Inhibition of MEK Signaling Attenuates Cancer Stem Cell Activity in Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is highly aggressive and has very limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity in ATC could underlie this recurrence and resistance to treatment. The recent approval by the U.S. Food and Drug Administration of the combined treatment of BRAF and MEK inhibitors for ATC patients has shown some efficacy in patients harboring the BRAFV600E mutation. However, it was unknown whether the combined treatment could affect the CSC activity. This study explores the effects of the BRAF and MEK inhibitors on CSC activity in human ATC cells. Methods: Using three human ATC cells, THJ-11T, THJ-16T, and 8505C cells, we evaluated the effects of dabrafenib (a BRAF kinase inhibitor), trametinib (an MEK inhibitor), or a combined treatment of the two drugs on the CSC activity by tumorsphere formation, Aldefluor assays, expression profiles of key CSC markers, immunohistochemistry, and in vivo xenograft mouse models. Furthermore, we also used confocal imaging to directly visualize the effects on drugs on CSCs by the SORE6-mCherry reporter in cultured cells and xenograft tumor cells. Results: The BRAF inhibitor, dabrafenib, had weak efficacy, while the MEK inhibitor, trametinib, showed strong efficacy in attenuating the CSC activity, as evidenced by suppression of CSC marker expression, tumorsphere formation, and Aldefluor assays. Using ATC cells expressing a fluorescent CSC SORE6 reporter, we showed reduction of CSC activity in the rank order of combined > trametinib > dabrafenib through in vitro and in vivo xenograft models. Molecular analyses showed that suppression of CSC activity by these drugs was, in part, mediated by attenuation of the transcription by dampening the RNA polymerase II activity. Conclusions: Our analyses demonstrated the presence of CSCs in ATC cells. The inhibition of CSC activity by the MEK signaling could partially account for the efficacy of the combined treatment shown in ATC patients. However, our studies also showed that not all CSC activity was totally abolished, which may account for the recurrence observed in ATC patients. Our findings have provided new insights into the molecular basis of efficacy and limitations of these drugs in ATC patients.

Thyroid hormone receptor α1: a novel regulator of thyroid cancer cell differentiation.

Thyroid hormone receptor α1 (TRα1) mediates the genomic actions of thyroid hormone (T3). The biology of TRα1 in growth and development has been well studied, but the functional role of TRα1 in cancers remains to be elucidated. Analysis of the human thyroid cancer database of The Cancer Genome Atlas (TCGA) showed that THRA gene expression is lost in highly dedifferentiated anaplastic thyroid cancer (ATC). We, therefore, explored the effects of TRα1 on the progression of ATC. We stably expressed TRα1 in two human ATC cell lines, THJ-11T (11T-TRα1 #2, #7, and #8) and THJ-16T (16T-TRα1 #3, #4, and #8) cells. We found that the expressed TRα1 inhibited ATC cell proliferation and induced apoptosis. TCGA data showed that THRA gene expression was best correlated with the paired box gene 8 (PAX8). Consistently, we found that the PAX8 expression was barely detectable in parental 11T and 16T cells. However, PAX8 gene expression was elevated in 11T- and 16T-TRα1-expressing cells at the mRNA and protein levels. Using various molecular analyses, we found that TRα1 directly regulated the expression of the PAX8 gene. Single-cell transcriptomic analyses (scRNA-seq) demonstrated that TRα1 functions as a transcription factor through multiple signaling pathways to suppress tumor growth. Importantly, scRNA-seq analysis showed that TRα1-induced PAX8, via its transcription program, shifts the cell landscape of ATC toward a differentiated state. The present studies suggest that TRα1 is a newly identified regulator of thyroid differentiation and could be considered as a potential therapeutic target to improve the outcome of ATC patients.

Reactivated thyroid hormone receptor ß attenuates anaplastic thyroid cancer (ATC) stem cell activity.

Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity contributes to therapeutic resistance and recurrence of ATC. We show that the expression of the endogenous thyroid hormone receptor ß gene (THRB) is silenced in ATC and demonstrate that the exogenously expressed TRß suppresses CSC activity. Decitabine is one of the demethylation agents to treat myelodysplastic syndrome and acute myeloid leukemia patients and is currently in clinical trials for hematopoietic malignancies and solid tumors. We aim to show that the re-expression of the endogenous THRB gene by decitabine can attenuate CSC activity to block ATC tumor growth. We treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRß on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRß, as evidenced by western blot and immunohistochemical analyses. The expressed TRß inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44, and ß-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation, and increasing apoptosis. Our findings suggest that re-expression of the endogenous TRß is a novel therapeutic approach for ATC via suppression of CSC activity.

Effect of Structural Design on the Pore Structure, Water Resistance, and Mechanical Properties of Engineered Wood/Bamboo Laminated Composites.

An important principle in rational manufacturing design is matching the properties of composites to their intended uses. Herein, six laminated composites (LCs) were manufactured using fibrous moso bamboo and poplar veneer units, and their pore structure, water resistance, and mechanical properties were evaluated. The LC density (640-1290 kg/m3) increased significantly with increasing bamboo veneer unit content. The LC surface texture and roughness depended on the density and type of surface layer. With increasing LC density, the water absorption rate (WAR), width swelling rate (WSR), and thickness swelling rate (TSR) decreased exponentially and the mechanical properties increased linearly. This behavior was closely related to the changes in pore structure caused by density. Notably, the water resistance and mechanical properties of the LCs with densities higher than 910 kg/m3 were superior to the highest levels specified in GB/T 20241-2006 for ''laminated veneer lumber'' and GB/T 30364-2013 for "bamboo scrimber flooring". Thus, these engineered materials are promising for outdoor structures and flooring.

High-Precision Semiconductor Laser Current Drive and Temperature Control System Design.

To solve the problem in which the output power and wavelength of semiconductor lasers in fiber optic sensing systems are easily affected by the drive current and temperature, a high-precision current drive and temperature control system was developed in this study. The embedded system was used to provide a stable drive current for the semiconductor laser through closed-loop negative feedback control; moreover, some measures, such as linear slow-start, current-limiting protection, and electrostatic protection, were adopted to ensure the stability and safety of the laser's operation. A mathematical model of the temperature control system was constructed using mechanism analysis, and model identification was completed using the M sequence and differential evolution (DE) algorithms. Finally, the control rules of the fuzzy proportional integral differentiation (PID) algorithm were optimized through system simulation to make it more suitable for the temperature control system designed in this research, and the accurate control of the working temperature of the semiconductor laser was realized. Experimental results showed that the system could achieve a linearly adjustable drive current in the range of 0-100 mA, with an output current accuracy of 0.01 mA and a temperature control accuracy of up to 0.005 °C.

Cell non-autonomous effect of hepatic growth differentiation factor 15 on the thyroid gland.

The thyroid gland plays an essential role in the regulation of body energy expenditure to maintain metabolic homeostasis. However, to date, there are no studies investigating the morphological and functional changes of the thyroid gland due to mitochondrial stress in metabolic organs such as the liver. We used data from the Genotype-Tissue Expression portal to investigate RNA expression patterns of the thyroid gland according to the expression of growth differentiation factor 15 (GDF15) such as the muscles and liver. To verify the effect of hepatic GDF15 on the thyroid gland, we compared the morphological findings of the thyroid gland from liver-specific GDF15 transgenic mice to that of wild type mice. High GDF15 expression in the muscles and liver was associated with the upregulation of genes related to hypoxia, inflammation (TGF-α via NFκB), apoptosis, and p53 pathway in thyroid glands. In addition, high hepatic GDF15 was related to epithelial mesenchymal transition and mTORC1 signaling. Electron microscopy for liver-specific GDF15 transgenic mice revealed short mitochondrial cristae length and small mitochondrial area, indicating reduced mitochondrial function. However, serum thyroid stimulating hormone (TSH) level was not significantly different. In our human cohort, those with a high serum GDF15 level showed high fasting glucose, alanine transaminase, and alkaline phosphatase but no difference in TSH, similar to the data from our mice model. Additionally, high serum GDF15 increased the risk of lymph node metastasis to lateral neck. The hepatic GDF15 affected thyroid morphogenesis via a TSH-independent mechanism, affecting aggressive features of thyroid cancers.

Photodegradation and Photostability of Bamboo: Recent Advances.

Bamboo and its products are widely used in indoor and outdoor fields. Photodegradation occurs easily on the surface when bamboo is exposed to ultraviolet (UV) light from solar radiation. This induces surface discoloration and degrades the physical properties of bamboo, which not only negatively affects its utility and aesthetic characteristics but also restricts its application in outdoor environments. In this work, we review the mechanism of bamboo photodegradation, in which the behavior of lignin is key. The changes in bamboo's microstructure, surface color, and chemical composition during photodegradation are described in detail. Methods for enhancing its photostability, including the application of transparent coatings containing UV absorbers and hindered amine light stabilizer compounds on bamboo surfaces, are then systematically summarized, and potential approaches to combat the photodegradation of bamboo surfaces are discussed. On the basis of the recent advances of photodegradation and photostability of bamboo, this review provides new insights into the scientific application and protection of bamboo in the outdoor field.

Hydrogen-bond activated ESIPT in naphthalimide-based fluorescent probe for sensing volatile amines.

Amines levels present important indicative value in food safety and human health. Although they are involved in some normal physiological responses of the organism, their overproduction or intake may cause pathological responses. Herein, we report a recyclable visual packaging bag for volatile amines detections based on the naphthylamide derivative N-S and its positive PL characteristics. Specifically, handmade test strips based on compound N-S have been applied to fish freshness labeling, and the cyclic fumigation experiment shows its restorable PL effect and efficiency. The possible PL transfer mechanism of naphthylamide derivative N-S is uncovered by the density functional theory (DFT) calculation and titration mass spectrometer and 1H NMR. This work expands a conjugation in a molecule by hydrogen-bond activated ESIPT (H-ESIPT) and provides a portable detection method for volatile amines detection.

Regulation of cancer stem cell activity by thyroid hormone receptor ß.

Increasing numbers of cancer stem cell markers have been recently identified. It is not known, however, whether a member of the nuclear receptor superfamily, thyroid hormone receptor ß (TRß), can function to regulate cancer stem cell (CSC) activity. Using anaplastic thyroid cancer cells (ATC) as a model, we highlight the role of TRß in CSC activity. ATC is one of the most aggressive solid cancers in humans and is resistant to currently available therapeutics. Recent studies provide evidence that CSC activity underlies aggressiveness and therapeutic resistance of ATC. Here we show that TRß inhibits CSC activity by suppressing tumor-sphere formation of human ATC cells and their tumor-initiating capacity. TRß suppresses the expression of CSC regulators, including ALDH, KLF2, SOX2, b-catenin, and ABCG2, in ATC cell-induced xenograft tumors. Single-cell transcriptomic analysis shows that TRß reduces CSC population in ATC-induced xenograft tumors. Analysis of The Cancer Genome Atlas (TCGA) database demonstrates that the inhibition of CSC capacity by TRß contributes to favorable clinical outcomes in human cancer. Our studies show that TRß is a newly identified transcription regulator that acts to suppress CSC activity and that TRß could be considered as a molecular target for therapeutic intervention of ATC.

Covalent modification of black phosphorus with alkoxy groups to improve the solubility and ambient stability.

Black phosphorus (BP), a new 2D material as a layered allotrope of phosphorus, has regained attention due to its outstanding semiconductor characteristics. However, the major hurdles of using few-layer BP for applications are its poor solution processability and low ambient stability. Here, we report a covalent modification of BP nanosheets by a chemical reaction with sodium alkoxide. Fourier transform infrared spectra, Raman spectra, X-ray photoemission spectra and thermogravimetric analyses all confirmed the successful introduction of alkoxy groups on the BP surface with P-O-C bonds, which increased the solubility and ambient stability of BP. The introduced alkoxy groups as soluble side chains on the BP surface not only increase the solubility of BP nanosheets by almost 3 times, but also decrease the degradation ratio of the modified BP by about 2 times because of the encapsulation. In this work we developed a facile synthetic strategy to covalently modify BP by introducing soluble side chains, suggesting an effective way to realize its full potential application in electronics.

Thyroid Hormone Receptor α Regulates Autophagy, Mitochondrial Biogenesis, and Fatty Acid Use in Skeletal Muscle.

Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone α (RTHα) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined the role of thyroid hormone receptor α (TRα), the predominant TR isoform in SM, on autophagy, mitochondrial biogenesis, and metabolism to demonstrate the molecular mechanism(s) underlying muscle weakness in these two conditions. Two genetic mouse models were used in this study: TRα1PV/+ mice, which express the mutant Thra1PV gene ubiquitously, and SM-TRα1L400R/+ mice, which express TRα1L400R in a muscle-specific manner. Gastrocnemius muscle from TRα1PV/+, SM-TRα1L400R/+, and their control mice was harvested for analyses. We demonstrated that loss of TRα1 signaling in gastrocnemius muscle from both the genetic mouse models led to decreased autophagy as evidenced by accumulation of p62 and decreased expression of lysosomal markers (lysosomal-associated membrane protein [LAMP]-1 and LAMP-2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), and estrogen-related receptor α (ERRα), key factors contributing to mitochondrial biogenesis as well as mitochondrial proteins, were decreased, suggesting that there was reduced mitochondrial biogenesis due to the expression of mutant TRα1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired and was associated with decreased acylcarnitines and tricarboxylic acid cycle intermediates in the SM from the mouse line expressing SM-specific mutant TRα1. Our results provide new insight into TRα1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired.

Willingness of Chinese, Studying in Germany to Fly Back to China Due to Their Risk Perception About COVID-19.

PURPOSE: In this study, we aimed to examine the risk perception of Chinese students studying in Germany, which is the country fifth-most affected by COVID-19 in the world, who wish to return to China. PATIENTS AND METHODS: After controlling the COVID-19 situation in the country, China reopened the entire country, including Wuhan, which was the epicenter of the COVID-19 pandemic. A well-structured questionnaire was sent to Chinese students through a WeChat survey, a special feature within this mobile application, similar to Google Docs. The link was sent to 2000 students studying in Germany, and we received 1232 responses. RESULTS: The study found that the majority of Chinese students are willing to come back to China, considering the current risk of COVID-19 in Germany. A higher mortality rate influences their wish to return to China. Additionally, the special family size of "One Child" in the family also a key driver of Chinese student's wish to get back home. CONCLUSION: This study provides useful information to policymakers to implement proactive measures to manage students who want to return to China, as they may be the cause of the second wave of COVID-19 in China.

Thyroid Hormone Receptor α1 Mutants Impair B Lymphocyte Development in a Mouse Model.

Background: Mutations of the thyroid hormone receptor α (THRA) gene cause resistance to thyroid hormone (RTHα). RTHα patients exhibit very mild abnormal thyroid function test results (serum triiodothyronine can be high-normal to high; thyroxine normal to low; thyrotropin is normal or mildly raised) but manifest hypothyroid symptoms with growth retardation, delayed bone development, and anemia. Much has been learned about the in vivo molecular actions in TRα1 mutants affecting abnormal growth, bone development, and anemia by using a mouse model of RTHα (Thra1PV/+ mice). However, it is not clear whether TRα1 mutants affect lymphopoiesis in RTHα patients. The present study addressed the question of whether TRα1 mutants could cause defective lymphopoiesis. Methods: We assessed lymphocyte abundance in the peripheral circulation and in the lymphoid organs of Thra1PV/+ mice. We evaluated the effect of thyroid hormone on B cell development in the bone and spleen of these mice. We identified key transcription factors that are directly regulated by TRα1 in the regulation of B cell development. Results: Compared with wild-type mice, a significant reduction in B cells, but not in T cells, was detected in the peripheral circulation, bone marrow, and spleen of Thra1PV/+ mice. The expression of key transcription regulators of B cell development, such as Ebf1, Tcf3, and Pax5, was significantly decreased in the bone marrow and spleen of Thra1PV/+ mice. We further elucidated that the Ebf1 gene, essential for lineage specification in the early B cell development, was directly regulated by TRα1. Thus, mutations of TRα1 could impair B cell development in the bone marrow via suppression of key regulators of B lymphopoiesis. Conclusions: Analysis of lymphopoiesis in a mouse model of RTHα showed that B cell lymphopoiesis was suppressed by TRα1 mutations. The suppressed development of B cells was, at least in part, via inhibition of the expression of key regulators, Ebf1, Tcf3, and Pax5, by TRα1 mutations. These findings suggest that the mutations of the THRA gene in patients could lead to B cell deficiency.

Multiple mechanisms regulate H3 acetylation of enhancers in response to thyroid hormone.

Hormone-dependent activation of enhancers includes histone hyperacetylation and mediator recruitment. Histone hyperacetylation is mostly explained by a bimodal switch model, where histone deacetylases (HDACs) disassociate from chromatin, and histone acetyl transferases (HATs) are recruited. This model builds on decades of research on steroid receptor regulation of transcription. Yet, the general concept of the bimodal switch model has not been rigorously tested genome wide. We have used a genomics approach to study enhancer hyperacetylation by the thyroid hormone receptor (TR), described to operate as a bimodal switch. H3 acetylation, HAT and HDAC ChIP-seq analyses of livers from hypo- and hyperthyroid wildtype, TR deficient and NCOR1 disrupted mice reveal three types of thyroid hormone (T3)-regulated enhancers. One subset of enhancers is bound by HDAC3-NCOR1 in the absence of hormone and constitutively occupy TR and HATs irrespective of T3 levels, suggesting a poised enhancer state in absence of hormone. In presence of T3, HDAC3-NCOR1 dissociates from these enhancers leading to histone hyperacetylation, suggesting a histone acetylation rheostat function of HDACs at poised enhancers. Another subset of enhancers, not occupied by HDACs, is hyperacetylated in a T3-dependent manner, where TR is recruited to chromatin together with HATs. Lastly, a subset of enhancers, is not occupied directly by TR yet requires TR for histone hyperacetylation. This indirect enhancer activation involves co-association with TR bound enhancers within super-enhancers or topological associated domains. Collectively, this demonstrates various mechanisms controlling hormone-dependent transcription and adds significant details to the otherwise simple bimodal switch model.

Potentiated anti-tumor effects of BETi by MEKi in anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited treatment options. We explored novel treatment modalities by targeting epigenetic modifications using inhibitors of BET (e.g. BRD4) activity. We evaluated the efficacy in the treatment of ATC of a novel BET inhibitor, PLX51107 (PLX), currently in clinical trials for other solid tumors and hematologic malignancies, alone or combined with a MEK inhibitor, PD0325901(PD). To elucidate the effects of these inhibitors on growth of ATC, we treated ATC cells derived from patient tumors (THJ-11T and THJ-16T cells) and mouse xenograft tumors with inhibitors. We found PLX and PD inhibitors singly inhibited proliferation of both human ATC cells lines, but together exhibited stronger inhibition of proliferation. In mouse xenografts, the combination treatment almost totally blocked growth in xenograft tumors derived from both ATC cells. PD effectively attenuated MEK-ERK signaling, which was further enhanced by PLX in the combined treatment in cultured cells and tumors. Importantly, the combination of PLX and PD acted synergistically to suppress MYC transcription to increase p27 in decreasing tumor cell proliferation. PLX and PD cooperated to upregulate pro-apoptotic proteins to promote apoptosis. These two inhibitors converged to reduce the binding of BRD4 to the MYC promoter to suppress the MYC expression. These findings indicate that combined treatment of BET and MEK-ERK inhibitors was more effective to treat ATC than single targeted treatment. Synergistic suppression of MYC transcription via collaborative actions on chromatin modifications suggested that targeting epigenetic modifications could provide novel treatment opportunities for ATC.

Genetic and Pharmacological Targeting of Transcriptional Repression in Resistance to Thyroid Hormone Alpha.

Background: Thyroid hormones act in bone and cartilage via thyroid hormone receptor alpha (TRα). In the absence of triiodothyronine (T3), TRα interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TRα cause resistance to thyroid hormone alpha (RTHα; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation, and bone dysplasia. Treatment with thyroxine has been of limited benefit, even in mildly affected individuals, and there is a need for new therapeutic strategies. It was hypothesized that (i) the skeletal manifestations of RTHα are mediated by the persistent TRα/NCoR1/HDAC repressor complex containing mutant TRα, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations. Methods: The skeletal phenotypes of (i) Thra1PV/+ mice, a well characterized model of RTHα; (ii) Ncor1ΔID/ΔID mice, which express an NCoR1 mutant that fails to interact with TRα; and (iii) Thra1PV/+Ncor1ΔID/ΔID double-mutant adult mice were determined. Wild-type, Thra1PV/+, Ncor1ΔID/ΔID, and Thra1PV/+Ncor1ΔID/ΔID double-mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. Results:Thra1PV/+ mice had a severe skeletal dysplasia, characterized by short stature, abnormal bone morphology, and increased bone mineral content. Despite normal bone length, Ncor1ΔID/ΔID mice displayed increased cortical bone mass, mineralization, and strength. Thra1PV/+Ncor1ΔID/ΔID double-mutant mice displayed only a small improvement of skeletal abnormalities compared to Thra1PV/+ mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bone structure, mineralization, or strength in wild-type or mutant mice. Conclusions: These studies indicate treatment with SAHA is unlikely to improve the skeletal manifestations of RTHα. Nevertheless, the findings (i) confirm that TRα1 has a critical role in the regulation of skeletal development and adult bone mass, (ii) suggest a physiological role for alternative co-repressors that interact with TR in skeletal cells, and (iii) demonstrate a novel role for NCoR1 in the regulation of adult bone mass and strength.

Loss of Primary Cilia Results in the Development of Cancer in the Murine Thyroid Gland.

Communications at the interface between the apical membrane of follicular cells and the follicular lumen are critical for the homeostasis of thyroid gland. Primary cilia at the apical membrane of thyroid follicular cells may sense follicular luminal environment and regulate follicular homeostasis, although their role in vivo remains to be determined. Here, mice devoid of primary cilia were generated by thyroid follicular epithelial cell-specific deletion of the gene encoding intraflagellar transport protein 88 (Ift88 ). Thyroid follicular cell-specific Ift88-deficient mice showed normal folliculogenesis and hormonogenesis; however, those older than 7 weeks showed irregularly dilated and destroyed follicles in the thyroid gland. With increasing age, follicular cells with malignant properties showing the characteristic nuclear features of human thyroid carcinomas formed papillary and solid proliferative nodules from degenerated thyroid follicles. Furthermore, malignant tumor cells manifested as tumor emboli in thyroid vessels. These findings suggest that loss-of-function of Ift88/primary cilia results in malignant transformation from degenerated thyroid follicles.

Synergistic effects of BET and MEK inhibitors promote regression of anaplastic thyroid tumors.

Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited options for treatment. Targeting epigenetic modifications via interfering with the interaction between the bromodomain and extra-terminal domain (BET) proteins and acetylated histones by using BET inhibitors (e.g., JQ1) has shown some efficacy in thyroid cancer. To improve the efficacy, an inhibitor of MEK, trametinib, was tested together with JQ1 as a combined treatment via cell-based approaches and xenograft studies. We examined the effects of combined treatment of JQ1 and trametinib on the proliferation of human ATC cell lines (THJ-11T and THJ-16) in vitro. We further evaluated the effects of the combined treatment on tumor development in vivo using mouse xenograft models. We elucidated the underlying molecular pathways affected by double treatment. We showed that the combined treatment totally blocked proliferation, while either JQ1 or trametinib alone only had partial effects. Combined treatment suppressed MYC expression more than single treatment, resulting in decreased expression of pro-survival regulators and increased pro-apoptotic regulators to collaboratively induce apoptosis. In xenograft studies, single treatment only partially inhibited tumor growth, but the combined treatment inhbited tumor growth by >90%. The reduction of tumor growth was mediated by synergistic suppression of MYC, to affect apoptotic regulators to markedly promote tumor apoptosis. Combined treatment of BET and MEK-ERK inhibitors was more effective to treat ATC than single targeted treatment. Synergistic suppression of MYC transcription via collaborative actions on chromatin modifications suggested that targeting epigenetic modifications could provide novel treatment opportunities for ATC.

Near-Net Forming Complex Shaped Zr-Based Bulk Metallic Glasses by High Pressure Die Casting.

Forming complex geometries using the casting process is a big challenge for bulk metallic glasses (BMGs), because of a lack of time of the window for shaping under the required high cooling rate. In this work, we open an approach named the "entire process vacuum high pressure die casting" (EPV-HPDC), which delivers the ability to fill die with molten metal in milliseconds, and create solidification under high pressure. Based on this process, various Zr-based BMGs were prepared by using industrial grade raw material. The results indicate that the EPV-HPDC process is feasible to produce a glassy structure for most Zr-based BMGs, with a size of 3 mm × 10 mm and with a high strength. In addition, it has been found that EPV-HPDC process allows complex industrial BMG parts, some of which are hard to be formed by any other metal processes, to be net shaped precisely. The BMG components prepared by the EVP-HPDC process possess the advantages of dimensional accuracy, efficiency, and cost compared with the ones formed by other methods. The EVP-HPDC process paves the way for the large-scale application of BMGs.

Analysis of Thyroid Tumorigenesis in Xenograft Mouse Model.

Analysis of thyroid tumorigenesis in xenograft mouse model is important to study human thyroid cancer. Recent studies have made big strides toward understanding the molecular mechanisms by which thyroid hormone nuclear receptors (TR) act to maintain normal cellular functions in growth, differentiation, and development. Despite growing interest, the role of TR in oncogenesis remains to be fully elucidated. Two TR genes give rise to three major TR isoforms: TRα1, TRß1, and TRß2. These TR subtypes express in a tissue- and development-dependent manner. Research has been directed at understanding the mechanisms by which TR could mediate aberrant cellular signaling that contributes to oncogenesis, at dissecting possible distinct roles of TR isoforms in oncogenesis, and at the differential susceptibility of target tissues to the oncogenic actions of TR. This chapter gives a brief overview of the current undersatanding of known molecular oncogenic actions of TR. Here, we describe analysis of thyroid tumorigenesis used in interrogating the in vivo oncogenic actions of TR.