Breast cancer, especially triple-negative breast cancer (TNBC), has limited treatment options. We repurposed the FDA-approved drug bazedoxifene as a novel inhibitor of interleukin 6/glycoprotein 130 ...signaling. In this study, we investigated the inhibitory effects of bazedoxifene alone or in combination with paclitaxel on several estrogen receptor positive and TNBC cells. Bazedoxifene inhibited the cell viability of these cells, as well as tumor growth of TNBC cells in a xenograft tumor model. Furthermore, bazedoxifene combined with paclitaxel exhibited more potent inhibition of cell viability, colony formation, and cell migration and induced more apoptosis in vitro, and generated stronger inhibition of tumor growth of TNBC in vivo than either drug alone. Western blotting showed that bazedoxifene inhibited estrogen receptor positive breast cancer cells by suppressing the expression of estrogen receptor, Cyclin D1, p-P70S6K, Survivin, c-Myc, and Bcl-2, and bazedoxifene inhibited TNBC cells by inhibiting the expression of phosphorylated STAT3 (Tyr705), Cyclin D1, p-P70S6K, c-Myc, p-AKT (Ser473) and p-ERK 1/2 (T202/Y 204) without changing the expression of total STAT3. When combined with paclitaxel, bazedoxifene may be a potential small molecule for the treatment of both estrogen receptor positive and triple-negative breast cancer.
•Bazedoxifene, a drug approved for the prevention and treatment of osteoporosis, may be effective in treating breast cancer.•Bazedoxifene inhibits the cell viability in vitro and tumor growth of triple-negative breast cancer in vivo.•Bazedoxifene and paclitaxel exhibit more potent inhibition of the malignant features of breast cancer than either drug alone.•Bazedoxifene inhibits estrogen receptor, phosphorylated STAT3 (Tyr705) and their downstream signaling molecules.
Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of ...tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions.
The epidermal growth factor receptor (EGFR) pathway is one of the most dysregulated molecular pathways in human cancers. Despite its well-established importance in tumor growth, progression and ...drug-resistant phenotype over the past several decades, targeted therapy designed to circumvent EGFR has yielded only modest clinical success in cancer patients, except those with non-small cell lung cancer (NSCLC) carrying EGFR activation mutations. However, almost all of these NSCLC patients eventually developed resistance to small molecule EGFR kinase inhibitors. These disappointing outcomes are, in part, due to the high complexity and the interactive nature of the EGFR signaling network. More recent compelling evidence further indicates that EGFR functionality can be dependent on its subcellular location. In this regard, EGFR undergoes translocation into different organelles where it elicits distinctly different functions than its best known activity as a plasma membrane-bound receptor tyrosine kinase. EGFR can be shuttled into the cell nucleus and mitochondrion upon ligand binding, radiation, EGFR-targeted therapy and other stimuli. Nuclear EGFR behaves as transcriptional regulator, tyrosine kinase, and mediator of other physiological processes. The role of mitochondrial EGFR remains poorly understood but it appears to regulate apoptosis and autophagy. While studies using patient tumors have shown nuclear EGFR to be an indicator for poor clinical outcomes in cancer patients, the impact of mitochondrial EGFR on tumor behavior and patient prognosis remains to be defined. Most recently, several lines of evidence suggest that mislocated EGFR may regulate tumor response to therapy and that plasma membrane-bound EGFR elicits survival signals independent of its kinase activity. In light of these recent progresses and discoveries, we will outline in this minireview an emerging line of research that uncovers and functionally characterizes several novel modes of EGFR signaling that take center stage in the cell nucleus, mitochondrion and other subcellular compartments. We will also discuss the clinical implications of these findings in the rationale design for therapeutic strategy that overcomes tumor drug resistance.
Lignocellulosic biomass is an abundant renewable resource and can be efficiently converted into bioenergy and green materials by using microwave pyrolysis. In this study, microwave pyrolysis of seven ...biomass feedstocks (corn stover, rice straw, rice husk, sugarcane bagasse, sugarcane peel, coffee grounds, and bamboo) was studied. The maximum temperature of microwave pyrolysis was highly correlated with the combustible content of the feedstocks. The influence of microwave power level on both maximum temperature and heating rate was substantial. Either maximum temperature or heating rate had a linear relationship with microwave power level. However, there was a breakpoint at a power level of 250 W. Compared with conventional pyrolysis, microwave pyrolysis was faster and needed less input energy. Microwave pyrolysis provided higher weight losses than conventional pyrolysis, and this difference was more substantial at lower temperatures. Kinetic parameters of microwave pyrolysis at lower and higher microwave power levels were different. Reaction rates at higher microwave power levels can be higher than those at lower power levels by approximately one order of magnitude. Compared with conventional pyrolysis, the rate constant of microwave pyrolysis was much higher, and its activation energy and pre-exponential factor were much lower.
•Both microwave power level and combustible content influenced heating performance.•Heating performances at power levels lower and higher than 250 W were different.•Heating performance of microwave pyrolysis was better than conventional pyrolysis.•Microwave pyrolysis would need less input energy and processing time.•Reaction rates at higher power levels can be higher by one order of magnitude.
Since its discovery, the STAT3 transcription factor has been extensively studied for its function as a transcriptional regulator and its role as a mediator of development, normal physiology, and ...pathology of many diseases, including cancers. These efforts have uncovered an array of genes that can be positively and negatively regulated by STAT3, alone and in cooperation with other transcription factors. Through regulating gene expression, STAT3 has been demonstrated to play a pivotal role in many cellular processes including oncogenesis, tumor growth and progression, and stemness. Interestingly, recent studies suggest that STAT3 may behave as a tumor suppressor by activating expression of genes known to inhibit tumorigenesis. Additional evidence suggested that STAT3 may elicit opposing effects depending on cellular context and tumor types. These mixed results signify the need for a deeper understanding of STAT3, including its upstream regulators, parallel transcription co-regulators, and downstream target genes. To help facilitate fulfilling this unmet need, this review will be primarily focused on STAT3 downstream target genes that have been validated to associate with tumorigenesis and/or malignant biology of human cancers.
Background
Cats in respiratory distress have limited tolerance for manipulation, hindering clinical monitoring. Minute volume (MV) can be utilized to rate dyspnea in humans, but its relationship with ...respiratory distress in cats remains poorly investigated.
Hypothesis
Cats with respiratory distress will show higher MV per kg body weight (MV/BW) than normal cats, and the MV/BW increase will correlate with survival.
Animals
Fifty‐two cats with respiratory distress from lung parenchymal disease, pleural space disease, lower airway obstruction (LAO), or upper airway obstruction were recruited since 2014.
Methods
This is a prospective observational study. Study cats were placed in a transparent chamber, allowing clinicians to easily observe their breathing status and record ventilation using barometric whole‐body plethysmography (BWBP). Ventilatory variables of the 52 cats were compared with those of 14 historic control cats. Follow‐up data, including disease category, clinical outcomes, and survival, were prospectively collected.
Results
Cats in respiratory distress demonstrated significantly higher MV/BW (397 mL/kg; range, 158‐1240) than normal cats (269 mL/kg; range, 168‐389; P < .001). Among the etiologies, cats with LAO, parenchymal, and pleural space disease exhibited higher‐than‐normal MV/BW trends. A cutoff value of 373 mL/kg (1.4‐fold increase) indicated abnormally increased breathing efforts (sensitivity, 67%; specificity, 93%). MV/BW was independently associated with increased cardiorespiratory mortality in cats with respiratory distress (adjusted hazard ratio 1.17, 95% confidence interval CI 1.02‐1.35; P = .03).
Conclusions and Clinical Importance
Breathing efforts in cats can be noninvasively quantified using BWBP. Measurement of MV/BW could serve as a prognostic index for monitoring cats experiencing respiratory distress.
Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic ...dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.
Highlights • Glioblastoma (GBM) is the deadliest and most common brain malignancy in adults with a dismal median survival of 14 months. • Its tendency to aggressively invade throughout the brain ...prevents complete removal of GBM by surgery and local radiotherapy. • GBM invasion can be regulated by the PI3K/Akt, Wnt, sonic hedgehog-GLI1, and microRNAs.
The major concept of "oxidative stress" is an excess elevated level of reactive oxygen species (ROS) which are generated from vigorous metabolism and consumption of oxygen. The precise harmonization ...of oxidative stresses between mitochondria and other organelles in the cell is absolutely vital to cell survival. Under oxidative stress, ROS produced from mitochondria and are the major mediator for tumorigenesis in different aspects, such as proliferation, migration/invasion, angiogenesis, inflammation, and immunoescape to allow cancer cells to adapt to the rigorous environment. Accordingly, the dynamic balance of oxidative stresses not only orchestrate complex cell signaling events in cancer cells but also affect other components in the tumor microenvironment (TME). Immune cells, such as M2 macrophages, dendritic cells, and T cells are the major components of the immunosuppressive TME from the ROS-induced inflammation. Based on this notion, numerous strategies to mitigate oxidative stresses in tumors have been tested for cancer prevention or therapies; however, these manipulations are devised from different sources and mechanisms without established effectiveness. Herein, we integrate current progress regarding the impact of mitochondrial ROS in the TME, not only in cancer cells but also in immune cells, and discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects.
Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathologic mechanism behind this development remains poorly understood. Here, we profiled long ...noncoding RNAs in brain metastatic tumors from patients with breast cancer and found that the X-inactive-specific transcript (XIST) was significantly downregulated in these tissues. XIST expression levels inversely correlated with brain metastasis, but not with bone metastasis in patients. Silencing of XIST preferentially promoted brain metastatic growth of XIST
cells in our xenograft models. Moreover, knockout of XIST in mice mammary glands accelerated primary tumor growth as well as metastases in the brain. Decreased expression of XIST stimulated epithelial-mesenchymal transition and activated c-Met via MSN-mediated protein stabilization, which resulted in the promotion of stemness in the tumor cells. Loss of XIST also augmented secretion of exosomal miRNA-503, which triggered M1-M2 polarization of microglia. This M1-M2 conversion upregulated immune suppressive cytokines in microglia that suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XIST
breast tumor cells and found that fludarabine blocked brain metastasis in our animal model. Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment and that the XIST-mediated pathway may serve as an effective target for treating brain metastasis.
These findings describe mechanisms of how loss of the lncRNA XIST promotes brain metastasis in breast cancer and identify fludarabine as a potential therapeutic agent that specifically eliminates XIST
tumor cells in the brain.
.
PDF
