Constitutive Epidermal Expression of Osteopontin in Osteopontin-Null Mice Restores Ultraviolet B-Induced Cutaneous Squamous Cell Carcinomas to Wild-Type Levels.

Studies of osteopontin (OPN)-null mice have supported the role of OPN as a critical factor in the promotion of skin tumorigenesis. OPN is a highly inducible integrin- and CD44-interacting acidic glycoprotein with pleiotropic functions. In various cancers, elevated levels of OPN from cancer and inflammatory cells are secreted into the microenvironment and the bloodstream.

Exploring Conceptualizations of COVID-19 Risk in Ideologically Distinct Online Communities: A Computational Grounded Theory Analysis.

Background: The COVID-19 pandemic has had a profound impact on societies and economies around the globe, and experts warn about the potential for similar crises in the future. Risk communication theories underscore that while the potential for harm is objective, risk perception is a subjective, socially derived interpretation. While there is broad literature on the social construction of risk, fewer studies examine the role of communities-online or offline-in developing and reinforcing distinct interpretations of the same risk event.

HDAC7 promotes renal cancer progression by reprogramming branched-chain amino acid metabolism.

Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits notable metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, we demonstrate that HDAC7 promotes aggressive phenotypes and in vivo tumor progression in RCC.

Paricalcitol and hydroxychloroquine modulates extracellular matrix and enhance chemotherapy efficacy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and limited therapeutic options. In a previous publication, our group defined some of the mechanisms that vitamin D analogue paricalcitol (P) and hydroxychloroquine (H) potentiated the effects of gemcitabine-based chemotherapy in PDAC. Based on this, we hypothesized that PH may potentiate 5-fluorouracil (5FU) and oxaliplatin-based chemotherapy, and this may involve a novel mechanism of extracellular matrix (ECM) modulation.

Intranasal replicon SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission.

While mRNA vaccines have been effective in combating SARS-CoV-2, the waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.

ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma.

Background: Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models.

Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine.

Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G).

A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer.

Activated RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis.

Cutting Edge: Low-dose Recombinant IL-2 Treatment Prevents Autoantibody Responses in Systemic Lupus Erythematosus via Regulatory T Cell-independent Depletion of T Follicular Helper Cells.

The expansion of T follicular helper (Tfh) cells correlates with disease progression in human and murine systemic lupus erythematosus (SLE). Unfortunately, there are no therapies to deplete Tfh cells. Importantly, low-dose rIL-2-based immunotherapy shows potent immunosuppressive effects in SLE patients and lupus-prone mice, primarily attributed to the expansion of regulatory T cells (Tregs).

Microbiota and B-1 B cell repertoire development in mice.

Microbiota-derived antigens play a critical role in the development of both the mucosal and systemic B cell repertoires; however, how glycan epitopes promote B cell repertoire selection is only recently being understood. The production of glycan-derived antigens by individual microbes within a host can be dynamic and influenced by interactions within other members of microbial communities, the composition of diet, and host-derived contents, including those of the mucosal immune system. The size and complexity of the emerging neonatal B cell repertoire are paralleled by the acquisition of a diverse microbiota from maternal and environmental sources, which is now appreciated to exert long-lasting influences on the nascent B cell repertoire.

Pulmonary Fibrosis Ferret Model Demonstrates Sustained Fibrosis, Restrictive Physiology, and Aberrant Repair.

Rationale: The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Unlabelled: Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007.

A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON. While patients with ZTTK syndrome live with numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome.

Breaking the stromal barrier in pancreatic cancer: Advances and challenges.

Pancreatic cancer (PC) remains a leading cause of mortality worldwide due to the absence of early detection methods and the low success rates of traditional therapeutic strategies. Drug resistance in PC is driven by its desmoplastic stroma, which creates a barrier that shields cancer niches and prevents the penetration of drugs. The PC stroma comprises heterogeneous cellular populations and non-cellular components involved in aberrant ECM deposition, immunosuppression, and drug resistance.

A mouse model of ZTTK syndrome reveals indispensable SON functions in organ development and hematopoiesis.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hamper our understanding of both SON and this complex syndrome.

Preclinical safety evaluation of continuous UV-A lighting in an operative setting.

Background: Germicidal ultraviolet (UV-C) light has been shown as an effective modality for disinfection in laboratory settings and in the operative room. Traditionally, short-wavelength UV-C devices, which have previously been shown to cause DNA damage, are utilized only for disinfection in pre- and post-operative settings and are not continuously active during operations. Continuous use of intraoperative UV light has potential to decrease pathogens and subsequent surgical site infections (SSIs), which arise in approximately 5-15% of operative cases.

Obesity associated pancreatic ductal adenocarcinoma: Therapeutic challenges.

Obesity is a prominent health issue worldwide and directly impacts pancreatic health, with obese individuals exhibiting a significant risk for increasing pancreatic ductal adenocarcinoma (PDAC). Several factors potentially explain the increased risk for the development of PDAC, including obesity-induced chronic inflammation within and outside of the pancreas, development of insulin resistance and metabolic dysfunction, promotion of immune suppression within the pancreas during inflammation, pre- and malignant stages, variations in hormones levels (adiponectin, ghrelin, and leptin) produced from the adipose tissue, and acquisition of somatic mutations in tumor once- and suppressor proteins critical for pancreatic tumorigenesis. In this manuscript, we will explore the broad impact of these obesity-induced risk factors on the development and progression of PDAC, focusing on changes within the tumor microenvironment (TME) as they pertain to prevention, current therapeutic strategies, and future directions for targeting obesity management as they relate to the prevention of pancreatic tumorigenesis.

In vitro and in vivo immune assessments of genetically-engineered pig skin grafts in New World (squirrel) monkeys.

Half a million patients in the USA alone require treatment for burns annually. Following an extensive burn, it may not be possible to provide sufficient autografts in a single setting. Genetic manipulations (GM) of pigs offer the possibility of reducing primate humoral and cellular rejection of pig skin xenografts and thus extending graft survival.

Pulmonary pathogenesis in a murine model of inhaled arsenical exposure.

Arsenic trioxide (ATO), an inorganic arsenical, is a toxic environmental contaminant. It is also a widely used chemical with industrial and medicinal uses. Significant public health risk exists from its intentional or accidental exposure.

Early Life Stress in Mice Leads to Impaired Colonic Corticosterone Production and Prolonged Inflammation Following Induction of Colitis.

Background: Early life stress (ELS) is an environmental trigger believed to promote increased risk of IBD. Our goal was to identify mechanisms whereby ELS in mice affects susceptibility to and/or severity of gut inflammation.

Methods: We utilized 2 published animal models of ELS.

Mucociliary transport deficiency and disease progression in Syrian hamsters with SARS-CoV-2 infection.

Substantial clinical evidence supports the notion that ciliary function in the airways is important in COVID-19 pathogenesis. Although ciliary damage has been observed in both in vitro and in vivo models, the extent or nature of impairment of mucociliary transport (MCT) in in vivo models remains unknown. We hypothesize that SARS-CoV-2 infection results in MCT deficiency in the airways of golden Syrian hamsters that precedes pathological injury in lung parenchyma.

A single intranasal administration of AdCOVID protects against SARS-CoV-2 infection in the upper and lower respiratory tracts.

The coronavirus disease 2019 (COVID-19) pandemic has illustrated the critical need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive approach for preventing COVID-19 as the nasal mucosa is the site of initial SARS-CoV-2 entry and viral replication prior to aspiration into the lungs. We previously demonstrated that a single intranasal administration of a candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain of the SARS-CoV-2 spike protein (AdCOVID) induced robust immunity in both the airway mucosa and periphery, and completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge.

Observations on hydronephrosis after pig kidney transplantation in baboons.

We have seen hydronephrosis (obstructive nephropathy) at necropsy in 3 of 11 (21%) genetically-engineered pig kidneys that functioned in baboons for >36 days, even when the clinical and histopathological features of rejection were minimal. We briefly report one such case and illustrate the macroscopic and microscopic appearances of such a kidney and ureter. The causes of the observed changes remain uncertain.