Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival.

Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present with advanced disease and are treated with cytotoxic therapy. Genomic biomarkers prognostic of disease outcomes have been challenging to identify.

Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.

The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4).

Necroptosis induced by ruthenium (II) complexes as mitochondrial disruptors.

Inducing necroptosis in cancer cells has emerged as an effective strategy to overcome drug resistance. However, while organic small molecules have been extensively studied for this purpose, metal-based compounds have received relatively little attention as triggers of necroptosis. The development of ruthenium (II) hybrid compounds, particularly those containing triazene (Ru-TRZ), highlights a novel avenue for modulating necroptotic cell death.

Target Identification in Anti-Tuberculosis Drug Discovery.

(Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation.

A step forward on the in vitro and in vivo assessment of a novel nanomedicine against melanoma.

Melanoma is the most aggressive form of skin cancer, with increasing incidence and mortality rates. To overcome current treatment limitations, a hybrid molecule (HM) combining a triazene and a sulfur L-tyrosine analogue, was recently synthesized, incorporated in long blood circulating liposomes (LIP HM) and validated in an immunocompetent melanoma model. The present work constitutes a step forward in the therapeutic assessment of HM formulations.

Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management.

The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma.

Sulfur Analogues of Tyrosine in the Development of Triazene Hybrid Compounds: A New Strategy against Melanoma.

Malignant melanoma is the major cause of death from skin cancer. Treatment of metastatic melanoma remains an enormous challenge. In this study we developed hybrid compounds and studied their potential use in malignant melanoma chemotherapy.

Discovery of a Necroptosis Inhibitor Improving Dopaminergic Neuronal Loss after MPTP Exposure in Mice.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, mainly characterized by motor deficits correlated with progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SN). Necroptosis is a caspase-independent form of regulated cell death mediated by the concerted action of receptor-interacting protein 3 (RIP3) and the pseudokinase mixed lineage domain-like protein (MLKL). It is also usually dependent on RIP1 kinase activity, influenced by further cellular clues.

Metabolism of N-ethylhexedrone and buphedrone: An in vivo study in mice using HPLC-MS/MS.

N-ethylhexedrone (NEH) and buphedrone (BUPH) are synthetic drugs structurally related to natural cathinone. These synthetic cathinones (SC) are members of the heterogenous family of new psychoactive substances (NPS), which have caused major concern in scientific and forensic communities over the past years, due to their widespread consume. Thus, there is a constant need for monitoring the use of these new substances and gather knowledge on their metabolism and excretion profiles, in order to try to identify markers of NPS consumption.

Anticancer Triazenes: from Bioprecursors to Hybrid Molecules.

Triazenes are a very useful and diverse class of compounds that have been studied for their potential in the treatment of many tumors including brain tumor, leukemia and melanoma. Novel compounds of this class continue to be developed as either anticancer compounds or even with other therapeutic applications. This review focused on several types of triazenes from the simplest ones like 1,3-dialkyl-3-acyltriazenes to the more complex ones like combi-triazenes with an emphasis on how triazenes have been developed as effective antitumor agents.

Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability.

Herein we report novel hybrid compounds based on valproic acid and DNA-alkylating triazene moieties, 1, with therapeutic potential for glioblastoma multiforme chemotherapy. We identified hybrid compounds 1d and 1e to be remarkably more potent against glioma and more efficient in decreasing invasive cell properties than temozolomide and endowed with chemical and plasma stability. In contrast to temozolomide, which undergoes hydrolysis to release an alkylating metabolite, the valproate hybrids showed a low potential to alkylate DNA.

Endoperoxide-8-aminoquinoline hybrids as dual-stage antimalarial agents with enhanced metabolic stability.

Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC values in the nM range, and with low cytotoxicity against mammalian cells.

The selective cytotoxicity of new triazene compounds to human melanoma cells.

Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell.

From hybrid compounds to targeted drug delivery in antimalarial therapy.

The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains.

Targeting the erythrocytic and liver stages of malaria parasites with s-triazine-based hybrids.

A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells.

Bayesian analyses demonstrate tissue blood volume is not decreased during acute sickle cell pain episodes: A preliminary study.

Background: Pain is the most common complication of Sickle Cell Disease (SCD). Tissue oximetry properties in SCD during steady state and acute pain are not well described.

Methods: This was a cross sectional study of tissue oximetry properties in individuals with SCD during steady state, acute pain and healthy controls without SCD.

Design and discovery of mushroom tyrosinase inhibitors and their therapeutic applications.

Introduction: Tyrosinase inhibitors could have a huge importance in medicine, cosmetics and agriculture. Although many tyrosinase inhibitors are available, they have demonstrated only mild efficacy and safety concerns. This has led to the discovery of novel tyrosinase inhibitors that are more safe, potent and efficacious.

Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: synthesis and stability of N-acylamino acid derivatives of triazenes.

A series of 3-[alpha-(acylamino)acyl]-1-aryl-3-methyltriazenes 6a-l, potential cytotoxic triazene prodrugs, were synthesised by coupling 1-aryl-3-methyltriazenes to N-acylamino acids. Their hydrolysis was studied in isotonic pH 7.4 phosphate buffer and in human plasma, while hydrolysis of the derivative 6a was studied in more depth across a range of pH values.