Coexistence of three EGFR mutations in an NSCLC patient: A brief report

The epidermal growth factor receptor (EGFR) represents a molecular target for tyrosine kinase inhibitors for non-small cell lung cancer (NSCLC) patients with a mutation in the EGFR gene. Mutations of the EGFR gene that occur at a single position in NSCLC tissue are found as single, whereas two or more mutations on the same allele are poorly detected and investigated

The role of primary cilia in cancer

Primary cilia are microtubule based organelles that sense and transduce multiple extracellular signals to the interior of the cell through several signaling pathways. Ciliary defects lead to different pathologies. Interestingly, decreased ciliary expression has been associated with different types of cancer. In this review, we discuss the function and dynamics of primary cilia, their relation to different diseases and in particular their role in cancer, and how they can be explored as potential therapeutic targets.Sociedad Argentina de Fisiologí

Synthetic conjugates of ursodeoxycholic acid inhibit cystogenesis in experimental models of polycystic liver disease

Background and aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and results: here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: these UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs

Criteria for preclinical models of cholangiocarcinoma:scientific and medical relevance

Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA

Cholangiopathies and the noncoding revolution

Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) among others, have attracted a great deal of attention for their potential role as master regulators of gene expression and as therapeutic targets. This review focuses on recent advances on the role of ncRNAs in the pathogenesis, diagnosis and treatment of diseases of the cholangiocytes (i.e. cholangiopathies)

Primers on molecular pathways - ion channels: key regulators of pancreatic physiology

Ion transport across the cellular plasma membrane is important in almost every physiological process. This phenomenon is driven by the coordinated action of carriers, pumps and channels, which move ions in and out the cells and between different organelles. Ion channels are transmembrane proteins that provide a continuous aqueous pore through which ions can selectively move. The interest in these molecules has increased due to the recognition of diverse pathologies related with mutations in genes encoding these transmembrane proteins, now known as channelopathies. Ion channels play a variety of functions in the pancreas. Here, we briefly describe ion transport characteristics as well as their role in pancreas physiology and pathophysiology

Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA