The Influence of Phosphoinositide Lipids in the Molecular Biology of Membrane Proteins: Recent Insights from Simulations.

The phosphoinositide family of membrane lipids play diverse and critical roles in eukaryotic molecular biology. Much of this biological activity derives from interactions of phosphoinositide lipids with integral and peripheral membrane proteins, leading to modulation of protein structure, function, and cellular distribution. Since the discovery of phosphoinositides in the 1940s, combined molecular biology, biophysical, and structural approaches have made enormous progress in untangling this vast and diverse cellular network of interactions.

Ligand-induced conformational changes in the β1-adrenergic receptor revealed by hydrogen-deuterium exchange mass spectrometry.

G Protein Coupled Receptors (GPCRs) constitute the largest family of signalling proteins responsible for translating extracellular stimuli into intracellular functions. They play crucial roles in numerous physiological processes and are major targets for drug discovery. Dysregulation of GPCRs is implicated in various diseases, making understanding their structural dynamics critical for therapeutic development.

Infrared Multiphoton Dissociation Enables Top-Down Characterization of Membrane Protein Complexes and G Protein-Coupled Receptors.

Membrane proteins are challenging to analyze by native mass spectrometry (MS) as their hydrophobic nature typically requires stabilization in detergent micelles that are removed prior to analysis via collisional activation. There is however a practical limit to the amount of energy which can be applied, which often precludes subsequent characterization by top-down MS. To overcome this barrier, we have applied a modified Orbitrap Eclipse Tribrid mass spectrometer coupled to an infrared laser within a high-pressure linear ion trap.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

Background: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.

Dysregulated expression of GATA2 and GATA6 transcription factors in adenomyosis: implications for impaired endometrial receptivity.

Objective: To study the effect of adenomyosis on the localized expression of the GATA binding proteins 2 and 6 (GATA2 and GATA6) zinc-finger transcription factors that are involved in proliferation of hematopoietic and endocrine cell lineages, cell differentiation, and organogenesis, potentially leading to impaired endometrial implantation.

Design: Laboratory based experimental study.

Setting: Academic hospital and laboratory.

Infrared Multiphoton Dissociation Enables Top-Down Characterization of Membrane Protein Complexes and G Protein-Coupled Receptors.

Membrane proteins are challenging to analyze by native mass spectrometry (MS) as their hydrophobic nature typically requires stabilization in detergent micelles that are removed prior to analysis via collisional activation. There is however a practical limit to the amount of energy which can be applied, which often precludes subsequent characterization by top-down MS. To overcome this barrier, we have applied a modified Orbitrap Eclipse Tribrid mass spectrometer coupled to an infrared laser within a high-pressure linear ion trap.

G Protein-Coupled Receptor Pharmacology-Insights from Mass Spectrometry.

G protein-coupled receptors (GPCRs) are key drug targets due to their involvement in many physiological processes. The complexity of receptor pharmacology, however, is influenced by multiple interactions with various types of ligands and protein transducers representing significant challenges for drug discovery. The ability of mass spectrometry (MS) to observe both the binding of ligand molecules, such as lipids, ions, or drugs, and their impact on interaction with transducers provides an exciting opportunity to probe many aspects that are difficult to track directly in cell-based systems.

Mass spectrometry captures biased signalling and allosteric modulation of a G-protein-coupled receptor.

G-protein-coupled receptors signal through cognate G proteins. Despite the widespread importance of these receptors, their regulatory mechanisms for G-protein selectivity are not fully understood. Here we present a native mass spectrometry-based approach to interrogate both biased signalling and allosteric modulation of the β-adrenergic receptor in response to various ligands.

Restoring tubal patency with laparoscopic tubocornual anastomosis.

Objective: To assess the technical feasibility of laparoscopic tubocornual anastomosis (TCA) at restoring tubal patency in patients with proximal tubal occlusions.

Materials And Methods: A retrospective analysis of fourteen females with identified proximal tubal occlusions seeking to restore their tubal patency in a university-affiliated tertiary hospital between 2011 and 2018. Tubal patency within one year after the surgery was evaluated.

A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors.

Background: Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab.

Predictors of 30-day mortality after endovascular thrombectomy for large vessel occlusion in the elderly.

Objectives: Elderly acute ischemic stroke (AIS) patients (≥80 years) would have dismal clinical outcomes even after successful endovascular revascularization for large vessel occlusion (LVO) in the anterior circulation. We aimed to identify predictors of 30-day mortality after endovascular thrombectomy (EVT) in the elderly.

Materials And Methods: We included older patients who underwent EVT for AIS due to LVO within 6 h after stroke onset in the anterior circulation between 2017 and 2019.

Radiomic Features at CT Can Distinguish Pancreatic Cancer from Noncancerous Pancreas.

Purpose To identify distinguishing CT radiomic features of pancreatic ductal adenocarcinoma (PDAC) and to investigate whether radiomic analysis with machine learning can distinguish between patients who have PDAC and those who do not. Materials and Methods This retrospective study included contrast material-enhanced CT images in 436 patients with PDAC and 479 healthy controls from 2012 to 2018 from Taiwan that were randomly divided for training and testing. Another 100 patients with PDAC (enriched for small PDACs) and 100 controls from Taiwan were identified for testing (from 2004 to 2011).

Correlating Glycoforms of DC-SIGN with Stability Using a Combination of Enzymatic Digestion and Ion Mobility Mass Spectrometry.

The immune scavenger protein DC-SIGN interacts with glycosylated proteins and has a putative role in facilitating viral infection. How these recognition events take place with different viruses is not clear and the effects of glycosylation on the folding and stability of DC-SIGN have not been reported. Herein, we report the development and application of a mass-spectrometry-based approach to both uncover and characterise the effects of O-glycans on the stability of DC-SIGN.

Keratoconus Screening Based on Deep Learning Approach of Corneal Topography.

Purpose: To develop and compare deep learning (DL) algorithms to detect keratoconus on the basis of corneal topography and validate with visualization methods.

Methods: We retrospectively collected corneal topographies of the study group with clinically manifested keratoconus and the control group with regular astigmatism. All images were divided into training and test datasets.

Efficacy and Safety of Ramucirumab in Asian and Non-Asian Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Individual Data Analysis of Two Randomized Studies.

Objective: REACH-2 and REACH were randomized, placebo-controlled, double-blind, multicenter phase 3 trials which showed survival benefits of ramucirumab treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). We evaluated the efficacy and safety of ramucirumab in Asian and non-Asian patients with AFP ≥400 ng/mL from REACH-2 and REACH.

Methods: We pooled Asian and non-Asian patients from the REACH-2 and REACH trials and performed an individual patient data meta-analysis.

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours.

Background: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers.

Methods: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]).

PtdIns(4,5)P stabilizes active states of GPCRs and enhances selectivity of G-protein coupling.

G-protein-coupled receptors (GPCRs) are involved in many physiological processes and are therefore key drug targets. Although detailed structural information is available for GPCRs, the effects of lipids on the receptors, and on downstream coupling of GPCRs to G proteins are largely unknown. Here we use native mass spectrometry to identify endogenous lipids bound to three class A GPCRs.

Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.

Background: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1.

Methods: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML.

Interferon-β Modulates Inflammatory Response in Cerebral Ischemia.

Background: Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade.

Cardiovascular, Bleeding, and Mortality Risks of Dabigatran in Asians With Nonvalvular Atrial Fibrillation.

Background And Purpose: Whether dabigatran is associated with different risks of cardiovascular, bleeding events, and mortality from warfarin in Asian patients with nonvalvular atrial fibrillation remains unclear.

Methods: We used the Taiwan National Health Insurance Research Database to obtain 9940 and 9913 nonvalvular atrial fibrillation patients taking dabigatran and warfarin, respectively, from June 1, 2012, to December 31, 2013, as the dynamic cohort. Inverse probability of treatment weighting using propensity scores was used to balance covariates across 2 study groups.

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation.

Mortality of Parkinson's disease by Hoehn-Yahr stage from community-based and clinic series [Keelung Community-based Integrated Screening (KCIS) no. 17)].

Purpose: We aimed to quantify the mortality reduction by which the early detection of Parkinson's disease (PD) within a community-based study could reduce the number of advanced cases.

Methods: Data used in this study were derived from two community-based surveys and from a clinical series of PD cases identified from a medical centre. The cumulative survival by Hoehn-Yahr (H-Y) scale was estimated and the mortality reduction derived from a community-based survey was predicted.

Natural history and effectiveness of early detection of Parkinson's disease: results from two community-based programmes in Taiwan (KCIS no. 11).

Objectives: The natural course of Parkinson's disease (PD), as measured on the Hoehn-Yahr (H-Y) scale, and the impact that early detection would have on prognosis for those with the disease, has barely been addressed since the introduction of L-dopa. This study aimed to elucidate the natural history of PD and effectiveness of early detection in reducing advanced disability and mortality.

Method: A total of 21 362 participants aged 40 years or older were invited to two community-based programmes for the early detection of PD.

Sensitivity and specificity of 99mTc-TRODAT-1 SPECT imaging in differentiating patients with idiopathic Parkinson's disease from healthy subjects.

Unlabelled: The imaging of dopamine transporter (DAT) with (99m)Tc-TRODAT-1 ([2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2']oxo-[1R-(exo-exo)]-(99m)Tc-technetium) and SPECT has been recently proposed to be a valuable and feasible means of assessment of the integrity of dopamine neurons. The purpose of this study was to further investigate the clinical correlations and the age-specific sensitivity and specificity of this new approach in the diagnosis of patients with idiopathic Parkinson's disease (PD) that manifests in patients >50 y of age.

Methods: SPECT imaging with (99m)Tc-TRODAT-1 was conducted in 78 consecutive PD patients and in 40 age-matched healthy subjects.