Clinical Remission by a Comprehensive Severe Asthma Management Strategy Guided by Airway Inflammometry and Bioimaging.

Clinical remission is a multicomponent treatment goal in severe asthma. However, only about 30% of patients achieve clinical remission when treatment decisions are guided using blood eosinophil counts and fractional exhaled nitric oxide concentrations. To assess the effectiveness of a comprehensive, individualized treatment strategy in achieving clinical remission over 24 months in patients with severe asthma.

Thiol-Based Redox Molecules: Potential Antidotes for Acrylamide Toxicity.

is a low-molecular weight, non-aromatic reagent, widely used in industry, such as in the manufacture of paper, textiles, plastics, cosmetics, and dyes. ACR is formed during the cooking of starchy food and its toxicity results mainly by conferring oxidative stress by elevating reactive oxygen species (ROS). To identify potential antidotes for ACR toxicity, we evaluated the efficacy of several thiol-based molecules known for ROS-scavenging, disulfide-reducing properties, and inhibition of oxidative stress-induced activation of the mitogen-activated protein kinases (MAPKs): the extracellular-signal-regulated-kinases (ERK1/2), p38-mitogen-activated-protein-kinases (p38), and c-Jun-N-terminal-kinases (JNKs).

Non-ionotropic voltage-gated calcium channel signaling.

Voltage-gated calcium channels (VGCCs) are the major conduits for calcium ions (Ca) within excitable cells. Recent studies have highlighted the non-ionotropic functionality of VGCCs, revealing their capacity to activate intracellular pathways independently of ion flow. This non-ionotropic signaling mode plays a pivotal role in excitation-coupling processes, including gene transcription through excitation-transcription (ET), synaptic transmission via excitation-secretion (ES), and cardiac contraction through excitation-contraction (EC).

Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs).

Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms.

CFI-400945 is a selective oral polo-like kinase 4 (PLK4) inhibitor that regulates centriole duplication. PLK4 is aberrantly expressed in patients with acute myeloid leukemia (AML). Preclinical studies indicate that CFI-400945 has potent in vivo efficacy in hematological malignancies and xenograft models, with activity in cells harboring TP53 mutations.

Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.

We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival.

Autism associated mutations in β subunit of voltage-gated calcium channels constitutively activate gene expression.

Membrane depolarization triggers gene expression through voltage-gated calcium channels (VGCC) in a process called Excitation-transcription (ET) coupling. Mutations in the channel subunits α1.2, or β, are associated with neurodevelopmental disorders such as ASD.

Elevated basal transcription can underlie timothy channel association with autism related disorders.

Timothy syndrome (TS) is a neurodevelopmental disorder caused by mutations in the pore-forming subunit α1.2 of the L-type voltage-gated Ca-channel Cav1.2, at positions G406R or G402S.

Ion occupancy of the channel pore is critical for triggering excitation-transcription (ET) coupling.

During membrane depolarization the voltage-gated calcium channel (VGCC) activates gene expression in excitable cells by means of a signal-transduction pathway termed excitation transcription (ET) coupling. The L-type calcium channel Cav1.2 can drive nuclear activity by either the ERK-CREB pathway, the Ca/calmodulin-dependent protein kinase II (CaMKII) cascade, or via the Ca-dependent protein phosphatase calcineurin.

β-Subunit of the voltage-gated Ca channel Cav1.2 drives signaling to the nucleus via H-Ras.

Depolarization-induced signaling to the nucleus by the L-type voltage-gated calcium channel Cav1.2 is widely assumed to proceed by elevating intracellular calcium. The apparent lack of quantitative correlation between Ca influx and gene activation suggests an alternative activation pathway.

Hemostatic efficacy of pathogen-inactivated vs untreated platelets: a randomized controlled trial.

Pathogen inactivation of platelet concentrates reduces the risk for blood-borne infections. However, its effect on platelet function and hemostatic efficacy of transfusion is unclear. We conducted a randomized noninferiority trial comparing the efficacy of pathogen-inactivated platelets using riboflavin and UV B illumination technology (intervention) compared with standard plasma-stored platelets (control) for the prevention of bleeding in patients with hematologic malignancies and thrombocytopenia.

The L-type Voltage-Gated Calcium Channel co-localizes with Syntaxin 1A in nano-clusters at the plasma membrane.

The secretory signal elicited by membrane depolarization traverses from the Ca-bound α1.2 pore-forming subunit of the L-type Ca-channel (Cav1.2) to syntaxin 1 A (Sx1A) via an intra-membrane signaling mechanism.

Sam68 Allows Selective Targeting of Human Cancer Stem Cells.

Targeting of human cancer stem cells (CSCs) requires the identification of vulnerabilities unique to CSCs versus healthy resident stem cells (SCs). Unfortunately, dysregulated pathways that support transformed CSCs, such as Wnt/β-catenin signaling, are also critical regulators of healthy SCs. Using the ICG-001 and CWP family of small molecules, we reveal Sam68 as a previously unappreciated modulator of Wnt/β-catenin signaling within CSCs.

Thioredoxin-mimetic peptide CB3 lowers MAPKinase activity in the Zucker rat brain.

Diabetes is a high risk factor for dementia. High glucose may be a risk factor for dementia even among persons without diabetes, and in transgenic animals it has been shown to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the activation of mitogen-activated kinsase (MAPKs), c-jun NH2-terminal kinase (JNK), p38 MAP kinases (p38(MAPK)), and extracellular activating kinsae1/2 (ERK1/2) and the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats and human neuroblastoma SH-SY5Y cells.

Intra-membrane signaling between the voltage-gated Ca2+-channel and cysteine residues of syntaxin 1A coordinates synchronous release.

The interaction of syntaxin 1A (Sx1A) with voltage-gated calcium channels (VGCC) is required for depolarization-evoked release. However, it is unclear how the signal is transferred from the channel to the exocytotic machinery and whether assembly of Sx1A and the calcium channel is conformationally linked to triggering synchronous release. Here we demonstrate that depolarization-evoked catecholamine release was decreased in chromaffin cells infected with semliki forest viral vectors encoding Sx1A mutants, Sx1A(C271V), or Sx1A(C272V), or by direct oxidation of these Sx1A transmembrane (TM) cysteine residues.

Adjuvant chemotherapy for breast cancer in a patient with primary autoimmune neutropenia.

We report an extremely rare and complex case of a 44-year-old woman diagnosed with an early stage triple negative breast cancer in the setting of primary autoimmune neutropenia with a pre-existing severe neutropenia. This case-report demonstrates that adjuvant chemotherapy for breast cancer can be administered in a patient with severe neutropenia. The management is however complicated and requires careful monitoring of side-effects related to both chemotherapy and treatment of autoimmune neutropenia.

Thioredoxin-mimetic peptides (TXM) reverse auranofin induced apoptosis and restore insulin secretion in insulinoma cells.

The thioredoxin reductase/thioredoxin system (TrxR/Trx1) plays a major role in protecting cells from oxidative stress. Disruption of the TrxR-Trx1 system keeps Trx1 in the oxidized state leading to cell death through activation of the ASK1-Trx1 apoptotic pathway. The potential mechanism and ability of tri- and tetra-oligopeptides derived from the canonical -CxxC- motif of the Trx1-active site to mimic and enhance Trx1 cellular activity was examined.

Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.

Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal.

Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels.

Ca(2+)-entry in the heart is tightly controlled by Cav1.2 inactivation, which involves Ca(2+)-dependent inactivation (CDI) and voltage-dependent inactivation (VDI) components. Timothy syndrome, a subtype-form of congenital long-QT syndrome, results from a nearly complete elimination of VDI by the G406R mutation in the α(1)1.

A review of pneumatosis intestinalis in the setting of systemic cancer treatments, including tyrosine kinase inhibitors.

Purpose: Pneumatosis intestinalis is a radiologic diagnosis that manifests in a variety of clinical settings. We report 4 cases of pneumatosis intestinalis in patients undergoing cancer treatments that included cytotoxic agents and/or tyrosine kinase inhibitors. These reports aim to provide insight into the clinical interpretation and pathogenesis of pneumatosis intestinalis in the setting of cancer treatments and demonstrate a potential association with tyrosine kinase inhibitors.

Alleviation of oxidative stress by potent and selective thioredoxin-mimetic peptides.

One of the major enzymatic cell defenses providing protection from oxidative injury is the TrxR-Trx system. It consists of NADPH and thioredoxin reductase (TrxR), which maintain thioredoxin (Trx) in a reduced state. Perturbing the TrxR-Trx system with the selective TrxR inhibitor auranofin (AuF; 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S-(triethylphosphine) gold) induces oxidative stress by keeping Trx in its oxidized state.

Lyl1 interacts with CREB1 and alters expression of CREB1 target genes.

The basic helix-loop-helix (bHLH) transcription factor family contains key regulators of cellular proliferation and differentiation as well as the suspected oncoproteins Tal1 and Lyl1. Tal1 and Lyl1 are aberrantly over-expressed in leukemia as a result of chromosomal translocations, or other genetic or epigenetic events. Protein-protein and protein-DNA interactions described so far are mediated by their highly homologous bHLH domains, while little is known about the function of other protein domains.

The L-type voltage-gated Ca2+ channel is the Ca2+ sensor protein of stimulus-secretion coupling in pancreatic beta cells.

L-type voltage-gated Ca2+ channels (Cav1.2) mediate a major part of insulin secretion from pancreatic beta-cells. Cav1.

Ion interaction at the pore of Lc-type Ca2+ channel is sufficient to mediate depolarization-induced exocytosis.

The coupling of voltage-gated Ca2+ channel (VGCC) to exocytotic proteins suggests a regulatory function for the channel in depolarization-evoked exocytosis. To explore this possibility we have examined catecholamine secretion in PC12 and chromaffin cells. We found that replacing Ca2+ with La3+ or other lanthanide ions supported exocytosis in divalent ion-free solution.