Side Chain Investigation of Imidazopyridazine as a Hinge Binder for Targeting Actionable Mutations of RET Kinase.

Actionable mutations of RET kinase have been identified as oncogenic drivers of solid tumors, including thyroid cancer, metastatic colorectal cancer, and nonsmall cell lung cancer. Although multikinase inhibitors and RET selective inhibitors are used to treat patients with RET alterations, there is insufficient research addressing certain issues: which actionable mutations arise from these therapies, how to improve the clinical response rate to RET inhibitors, and how to design new inhibitors to overcome drug resistance. Therefore, the development of sophisticated tool compounds is required to investigate the molecular mechanisms of actionable mutations and to develop breakthrough therapeutics for different RET alterations.

Full-wave Image Reconstruction in Transcranial Photoacoustic Computed Tomography using a Finite Element Method.

Transcranial photoacoustic computed tomography presents challenges in human brain imaging due to skull-induced acoustic aberration. Existing full-wave image reconstruction methods rely on a unified elastic wave equation for skull shear and longitudinal wave propagation, therefore demanding substantial computational resources. We propose an efficient discrete imaging model based on finite element discretization.

De-aberration for transcranial photoacoustic computed tomography through an adult human skull.

Noninvasive transcranial photoacoustic computed tomography (PACT) of the human brain, despite its clinical potential, remains impeded by the acoustic distortion induced by the human skull. The distortion, which is attributed to the markedly different material properties of the skull relative to soft tissue, results in heavily aberrated PACT images -- a problem that has remained unsolved in the past two decades. Herein, we report the first successful experimental demonstration of the de-aberration of PACT images through an ex-vivo adult human skull using a homogeneous elastic model for the skull.

Immunity from NK Cell Subsets Is Important for Vaccine-Mediated Protection in HPV+ Cancers.

High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential.

Single-shot 3D photoacoustic computed tomography with a densely packed array for transcranial functional imaging.

Photoacoustic computed tomography (PACT) is emerging as a new technique for functional brain imaging, primarily due to its capabilities in label-free hemodynamic imaging. Despite its potential, the transcranial application of PACT has encountered hurdles, such as acoustic attenuations and distortions by the skull and limited light penetration through the skull. To overcome these challenges, we have engineered a PACT system that features a densely packed hemispherical ultrasonic transducer array with 3072 channels, operating at a central frequency of 1 MHz.

A method for the geometric calibration of ultrasound transducer arrays with arbitrary geometries.

Geometric calibration of ultrasound transducer arrays is critical to optimizing the performance of photoacoustic computed tomography (PACT) systems. We present a geometric calibration method that is applicable to a wide range of PACT systems. We obtain the speed of sound and point source locations using surrogate methods, which results in a linear problem in the transducer coordinates.

Immune environment and antigen specificity of the T cell receptor repertoire of malignant ascites in ovarian cancer.

We evaluated the association of disease outcome with T cell immune-related characteristics and T cell receptor (TCR) repertoire in malignant ascites from patients with high-grade epithelial ovarian cancer. Ascitic fluid samples were collected from 47 high-grade epithelial ovarian cancer patients and analyzed using flow cytometry and TCR sequencing to characterize the complementarity determining region 3 TCR β-chain. TCR functions were analyzed using the McPAS-TCR and VDJ databases.

A Contemporary Exploration of Traditional Indian Snake Envenomation Therapies.

Snakebite being a quick progressing serious situation needs immediate and aggressive therapy. Snake venom antiserum is the only approved and effective treatment available, but for selected snake species only. The requirement of trained staff for administration and serum reactions make the therapy complicated.

Mucosal Vaccination With Recombinant WAP49 Protein Induces Protective Humoral and Cellular Immunity Against Experimental Trichuriasis in AKR Mice.

Trichuriasis is one of the most common neglected tropical diseases of the world's poorest people. A recombinant vaccine composed of WAP49, an immunodominant antigen secreted by adult stichocytes into the mucosa of the cecum to which the parasite attaches, is under development. The prototype is being evaluated in a mouse model of infection, with the ultimate goal of producing a mucosal vaccine through intranasal delivery.

Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment during Chemoradiotherapy Is Prognostic in HPV16 Cancers.

Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival.

A recombinant bovine adenoviral mucosal vaccine expressing mycobacterial antigen-85B generates robust protection against tuberculosis in mice.

Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv) and bovine adenovirus (BAdv) vectors.

Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates.

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment.

Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2.

With continued expansion of the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), both antiviral drugs as well as effective vaccines are desperately needed to treat patients at high risk of life-threatening disease. Here, we present in vitro evidence for significant inhibition of SARS-CoV-2 by oleandrin and a defined extract of N. oleander (designated as PBI-06150).

Gut microbiome diversity is an independent predictor of survival in cervical cancer patients receiving chemoradiation.

Diversity of the gut microbiome is associated with higher response rates for cancer patients receiving immunotherapy but has not been investigated in patients receiving radiation therapy. Additionally, current studies investigating the gut microbiome and outcomes in cancer patients may not have adjusted for established risk factors. Here, we sought to determine if diversity and composition of the gut microbiome was independently associated with survival in cervical cancer patients receiving chemoradiation.

Mucoadhesive wafers composed of binary polymer blends for sublingual delivery and preservation of protein vaccines.

The objective of this study is to develop a simple biopolymer platform of mucoadhesive wafers that enables effective sublingual delivery and preservation of protein vaccines. The wafers were composed of a series of binary polymer blends of carboxymethylcellulose (CMC) and alginate (ALG). Varying the ratio between CMC and ALG resulted in wafers with different microstructure, mechanical properties, disintegration time, and release kinetics of model compounds.

A Neutrophil-Driven Inflammatory Signature Characterizes the Blood Transcriptome Fingerprint of Psoriasis.

Transcriptome profiling approaches have been widely used to investigate the mechanisms underlying psoriasis pathogenesis. Most researchers have measured changes in transcript abundance in skin biopsies; relatively few have examined transcriptome changes in the blood. Although less relevant to the study of psoriasis pathogenesis, blood transcriptome profiles can be readily compared across various diseases.

Antiviral Effects of Oleandrin.

Over the past 15 years, investigators have reported on the utility and safety of cardiac glycosides for numerous health benefits including those as treatments for malignant disease, stroke-mediated ischemic injury and certain neurodegenerative diseases. In addition to those, there is a growing body of evidence for novel antiviral effects of selected cardiac glycoside molecules. One unique cardiac glycoside, oleandrin derived from , has been reported to have antiviral activity specifically against 'enveloped' viruses including HIV and HTLV-1.

Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant.

HIV-1 is a chronic disease managed by strictly adhering to daily antiretroviral therapy (ART). However, not all people living with HIV-1 have access to ART, and those with access may not adhere to treatment regimens increasing viral load and disease progression. Here, a subcutaneous nanofluidic implant was used as a long-acting (LA) drug delivery platform to address these issues.

Multiple signaling pathways converge on proapoptotic protein BAD to promote survival of melanocytes.

Melanocyte survival is mediated by diverse signaling pathways. However, the molecular mechanisms they use and molecules that they target are incompletely understood. Here, we show that melanocyte survival is mediated by diverse, nonredundant signaling pathways, including ERK1/2, AKT, PKA, and PKC.

Effect of Antibiotics on Gut and Vaginal Microbiomes Associated with Cervical Cancer Development in Mice.

Antibiotics affect microbial diversity in the gut, leading to dysbiosis and impaired immunity. However, the impact of antibiotics on microbial communities at other sites, such as vagina is less understood. It is also not clear whether changes induced by antibiotics in both microbiomes affect the development of cervical cancer.

Prophylactic and Therapeutic Inhibition of In Vitro SARS-CoV-2 Replication by Oleandrin.

Unlabelled: With continued expansion of the COVID-19 pandemic, antiviral drugs are desperately needed to treat patients at high risk of life-threatening disease and even to limit spread if administered early during infection. Typically, the fastest route to identifying and licensing a safe and effective antiviral drug is to test those already shown safe in early clinical trials for other infections or diseases. Here, we tested oleandrin, derived from the plant and shown previously to have inhibitory activity against several viruses.

Trans-urocanic acid enhances tenofovir alafenamide stability for long-acting HIV applications.

Long-acting (LA) pre-exposure prophylaxis (PrEP) for HIV prevention is poised to address non-adherence and implementation challenges by alleviating the burden of user-dependent dosing. Due to its potency, tenofovir alafenamide (TAF) is a viable candidate for LA PrEP. However, the inherent hydrolytic instability of TAF presents a challenge for application in LA systems.

Compressive sensing approaches for the prediction of scattered electromagnetic fields.

We present a novel method based on Huygens' principle and compressive sensing to predict the electromagnetic (EM) fields in arbitrary scattering environments by making a few measurements of the field. In doing so, we assume a homogeneous medium between the scatterers, though we do not assume prior knowledge of the permittivities or the exact geometry of the scatterers. The major contribution of this work is a compressive sensing-based subspace optimization method (CS-SOM).