Pharmacological profiling of small molecule modulators of the TMEM16A channel and their implications for the control of artery and capillary function.

Background And Purpose: TMEM16A chloride channels constitute a depolarising mechanism in arterial smooth muscle cells (SMCs) and contractile cerebral pericytes. TMEM16A pharmacology is incompletely defined. We elucidated the mode of action and selectivity of a recently identified positive allosteric modulator of TMEM16A (PAM_16A) and of a range of TMEM16A inhibitors.

Expression of the large amino acid transporter SLC7A5/LAT1 on immune cells is enhanced in primary sclerosing cholangitis-associated cholangiocarcinoma and correlates with poor prognosis in cholangiocarcinoma.

Biliary tract cancers (BTC) are rare lethal malignancies arising along the biliary tree. Unfortunately, effective therapeutics are lacking and the prognosis remains dismal even for patients eligible for surgical resection. Therefore, novel therapeutic approaches along with early detection strategies and prognostic markers are urgently needed.

Melanoma Brain Metastases Patient-Derived Organoids: An In Vitro Platform for Drug Screening.

Background And Aims: Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status.

Incidence of treatment-resistant depression during the first mood depressive episode.

Introduction: In spite of several approaches and therapeutic measures, treatment-resistant depression (TRD) continues to inflict serious, individual and collective consequences. Therefore, there is a persistent need to scrutinize the concept of TRD in order to adapt the therapeutic strategies.

Aim: To estimate the incidence of TRD in patients with a first major depressive episode (MDD), and study factors associated with resistance.

The TMEM16A channel as a potential therapeutic target in vascular disease.

Purpose Of Review: The transmembrane protein 16A (TMEM16A) Ca 2+ -activated Cl - channel constitutes a key depolarising mechanism in vascular smooth muscle and contractile pericytes, while in endothelial cells the channel is implicated in angiogenesis and in the response to vasoactive stimuli. Here, we offer a critical analysis of recent physiological investigations and consider the potential for targeting TMEM16A channels in vascular disease.

Recent Findings: Genetic deletion or pharmacological inhibition of TMEM16A channels in vascular smooth muscle decreases artery tone and lowers systemic blood pressure in rodent models.