Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice.

Introduction: We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS).

The MmpL3 inhibitor MSU-43085 is active in a mouse model of infection.

MmpL3 is a protein that is required for the survival of bacteria that cause tuberculosis (TB) and nontuberculous mycobacterial (NTM) infections. This report describes the discovery and characterization of a new small molecule, MSU-43085, that targets MmpL3 and is a potent inhibitor of (Mtb) and survival. MSU-43085 is shown to be orally bioavailable and efficacious in an acute model of Mtb infection.

Transthoracic Echocardiography in the Preoperative Assessment of Newborn Coarctation: Limiting Risks Associated with Advanced Imaging Techniques.

A newborn male child with prenatally identified aortic arch hypoplasia presented to our facility for cardiac management. He had been started on prostaglandins at the delivery facility and was subsequently placed on a high-flow nasal cannula due to associated apnea. On the day of life three, the patient underwent cardiac computed tomography scan for delineation of his anatomy.

Isolated Right Subclavian Artery From the Pulmonary Artery in D-Transposition of the Great Arteries.

• Isolated RSCA from the PA is a rare finding in d-TGA. • Atypical differential cyanosis in d-TGA may indicate abnormal aortic branching. • Fetal imaging can provide evidence of an isolated RSCA.

The Novel RXR Agonist MSU-42011 Differentially Regulates Gene Expression in Mammary Tumors of MMTV-Neu Mice.

Retinoid X receptor (RXR) agonists, which activate the RXR nuclear receptor, are effective in multiple preclinical cancer models for both treatment and prevention. While RXR is the direct target of these compounds, the downstream changes in gene expression differ between compounds. RNA sequencing was used to elucidate the effects of the novel RXRα agonist MSU-42011 on the transcriptome in mammary tumors of HER2+ mouse mammary tumor virus (MMTV)-Neu mice.

Tangled in a Web: Management Type and Vegetation Shape the Occurrence of Web-Building Spiders in Protected Areas.

Land management of parks and vegetation complexity can affect arthropod diversity and subsequently alter trophic interactions between predators and their prey. In this study, we examined spiders in five parks with varying management histories and intensities to determine whether certain spider species were associated with particular plants. We also determined whether web architecture influenced spider occurrence.

Anti-fibrillization effects of sulfonamide derivatives on -synuclein and hyperphosphorylated tau isoform 1N4R.

In contrast to A plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer's disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea (), sulfonylurea (), and sulfonamide () series and evaluated their anti-aggregation effects with biophysical methods (thioflavin T and S fluorescence assays, transmission electron microscopy) and intracellular inclusion cell-based assays.

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers.

Greater sage-grouse respond positively to intensive post-fire restoration treatments.

Habitat loss is the most prevalent threat to biodiversity in North America. One of the most threatened landscapes in the United States is the sagebrush ( spp.) ecosystem, much of which has been fragmented or converted to non-native grasslands via the cheatgrass-fire cycle.

Machine Learning Analysis of Cocaine Addiction Informed by DAT, SERT, and NET-Based Interactome Networks.

Cocaine addiction is a psychosocial disorder induced by the chronic use of cocaine and causes a large number of deaths around the world. Despite decades of effort, no drugs have been approved by the Food and Drug Administration (FDA) for the treatment of cocaine dependence. Cocaine dependence is neurological and involves many interacting proteins in the interactome.

Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.

Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA).

The RXR Agonist MSU42011 Is Effective for the Treatment of Preclinical HER2+ Breast Cancer and Kras-Driven Lung Cancer.

(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as a standard of care in clinical practice. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and upon ligand binding, function as transcription factors to modulate multiple cell functions.

Risk Factors and Antipsychotic Usage Patterns Associated With Terminal Delirium in a Veteran Long-Term Care Hospice Population.

Background: The development of delirium is very common in terminally ill patients. However, risk factors for terminal delirium in the veteran population are poorly identified. The purpose of this study was to (1) Identify risk factors for terminal delirium in a US Department of Veterans Affairs inpatient hospice population; (2) Assess usage patterns of antipsychotics for treatment of terminal delirium; and (3) Describe nursing assessment, nonpharmacologic interventions, and documentation of terminal delirium.

The novel rexinoid MSU-42011 is effective for the treatment of preclinical Kras-driven lung cancer.

Effective drugs are needed for lung cancer, as this disease remains the leading cause of cancer-related deaths. Rexinoids are promising drug candidates for cancer therapy because of their ability to modulate genes involved in inflammation, cell proliferation or differentiation, and apoptosis through activation of the retinoid X receptor (RXR). The only currently FDA-approved rexinoid, bexarotene, is ineffective as a single agent for treating epithelial cancers and induces hypertriglyceridemia.

Therapeutic potential of targeting mixed lineage kinases in cancer and inflammation.

Dysregulation of intracellular signaling pathways is a key attribute of diseases associated with chronic inflammation, including cancer. Mitogen activated protein kinases have emerged as critical conduits of intracellular signal transmission, yet due to their ubiquitous roles in cellular processes, their direct inhibition may lead to undesired effects, thus limiting their usefulness as therapeutic targets. Mixed lineage kinases (MLKs) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that interact with scaffolding proteins and function upstream of p38, JNK, ERK, and NF-kappaB to mediate diverse cellular signals.

Inhibiting DosRST Signaling by Targeting Response Regulator DNA Binding and Sensor Kinase Heme.

(Mtb) possesses a two-component regulatory system, DosRST, that enables Mtb to sense host immune cues and establish a state of nonreplicating persistence (NRP). NRP bacteria are tolerant to several antimycobacterial drugs and are thought to play a role in the long course of tuberculosis therapy. Previously, we reported the discovery of six novel chemical inhibitors of DosRST, named HC101A-106A, from a whole cell, reporter-based phenotypic high throughput screen.

Identification of New MmpL3 Inhibitors by Untargeted and Targeted Mutant Screens Defines MmpL3 Domains with Differential Resistance.

The mycolate flippase MmpL3 has been the proposed target for multiple inhibitors with diverse chemical scaffolds. This diversity in chemical scaffolds has made it difficult to predict compounds that inhibit MmpL3 without whole-genome sequencing of isolated resistant mutants. Here, we describe the identification of four new inhibitors that select for resistance mutations in Using these resistant mutants, we conducted a targeted whole-cell phenotypic screen of 163 novel growth inhibitors for differential growth inhibition of wild-type compared to the growth of a pool of 24 unique mutants.

Spermine in semen of male sea lamprey acts as a sex pheromone.

Semen is fundamental for sexual reproduction. The non-sperm part of ejaculated semen, or seminal plasma, facilitates the delivery of sperm to the eggs. The seminal plasma of some species with internal fertilization contains anti-aphrodisiac molecules that deter promiscuity in post-copulatory females, conferring fitness benefits to the ejaculating male.

The Roles Of Assisters And Automated Decision Support Tools In Consumers' Marketplace Choices: Room For Improvement.

Assisters provide in-person and phone-based support to help consumers narrow their plan options on the Affordable Care Act's health insurance Marketplaces. We elicited the perspectives of a national sample of thirty-two assisters from ten states on consumer plan selection and available Marketplace decision support tools (for example, total cost estimators and provider network look-up tools). Assisters identified several shortcomings that limited their use of decision support tools, such as nonspecific cost estimates and inaccurate provider network data.

Review on Abyssomicins: Inhibitors of the Chorismate Pathway and Folate Biosynthesis.

Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors.

The neural basis of understanding the expression of the emotions in man and animals.

Humans cannot help but attribute human emotions to non-human animals. Although such attributions are often regarded as gratuitous anthropomorphisms and held apart from the attributions humans make about each other's internal states, they may be the product of a general mechanism for flexibly interpreting adaptive behavior. To examine this, we used functional magnetic resonance imaging (fMRI) in humans to compare the neural mechanisms associated with attributing emotions to humans and non-human animal behavior.

Additions to Philippine Slender Skinks of the Brachymeles bonitae Complex (Reptilia: Squamata: Scincidae) I: a new species from Lubang Island.

A new species of slender skink is described from the Philippines. The species is endemic to Lubang Island, and is assigned to the Brachymeles bonitae Complex based on phenotypic and genetic data. Specimens were collected from Lubang Island between 1991 and 2012, and were examined based on morphological data (qualitative traits, meristic counts, and mensural measurements).

Managing incidental pancreatic cystic neoplasms with integrated molecular pathology is a cost-effective strategy.

Background And Study Aims: Current guidelines recommend using endoscopic ultrasound (EUS), carcinoembryonic antigen (CEA) testing and cytology to manage incidental pancreatic cystic neoplasms (PCN); however, studies suggest a strategy including integrated molecular pathology (IMP) of cyst fluid may further aid in predicting risk of malignancy. Here, we evaluate several strategies for diagnosing and managing asymptomatic PCN using healthcare economic modeling.

Patients And Methods: A third-party-payer perspective Markov decision model examined four management strategies in a hypothetical cohort of 1000 asymptomatic patients incidentally found to have a 3 cm solitary pancreatic cystic lesion.