DNA Ligase 4 Inhibition Sensitizes Prostate Cancer to Immune Checkpoint Blockade .

Background/aim: Prostate cancer is a common malignant tumor in men. DNA ligase IV (LIG4) expression correlated with poor prognosis in prostate cancer patients. LIG4 joins DNA double strand breaks and is essential for repair of these genetic lesions.

Lysine Methyltransferase 2D Regulates Immune Response and Metastasis in Head and Neck Cancer.

Background/aim: The most frequently altered epigenetic modifier in head and neck squamous carcinoma (HNSC) is the histone methyltransferase KMT2D. KMT2D catalyzes methylation of histone H3K4 resulting in open chromatin and the activation of target genes. Tumor-associated macrophages (TAMs) promote cancer growth by causing T lymphocyte exhaustion.

A prefrontal network model operating near steady and oscillatory states links spike desynchronization and synaptic deficits in schizophrenia.

Schizophrenia results in part from a failure of prefrontal networks but we lack full understanding of how disruptions at a synaptic level cause failures at the network level. This is a crucial gap in our understanding because it prevents us from discovering how genetic mutations and environmental risks that alter synaptic function cause prefrontal network to fail in schizophrenia. To address that question, we developed a recurrent spiking network model of prefrontal local circuits that can explain the link between NMDAR synaptic and 0-lag spike synchrony deficits we recently observed in a pharmacological monkey model of prefrontal network failure in schizophrenia.

XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies.

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain.

Outcomes of Upper Lip Mohs Surgery Repairs Using Standardized Scar Scales With Particular Emphasis on Vermillion Border Involvement.

Background: The lips are a common location for skin cancer, and thus, a common site for Mohs micrographic surgery (MMS). As an important cosmetic and functional facial unit, MMS defects and reconstruction can affect patient perception on functional and aesthetic outcomes.

Objective: The objective of this study was to compare aesthetic and functional outcomes after upper lip MMS between patients with vermillion sparing repairs (VSR) versus vermillion crossing repairs (VCR).

Lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.

The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) binds inflammatory mediators in obesity and its expression is reduced in human breast cancer. We created a new model to better understand how the obese microenvironment alters nuclear receptor function in breast cancer.

Using innovative tools for absorption, distribution, metabolism and excretion studies to efficiently and effectively support drug development.

Drug development is a complicated and lengthy process requiring a significant amount of intellectual and capital input, as well as extensive collaborations among various organizations and institutions. Contract research organizations play important roles at some or even all stages of the drug development process. To provide better service in drug absorption, disposition, metabolism and excretion studies, maintain data accuracy and promote work efficiency, we developed an integrated information system termed the 'Drug Metabolism Information System', and it is being used routinely by our drug metabolism department.

Evaluating the consistency with guideline recommendations for diagnosis and management of idiopathic pulmonary fibrosis in non-academic settings.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with elevated mortality. Delay in diagnosis lead to worse outcomes. Guidelines developed at academic medical centers are difficult to replicate in the community.

Shared Neural Activity But Distinct Neural Dynamics for Cognitive Control in Monkey Prefrontal and Parietal Cortex.

To better understand how prefrontal networks mediate forms of cognitive control disrupted in schizophrenia, we translated a variant of the AX continuous performance task that measures specific deficits in the human disease to 2 male monkeys and recorded neurons in PFC and parietal cortex during task performance. In the task, contextual information instructed by cue stimuli determines the response required to a subsequent probe stimulus. We found parietal neurons encoding the behavioral context instructed by cues that exhibited nearly identical activity to their prefrontal counterparts (Blackman et al.

Safety and activity of anti-CD14 antibody IC14 (atibuclimab) in ALS: Experience with expanded access protocol.

Introduction/aims: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 in an acute treatment setting. We provided long-term treatment with IC14 to individuals with ALS via an expanded access protocol (EAP) and documented target engagement, biomarker, safety, and disease endpoints.

Assessment of the Immunogenicity Potential for Oligonucleotide-Based Drugs.

Therapeutic oligonucleotides (ONs) have characteristics of both small molecules and biologics. Although safety assessment of ONs largely follows guidelines established for small molecules, the unique characteristics of ONs often require incorporation of concepts from the safety assessment of biologics. The assessment of immunogenicity for ON therapeutics is one area where the approach is distinct from either established small molecule or biologic platforms.

Mimicking the mimicker: Necrotizing sarcoid granulomatosis.

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that shares similarities with pulmonary vasculitides and sarcoidosis. This is a report of two cases of NSG with a review of literature. The first case is a 33-year-old black female with a one-year history of malaise and cough.

DNA Double-strand Break Signaling Is a Therapeutic Target in Head and Neck Cancer.

Background: Head and neck cancer (HNC) is common worldwide. Given poor outcomes for patients with HNC, research into targeted therapies is needed. Ataxia telangiectasia mutated (ATM) is a DNA damage kinase which is activated by double-strand DNA breaks.

PARP5B is required for nonhomologous end joining during tumorigenesis in vivo.

Poly(ADP-ribose) polymerases (PARP) act as DNA damage sensors that produce poly(ADP-ribose) (PAR) chains at double-strand breaks, facilitating the recruitment of repair factors. Cancers with homologous recombination defects are sensitive to small molecule PARP inhibitors. Despite PARP5B gene copy number changes in many cancers, the effects of this genetic alteration on tumor phenotype are largely unknown.

Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis.

Background: The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers.

Methods: In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263).

Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits.

Schizophrenia results from hundreds of known causes, including genetic, environmental, and developmental insults that cooperatively increase risk of developing the disease. In spite of the diversity of causal factors, schizophrenia presents with a core set of symptoms and brain abnormalities (both structural and functional) that particularly impact the prefrontal cortex. This suggests that many different causal factors leading to schizophrenia may cause prefrontal neurons and circuits to fail in fundamentally similar ways.

Optical design and intensity interferometry simulations in support of the Kilometer Space Telescope.

Very large telescopes will be needed for the future of space science, space laser-com, and other interstellar or interplanetary applications. However, as telescopes' diameters increase, their weight and cost increase dramatically. An approximation for ground-based observatories is that their cost increases to the power of 2.

New Developments in the Management of Cutaneous Squamous Cell Carcinoma.

Learning Objectives: After studying this article, the participant should be able to: 1. List important prognostic features that affect cutaneous squamous cell carcinoma risk. 2.

Two Supervised Machine Learning Approaches for Wind Velocity Estimation Using Multi-Rotor Copter Attitude Measurements.

In this work we address the adequacy of two machine learning methods to tackle the problem of wind velocity estimation in the lowermost region of the atmosphere using on-board inertial drone data within an outdoor setting. We fed these data, and accompanying wind tower measurements, into a K-nearest neighbor (KNN) algorithm and a long short-term memory (LSTM) neural network to predict future windspeeds, by exploiting the stabilization response of two hovering drones in a wind field. Of the two approaches, we found that LSTM proved to be the most capable supervised learning model during more capricious wind conditions, and made competent windspeed predictions with an average root mean square error of 0.

Club Cell Heme Oxygenase-1 Deletion: Effects in Hyperoxia-Exposed Adult Mice.

Thioredoxin reductase-1 (TXNRD1) inhibition activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and prevents acute lung injury (ALI). Heme oxygenase-1 (HO-1) induction following TXNRD1 inhibition is Nrf2-dependent in airway epithelial (club) cells . The influence of club cell HO-1 on lung development and lung injury responses is poorly understood.

Cognitive Control Errors in Nonhuman Primates Resembling Those in Schizophrenia Reflect Opposing Effects of NMDA Receptor Blockade on Causal Interactions Between Cells and Circuits in Prefrontal and Parietal Cortices.

Background: The causal biology underlying schizophrenia is not well understood, but it is likely to involve a malfunction in how neurons adjust synaptic connections in response to patterns of activity in networks. We examined statistical dependencies between neural signals at the cell, local circuit, and distributed network levels in prefrontal and parietal cortices of monkeys performing a variant of the AX continuous performance task paradigm. We then quantified changes in the pattern of neural interactions across levels of scale following NMDA receptor (NMDAR) blockade and related these changes to a pattern of cognitive control errors closely matching the performance of patients with schizophrenia.