A STAT3-STING-IFN axis controls the metastatic spread of small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by a high metastatic potential with an overall survival rate of ~5%. The transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed by >50% of tumors, including SCLC, but its role in SCLC development and metastasis is unclear. Here, we show that, while STAT3 deletion restricts primary tumor growth, it paradoxically enhances metastatic spread by promoting immune evasion.

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos.

Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis.

MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat.

Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease.

Liver SBRT dose accumulation to assess the impact of anatomic variations on normal tissue doses and toxicity in patients treated with concurrent sorafenib.

Background And Purpose: Unexpected liver volume reductions occurred during trials of liver SBRT and concurrent sorafenib. The aims were to accumulate liver SBRT doses to assess the impact of these anatomic variations on normal tissue dose parameters and toxicity.

Materials And Methods: Thirty-two patients with hepatocellular carcinoma (HCC) or metastases treated on trials of liver SBRT (30-57 Gy, 6 fractions) and concurrent sorafenib were analyzed.

Evaluation of dosimetric predictors of toxicity after IMRT with concurrent chemotherapy for anal cancer.

Background: This study investigates the impact of dosimetric parameters on acute and late toxicity for patients with anal squamous cell carcinoma (SCC) treated with image-guided intensity modulated radiation therapy (IG-IMRT) and concurrent chemotherapy.

Materials And Methods: Patients were enrolled in an observational cohort study between 2008 and 2013 (median follow-up 3.4 years).

Consequences of PDGFRα fibroblast reduction in adult murine hearts.

Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury.

Blood Chromium Levels and Their Association with Cardiovascular Diseases, Diabetes, and Depression: National Health and Nutrition Examination Survey (NHANES) 2015-2016.

Currently, there is no global consensus about the essentiality of dietary chromium. To provide evidence to this debate, an examination of blood chromium levels and common chronic health conditions was undertaken. Using a subsample from the 2015−2016 US National Health and Nutrition Examination Survey (n = 2894; 40 years+), chi-square and binary logistic regression analyses were conducted to examine blood chromium levels (0.

Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth in vivo.

Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC 0.

Lineage-restricted neoplasia driven by Myc defaults to small cell lung cancer when combined with loss of p53 and Rb in the airway epithelium.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by loss of function TP53 and RB1 mutations in addition to mutations in other oncogenes including MYC. Overexpression of MYC together with Trp53 and Rb1 loss in pulmonary neuroendocrine cells of the mouse lung drives an aggressive neuroendocrine low variant subtype of SCLC. However, the transforming potential of MYC amplification alone on airway epithelium is unclear.

Treatment of Rotator Cuff Tears with platelet rich plasma: a prospective study with 2 year follow-up.

Background: Surgical treatment of full-thickness rotator cuff (RC) tears is associated with generally good results. There is no consensus regarding treatment of partial thickness tears that fail conservative treatment. The purpose of this study was to look at the efficacy and confirm the safety of dual injection PRP into the shoulder of patients with rotator cuff pathology who have failed conservative treatment with followup to two years.

Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors.

We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of ()-azetidine-2-carboxamide analogues that have sub-micromolar potencies. , and have STAT3-inhibitory potencies (IC) of 0.55, 0.

A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown.

Evaluation of Bony Anatomy Versus Endobiliary Stents as Surrogates for Volumetric Image Guidance in Pancreatic Cancer.

Purpose: Online treatment setup verification through cone-beam computed tomography (CBCT) in pancreatic cancer patients is limited by low soft tissue contrast. This study aims to quantify the relative positional displacements between bony anatomy and endobiliary stents as surrogates for pancreatic cancers.

Methods: Under ethics approval, 258 localization CBCT images from 15 pancreatic patients with endobiliary stents were evaluated.

Dataset on Galanin Receptor 3 mutants that improve recombinant receptor expression and stability in an agonist and antagonist bound form.

Galanin Receptor 3 (GALR3) is a G-protein-coupled receptor with a widespread distribution in the brain and plays a role in a variety of physiologic processes including cognition/memory, sensory/pain processing, hormone secretion, and feeding behavior. Therefore, GALR3 is considered an attractive CNS drug target (Freimann et al., 2015) [1].

Method for rapid optimization of recombinant GPCR protein expression and stability using virus-like particles.

Recent innovative approaches to stabilize and crystallize GPCRs have resulted in an unprecedented breakthrough in GPCR crystal structures as well as application of the purified receptor protein in biophysical and biochemical ligand binding assays. However, the protein optimization process to enable these technologies is lengthy and requires iterative overexpression, solubilization, purification and functional analysis of tens to hundreds of protein variants. Here, we report a new and versatile method to screen in parallel hundreds of GPCR variants in HEK293 produced virus-like particles (VLPs) for protein yield, stability, functionality and ligand binding.

The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer.

Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer.

Bioimaging real-time PXR-dependent mdr1a gene regulation in mdr1a.fLUC reporter mice.

The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors human steroid and xenobiotic receptor (SXR) and constitutive androstane receptor (CAR) are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression.

Translation and validation of the Farage Quality of Life (FQoL™) instrument for consumer products into traditional Chinese.

The Farage Quality of Life™ questionnaire (FQoL™) was developed specifically to assess the impact of consumer products. The objective of this investigation was to achieve a Chinese language instrument. The FQoL™ underwent a forward and backward translation, with cognitive testing by 13 subjects.

Water-soluble PDE4 inhibitors for the treatment of dry eye.

PDE4 inhibitors have the potential to alleviate the symptoms and underlying inflammation associated with dry eye. Disclosed herein is the development of a novel series of water-soluble PDE4 inhibitors. Our studies led to the discovery of coumarin 18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.

Peroxisome proliferator-activated receptor gamma inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells.

Using a cDNA array consisting only of cell cycle genes, we found that a novel nonthiazolidinedione partial peroxisome proliferator-activated receptor gamma (PPARgamma) agonist (nTZDpa) inhibited expression of minichromosome maintenance (MCM) proteins 6 and 7 in vascular smooth muscle cells. MCM proteins are required for the initiation and elongation stages of DNA replication and are regulated by the transcription factor E2F. Mitogen-induced MCM6 and MCM7 mRNA expression was potently inhibited by nTZDpa and to a lesser degree by the full PPARgamma agonist, rosiglitazone.

Identification of gene-selective modulators of the bile acid receptor FXR.

BAR is a nuclear bile acid receptor (BAR) (FXR) receptor that regulates gene networks involved in cholesterol and bile acid homeostasis. We have identified two classes of synthetic compounds that differentially modulate BAR activity. The first class activates BAR target genes in the predicted fashion and is 25-fold more potent than endogenous bile acids.

Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated nuclear receptor that has an essential role in adipogenesis and glucose homeostasis. PPAR-gamma is expressed in vascular tissues including endothelial cells (ECs). PPAR-gamma activity can be regulated by many pathophysiological and pharmacological agonists.