Cytokinin Determines Thiol-Mediated Arsenic Tolerance and Accumulation

The presence of arsenic in soil and water is a constant threat to plant growth in many regions of the world. Phytohormones act in the integration of growth control and stress response, but their role in plant responses to arsenic remains to be elucidated. Here, we show that arsenate [As(V)], the most prevalent arsenic chemical species in nature, causes severe depletion of endogenous cytokinins (CKs) in the model plant Arabidopsis (Arabidopsis thaliana). We found that CK signaling mutants and transgenic plants with reduced endogenous CK levels showed an As(V)-tolerant phenotype. Our data indicate that in CK-depleted plants exposed to As(V), transcript levels of As(V)/phosphate-transporters were similar or even higher than in wild-type plants. In contrast, CK depletion provoked the coordinated activation of As(V) tolerance mechanisms, leading to the accumulation of thiol compounds such as phytochelatins and glutathione, which are essential for arsenic sequestration. Transgenic CK-deficient Arabidopsis and tobacco lines show a marked increase in arsenic accumulation. Our findings indicate that CK is an important regulatory factor in plant adaptation to arsenic stress

Is antibiotic prophylaxis necessary after endoscopic ultrasound–guided fine-needle aspiration of pancreatic cysts?

Background/Aims: Current society guidelines recommend antibiotic prophylaxis for 3 to 5 days after endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) of pancreatic cystic lesions (PCLs). The overall quality of the evidence supporting this recommendation is low. In this study, we aimed to assess cyst infection and adverse event rates after EUS-FNA of PCLs among patients treated with or without postprocedural prophylactic antibiotics. Methods: We retrospectively reviewed all patients who underwent EUS-FNA of PCLs between 2015 and 2019 at two large-volume academic medical centers with different practice patterns of postprocedural antibiotic prophylaxis. Data on patient demographics, cyst characteristics, fine-needle aspiration technique, periprocedural and postprocedural antibiotic prophylaxis, and adverse events were retrospectively extracted. Results: A total of 470 EUS-FNA procedures were performed by experienced endosonographers for the evaluation of PCLs in 448 patients, 58.7% of whom were women. The mean age was 66.3±12.8 years. The mean cyst size was 25.7±16.9 mm. Postprocedural antibiotics were administered in 274 cases (POSTAB+ group, 58.3%) but not in 196 cases (POSTAB– group, 41.7%). None of the patients in either group developed systemic or localized infection within the 30-day follow-up period. Procedure-related adverse events included mild abdominal pain (8 patients), intra-abdominal hematoma (1 patient), mild pancreatitis (1 patient), and perforation (1 patient). One additional case of pancreatitis was recorded; however, the patient also underwent endoscopic retrograde cholangiopancreatography. Conclusions: The incidence of infection after EUS-FNA of PCLs is negligible. Routine use of postprocedural antibiotics does not add a significant benefit

Influence of Total Coronary Occlusion on Clinical Outcomes (from the Bypass Angioplasty Revascularization Investigation 2 DiabetesTrial)

Our aim was to evaluate the influence of chronic total occlusions (CTOs) on long-term clinical outcomes of patients with coronary heart disease and diabetes mellitus. We evaluated patients with coronary heart disease and diabetes mellitus enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes, who underwent either prompt revascularization (PR) with intensive medical therapy (IMT) or IMT alone according to the presence or absence of CTO. Of 2,368 patients enrolled in the trial, 972 patients (41%) had CTO of coronary arteries. Of those, 482 (41%) and 490 (41%) were in the PR with IMT versus IMT only groups, respectively. In the PR group, patients with CTO were more likely to be selected for the coronary artery bypass grafting stratum (coronary artery bypass grafting 62% vs percutaneous coronary intervention 31%, p <0.001). Compared to the non-CTO group, patients with CTO had more abnormal Q wave, abnormal ST depression, and abnormal T waves. The myocardial jeopardy score was higher in the CTO versus non-CTO group (52 [36 to 69] vs 37 [21 to 53], p <0.001). After adjustment, 5-year mortality rate was significantly higher in the CTO group in the entire cohort (hazard ratio [HR] 1.35, p = 0.013) and in patients with CTO managed with IMT (HR 1.46, p = 0.031). However, the adjusted risk of death was not increased in patients managed with PR (HR 1.26, p = 0.180). In conclusion, CTO of coronary arteries is associated with increased mortality in patients treated medically. However, the presence of a CTO may not increase mortality in patients treated with revascularization. Larger randomized trials are needed to evaluate the effects of revascularization on long-term survival in patients with CTO

Tumor membrane-based vaccine immunotherapy in combination with anti-CTLA-4 antibody confers protection against immune checkpoint resistant murine triple-negative breast cancer

Triple-negative breast cancer (TNBC) afflicts women at a younger age than other breast cancers and is associated with a worse clinical outcome. This poor clinical outcome is attributed to a lack of defined targets and patient-to-patient heterogeneity in target antigens and immune responses. To address such heterogeneity, we tested the efficacy of a personalized vaccination approach for the treatment of TNBC using the 4T1 murine TNBC model. We isolated tumor membrane vesicles (TMVs) from homogenized 4T1 tumor tissue and incorporated glycosyl phosphatidylinositol (GPI)-anchored forms of the immunostimulatory B7-1 (CD80) and IL-12 molecules onto these TMVs to make a TMV vaccine. Tumor-bearing mice were then administered with the TMV vaccine either alone or in combination with immune checkpoint inhibitors. We show that TMV-based vaccine immunotherapy in combination with anti-CTLA-4 mAb treatment upregulated immunomodulatory cytokines in the plasma, significantly improved survival, and reduced pulmonary metastasis in mice compared to either therapy alone. The depletion of CD8+ T cells, but not CD4+ T cells, resulted in the loss of efficacy. This suggests that the vaccine acts via tumor-specific CD8+ T cell immunity. These results suggest TMV vaccine immunotherapy as a potential enhancer of immune checkpoint inhibitor therapies for metastatic triple-negative breast cancer