVAS scores showed somewhat more reduction of stress for breaks spent in the garden than indoors, although these differences were not statistically significant. CONCLUSION: Creating an unlocked garden with abundant nature located close to an ICU can be an effective intervention for significantly mitigating state stress in family members of ICU patients and can be somewhat more effective than indoor areas expressly designed for family respite and relaxation.

Dysregulation of adenosine kinase isoforms in breast cancer.

Dysregulated adenosine signaling pathway has been evidenced in the pathogenesis of breast cancer. However, the role of adenosine kinase (ADK) in tumorigenesis remains unclear while it crucially regulates the removal and availability of adenosine. ADK has two isoforms that localize to discrete subcellular spaces: i.e., nuclear, long-isoform (ADK-L) and cytosolic, short-isoform (ADK-S). We hypothesized that these two ADK isoforms would be differentially expressed in breast cancer and may contribute to divergent cellular actions in cancer. In this study, we examined the expression profiles of ADK isoforms in breast cancer tissues from 46 patient and followed up with an in vitro investigation by knocking down the expression of ADK-L or ADK-S using CRISPR gene editing to evaluate the role of ADK isoform in cancer progression and metastasis of cultured triple-negative breast cancer cell line MDA-MB-231. We demonstrated that (i) ADK-L expression level was significantly increased in breast cancer tissues versus paired normal tissues adjacent to tumor, whereas the ADK-S expression levels were not significantly different between cancerous and normal tissues; (ii) CRISPR/Cas9-mediated downregulation of ADK isoforms, led to suppressed cellular proliferation, division, and migration of cultured breast cancer cells; (iii) ADK-L knockdown significantly upregulated gene expression of matrix metalloproteinase (ADAM23, 9.93-fold; MMP9, 24.58-fold) and downregulated expression of cyclin D2 (CCND2, -30.76-fold), adhesive glycoprotein THBS1 (-8.28-fold), and cystatin E/M (CST6, -16.32-fold). Our findings suggest a potential role of ADK-L in mitogenesis, tumorigenesis, and tumor-associated tissue remodeling and invasion; and the manipulation of ADK-L holds promise as a therapeutic strategy for aggressive breast cancer.

Impact of Nurses Taking Daily Work Breaks in a Hospital Garden on Burnout.

BACKGROUND: Nurses working in hospital environments are at risk for burnout. Exposure to nature has psychological benefits, but the effect of hospital gardens on nurse burnout is less understood. OBJECTIVE: To compare the effect on nurse burnout of taking daily work breaks in a hospital-integrated garden with the effect of indoor-only breaks. METHODS: A prospective crossover trial was conducted of nurses assigned to either 6 weeks of a work break in an outdoor hospital garden or 6 weeks of indoor-only breaks. After a 1-week washout period, break assignments were switched for a subsequent 6 weeks. The Maslach Burnout Inventory was administered at the beginning and end of each 6-week period, and a Present Functioning Visual Analogue Scale was completed at the start and end of each break to capture immediate psychological symptoms. Change scores were analyzed by using generalized estimating equations. RESULTS: For 29 nurses, for garden compared with indoor breaks, significant improvement was apparent in scores on the Maslach Burnout Inventory subscales for emotional exhaustion (4.5 vs -0.2; P < .001) and depersonalization (1.8 vs 0.0; P = .02) but not for personal accomplishment (-0.6 vs -0.0; P = .55). Compared with indoor breaks, total symptom scores on the Present Functioning Visual Analog Scale improved significantly when nurses took a break in the garden (garden vs indoor breaks, 4.0 vs 2.4; P = .04). CONCLUSIONS: Taking daily work breaks in an outdoor garden may be beneficial in mitigating burnout for nurses working in hospital environments.

PAs reduce rounding interruptions in the pediatric intensive care unit.

OBJECTIVE: We investigated the proportion of encounters that were interrupted during family-centered rounds in the pediatric intensive care unit (PICU) to determine whether the use of a physician assistant (PA) significantly affected the proportion of interrupted encounters. METHODS: We evaluated 2,657 rounding encounters in our 24-bed regional referral unit. The duration of each rounding encounter and total rounding duration were recorded. The presence or absence of a PA during each rounding encounter, the occurrence of an interruption, and other potential predictors of interruptions were recorded. RESULTS: The presence of a PA during PICU rounds was significantly associated (P < .001) with a 35.4% lower likelihood of an interruption. CONCLUSIONS: Family-centered rounds in the PICU are less likely to be interrupted when a PA is present. PAs help physicians and improve rounding efficiency by safely and effectively handling certain interruptions.

Roadmap to Wellness: Exploring Live Customized Music at the Bedside for Hospitalized Children.

BACKGROUND: Randomized trials on clinical outcomes of music are conflicting, with few performed in the postoperative pediatric population. We aimed to determine if there was a benefit of a live, customized bedside music delivery program (MyMusicRx®) for children hospitalized after pediatric surgery. We present our perspective on the utility of music medicine, review others' work in this area, and discuss future directions. METHODS: All admitted postsurgical patients aged between 5 and 18 years were considered. One live, customized music session was delivered by a MyMusicRx® music specialist to intervention participants, and compared with matched controls who did not receive music intervention. Pain, cumulative analgesia dosage, and vital signs within 12 h after unit arrival were compared between groups. RESULTS: Thirty-two participants (16 intervention, 16 controls; 8:8 females:males per group) were enrolled. No differences in age, surgery length, or duration of music intervention were found between groups. No differences in pain scores (p = 0.73), heart rate (p = 0.82), respirations (p = 84), narcotic (p = 0.92) or non-narcotic medication usage (p = 0.88, 0.86, 0.95; ibuprofen, acetaminophen, and ketorolac, respectively), or time to first narcotic dose (p = 0.64) were found. CONCLUSION: A single music intervention in the acute postoperative period did not appear to be adequate to augment traditional methods of pain and hemodynamic control. Prior studies have similar outcome measures but conflicting results. We did not evaluate psychological well-being, patient engagement, or family perception in this pilot study. Future directions include developing and validating a tool that explores the observable impact of music medicine on children's emotions and behaviors.

Progressive Consent and Specimen Accrual Models to Address Sustainability: A Decade's Experience at an Oregon Biorepository.

BACKGROUND: The Legacy Biorepository is a College of American Pathologists-accredited biorepository operating within a seven-hospital healthcare system, with a decade's experience in specimen accrual, storage, and distribution. While standardization of our practices through accreditation remains a priority, we along with others face challenges with regard to sustainability. Purposeful changes in our consent process, which we term "progressive consent," are expected to improve sustainability and operational flexibility while increasing our scientific impact. METHODS: Until 2015, informed consent was performed primarily by biorepository staff at an estimated time of 1 hour per case. After a process improvement exercise, we successfully changed our informed consent process to a modified front-door model, with use of material and data for research as an opt-in or opt-out selection on the institutional patient informed consent form provided to surgery patients in the healthcare system. Successful implementation of this change required the engagement and participation of multiple stakeholders in healthcare system leadership, hospital administration, research, legal, regulatory, and patient care levels. RESULTS: A modified front-door consent enabled us to collect an additional 38 specimens in the first two quarters of 2016, with a time commitment of 15.75 hours, a time savings per specimen increasing in Q2 over Q1. We estimate a potential savings of 43 hours in 2016. This progressive model allowed us to maintain our frozen sample collection while increasing the availability of paraffin-embedded tissue and bodily fluids. Augmenting our tissue collection added little expense per case (approximately half that of each frozen tissue aliquot) and increased the range of biospecimens collected. CONCLUSIONS: Biorepository financial sustainability is a critical issue. Thorough evaluation and modification of existing procedures and collection models, as well as cost recovery initiatives, can translate into savings. Sustainability, process improvement, and scientific impact broadly overlap and continue to require operational critique and implementation of strategic changes.

The Effect of Family Presence on Rounding Duration in the PICU.

BACKGROUND AND OBJECTIVE: The incorporation of family-centered rounds has become standard in PICUs across the United States. We compared rounding times in our institution, with and without family members present, to determine the effect on total rounding time and work flow. METHODS: This observational study of a convenience sample was conducted over a 17-month period (May 2014-October 2015), accounting for typical seasonal variation in the PICU. The individual patient rounding times for 2657 encounters were recorded. The presence of family members, intubation status, physician assistant participation, interruptions during rounds, attending physician's full- or part-time status, and patient census were documented. The effect of family presence on per-patient rounding time was analyzed, while controlling for influential variables. RESULTS: Family members were present during 1743 of 2657 (66%) rounding encounters. The average per-patient rounding time with and without family members present was 8.6 minutes and 7.3 minutes, respectively, a difference of 1.3 minutes per patient. In statistical models that accounted for other influential variables, the presence of family members was associated with a highly significant (20.4%, P < .001) increase in the per-patient rounding time. CONCLUSIONS: The presence of family members increases per-patient rounding times in the PICU. Family presence on rounds may have benefits that outweigh the additional time required to complete each patient interaction.

Model for Team Training Using the Advanced Trauma Operative Management Course: Pilot Study Analysis.

BACKGROUND: Education and training of surgeons has traditionally focused on the development of individual knowledge, technical skills, and decision making. Team training with the surgeon's operating room staff has not been prioritized in existing educational paradigms, particularly in trauma surgery. We aimed to determine whether a pilot curriculum for surgical technicians and nurses, based on the American College of Surgeons' Advanced Trauma Operative Management (ATOM) course, would improve staff knowledge if conducted in a team-training environment. METHODS: Between December 2012 and December 2014, 22 surgical technicians and nurses participated in a curriculum complementary to the ATOM course, consisting of 8 individual 8-hour training sessions designed by and conducted at our institution. Didactic and practical sessions included educational content, hands-on instruction, and alternating role play during 5 system-specific injury scenarios in a simulated operating room environment. A pre- and postcourse examination was administered to participants to assess for improvements in team members' didactic knowledge. RESULTS: Course participants displayed a significant improvement in didactic knowledge after working in a team setting with trauma surgeons during the ATOM course, with a 9-point improvement on the postcourse examination (83%-92%, p = 0.0008). Most participants (90.5%) completing postcourse surveys reported being "highly satisfied" with course content and quality after working in our simulated team-training setting. CONCLUSIONS: Team training is critical to improving the knowledge base of surgical technicians and nurses in the trauma operative setting. Improved communication, efficiency, appropriate equipment use, and staff awareness are the desired outcomes when shifting the paradigm from individual to surgical team training so that improved patient outcomes, decreased risk, and cost savings can be achieved. OBJECTIVE: Determine whether a pilot curriculum for surgical technicians and nurses, based on the American College of Surgeons' ATOM course, improves staff knowledge if conducted in a team-training environment. DESIGN: Surgical technicians and nurses participated in a curriculum complementary to the ATOM course. In all, 8 individual 8-hour training sessions were conducted at our institution and contained both didactic and practical content, as well as alternating role play during 5 system-specific injury scenarios. A pre- and postcourse examination was administered to assess for improvements in didactic knowledge. SETTING: The course was conducted in a simulated team-training setting at the Legacy Institute for Surgical Education and Innovation (Portland, OR), an American College of Surgeons Accredited Educational Institute. PARTICIPANTS: In all, 22 surgical technicians and operating room nurses participated in 8 separate ATOM(s) courses and had at least 1 year of surgical scrubbing experience in general surgery with little or no exposure to Level I trauma surgical care. Of these participants, 16 completed the postcourse examination. RESULTS: Participants displayed a significant improvement in didactic knowledge (83%-92%, p = 0.0008) after the ATOM(s) course. Of the 14 participants who completed postcourse surveys, 90.5% were "highly satisfied" with the course content and quality. CONCLUSIONS: Team training is critical to improving the knowledge base of surgical technicians and nurses in the trauma operative setting and may contribute to improved patient outcomes, decreased risk, and hospital cost savings.

Addressing the global burden of surgical disease: proceedings from the 2nd annual symposium at the American College of Surgeons.

In the past decade, interest in surgery as a means to improve public health and engage in international service has increased significantly. International organizations, academic institutions, professional associations, and humanitarian aid organizations recognize that disparate access to surgical care affects global health and they have recently joined forces to address access to surgical care. Current initiatives focus on quantitatively defining surgical disparity, prioritizing a surgical agenda, and developing economically sustainable models for health care assistance, training, and delivery. The Global Burden of Surgical Disease Working Group (GBoSD WG) strives to (1) quantitatively define global disparity in surgical care; (2) assess unmet surgical need; (3) identify priorities; (4) develop sustainable models for improved health care delivery; and (5) advocate for a surgical presence within the global public health agenda. This article formally introduces the GBoSD Working Group and papers presented during the 2009 Symposium at the American College of Surgeons in Chicago.

Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR.

INTRODUCTION: Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients. METHODS: Peripheral blood and breast carcinoma specimens from 24 patients were collected. DNA was extracted and then amplified by MGB-TaqMan real time PCR. RESULTS: Of 24 breast tumor specimens, 11 (46%) were positive for EBV DNA. Of these 11 breast tumor specimens, 7 (64%) were also positive for EBV DNA in the peripheral blood, while 4 (36%) were positive for EBV DNA in the tumor, but negative in the blood. CONCLUSION: EBV was found at extremely low levels, with a mean of 0.00004 EBV genomes per cell (range 0.00014 to 0.00001 EBV genomes per cell). Furthermore, our finding of the presence of EBV in the tumor specimens coupled to the absence of detection of EBV genomic DNA in the peripheral blood is consistent with the epithelial nature of the virus. Because of the low levels of viral DNA in tumor tissue, further studies are needed to assess the biological input of EBV in breast cancer.

c-Myc inhibition negatively impacts lymphoma growth.

BACKGROUND: Proto-oncogene c-Myc dysregulation is commonly found in aggressive tumors. Dysregulation is central to lymphomagenesis in Burkitt lymphoma and other non-Hodgkin's lymphomas. This suggests targeting c-Myc as a treatment for myc-associated malignancies. METHODS: Microarrays showed c-Myc dysregulation in a B-lymphoblastoid line, TIB-215. This was confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and extended to 3 additional Burkitt lymphoma lines. Growth effects of a c-Myc inhibitor, compound 10058-F4, were determined in these 4 lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses and direct cell counts. Drug effects on c-Myc gene expression levels were measured using minor groove binding-TaqMan real-time reverse transcriptase-polymerase chain reaction. Drug specificity was analyzed in rat c-Myc knockout (-/-) and Myc-transfected cells. RESULTS: c-Myc dysregulation was shown to be cell-cycle independent without rapid decay of c-Myc mRNA levels in all 4 lines. Using a c-Myc inhibitor, we found that growth inhibition was time- and dose-dependent. This inhibition caused unexpected downregulation (> or =65%) of c-Myc mRNAs. CONCLUSIONS: The inhibition of c-Myc decreased growth in aggressive lymphoma cells. This mechanism included c-Myc mRNA downregulation and dissociation of c-Myc/Max protein heterodimer. These results support targeting c-Myc in tumors with high morbidity and mortality.