Immunotherapy in melanoma: advances, pitfalls, and future perspectives.

Cutaneous melanoma is the deadliest and most aggressive form of skin cancer owing to its high capacity for metastasis. Over the past few decades, the management of this type of malignancy has undergone a significant revolution with the advent of both targeted therapies and immunotherapy, which have greatly improved patient quality of life and survival. Nevertheless, the response rates are still unsatisfactory for the presence of side effects and development of resistance mechanisms.

HAX1 is a novel binding partner of Che-1/AATF. Implications in oxidative stress cell response.

HAX1 is a multifunctional protein involved in the antagonism of apoptosis in cellular response to oxidative stress. In the present study we identified HAX1 as a novel binding partner for Che-1/AATF, a pro-survival factor which plays a crucial role in fundamental processes, including response to multiple stresses and apoptosis. HAX1 and Che-1 proteins show extensive colocalization in mitochondria and we demonstrated that their association is strengthened after oxidative stress stimuli.

AATF/Che-1 RNA polymerase II binding protein overexpression reduces the anti-tumor NK-cell cytotoxicity through activating receptors modulation.

Introduction: AATF/Che-1 over-expression in different tumors is well known and its effect on tumorigenicity is mainly due to its central role demonstrated in the oncogenic pathways of solid tumors, where it controls proliferation and viability. The effect exerted by tumors overexpressing Che-1 on the immune response has not yet been investigated.

Methods: Starting from ChIP-sequencing data we confirmed Che-1 enrichment on Nectin-1 promoter.

CK2-mediated phosphorylation of Che-1/AATF is required for its pro-proliferative activity.

Background: Che-1/AATF (Che-1) is an RNA polymerase II binding protein involved in several cellular processes, including proliferation, apoptosis and response to stress. We have recently demonstrated that Che-1 is able to promote cell proliferation by sustaining global histone acetylation in multiple myeloma (MM) cells where it interacts with histone proteins and competes with HDAC class I members for binding.

Methods: Site-directed Mutagenesis was performed to generate a Che-1 mutant (Che-1 3S) lacking three serine residues (Ser, Ser and Ser) in 308-325 aa region.

Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression.

An Ensemble Deep Learning Model for Drug Abuse Detection in Sparse Twitter-Sphere.

As the problem of drug abuse intensifies in the U.S., many studies that primarily utilize social media data, such as postings on Twitter, to study drug abuse-related activities use machine learning as a powerful tool for text classification and filtering.

Che-1 is targeted by c-Myc to sustain proliferation in pre-B-cell acute lymphoblastic leukemia.

Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified.

Relationship between ivermectin concentrations at the injection site, muscle and fat of steers treated with traditional and long-acting preparations.

Ivermectin (IVM) is broad-spectrum compound active against endo and ecto-parasites of clinical relevance in veterinary and human medicine. It is commercially available to use in livestock animals as injectable formulations containing 1% IVM and also as a concentrated (3.15%) long-acting (LA) preparation.

Che-1 sustains hypoxic response of colorectal cancer cells by affecting Hif-1α stabilization.

Background: Solid tumours are less oxygenated than normal tissues. Consequently, cancer cells acquire to be adapted to a hypoxic environment. The poor oxygenation of solid tumours is also a major indicator of an adverse cancer prognosis and leads to resistance to conventional anticancer treatments.

Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells.

Multiple myeloma (MM) is a malignant disorder of plasma cells characterized by active production and secretion of monoclonal immunoglobulins (IgG), thus rendering cells prone to endoplasmic reticulum (ER) stress. For this reason, MM cell survival requires to maintain ER homeostasis at basal levels. Deptor is an mTOR binding protein, belonging to the mTORC1 and mTORC2 complexes.

Che-1/AATF: A Critical Cofactor for Both Wild-Type- and Mutant-p53 Proteins.

The p53 protein is a key player in a wide range of protein networks that allow the state of "good health" of the cell. Not surprisingly, mutations of the TP53 gene are one of the most common alterations associated to cancer cells. Mutated forms of p53 (mtp53) not only lose the ability to protect the integrity of the genetic heritage of the cell but also acquire pro-oncogenic functions, behaving like dangerous accelerators of transformation and tumor progression.

Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53.

The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53.

Discovering Che-1/AATF: a new attractive target for cancer therapy.

The transcriptional cofactor Che-1/AATF is currently emerging as an important component of the DNA damage response (DDR) machinery, the complex signaling network that maintains genome integrity and prevents tumorigenesis. Moreover this protein is involved in a wide range of cellular pathways, regulating proliferation and survival in both physiological and pathological conditions. Notably, some evidence indicates that dysregulation of Che-1/AATF levels are associated with the transformation process and elevated levels of Che-1/AATF are required for tumor cell survival.

Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy.

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che-1, a RNA polymerase II-binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions.

HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation.

Che-1/AATF is an RNA polymerase II-binding protein that is involved in the regulation of gene transcription, which undergoes stabilization and accumulation in response to DNA damage. We have previously demonstrated that following apoptotic induction, Che-1 protein levels are downregulated through its interaction with the E3 ligase HDM2, which leads to Che-1 degradation by ubiquitylation. This interaction is mediated by Pin1, which determines a phosphorylation-dependent conformational change.

Closantel plasma and milk disposition in dairy goats: assessment of drug residues in cheese and ricotta.

Closantel (CLS) is currently used in programs for the strategic control of gastrointestinal nematodes. CLS is extralabel used in different dairy goat production systems. From available data in dairy cows, it can be concluded that residues of CLS persist in milk.

Centrosomal Che-1 protein is involved in the regulation of mitosis and DNA damage response by mediating pericentrin (PCNT)-dependent Chk1 protein localization.

To combat threats posed by DNA damage, cells have evolved mechanisms, collectively termed DNA damage response (DDR). These mechanisms detect DNA lesions, signal their presence, and promote their repair. Centrosomes integrate G2/M checkpoint control and repair signals in response to genotoxic stress, acting as an efficient control mechanism when G2/M checkpoint function fails and mitosis begins in the presence of damaged DNA.

Residual concentrations of the flukicidal compound triclabendazole in dairy cows' milk and cheese.

Triclabendazole (TCBZ) is a flukicidal halogenated benzimidazole compound extensively used in veterinary medicine. Liver fluke control in lactating dairy cattle is difficult because treatment should be implemented only during the dry period to avoid milk residues. However, control in endemic areas is usually implemented as regular treatments three to four times a year, even during the lactating period.

Che-1 promotes tumor cell survival by sustaining mutant p53 transcription and inhibiting DNA damage response activation.

Che-1 is a RNA polymerase II binding protein involved in the regulation of gene transcription and, in response to DNA damage, promotes p53 transcription. In this study, we investigated whether Che-1 regulates mutant p53 expression. We found that Che-1 is required for sustaining mutant p53 expression in several cancer cell lines, and that Che-1 depletion by siRNA induces apoptosis both in vitro and in vivo.

Hydrogeological studies for radiological monitoring of shallow groundwater in the Eurex plant of Saluggia (Vercelli, Italy).

In 2004, contaminated water was found inside the safety interspace around the spent fuel pool; therefore, an ample monitoring programme of the structure, soils and shallow groundwater was started in order to detect any radioactive leakage into the environment. A first group of piezometers was installed. In the one nearest to the pool, an anomalous activity of (90)Sr ( approximately 10(-2) Bq l(-1)) was found, calling for the following actions: gradual enlarging of the monitoring network, implementation of in situ permeability tests and groundwater tracer test and study of groundwater mobility of the main radionuclides contained in the pool water: (90)Sr, (137)Cs, (241)Am and (239/240)Pu.

Che-1 activates XIAP expression in response to DNA damage.

X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis proteins family that selectively binds and inhibits caspase-3, -7 and -9. As such, XIAP is an extremely potent suppressor of apoptosis and an attractive target for cancer treatment. Che-1 is an antiapoptotic agent involved in the control of gene transcription and cell proliferation.

NRAGE associates with the anti-apoptotic factor Che-1 and regulates its degradation to induce cell death.

Neurotrophin receptor-interacting MAGE homolog (NRAGE) has been recently identified as a cell-death inducer, involved in molecular events driving cells through apoptotic networks during neuronal development. Recently, we have focused on the functional role of Che-1, also known as apoptosis-antagonizing transcription factor (AATF), a protein involved in cell cycle control and gene transcription. Increasing evidence suggests that Che-1 is involved in apoptotic signalling in neural tissues.

The prolyl isomerase Pin1 affects Che-1 stability in response to apoptotic DNA damage.

We have previously demonstrated that DNA damage leads to stabilization and accumulation of Che-1, an RNA polymerase II-binding protein that plays an important role in transcriptional activation of p53 and in maintenance of the G(2)/M checkpoint. Here we show that Che-1 is down-regulated during the apoptotic process. We found that the E3 ligase HMD2 physically and functionally interacts with Che-1 and promotes its degradation via the ubiquitin-dependent proteasomal system.

Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint.

Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage.