Emerging roles of ATF2 and the dynamic AP1 network in cancer

Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lau, Eric . Burnham Institute for Medical Research; Estados UnidosFil: Ronai, Zeev . Burnham Institute for Medical Research; Estados Unido

Systemic Therapies for the Management of Non–Clear Cell Renal Cell Carcinoma: What Works, What Doesn't, and What the Future Holds

Non–clear cell renal cell carcinoma (nccRCC) is a broad term that refers to a diverse group of tumors, each with its own distinct biologic and therapeutic profile. The management of nccRCCs is often based on extrapolating data from clinical trials in the more common clear cell renal cell carcinoma, but our emerging prospective and retrospective clinical experience in nccRCC allows us to make more precise recommendations tailored to each histology. The systemic therapy options for metastatic nccRCC include targeted therapies such as tyrosine kinase inhibitors, immune checkpoint inhibitors, and, for specific rare subtypes, cytotoxic chemotherapy. Each nccRCC histology may respond differently to these regimens, which makes accurate pathologic diagnosis imperative. In the present review, we discuss the available clinical and biological data that can help guide systemic therapy recommendations for specific nccRCC subtypes. © 2020 Elsevier Inc

DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival

Head and neck cancer (HNC) is a term collectively used to describe a heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx, and represents the sixth most common type of malignancy worldwide. Despite advances in multimodality treatment, the disease has a recurrence rate of around 50%, and the prognosis of metastatic patients remains poor. HNCs are characterized by a high degree of genomic instability, which involves a vicious circle of accumulating DNA damage, defective DNA damage repair (DDR), and replication stress. Nonetheless, the damage that is induced on tumor cells by chemo and radiotherapy relies on defective DDR processes for a successful response to treatment, and may play an important role in the development of novel and more effective therapies. This review summarizes the current knowledge on the genes and proteins that appear to be deregulated in DDR pathways, their implication in HNC pathogenesis, and the rationale behind targeting these genes and pathways for the development of new therapies. We give particular emphasis on the therapeutic targets that have shown promising results at the pre-clinical stage and on those that have so far been associated with a therapeutic advantage in the clinical setting

Venous Thromboembolism in Pregnancy: Challenges and Solutions

Dimitrios Varrias,1,2,* Michail Spanos,3,* Damianos G Kokkinidis,4 Panagiotis Zoumpourlis,1,2 Dimitrios Rafail Kalaitzopoulos5 1Department of Medicine, Jacobi Medical Center, Bronx, NY, 10461, USA; 2Albert Einstein College of Medicine, Bronx, NY, 10461, USA; 3Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; 4Section of Cardiovascular Medicine, Yale University School of Medicine, Yale New Haven Hospital, New Haven, CT, USA; 5Department of Gynecology and Obstetrics, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland*These authors contributed equally to this workCorrespondence: Dimitrios Varrias, Jacobi NYCHHC, 1400 Pelham Parkway South, 3N1, Bronx, NY, 10461, USA, Tel +1 7189185000, Email [email protected]: Venous thromboembolism (VTE) is a serious medical condition that can lead to severe morbidity and mortality, making it a significant public health concern. VTE is a multifactorial condition that results from the interaction of genetic, acquired, and environmental factors. Physiological changes during pregnancy increase the risk of VTE as they express Virchow’s triad (increased coagulation factors, decreased fibrinolysis, trauma, and venous stasis). Moreover, pregnancy-related risk factors, such as advanced maternal age, obesity, multiple gestations, and cesarean delivery, further increase the risk of VTE. Managing VTE in pregnancy is challenging due to the complexity of balancing the risks and benefits of anticoagulant therapy for both the mother and the fetus. A multidisciplinary approach involving obstetricians, hematologists, and neonatologists, is necessary to ensure optimal outcomes for both the mother and baby. This review aims to discuss the current challenges associated with VTE in pregnancy and identify potential solutions for improving outcomes for pregnant women at risk for VTE.Keywords: venous embolism, thrombosis, pregnancy, VTE, anticoagulatio

Outcomes after intra-aortic balloon pump insertion in cardiac surgery patients

Objective: To assess whether preoperative versus intraoperative insertion of an intra-aortic balloon pump is associated with lower 30-day mortality or reduced length of hospital stay among patients who had an intra-aortic balloon pump inserted for cardiac surgery. Methods: This was an observational study of patients who had an intraaortic balloon pump inserted in the preoperative or intraoperative period of cardiac surgery in our department between 2000 and 2012. We assessed the association between preoperative versus intraoperative insertion of an intra-aortic balloon pump and 30-day mortality in a multivariable logistic regression analysis, including preoperative New York Heart Association class, postoperative atrial fibrillation, reoperation, postoperative creatinine and isolated coronary bypass grafting as cofactors. We used a multivariate linear model to assess whether a preoperative versus intraoperative intra-aortic balloon pump was associated with length of postoperative hospital stay, adjusting for reoperation, isolated coronary bypass grafting, heart valve surgery, sex, age, cardiopulmonary bypass time, aortic cross-clamp time, preoperative patients' status (elective, urgency or emergency surgery) and preoperative myocardial infarction. Results: Overall, 7,540 consecutive patients underwent open heart surgery in our department, and an intra-aortic balloon pump was inserted pre- or intraoperatively in 322 (4.2%) patients. The mean age was 67 ± 10.2 years old, the 30-day mortality was 12.7%, and the median length of hospital stay was 9 days (7 - 13). Preoperative versus intraoperative intra-aortic balloon pump insertion did not affect the incidence of 30-day mortality (adjusted OR = 0.69; 95% CI, 0.15 - 3.12; p = 0.63) and length of postoperative hospital stay (β = 5.3; 95%CI, -1.6 to 12.8; p = 0.13). Conclusion: Preoperative insertion of an intra-aortic balloon pump was not associated with a lower 30- day mortality or reduced length of postoperative hospital stay compared to intraoperative insertion. © 2020 Associacao de Medicina Intensiva Brasileira - AMIB. All rights reserved

Serum neopterin levels in women with preeclampsia: a systematic review

Objective: Neopterin is a pteridine that is produced following activation of human macrophages upon stimulation with the cytokine interferon-gamma. Several studies suggest its association with preeclampsia and the purpose of the present study is to evaluate this assumption. Methods: We searched the Medline (1992–2018), Scopus (1993–2018) and Google Scholar (1993–2018) databases. All articles that evaluated serum neopterin levels in patients with preeclampsia were held eligible for inclusion, regardless of the trimester of pregnancy in which the measurement was performed. Case reports, animal studies and previous reviews were excluded. Results: A total of 10 studies were finally included in the present review, with a total number of 3,529 pregnant women. Among them 446 were diagnosed with preeclampsia. The majority of included studies reported that serum neopterin was significantly higher in patients with preeclampsia, compared to normotensive pregnant women (p <.05). One study reported that serum levels seem to correlate with the severity of the disease; as patients with HELLP had significantly higher values of neopterin compared to patients with mild and severe preeclampsia. None of the included studies proposed a cut-off value that would help assess the predictive accuracy of this protein for the detection of preeclampsia. Conclusion: Although current data seem to be promising, neopterin remains far from being used in current clinical practice as a biomarker that would help predict and follow-up patients that develop preeclampsia. Future studies are needed, to determine the optimal timing for its measurement and to propose potential cut-off values that would help in this direction. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group

Overexpression of activating transcription factor-2 is required for tumor growth and progression in mouse skin tumors

Activating transcription factor (ATF)-2 is a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. It has been shown, in vitro, to possess growth factor-independent proliferation and transformation capacity. The information concerning the involvement of ATF-2 in carcinogenesis is rather limited. In a previous report, we showed a progressive increase in the levels of various activator protein (AP)-1 components, including phosphorylated ATF-2, in a series of mouse skin cell lines that represented developmental stages of the mouse skin carcinogenesis system. In the present study, we examined in detail the role of ATF-2 in the development of mouse skin spindle cells A5 and CarB, which correspond to the late and most aggressive stage of the mouse skin carcinogenesis model. To address this issue, we overexpressed a dominant negative form of ATF-2 in the A5 and CarB cell lines and examined their behavior in vitro and in vivo at the molecular and cellular level. The stable transfectants expressed decreased levels of phosphorylated ATF-2 and c-Jun. Subsequently, we observed that dominant negative ATF-2 affected the composition and reduced the activity of AP-1. The above biochemical changes were followed, both in vitro and in vivo in BALB/c severe combined inummodeficient mice, by suppression of the aggressive characteristics of the A5 and CarB mouse skin spindle cells. We attributed this behavior to the significant down-regulation of cyclin D1, cyclin A, and ATF-3, known AP-1 targets implicated in cell cycle control and promotion. In conclusion, our findings underscore a key regulatory role of ATF-2 in tumor growth and progression of mouse skin tumors

Article bromamine T (BAT) exerts stronger anti-cancer properties than taurine (tau)

Background: Taurine (Tau) ameliorates cancer pathogenesis. Researchers have focused on the functional properties of bromamine T (BAT), a stable active bromine molecule. Both N-bromotaurine (TauNHBr) and BAT exert potent anti-inflammatory properties, but the landscape remains obscure concerning the anti-cancer effect of BAT. Methods: We used Crystal Violet, colony formation, flow cytometry and Western blot experiments to evaluate the effect of BAT and Tau on the apoptosis and autophagy of cancer cells. Xenograft experiments were used to determine the in vivo cytotoxicity of either agent. Results: We demonstrated that both BAT and Tau inhibited the growth of human colon, breast, cervical and skin cancer cell lines. Among them, BAT exerted the greatest cytotoxic effect on both RKO and MDA-MB-468 cells. In particular, BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK12 ), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK12 ), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. In contrast, Tau exerted its cytotoxic effect by upregulating JNK12 forms, thus triggering mitochondrial apoptosis in RKO cells. Accordingly, colon cancer growth was impaired in vivo. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities. © 2021 by the authors. Licensee MDPI, Basel, Switzerland