Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the -terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease.

Beyond isotropic repulsion: Classical anisotropic repulsion by inclusion of p orbitals.

Accurate modeling of intermolecular repulsion is an integral component in force field development. Although repulsion can be explicitly calculated by applying the Pauli exclusion principle, this approach is computationally viable only for systems of limited sizes. Instead, it has previously been shown that repulsion can be reformulated in a "classical" picture: the Pauli exclusion principle prohibits electrons from occupying the same state, leading to a depletion of electronic charge between atoms, giving rise to an enhanced nuclear-nuclear electrostatic repulsion.

Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers.

The unique virus-cell interaction in Epstein-Barr virus (EBV)-associated malignancies implies targeting the viral latent-lytic switch is a promising therapeutic strategy. However, the lack of specific and efficient therapeutic agents to induce lytic cycle in these cancers is a major challenge facing clinical implementation. We develop a synthetic transcriptional activator that specifically activates endogenous BZLF1 and efficiently induces lytic reactivation in EBV-positive cancer cells.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies.

Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site.

Randomized Trial of Prophylactic Antibiotics for Endoscopic Retrograde Cholangiopancreatography in Patients With Biliary Obstruction.

Introduction: The incidence of postendoscopic retrograde cholangiopancreatography (ERCP) infections is reported to be up to 18% in patients with biliary obstruction. Antibiotic prophylaxis may reduce the risk of infectious complications after ERCP; however, the clinical value of prophylactic antibiotics in ERCP remains controversial.

Methods: We conducted a double-blind, placebo-controlled, randomized trial to investigate whether the use of prophylactic antibiotics would reduce infectious complications after ERCP in patients with biliary obstruction.

Dual antiplatelet therapy de-escalation in acute coronary syndrome: an individual patient meta-analysis.

Aims: Dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is the standard treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). De-escalation of the potent P2Y12 inhibtor is an appealing concept to balance the ischaemic and bleeding risks after PCI. An individual patient data meta-analysis was performed to compare de-escalation versus standard DAPT in patients with ACS.

Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial.

Background: Long-term comparative outcomes after percutaneous coronary intervention (PCI) with everolimus-eluting stents and coronary artery bypass grafting (CABG) are limited in patients with multivessel coronary artery disease.

Methods: This prospective, multicenter, randomized controlled trial was conducted in 27 international heart centers and was designed to randomly assign 1776 patients with angiographic multivessel coronary artery disease to receive PCI with everolimus-eluting stents or CABG. After inclusion of 880 patients (438 in the PCI group and 442 in the CABG group) between July 2008 and September 2013, the study was terminated early because of slow enrollment.

Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.

Background: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane.

Methods: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety.

Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells.

Although hydroxychloroquine (HCQ) has long been used to treat autoimmune diseases, its mechanism of action remains poorly understood. In CD4 T-cells, we found that a clinically relevant concentration of HCQ inhibited the mitochondrial antioxidant system triggered by TCR crosslinking, leading to increased mitochondrial superoxide, impaired activation-induced autophagic flux, and reduced proliferation of CD4 T-cells. In antigen-presenting cells, HCQ also reduced constitutive activation of the endo-lysosomal protease legumain and toll-like receptor 9, thereby reducing cytokine production, but it had little apparent impact on constitutive antigen processing and peptide presentation.

Perivascular Spaces in the Basal Ganglia and Long-term Motor Prognosis in Newly Diagnosed Parkinson Disease.

Objective: To investigate the association between enlarged perivascular spaces (PVS) in the basal ganglia (BG-PVS) and long-term motor outcomes in Parkinson disease (PD).

Methods: We reviewed the medical records of 248 patients with drug-naive early-stage PD (follow-up >3 years, mean age 67.44 ± 8.

Reactive Oxygen Species Scavenger in Acute Intracerebral Hemorrhage Patients: A Multicenter, Randomized Controlled Trial.

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Machine Learning-Based Automatic Rating for Cardinal Symptoms of Parkinson Disease.

Objective: We developed and investigated the feasibility of a machine learning-based automated rating for the 2 cardinal symptoms of Parkinson disease (PD): resting tremor and bradykinesia.

Methods: Using OpenPose, a deep learning-based human pose estimation program, we analyzed video clips for resting tremor and finger tapping of the bilateral upper limbs of 55 patients with PD (110 arms). Key motion parameters, including resting tremor amplitude and finger tapping speed, amplitude, and fatigue, were extracted to develop a machine learning-based automatic Unified Parkinson's Disease Rating Scale (UPDRS) rating using support vector machine (SVM) method.

Novel Mutations and Decreased Expression of the Epigenetic Regulator in Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in and 16 other genes; however, these mutations occur in <25% of patients with idiopathic PAH and are rare in PAH associated with connective tissue diseases. Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH.

Clinical factors influencing the impact of cluster headache from a prospective multicenter study.

Although many patients with cluster headaches (CH) are disabled by their condition, few studies have examined this in detail. This cross-sectional, multicenter observational study prospectively collected demographic and clinical questionnaire data from 224 consecutive patients with CH. We assessed headache impact using the six-item Headache Impact Test (HIT-6) and evaluated the factors associated with the impact of CH.

Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis.

Background: The timing and indications for surgical intervention in asymptomatic patients with severe aortic stenosis remain controversial.

Methods: In a multicenter trial, we randomly assigned 145 asymptomatic patients with very severe aortic stenosis (defined as an aortic-valve area of ≤0.75 cm with either an aortic jet velocity of ≥4.

Urodynamic study for distinguishing multiple system atrophy from Parkinson disease.

Objective: To evaluate the differences in urodynamic findings between multiple system atrophy (MSA) and Parkinson disease (PD) and to identify the differential diagnostic ability of urodynamic study.

Methods: We reviewed patients with MSA or PD who underwent urodynamic studies between January 2011 and August 2018. Patients with probable MSA and PD determined by movement disorder specialists at our center were included.

Key Population Health Outcomes for Children with Medical Complexity: A Systematic Review.

Introduction: Despite the significant healthcare policy and program implications, a summary measure of health for children with medical complexity (CMC) has not been identified. It is unclear whether existing population health approaches apply to CMC. We conducted a systematic review of the existing peer-reviewed research literature on CMC to describe the health outcomes currently measured for CMC.

Alternative polyadenylation of single cells delineates cell types and serves as a prognostic marker in early stage breast cancer.

Alternative polyadenylation (APA) in 3' untranslated regions (3' UTR) plays an important role in regulating transcript abundance, localization, and interaction with microRNAs. Length-variation of 3'UTRs by APA contributes to efficient proliferation of cancer cells. In this study, we investigated APA in single cancer cells and tumor microenvironment cells to understand the physiological implication of APA in different cell types.