Aspartate signalling drives lung metastasis via alternative translation.

Lung metastases occur in up to 54% of patients with metastatic tumours. Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells. Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells.

Novel Far-Red Fluorescent 1,4-Dihydropyridines for L-Type Calcium Channel Imaging.

Upregulation of L-type calcium channels (LTCCs) is implicated in a range of cardiovascular and neurological disorders. Therefore, the development of toolboxes that unlock fast imaging protocols in live cells is coveted. Herein, we report a library of first-in-class far-red small-molecule-based fluorescent ligands (FluoDiPines), able to target LTCCs.

Intracellular BAPTA directly inhibits PFKFB3, thereby impeding mTORC1-driven Mcl-1 translation and killing MCL-1-addicted cancer cells.

Intracellular Ca signals control several physiological and pathophysiological processes. The main tool to chelate intracellular Ca is intracellular BAPTA (BAPTA), usually introduced into cells as a membrane-permeant acetoxymethyl ester (BAPTA-AM). Previously, we demonstrated that BAPTA enhanced apoptosis induced by venetoclax, a BCL-2 antagonist, in diffuse large B-cell lymphoma (DLBCL).

Cardiomyocyte differentiation from human induced pluripotent stem cells is delayed following knockout of Bcl-2.

Anti-apoptotic B-cell lymphoma 2 (Bcl-2) regulates a wide array of cellular functions involved in cell death, cell survival and autophagy. Less known is its involvement in the differentiation of cardiomyocytes. As a consequence, mechanisms by which Bcl-2 contributes to cardiac differentiation remain to be elucidated.

Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression.

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived induced pluripotent stem cells (DMD-COs) and isogenic-corrected controls (DMD-Iso-COs) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days).

Bcl-xL acts as an inhibitor of IPR channels, thereby antagonizing Ca-driven apoptosis.

Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca dynamics by controlling IP receptor (IPR) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IPRs and preventing pro-apoptotic Ca release and Bcl-xL sensitizing IPRs to low [IP] and promoting pro-survival Ca oscillations.

Corrigendum to "Superoxide Anion Production and Bioenergetic Profile in Young and Elderly Human Primary Myoblasts".

[This corrects the article DOI: 10.1155/2018/2615372.].

BIRD-2, a BH4-domain-targeting peptide of Bcl-2, provokes Bax/Bak-independent cell death in B-cell cancers through mitochondrial Ca-dependent mPTP opening.

Anti-apoptotic Bcl-2 critically controls cell death by neutralizing pro-apoptotic Bcl-2-family members at the mitochondria. Bcl-2 proteins also act at the endoplasmic reticulum, the main intracellular Ca-storage organelle, where they inhibit IP receptors (IPR) and prevent pro-apoptotic Ca-signaling events. IPR channels are targeted by the BH4 domain of Bcl-2.

Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery.

The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson's disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility.

BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models.

Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2's hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells.

MICAL2 is essential for myogenic lineage commitment.

Contractile myofiber units are mainly composed of thick myosin and thin actin (F-actin) filaments. F-Actin interacts with Microtubule Associated Monooxygenase, Calponin And LIM Domain Containing 2 (MICAL2). Indeed, MICAL2 modifies actin subunits and promotes actin filament turnover by severing them and preventing repolymerization.

APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin.

The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB).

Extracellular and ER-stored Ca contribute to BIRD-2-induced cell death in diffuse large B-cell lymphoma cells.

The anti-apoptotic protein Bcl-2 is upregulated in several cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In a subset of these cancer cells, Bcl-2 blocks Ca-mediated apoptosis by suppressing the function of inositol 1,4,5-trisphosphate (IP) receptors (IPRs) located at the endoplasmic reticulum (ER). A peptide tool, called Bcl-2/IP receptor disruptor-2 (BIRD-2), was developed to disrupt Bcl-2/IPR complexes, triggering pro-apoptotic Ca signals and killing Bcl-2-dependent cancer cells.

Superoxide Anion Production and Bioenergetic Profile in Young and Elderly Human Primary Myoblasts.

Sarcopenia is the age-related loss of skeletal muscle mass, strength, and function. It is associated with regenerative difficulties by satellite cells, adult muscle stem cells, and alteration of oxidative management, mainly the increase in superoxide anions (O). We aimed to investigate the relation between regenerative deficit in elderly and increase in O production along with mitochondrial alterations.

Constitutive IP signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP receptor disruptor BIRD-2.

Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP) receptor (IPR)-mediated Ca-signaling. A peptide tool (Bcl-2/IPR Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IPRs by targeting Bcl-2's BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines.

A double point mutation at residues Ile14 and Val15 of Bcl-2 uncovers a role for the BH4 domain in both protein stability and function.

B-cell lymphoma 2 (Bcl-2) protein is the archetype apoptosis suppressor protein. The N-terminal Bcl-2-homology 4 (BH4) domain of Bcl-2 is required for the antiapoptotic function of this protein at the mitochondria and endoplasmic reticulum (ER). The involvement of the BH4 domain in Bcl-2's antiapoptotic functions has been proposed based on Gly-based substitutions of the Ile14/Val15 amino acids, two hydrophobic residues located in the center of Bcl-2's BH4 domain.

Aortic aneurysm in a patient with syphilis-related spinal pain and paraplegia.

The tertiary stage of syphilis is nowadays extremely rare, showing predilection for the cardiovascular and nervous systems. A 57-year-old Caucasian man sought medical assistance due to back pain that evolved to paraplegia of the lower limbs. A thoracic CT scan demonstrated an important aneurysmatic lesion of the descending thoracic aorta causing erosion of the vertebral bodies and VDRL and FTA-abs positivity.

Endoplasmic Reticulum-Mitochondrial Ca Fluxes Underlying Cancer Cell Survival.

Calcium ions (Ca) are crucial, ubiquitous, intracellular second messengers required for functional mitochondrial metabolism during uncontrolled proliferation of cancer cells. The mitochondria and the endoplasmic reticulum (ER) are connected "mitochondria-associated ER membranes" (MAMs) where ER-mitochondria Ca transfer occurs, impacting the mitochondrial biology related to several aspects of cellular survival, autophagy, metabolism, cell death sensitivity, and metastasis, all cancer hallmarks. Cancer cells appear addicted to these constitutive ER-mitochondrial Ca fluxes for their survival, since they drive the tricarboxylic acid cycle and the production of mitochondrial substrates needed for nucleoside synthesis and proper cell cycle progression.

An Autoimmune Haemolytic Anaemia Secondary to Ipilimumab Treatment.

Background: Melanoma is one of the fastest growing neoplasms worldwide. Treatment of metastatic disease has swiftly shifted in the last decade from generally ineffective chemotherapy regimens to highly effective targeted treatments or immunotherapy, with a range of side effects that differ completely from those of previous treatments for this disease.

Case: We present a case of a 71-year-old man with diagnosis metastatic melanoma.

IP Receptor Properties and Function at Membrane Contact Sites.

The inositol 1,4,5-trisphosphate (IP) receptor (IPR) is a ubiquitously expressed Ca-release channel localized in the endoplasmic reticulum (ER). The intracellular Ca signals originating from the activation of the IPR regulate multiple cellular processes including the control of cell death versus cell survival via their action on apoptosis and autophagy. The exact role of the IPRs in these two processes does not only depend on their activity, which is modulated by the cytosolic composition (Ca, ATP, redox status, …) and by various types of regulatory proteins, including kinases and phosphatases as well as by a number of oncogenes and tumor suppressors, but also on their intracellular localization, especially at the ER-mitochondrial and ER-lysosomal interfaces.

Human periodontal ligament stem cells cultured onto cortico-cancellous scaffold drive bone regenerative process.

The purpose of this work was to test, in vitro and in vivo, a new tissue-engineered construct constituted by porcine cortico-cancellous scaffold (Osteobiol Dual Block) (DB) and xeno-free ex vivo culture of human Periodontal Ligament Stem Cells (hPDLSCs). hPDLSCs cultured in xeno-free media formulation preserved the stem cells' morphological features, the expression of stemness and pluripotency markers, and their ability to differentiate into mesenchymal lineage. Transmission electron microscopy analysis suggested that after one week of culture, both noninduced and osteogenic differentiation induced cells joined and grew on DB secreting extracellular matrix (ECM) that in osteogenic induced samples was hierarchically assembled in fibrils.