The regulatory function of sphingosine-1-phosphate signaling axis on regulatory T cells in colorectal cancer

In tumors associated with inflammation such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), high numbers of regulatory T cells (Tregs) are associated with both favorable and poor prognoses. The functions of Tregs in CRC remain elusive and have yet to be clearly defined. With new evidence supporting many subsets of Tregs, the research on the development and functions of these cells has begun to come to fruition. The sphingosine 1 phosphate (S1P) pathway was recently reported to regulate the development and function of regulatory T cells. This pathway may shine new light into the pleiotropic nature of these cells in cancer. In this review, we will examine current literature on the many functions of Tregs in CRC and highlight the significance of the S1P signaling pathway in Treg development/function with the implication of novel therapeutic strategies in treatment of CRC patients

Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages

Genetic depletion of macrophages in Polyoma Middle T oncoprotein (PyMT)‐induced mammary tumors in mice delayed the angiogenic switch and the progression to malignancy. To determine whether vascular endothelial growth factor A (VEGF‐A) produced by tumor‐associated macrophages regulated the onset of the angiogenic switch, a genetic approach was used to restore expression of VEGF‐A into tumors at the benign stages. This stimulated formation of a high‐density vessel network and in macrophage‐depleted mice, was followed by accelerated tumor progression. The expression of VEGF‐A led to a massive infiltration into the tumor of leukocytes that were mostly macrophages. This study suggests that macrophage‐produced VEGF regulates malignant progression through stimulating tumor angiogenesis, leukocytic infiltration and tumor cell invasion

Positron emission tomography agent 2-deoxy-2-[(18)F]fluoro-D-glucose has a therapeutic potential in breast cancer

BACKGROUND: Novel approaches are needed for breast cancer patients in whom standard therapy is not effective. 2-Deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) was evaluated as a potential radiomolecular therapy agent in breast cancer animal models and, retrospectively, in patients with metastatic breast cancer. METHODS: Polyoma middle T antigen (PyMT) and mouse mammary tumor virus-NeuT transgenic mice with tumors 0.5–1 cm in diameter were imaged with (18)F-FDG, and tumor to liver ratios (TLRs) were calculated. The radiotoxicity of (18)F-FDG administration was determined in healthy mice. PyMT mice with small (0.15–0.17 cm) and large (more than 1 cm) tumors were treated with 2–4 mCi of (18)F-FDG, and control C3H/B6 mice with 3 mCi of (18)F-FDG. At 10 days after treatment the tumors and control mammary glands were analyzed for the presence of apoptotic and necrotic cells. Five patients with breast cancer and metastatic disease were evaluated and standardized uptake values (SUVs) in tumors, maximum tolerated dose, and the doses to the tumor were calculated. RESULTS: Doses up to 5 mCi proved to be non-radiotoxic to normal organs. The (18)F-FDG uptake in mouse tumors showed an average TLR of 1.6. The treatment of mice resulted in apoptotic cell death in the small tumors. Cell death through the necrotic pathway was seen in large tumors, and was accompanied by tumor fragmentation and infiltration with leukocytes. Normal mammary tissues were not damaged. A human (18)F-FDG dose delivering 200 rad to the red marrow (less than 5% damage) was calculated to be 4.76 Ci for a 70 kg woman, and the dose to the tumors was calculated to be 220, 1100 and 2200 rad for SUVs of 1, 5 and 10, respectively. CONCLUSION: We have shown that positrons delivered by (18)F-FDG to mammary tumors have a tumoricidal effect on cancer cells. The study of breast cancer patients suggests that the tumor and normal organ dosimetry of (18)F-FDG makes it suitable for therapy of this malignancy

Primary coronary artery bypass surgery in the presence of decreasing preoperative renal function: effect on short-term outcomes

Background: This study evaluated the impact of decreasing renal function on short-term outcomes in patients undergoing primary coronary artery bypass grafting (CABG). Methods: The study period was from February 1999 to February 2009. Data on 4050 patients undergoing primary CABG were prospectively collected and analyzed retrospectively. The study population was divided into 3 groups: the CABG:N group, patients with preoperative serum creatinine levels 2 mg/dL (n = 87); and the CABG:D group, patients on dialysis (n = 16). Results: The significant differences between the groups (CABG:D > CABG:RF > CABG:N) in short-term outcomes were with respect to blood product use (P < .001), postoperative acute myocardial infarction (P < .001), pulmonary complications (P .001), infection (P < .001), and death (P < .001). The risk of short-term death (30 days) in the CABG:D group (4/16, 25%) was 25 times greater than that in the CABG:N group (38/3947, 0.96%). Conclusion: CABG in the presence of renal failure is associated with significant morbidity and mortality

Cardiac arrhythmias in patients with COVID-19.

The emergence of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major global public health concern. Although SARS-CoV-2 causes primarily respiratory problems, concurrent cardiac injury cannot be ignored since it may be an independent predictor for adverse outcomes. Cardiac arrhythmias are often observed in patients with COVID-19, especially in severe cases, and more likely contribute to the high risk of adverse outcomes. Arrhythmias should be regarded as one of the main complications of COVID-19. Mechanistically, a number of ion channels can be adversely affected in COVID-19, leading to alterations in cardiac conduction and/or repolarization properties, as well as calcium handling, which can predispose to cardiac arrhythmogenesis. In addition, several antimicrobials that are currently used as potential therapeutic agents for COVID-19, such as chloroquine, hydroxychloroquine and azithromycin, have uncertain benefit, and yet may induce electrocardiographic QT prolongation with potential ventricular pro-arrhythmic effects. Continuous electrocardiogram monitoring, accurate and prompt recognition of arrhythmias are important. The present review focuses on cardiac arrhythmias in patients with COVID-19, its underlying mechanisms, and proposed preventive and therapeutic strategies

Clinically Stable COVID-19 Patients Presenting to Acute Unscheduled Episodic Care Venues Have Increased Risk of Hospitalization: Secondary Analysis of a Randomized Control Trial

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p \u3c 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations

Acyclovir for treating varicella in otherwise healthy children and adolescents: a systematic review of randomised controlled trials

BACKGROUND: Acyclovir has the potential to shorten the course of chickenpox which may result in reduced costs and morbidity. We conducted a systematic review of randomised controlled trials that evaluated acyclovir for the treatment of chickenpox in otherwise healthy children. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched. The reference lists of relevant articles were examined and primary authors and Glaxo Wellcome were contacted to identify additional trials. Two reviewers independently screened studies for inclusion, assessed study quality using the Jadad scale and allocation concealment, and extracted data. Continuous data were converted to a weighted mean difference (WMD). Overall estimates were not calculated due to differences in the age groups studied. RESULTS: Three studies were included. Methodological quality was 3 (n = 2) and 4 (n = 1) on the Jadad scale. Acyclovir was associated with a significant reduction in the number of days with fever, from -1.0 (95% CI -1.5,-0.5) to -1.3 (95% CI -2.0,-0.6). Results were inconsistent with respect to the number of days to no new lesions, the maximum number of lesions and relief of pruritis. There were no clinically important differences between acyclovir and placebo with respect to complications or adverse effects. CONCLUSION: Acyclovir appears to be effective in reducing the number of days with fever among otherwise healthy children with chickenpox. The results were inconsistent with respect to the number of days to no new lesions, the maximum number of lesions and the relief of itchiness. The clinical importance of acyclovir treatment in otherwise healthy children remains controversial