The aim of the present study was to assess the impact of angiographic embolization in view of expanding indications for the conservative management of grade III-IV liver injuries.
Fifty adult ...patients with grade III-IV hepatic trauma were admitted to our Hepato-Biliary-Pancreatic Surgery and Level II Regional Trauma Center from 1993 to 2010 and retrospectively analyzed. Injury severity, management strategies and outcomes of patients admitted between 1993 and 2005 were analyzed and compared with those admitted between 2005 and 2010. Univariable and multivariable logistic models were fitted to investigate the differences between the two time windows studied, in particular with regard to morbidity, mortality, treatment and outcomes, the use of non-operative management and of angiographic embolization.
At univariable analysis the majority of the patients treated after 2005 were more likely to have undergone arterial embolization, and less likely to have incurred morbidity, conversion to surgery, or to be admitted to the Intensive Care Unit after initial treatment (baseline category). At multivariable analysis the patients treated before 2005 were more likely to be older than 25 years to receive angiographic embolization and less likely to undergo conversion to surgery after failure of non-operative management.
The criteria for the conservative treatment of blunt liver trauma is presently often based on hemodynamic stability in injured patients, but its successful management should, instead, be based also on early CT recognition of arterial bleeding and prompt use of angiographic embolization to control it.
Melanoma is the most lethal form of skin cancer and treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors show only temporary benefit due the occurrence of resistance and ...immunotherapy is effective only in a subset of patients. To improve patient survival, there is a need to better understand molecular mechanisms that drive melanoma growth and operate downstream of the mitogen activated protein kinase (MAPK) signaling. The Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a critical role in embryonic development, stemness and cancer, where it can act either as oncogene or tumor suppressor. KLF4 is highly expressed in post-mitotic epidermal cells, but its role in melanoma remains unknown. Here, we address the function of KLF4 in melanoma and its interaction with the MAPK signaling pathway. We find that KLF4 is highly expressed in a subset of human melanomas. Ectopic expression of KLF4 enhances melanoma cell growth by decreasing apoptosis. Conversely, knock-down of KLF4 reduces melanoma cell proliferation and induces cell death. In addition, depletion of KLF4 reduces melanoma xenograft growth in vivo. We find that the RAS/RAF/MEK/ERK signaling positively modulates KLF4 expression through the transcription factor E2F1, which directly binds to KLF4 promoter. Overall, our data demonstrate the pro-tumorigenic role of KLF4 in melanoma and uncover a novel ERK1/2-E2F1-KLF4 axis. These findings identify KLF4 as a possible new molecular target for designing novel therapeutic treatments to control melanoma growth.
Impact of ERK5 on the Hallmarks of Cancer Stecca, Barbara; Rovida, Elisabetta
International journal of molecular sciences,
03/2019, Letnik:
20, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Extracellular signal-regulated kinase 5 (ERK5) belongs to the mitogen-activated protein kinase (MAPK) family that consists of highly conserved enzymes expressed in all eukaryotic cells and elicits ...several biological responses, including cell survival, proliferation, migration, and differentiation. In recent years, accumulating lines of evidence point to a relevant role of ERK5 in the onset and progression of several types of cancer. In particular, it has been reported that ERK5 is a key signaling molecule involved in almost all the biological features of cancer cells so that its targeting is emerging as a promising strategy to suppress tumor growth and spreading. Based on that, in this review, we pinpoint the hallmark-specific role of ERK5 in cancer in order to identify biological features that will potentially benefit from ERK5 targeting.
The Hedgehog-GLI (HH-GLI) pathway is a highly conserved signaling that plays a critical role in controlling cell specification, cell-cell interaction and tissue patterning during embryonic ...development. Canonical activation of HH-GLI signaling occurs through binding of HH ligands to the twelve-pass transmembrane receptor Patched 1 (PTCH1), which derepresses the seven-pass transmembrane G protein-coupled receptor Smoothened (SMO). Thus, active SMO initiates a complex intracellular cascade that leads to the activation of the three GLI transcription factors, the final effectors of the HH-GLI pathway. Aberrant activation of this signaling has been implicated in a wide variety of tumors, such as those of the brain, skin, breast, gastrointestinal, lung, pancreas, prostate and ovary. In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in
or gain-of-function mutations in
, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma. Besides the classical canonical ligand-PTCH1-SMO route, mounting evidence points toward additional, non-canonical ways of GLI activation in cancer. By non-canonical we refer to all those mechanisms of activation of the GLI transcription factors occurring independently of SMO. Often, in a given cancer type canonical and non-canonical activation of HH-GLI signaling co-exist, and in some cancer types, more than one mechanism of non-canonical activation may occur. Tumors harboring non-canonical HH-GLI signaling are less sensitive to SMO inhibition, posing a threat for therapeutic efficacy of these antagonists. Here we will review the most recent findings on the involvement of alternative signaling pathways in inducing GLI activity in cancer and stem cells. We will also discuss the rationale of targeting these oncogenic pathways in combination with HH-GLI inhibitors as a promising anti-cancer therapies.
Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. ...Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes in cancer yields to cancer-specific alterations of glycoprotein sialylation. Mounting evidence indicate that hypersialylation is closely associated with cancer progression and metastatic spread, and can be of prognostic significance in human cancer. Aberrant sialylation is not only a result of cancer, but also a driver of malignant phenotype, directly impacting key processes such as tumor cell dissociation and invasion, cell-cell and cell-matrix interactions, angiogenesis, resistance to apoptosis, and evasion of immune destruction. In this review we provide insights on the impact of sialylation in tumor progression, and outline the possible application of sialyltransferases as cancer biomarkers. We also summarize the most promising findings on the development of sialyltransferase inhibitors as potential anti-cancer treatments.
Abstract The Hedgehog-GLI (HH-GLI) signaling is of critical importance during embryonic development, where it regulates a number of cellular processes, including patterning, proliferation and ...differentiation. Its aberrant activation has been linked to several types of cancer. HH-GLI signaling is triggered by binding of ligands to the transmembrane receptor patched and is subsequently mediated by transcriptional effectors belonging to the GLI family, whose function is fine tuned by a series of molecular interactions and modifications. Several HH-GLI inhibitors have been developed and are in clinical trials. Similarly, the mitogen-activated protein kinases (MAPK) are involved in a number of biological processes and play an important role in many diseases including cancer. Inhibiting molecules targeting MAPK signaling, especially those elicited by the MEK1/2-ERK1/2 pathway, have been developed and are moving into clinical trials. ERK1/2 may be activated as a consequence of aberrant activation of upstream signaling molecules or during development of drug resistance following treatment with kinase inhibitors such as those for PI3K or BRAF. Evidence of a crosstalk between HH-GLI and other oncogenic signaling pathways has been reported in many tumor types, as shown by recent reviews. Here we will focus on the interaction between HH-GLI and the final MAPK effectors ERK1/2, p38 and JNK in cancer in view of its possible implications for cancer therapy. Several reports highlight the existence of a consistent crosstalk between HH signaling and MAPK, especially with the MEK1/2-ERK1/2 pathway, and this fact should be taken into consideration for designing optimal treatment and prevent tumor relapse.
Pancreatitis is a common disease of the digestive system with a high mortality and complication rate. The successful management of patients requires a multidisciplinary team of gastroenterologists, ...surgeons, interventional radiologists, and specialists in critical care medicine and nutrition. The odyssey in managing pancreatitis is a notable example of how evidence-based knowledge leads to improvement in patient care. In the last decades, operative treatment has moved towards minimally invasive techniques such as laparoscopy and endoscopic or percutaneous retroperitoneal approaches. New insights into nutritional and anesthesiology management have further improved the treatment and outcomes of pancreatitis. This book provides a comprehensive overview of this condition with chapters on physiology and pathophysiology, surgical and endoscopic management, enteral and parenteral nutritional interventions, and much more.
In this paper, we analyze the performance of several noncohesive bank erosion algorithms to be embedded into two‐dimensional models for river hydromorphodynamics on nonmoving meshes. To avoid the ...complexity of analyzing two‐dimensional model results arising from the nonlinear interaction between flow, fluvial transport, and bank erosion, we develop a simplified framework. In detail, we reduce the two‐dimensional morphodynamic model to a cross‐sectional model under the assumption of longitudinal morphodynamic equilibrium, and apply bank erosion algorithms therein. To build candidate bank erosion models, we break down bank erosion algorithms into three modeling steps: identification of the bank, computation of sediment fluxes due to bank erosion, and bank updating. Different potential models are created by choosing different options for each step. We assess model performance against surveyed bank erosion over a flood event in the transitional Selwyn River, New Zealand. This study is preliminary to implementation of bank erosion in a fully two‐dimensional setting, to model braided planform dynamics.
Key Points
We provide a novel and simple framework for assessing bank erosion algorithms
We identify two suitability criteria for bank erosion algorithms: seamless convergence to observed shift and consistency across resolutions
Model capability to reproduce event‐scale changes despite streamwise equilibrium assumption demonstrates importance of transverse processes
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