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Tong, Wenjie, Wanming Li, Ximin Zang, Huabing Li, Zhouhua Jiang, and Dejun Li. "A Comprehensive Mathematical Model of Electroslag Remelting with Two Series-Connected Electrodes Based on Sequential Coupling Simulation Method." Metals 10, no. 5 (May 19, 2020): 658. http://dx.doi.org/10.3390/met10050658.
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A comprehensive mathematical model of electroslag remelting with two series-connected electrodes (TSCE-ESR) was constructed based on sequential coupling method. The influence of droplet effect on electroslag remelting process (ESR) was considered in this model. Compared with one-electrode electroslag remelting (OE-ESR), the multi-physics field, droplet formation and dripping behavior, and molten metal pool structure of TSCE-ESR process were studied. The results show that during the process of TSCE-ESR, the proximity effect of the electrodes suppresses the skin effect, and Joule heat is concentrated in the area between the two electrodes of slag pool, making the temperature distribution of the slag pool more uniform. The heat used to melt the electrode in the process of TSCE-ESR accounts for about 34% of the total Joule heat, which is lower than the OE-ESR (17%). Therefore, it makes a higher melting rate and a smaller droplet size in the process of TSCE-ESR. Compared with OE-ESR, TSCE-ESR process can realize the unification of higher melting rate and shallow flat molten metal pool. Compared with the results without droplet effect, it is found that in the simulation results with droplet effect, the depth and the cylindrical section of molten metal pool increased, and the width of the mushy zone is significantly reduced, which is more consistent with the actual electroslag remelting process.
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Heidenreich, Wolfgang F., E. Georg Luebeck, and Suresh H. Moolgavkar. "Effects of Exposure Uncertainties in the TSCE Model and Application to the Colorado Miners Data." Radiation Research 161, no. 1 (January 2004): 72–81. http://dx.doi.org/10.1667/rr3089.
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Tong, Wenjie, Wanming Li, Ximin Zang, Huabing Li, Zhouhua Jiang, and Yu Han. "Droplet Formation and Dripping Behavior during the Electroslag Remelting Process with Two Series-Connected Electrodes." Metals 10, no. 3 (March 18, 2020): 386. http://dx.doi.org/10.3390/met10030386.
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The formation and dripping behavior of droplets in the process of the electroslag remelting with two series-connected electrodes (TSCE-ESR) has an important influence on the optimization of power supply parameters and the purity of the electroslag ingot. In this article, through numerical simulation based on the VOF (volume of fluid) model, combined with the transparent experimental device for physical simulation, the mechanism of metal droplet formation and the effect of the filling rate on its droplet behavior were studied. The results showed that the proximity effect, instead of the skin effect, is a major factor influencing droplet formation in TSCE-ESR process. The proximity effect makes the region inside the two electrode tip melt first, and the molten steel converges at the electrode tips to form a droplet source. The process of droplet formation and dropping can be divided into three stages: formation of molten layer, droplet stretching and necking, and detachment. In the stage of droplet stretching and necking, the increase in the contact area between the droplet and the slag and the instantaneous increase of the current provide good thermodynamic and dynamic conditions for the removal of non-metallic inclusions. After the droplet drops into the slag pool, it promotes the flow of slag and improves the heat and mass transfer efficiency of the slag/metal interface. The relatively large filling rate can form smaller and dispersed droplets, which improves the refining effect. At the same time, the increase of the filling rate can improve the input power and the electrode remelting rate.
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Zarei, Mahsa, Heng Du, Amin H. Nassar, Rachel E. Yan, Krinio Giannikou, Sneha H. Johnson, Hilaire C. Lam, et al. "Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion." Journal of Experimental Medicine 216, no. 11 (September 10, 2019): 2635–52. http://dx.doi.org/10.1084/jem.20190251.
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Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/− mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2.
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Mrozek, Evelyn M., Vineeta Bajaj, Yanan Guo, Izabela A. Malinowska, Jianming Zhang, and David J. Kwiatkowski. "Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer." PLOS ONE 16, no. 4 (April 23, 2021): e0248380. http://dx.doi.org/10.1371/journal.pone.0248380.
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Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.
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Sampson, J. R. "TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis." Biochemical Society Transactions 31, no. 3 (June 1, 2003): 592–96. http://dx.doi.org/10.1042/bst0310592.
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The tuberous sclerosis complex genes TSC1 and TSC2 were first identified by positional cloning strategies in the heritable human disorder tuberous sclerosis. They encode previously unknown proteins, termed hamartin and tuberin respectively, that form a functional complex. The phenotypic manifestations of tuberous sclerosis are extremely diverse and suggest normal roles for TSC1 and TSC2 in regulating the growth, proliferation, migration and differentiation of many cell types. Investigations of TSC1 and TSC2 in a number of model organisms and cell-culture systems have provided new insights into the mechanisms through which these roles are effected. Most promisingly, the hamartin–tuberin complex has been shown to function as a negtive regulator of the insulin receptor/phosphoinositide 3-kinase/S6 kinase pathway. Drugs that act to inhibit this pathway may have therapeutic potential for tuberous sclerosis and the related disorder lymphangioleiomyomatosis.
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Dickson, Mark Andrew, Vinod Ravi, Kristen N. Ganjoo, and Gopa Iyer. "Institutional experience with nab-sirolimus in patients with malignancies harboring TSC1 or TSC2 mutations." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3111. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3111.
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3111 Background: TSC1/ TSC2 genes are tumor suppressors in the mTOR pathway; mutated at low frequency across tumor types (̃1–2%). Retrospective analyses of patients (pts) with mTOR pathway mutations treated with everolimus did not show improved outcomes vs the wild type (Voss et al. Clin Cancer Res 2019. PMID 30327302). In NCT02201212, pts with TSC1/TSC2 mutations treated with everolimus had a 7% (2/30) response rate. In the AMPECT study, pts with advanced PEComa treated with a novel mTOR inhibitor (mTORi), nab-sirolimus ( nab-S, ABI-009), the subset of pts with TSC1/TSC2 mutations had a response rate of 64% (9/14) (Wagner et al. CTOS 2020. #3463014). In a xenograft model, nab-S showed significantly higher tumor accumulation, target suppression (pS6) and antitumor activity vs everolimus or sirolimus (Hou et al. AACR 2019. #348). In an expanded access program (NCT03817515), pts with advanced tumors bearing TSC1/ TSC2 mutations were treated with nab-S and outcomes in pts with malignancies other than PEComa are reported herein. Methods: Eligible pts (ECOG 0–2) received nab-S 100 mg/m2 IV, once weekly for 2 of every 3 weeks at 3 US sites between 7/2019 and 11/2020. Results: 7 pts with TSC1/ TSC2 mutations have been consecutively enrolled and are reported here. 6/7 pts had multiple prior therapies including 2 pts previously progressing on an mTORi. 4/7 pts had partial response (PR), all in mTORi naïve pts. 2/7 pts had stable disease (SD). In 2 pts previously treated with an mTORi, 1 had SD and 1 came off treatment after 1 cycle (CA125 ↑) with no follow-up scan. Treatment-related serious adverse events (SAEs; hyperglycemia and infection) and dose reduction were reported in 1 pt with metastatic angiosarcoma; SAEs resolved and the pt continued Rx. No other SAE or dose limiting event was reported Conclusions: Patients with various malignancies bearing TSC1 or TSC2 mutations, most with progression on multiple prior therapies, showed evidence of response and manageable toxicities during treatment with nab-S. A basket trial of nab-S in malignancies with TSC1/ TSC2 mutations is planned. Clinical trial information: NCT03817515. [Table: see text]
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Langkau, Nicola, Nicola Martin, Regine Brandt, Karin Zügge, Stefanie Quast, Gerd Wiegele, Anna Jauch, et al. "TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/TSC2 frequency ratios." European Journal of Pediatrics 161, no. 7 (June 8, 2002): 393–402. http://dx.doi.org/10.1007/s00431-001-0903-7.
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Zahedi, Kamyar, Sharon Barone, Marybeth Brooks, Tracy Murray Stewart, Robert A. Casero, and Manoocher Soleimani. "Renal Transcriptome and Metabolome in Mice with Principal Cell-Specific Ablation of the Tsc1 Gene: Derangements in Pathways Associated with Cell Metabolism, Growth and Acid Secretion." International Journal of Molecular Sciences 23, no. 18 (September 13, 2022): 10601. http://dx.doi.org/10.3390/ijms231810601.
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Tuberous sclerosis complex (TSC) is caused by mutations in the hamartin (TSC1) or tuberin (TSC2) genes. Using a mouse model of TSC renal cystogenesis that we have previously described, the current studies delineate the metabolic changes in the kidney and their relation to alterations in renal gene expression. To accomplish this, we compared the metabolome and transcriptome of kidneys from 28-day-old wildtype (Wt) and principal cell-specific Tsc1 KO (Tsc1 KO) mice using targeted 1H nuclear magnetic resonance targeted metabolomic and RNA-seq analyses. The significant changes in the kidney metabolome of Tsc1 KO mice included reductions in the level of several amino acids and significant decreases in creatine, NADH, inosine, UDP-galactose, GTP and myo-inositol levels. These derangements may affect energy production and storage, signal transduction and synthetic pathways. The pertinent derangement in the transcriptome of Tsc1 KO mice was associated with increased collecting duct acid secretion, active cell division and the up-regulation of signaling pathways (e.g., MAPK and AKT/PI3K) that suppress the TSC2 GTPase-activating function. The combined renal metabolome and transcriptome alterations observed in these studies correlate with the unregulated growth and predominance of genotypically normal A-intercalated cells in the epithelium of renal cysts in Tsc1 KO mice.
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Liang, Ning, Chi Zhang, Patricia Dill, Ganna Panasyuk, Delphine Pion, Vonda Koka, Morgan Gallazzini, et al. "Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex." Journal of Experimental Medicine 211, no. 11 (October 6, 2014): 2249–63. http://dx.doi.org/10.1084/jem.20140341.
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Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1–TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.
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Kapfhamer, David, James McKenna, Caroline J. Yoon, Tracy Murray-Stewart, Robert A. Casero, and Michael J. Gambello. "Ornithine decarboxylase, the rate-limiting enzyme of polyamine synthesis, modifies brain pathology in a mouse model of tuberous sclerosis complex." Human Molecular Genetics 29, no. 14 (June 26, 2020): 2395–407. http://dx.doi.org/10.1093/hmg/ddaa121.
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Abstract Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder characterized by variable expressivity. TSC results from inactivating variants within the TSC1 or TSC2 genes, leading to constitutive activation of mechanistic target of rapamycin complex 1 signaling. Using a mouse model of TSC (Tsc2-RG) in which the Tsc2 gene is deleted in radial glial precursors and their neuronal and glial descendants, we observed increased ornithine decarboxylase (ODC) enzymatic activity and concentration of its product, putrescine. To test if increased ODC activity and dysregulated polyamine metabolism contribute to the neurodevelopmental defects of Tsc2-RG mice, we used pharmacologic and genetic approaches to reduce ODC activity in Tsc2-RG mice, followed by histologic assessment of brain development. We observed that decreasing ODC activity and putrescine levels in Tsc2-RG mice worsened many of the neurodevelopmental phenotypes, including brain growth and neuronal migration defects, astrogliosis and oxidative stress. These data suggest a protective effect of increased ODC activity and elevated putrescine that modify the phenotype in this developmental Tsc2-RG model.
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Cheah, Pike-See, Shilpa Prabhakar, David Yellen, Roberta L. Beauchamp, Xuan Zhang, Shingo Kasamatsu, Roderick T. Bronson, et al. "Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin." Science Advances 7, no. 2 (January 2021): eabb1703. http://dx.doi.org/10.1126/sciadv.abb1703.
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Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of TSC2 using an adeno-associated virus (AAV) vector carrying the complementary for a “condensed” form of human tuberin (cTuberin). Functionality of cTuberin was verified in culture. A mouse model of TSC2 was generated by AAV-Cre recombinase disruption of Tsc2-floxed alleles at birth, leading to a shortened lifespan (mean 58 days) and brain pathology consistent with TSC. When these mice were injected intravenously on day 21 with AAV9-cTuberin, the mean survival was extended to 462 days with reduction in brain pathology. This demonstrates the potential of treating life-threatening TSC2 lesions with a single intravenous injection of AAV9-cTuberin.
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Ramesh, V. "Aspects of tuberous sclerosis complex (TSC) protein function in the brain." Biochemical Society Transactions 31, no. 3 (June 1, 2003): 579–83. http://dx.doi.org/10.1042/bst0310579.
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Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumour-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at both TSC1 and TSC2 loci. LOH has been documented in renal angiomyolipomas, but loss of the wild-type allele in cortical tubers appears very uncommon. We analysed 24 hamartomas from 10 patients for second-hit mutations by several methods, and found no evidence for the inactivation of the second allele in many of the central nervous system (CNS) lesions, including tumours that appear to be clonally derived. We believe that somatic mutations in TSC1 and TSC2 resulting in the loss of wild-type alleles may not be necessary in some tumour types, and other mechanisms may contribute to tumorigenesis in this setting. We have shown that hamartin interacts with neurofilament light chain (NF-L) and could integrate the neuronal cytoskeleton through its direct interaction with NF-L and ERM (ezrin/radixin/moeisin) proteins. Our unpublished work further documents the binding of tuberin with Pam, a protein associated with c-Myc, which is enriched in brain. All these observations suggest that the tuberin–hamartin complex is likely to have distinct functions in the CNS.
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Czapski, Grzegorz A., Lidia Babiec, Henryk Jęśko, Magdalena Gąssowska-Dobrowolska, Magdalena Cieślik, Marta Matuszewska, Małgorzata Frontczak-Baniewicz, Karolina Zajdel, and Agata Adamczyk. "Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders." International Journal of Molecular Sciences 22, no. 18 (September 17, 2021): 10058. http://dx.doi.org/10.3390/ijms221810058.
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Tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease with serious neurological and mental symptoms, including autism. Mutations in the TSC1/TSC2 genes lead to the overactivation of mTOR signalling, which is also linked to nonsyndromic autism. Our aim was to analyse synaptic pathology in a transgenic model of TSC: two-month-old male B6;129S4-Tsc2tm1Djk/J mice with Tsc2 haploinsufficiency. Significant brain-region-dependent alterations in the expression of several synaptic proteins were identified. The most prominent changes were observed in the immunoreactivity of presynaptic VAMP1/2 (ca. 50% increase) and phospho-synapsin-1 (Ser62/67) (ca. 80% increase). Transmission electron microscopy demonstrated serious ultrastructural abnormalities in synapses such as a blurred structure of synaptic density and a significantly increased number of synaptic vesicles. The impairment of synaptic mitochondrial ultrastructure was represented by excessive elongation, swelling, and blurred crista contours. Polyribosomes in the cytoplasm and swollen Golgi apparatus suggest possible impairment of protein metabolism. Moreover, the delamination of myelin and the presence of vacuolar structures in the cell nucleus were observed. We also report that Tsc2+/− mice displayed increased brain weights and sizes. The behavioural analysis demonstrated the impairment of memory function, as established in the novel object recognition test. To summarise, our data indicate serious synaptic impairment in the brains of male Tsc2+/− mice.
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Pollizzi, Kristen, Izabela Malinowska-Kolodziej, Cheryl Doughty, Charles Betz, Jian Ma, June Goto, and David J. Kwiatkowski. "A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles." Human Molecular Genetics 18, no. 13 (April 8, 2009): 2378–87. http://dx.doi.org/10.1093/hmg/ddp176.
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Bassetti, Davide, Aniello Lombardi, Sergei Kirischuk, and Heiko J. Luhmann. "Haploinsufficiency of Tsc2 Leads to Hyperexcitability of Medial Prefrontal Cortex via Weakening of Tonic GABAB Receptor-mediated Inhibition." Cerebral Cortex 30, no. 12 (July 24, 2020): 6313–24. http://dx.doi.org/10.1093/cercor/bhaa187.
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Abstract Loss-of-function mutation in one of the tumor suppressor genes TSC1 or TSC2 is associated with several neurological and psychiatric diseases, including autism spectrum disorders (ASDs). As an imbalance between excitatory and inhibitory neurotransmission, E/I ratio is believed to contribute to the development of these disorders, we investigated synaptic transmission during the first postnatal month using the Tsc2+/− mouse model. Electrophysiological recordings were performed in acute brain slices of medial prefrontal cortex. E/I ratio at postnatal day (P) 15–19 is increased in Tsc2+/− mice as compared with wildtype (WT). At P25–30, facilitated GABAergic transmission reduces E/I ratio to the WT level, but weakening of tonic GABAB receptor (GABABR)-mediated inhibition in Tsc2+/− mice leads to hyperexcitability both at single cell and neuronal network level. Short (1 h) preincubation of P25–30 Tsc2+/− slices with baclofen restores the GABABR-mediated inhibition and reduces network excitability. Interestingly, the same treatment at P15–19 leads to weakening of GABABR-mediated inhibition. We hypothesize that a dysfunction of tonic GABABR-mediated inhibition might contribute to the development of ASD symptoms and suggest that GABABR activation within an appropriate time window may be considered as a therapeutic target in ASD.
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Krishna, Sruti, Jialong Yang, Hongxia Wang, Yurong Qiu, and Xiao-Ping Zhong. "Role of Tumor Suppressor TSC1 in Regulating Antigen-Specific Primary and Memory CD8 T Cell Responses to Bacterial Infection." Infection and Immunity 82, no. 7 (May 12, 2014): 3045–57. http://dx.doi.org/10.1128/iai.01816-14.
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ABSTRACTThe serine/threonine kinase mammalian/mechanistic target of rapamycin (mTOR) integrates various environmental cues such as the presence of antigen, inflammation, and nutrients to regulate T cell growth, metabolism, and function. The tuberous sclerosis 1 (TSC1)/TSC2 complex negatively regulates the activity of an mTOR-containing multiprotein complex called mTOR complex 1. Recent studies have revealed an essential cell-intrinsic role for TSC1 in T cell survival, quiescence, and mitochondrial homeostasis. Given the emerging role of mTOR activity in the regulation of the quantity and quality of CD8 T cell responses, in this study, we examine the role of its suppressor, TSC1, in the regulation of antigen-specific primary and memory CD8 T cell responses to bacterial infection. Using an established model system of transgenic CD8 cell adoptive transfer and challenge withListeria monocytogenesexpressing a cognate antigen, we found that TSC1 deficiency impairs antigen-specific CD8 T cell responses, resulting in weak expansion, exaggerated contraction, and poor memory generation. Poor expansion of TSC1-deficient cells was associated with defects in survival and proliferationin vivo, while enhanced contraction was correlated with an increased ratio of short-lived effectors to memory precursors in the effector cell population. This perturbation of effector-memory differentiation was concomitant with decreased expression of eomesodermin among activated TSC1 knockout cells. Upon competitive adoptive transfer with wild-type counterparts and antigen rechallenge, TSC1-deficient memory cells showed moderate defects in expansion but not cytokine production. Taken together, these findings provide direct evidence of a CD8 T cell-intrinsic role for TSC1 in the regulation of antigen-specific primary and memory responses.
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Prizant, Hen, Aritro Sen, Allison Light, Sung-Nam Cho, Francesco J. DeMayo, John P. Lydon, and Stephen R. Hammes. "Uterine-Specific Loss of Tsc2 Leads to Myometrial Tumors in Both the Uterus and Lungs." Molecular Endocrinology 27, no. 9 (September 1, 2013): 1403–14. http://dx.doi.org/10.1210/me.2013-1059.
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Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. Although the origin of LAM cells is unknown, several features of LAM provide clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas and might lead to novel therapeutic strategies for both diseases.
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Qi, Ruifang, Yabin Xie, Xiaolu Zhang, Shuyuan Jiang, Xiaolei Liu, Wei Xie, Xiaoe Jia, et al. "Possible Involvement of DNA Methylation in TSC1 Gene Expression in Neuroprotection Induced by Hypoxic Preconditioning." Oxidative Medicine and Cellular Longevity 2022 (September 9, 2022): 1–15. http://dx.doi.org/10.1155/2022/9306097.
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Background. It has been reported that ischemia and ischemic preconditioning (IPC) have different effects on the expression of tuberous sclerosis complex 1 (TSC1), which may contribute to the tolerance to ischemia/hypoxia with the increase of autophagy. The mechanisms of TSC1 differential expression are still unclear under ischemia/IPC conditions in hippocampal Cornu Ammon 1 (CA1) and Cornu Ammon 3 (CA3) area neuronal cells. While we have shown that 5-Aza-CdR, a DNA methyltransferase inhibitor, can upregulate TSC1 and increase hypoxic tolerance by autophagy in vivo and in vitro, in this study, we examined whether DNA methylation was involved in the differential expression of TSC1 in the CA1 and CA3 regions induced by hypoxic preconditioning (HPC). Methods. Level of rapamycin (mTOR) autophagy, a downstream molecular pathway of TSC1/TSC2 complex, was detected in HPC mouse hippocampal CA1 and CA3 areas as well as in the HPC model of mouse hippocampal HT22 cells. DNA methylation level of TSC1 promoter (-720 bp~ -360 bp) was determined in CA1 and CA3 areas by bisulfite-modified DNA sequencing (BMDS). At the same time, autophagy was detected in HT22 cells transfected with GFP-LC3 plasmid. The role of TSC1 in neuroprotection was measured by cell viability and apoptosis, and the role of TSC1 in metabolism was checked by ATP assay and ROS assay in HT22 cells that overexpressed/knocked down TSC1. Results. HPC upregulated the expression of TSC1, downregulated the level of P-mTOR (Ser2448) and P-p70S6K (Thr389), and enhanced the activity of autophagy in both in vivo and in vitro. The increased expression of TSC1 in HPC may depend on its DNA hypomethylation in the promoter region in vivo. HPC also could reduce energy consumption in HT22 cells. Overexpression and knockdown of TSC1 can affect cell viability, cell apoptosis, and metabolism in HT22 cells exposed to hypoxia. Conclusion. TSC1 expression induced by HPC may relate to the downregulation of its DNA methylation level with the increase of autophagy and the decrease of energy demand.
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Bernardelli, Clara, Eloisa Chiaramonte, Silvia Ancona, Silvia M. Sirchia, Amilcare Cerri, and Elena Lesma. "Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model." International Journal of Molecular Sciences 23, no. 17 (August 26, 2022): 9713. http://dx.doi.org/10.3390/ijms23179713.
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Cutaneous lesions are one of the hallmarks of tuberous sclerosis complex (TSC), a genetic disease in which mTOR is hyperactivated due to the lack of hamartin or tuberin. To date, novel pharmacological treatments for TSC cutaneous lesions that are benign but still have an impact on a patient’s life are needed, because neither surgery nor rapamycin administration prevents their recurrence. Here, we demonstrated that primary TSC2-/meth cells that do not express tuberin for an epigenetic event caused cutaneous lesions and follicular neogenesis when they were subcutaneously injected in nude mice. Tuberin-null cells localized in the hair bulbs and alongside mature hairs, where high phosphorylation of S6 and Erk indicated mTOR hyperactivation. Interestingly, 5-azacytidine treatment reduced hair follicles, indicating that chromatin remodeling agents might be effective on TSC lesions in which cells lack tuberin for an epigenetic event. Moreover, we demonstrated that the primary TSC2-/meth cells had metastatic capability: when subcutaneously injected, they reached the bloodstream and lymphatics and invaded the lungs, causing the enlargement of the alveolar walls. The capability of TSC2-/meth cells to survive and migrate in vivo makes our mouse model ideal to follow the progression of the disease and test potential pharmacological treatments in a time-dependent manner.
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Bassetti, Davide, Heiko J. Luhmann, and Sergei Kirischuk. "Presynaptic GABAB receptor–mediated network excitation in the medial prefrontal cortex of Tsc2+/- mice." Pflügers Archiv - European Journal of Physiology 473, no. 8 (July 19, 2021): 1261–71. http://dx.doi.org/10.1007/s00424-021-02576-5.
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AbstractThe TSC1 and TSC2 tumor suppressor genes control the activity of mechanistic target of rapamycin (mTOR) pathway. Elevated activity of this pathway in Tsc2+/- mouse model leads to reduction of postsynaptic GABAB receptor–mediated inhibition and hyperexcitability in the medial prefrontal cortex (mPFC). In this study, we asked whether presynaptic GABAB receptors (GABABRs) can compensate this shift of hyperexcitability. Experiments were performed in brain slices from adolescent wild-type (WT) and Tsc2+/- mice. Miniature and spontaneous postsynaptic currents (m/sPSCs) were recorded from layer 2/3 pyramidal neurons in mPFC using patch-clamp technique using a Cs+-based intrapipette solution. Presynaptic GABABRs were activated by baclofen (10 µM) or blocked by CGP55845 (1 µM). Independent on genotype, GABABR modulators bidirectionally change miniature excitatory postsynaptic current (mEPSC) frequency by about 10%, indicating presynaptic GABABR-mediated effects on glutamatergic transmission are comparable in both genotypes. In contrast, frequencies of both mIPSCs and sIPCSs were suppressed by baclofen stronger in Tsc2+/- neurons than in WT ones, whereas CGP55845 significantly increased (m/s)IPSC frequencies only in WT cells. Effects of baclofen and CGP55845 on the amplitudes of evoked (e)IPSCs confirmed these observations. These data indicate (1) that GABAergic synapses are inhibited by ambient GABA in WT but not in Tsc2+/- slices, and (2) that baclofen shifts the E/I ratio, determined as the ratio of (m/s)EPSC frequency to (m/s)IPSC frequency, towards excitation only in Tsc2+/- cells. This excitatory presynaptic GABABR-mediated action has to be taken into account for a possible medication of mental disorders using baclofen. Graphical abstract
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Klover, P., S. Li, J. Kato, J. Wang, J. Moss, and T. Darling. "790 Tsc2 haploinsufficiency accelerates tumor progression in a mouse model of TSC skin tumors." Journal of Investigative Dermatology 138, no. 5 (May 2018): S134. http://dx.doi.org/10.1016/j.jid.2018.03.800.
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Gąssowska-Dobrowolska, Magdalena, Grzegorz A. Czapski, Magdalena Cieślik, Karolina Zajdel, Małgorzata Frontczak-Baniewicz, Lidia Babiec, and Agata Adamczyk. "Microtubule Cytoskeletal Network Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders." International Journal of Molecular Sciences 24, no. 8 (April 15, 2023): 7303. http://dx.doi.org/10.3390/ijms24087303.
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Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder caused by loss-of-function mutations in the tumour suppressors TSC1/TSC2, both of which are negative regulators of the mammalian target of rapamycin (mTOR) kinase. Importantly, mTOR hyperactivity seems to be linked with the pathobiology of autism spectrum disorders (ASD). Recent studies suggest the potential involvement of microtubule (MT) network dysfunction in the neuropathology of “mTORopathies”, including ASD. Cytoskeletal reorganization could be responsible for neuroplasticity disturbances in ASD individuals. Thus, the aim of this work was to study the effect of Tsc2 haploinsufficiency on the cytoskeletal pathology and disturbances in the proteostasis of the key cytoskeletal proteins in the brain of a TSC mouse model of ASD. Western-blot analysis indicated significant brain-structure-dependent abnormalities in the microtubule-associated protein Tau (MAP-Tau), and reduced MAP1B and neurofilament light (NF-L) protein level in 2-month-old male B6;129S4-Tsc2tm1Djk/J mice. Alongside, pathological irregularities in the ultrastructure of both MT and neurofilament (NFL) networks as well as swelling of the nerve endings were demonstrated. These changes in the level of key cytoskeletal proteins in the brain of the autistic-like TSC mice suggest the possible molecular mechanisms responsible for neuroplasticity alterations in the ASD brain.
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Piedimonte, Leandro R., Ian K. Wailes, and Howard L. Weiner. "Retracted Tuberous sclerosis complex: molecular pathogenesis and animal models." Neurosurgical Focus 20, no. 1 (January 2006): 1–6. http://dx.doi.org/10.3171/foc.2006.20.1.5.
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Mutations in one of two genes, TSC1 and TSC2, result in a similar disease phenotype by disrupting the normal interaction of their protein products, hamartin and tuberin, which form a functional signaling complex. Disruption of these genes in the brain results in abnormal cellular differentiation, migration, and proliferation, giving rise to the characteristic brain lesions of tuberous sclerosis complex (TSC) called cortical tubers. The most devastating complications of TSC affect the central nervous system and include epilepsy, mental retardation, autism, and glial tumors. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and the way in which disruption of their expression gives rise to the variety of clinical features that characterize TSC. In the future, these animals will be invaluable preclinical models for the development of highly specific and efficacious treatments for children affected with TSC.
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Serfontein, Jaco, R. Ellen R. Nisbet, Christopher J. Howe, and Petrus J. de Vries. "Conservation of Structural and Functional Elements of TSC1 and TSC2: A Bioinformatic Comparison Across Animal Models." Behavior Genetics 41, no. 3 (January 18, 2011): 349–56. http://dx.doi.org/10.1007/s10519-010-9440-3.
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Shah, O. Jameel, and Tony Hunter. "Turnover of the Active Fraction of IRS1 Involves Raptor-mTOR- and S6K1-Dependent Serine Phosphorylation in Cell Culture Models of Tuberous Sclerosis." Molecular and Cellular Biology 26, no. 17 (September 1, 2006): 6425–34. http://dx.doi.org/10.1128/mcb.01254-05.
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ABSTRACT The TSC1-TSC2/Rheb/Raptor-mTOR/S6K1 cell growth cassette has recently been shown to regulate cell autonomous insulin and insulin-like growth factor I (IGF-I) sensitivity by transducing a negative feedback signal that targets insulin receptor substrates 1 and 2 (IRS1 and -2). Using two cell culture models of the familial hamartoma syndrome, tuberous sclerosis, we show here that Raptor-mTOR and S6K1 are required for phosphorylation of IRS1 at a subset of serine residues frequently associated with insulin resistance, including S307, S312, S527, S616, and S636 (of human IRS1). Using loss- and gain-of-function S6K1 constructs, we demonstrate a requirement for the catalytic activity of S6K1 in both direct and indirect regulation of IRS1 serine phosphorylation. S6K1 phosphorylates IRS1 in vitro on multiple residues showing strong preference for RXRXXS/T over S/T,P sites. IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb. These studies suggest that, through serine phosphorylation, Raptor-mTOR and S6K1 cell autonomously promote the depletion of IRS1 from specific intracellular pools in pathological states of insulin and IGF-I resistance and thus potentially in lesions associated with tuberous sclerosis.
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Gibbons, Erin, Stephen Hammes, and Manisha Taya. "RF19 | PSUN351 Glycoprotein-NMB (GPNMB) is Pro-Tumorigenic in Lymphangioleiomyomatosis (LAM)." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A898. http://dx.doi.org/10.1210/jendso/bvac150.1860.
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Abstract Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM is characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout the lungs, resulting in the formation of large cysts that replace normal alveolar space. Growth of these tumors and progression of cyst development leads to loss of pulmonary function, and sometimes subsequent lung transplantation. LAM tumor cells contain mutations in one of the tuberous sclerosis genes (TSC1 or TSC2), leading to constitutive activation of the mTORC1 pathway. In fact, mTOR inhibitors are commonly used to treat LAM; however, these drugs are not always effective and have significant side effects, suggesting the need for new therapeutic targets. Additionally, tumors recur even after lung transplantation and LAM cells are found in circulating body fluids, suggesting a metastatic nature of LAM, and a question of the origin of the LAM cell. Due to LAM's estrogen sensitivity, female specificity, and metastatic nature, we previously proposed that LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all of the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Notably, our collaborators recently utilized single cell RNA sequencing with human LAM lung lesions, and found that TSC2-null cells have a strong uterine profile. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). GPNMB is known to be oncogenic in other cancers and has been shown to be expressed intracellularly in benign cells, but both intracellularly and on the cell surface of tumor cells making GPNMB a good cell surface drug target. This melanocytic marker was not only highly expressed in our mouse model, it was also expressed in TSC2-null cell lines, as well as in human LAM patient lung and uteri samples. Knocking down GPNMB expression by siRNA directed against GPNMB mRNA decreased proliferation, migration, and invasion in TSC2-null cells. We also found that GPNMB's large ectodomain is released from the cell surface of TSC2-null cells and potentially mediated by the protease, Adam10. The ectodomain specifically is implicated in mediating GPNMB's effects on tumor growth. Finally, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 decreased xenograft tumor growth in mice. Overall, our data thus far demonstrate that GPNMB promotes TSC2-null tumor growth and metastasis. Importantly, the GPNMB ectodomain is a potential biomarker of human LAM, as we detect a significant difference in GPNMB ectodomain levels in patient blood as compared with healthy controls. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.
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Park, Hye Jung, Yong Jun Choi, Chul Hwan Park, Tae Hoon Kim, Sung Soo Lee, Duk Hwan Moon, Kyung-A. Lee, et al. "Outstanding Characteristics of Birt–Hogg–Dube Syndrome in Korea." Diagnostics 13, no. 12 (June 13, 2023): 2047. http://dx.doi.org/10.3390/diagnostics13122047.
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Birt–Hogg–Dube (BHD) is a rare genetic disorder characterized by multiple lung cysts, typical skin manifestations, and renal tumors. We prospectively enrolled thirty-one subjects from four South Korean institutions with typical lung cysts, and next-generation sequencing was conducted. We prospectively enrolled thirty-one subjects from four Korean institutions with typical lung cysts. Next-generation sequencing was performed to investigate mutations in the following genes: FLCN, TSC1, TSC2, CFTR, EFEMP2, ELN, FBLN5, LTBP4, and SERPINA1. BHD was diagnosed in 11 of the 31 enrolled subjects (35.5%; FLCN mutations). Notably, we identified three novel mutations (c.1098G>A, c.139G>T, and c.1335del) that have not been previously reported. In addition to FLCN mutations, we also observed mutations in CFTR (16.1%), LTBP4 (9.7%), TSC2 (9.7%), TSC1 (3.2%), ELN (3.2%), and SERPINA1 (3.2%). According to a systematic review of 45 South Korean patients with BHD, the prevalence of pneumothorax (72.7%) was greater in South Korea than in the rest of the world (50.9%; p = 0.003). The prevalence of skin manifestations (13.6%) and renal tumors (9.1%) was lower in Korea than in the rest of the world, at 47.9% [p < 0.001] and 22.5% [p = 0.027], respectively). This study confirmed a significant prediction model for BHD based on age, number of lung cysts (>40), and maximal diameter of lung cysts (>2 cm) regardless of skin manifestations and renal tumors. Importantly, three novel mutations (c.1098G>A, c.139G>T, and c.1335del) were identified. In conclusion, South Korean patients with BHD display characteristics that are different from those observed in patients of other nationalities. Detailed characterization of lung cysts is needed to define BHD, especially in South Korea, even if patients do not present with skin or renal lesions.
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Jones, I., A. C. Ha gglund, G. To rnqvist, C. Nord, U. Ahlgren, and L. Carlsson. "A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development." Disease Models & Mechanisms 8, no. 12 (October 8, 2015): 1517–29. http://dx.doi.org/10.1242/dmm.021972.
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Gibbons, Erin, Manisha Taya, Briaunna Minor, Christina Seger, and Stephen R. Hammes. "Pro-Tumorigenic Role of Neutrophil Elastase in Lymphangioleiomyomatosis (LAM)." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A982. http://dx.doi.org/10.1210/jendso/bvab048.2009.
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Abstract Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM is characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout the lungs, resulting in the formation of large cysts that replace normal alveolar space. Growth of these tumors and progression of the cyst development leads to loss of pulmonary function, and sometimes subsequent lung transplantation. LAM tumor cells contain mutations in one of the tuberous sclerosis genes (TSC1 or TSC2), leading to activation of the mTORC1 pathway. In fact, mTOR inhibitors are commonly used to treat LAM; however, these drugs are not always effective and have significant side effects, suggesting the need for new therapeutic targets. Additionally, tumors recur even after lung transplantation and LAM cells are found in circulating body fluids, suggesting a metastatic nature of LAM, and a question of the origin of the LAM cell. Due to LAM’s estrogen sensitivity, female specificity, and metastatic nature, we previously proposed that LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all the mice generate uterine tumors characteristic of LAM and half develop lung metastases. Using RNASeq analysis of uterine tissue from this mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered significant upregulation of inflammatory proteases such as Neutrophil Elastase (NE). NE is secreted by myeloid cells such as polymorphonuclear cells (PMNs) and has been reported to promote invasion, migration, and proliferation in various cancers. We found this to be true in LAM as well, as depleting myeloid cells with an antibody directed against PMNs, or inhibiting NE with the NE inhibitor, sivelestat, markedly decreased TSC2-null uterine tumor growth. NE is released when PMNs undergo Neutrophil Extracellular Trap release, or NETosis. NETosis has been shown to have a pro-tumorigenic role in various cancers and we are investigating the effects of NETosis in LAM. We have also generated a novel uterine-specific TSC2-null mouse in the background of no NE to determine whether uterine tumor burden and lung metastases are reduced in NE-null mice and if these mice have PMNs capable of undergoing NETosis in the absence of NE. Overall, our results suggest that NE release from PMNs is critical for LAM tumor development and may be a novel target for its treatment.
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Stafstrom, Carl E. "Progress toward Understanding Epileptogenesis in Tuberous Sclerosis Complex: Two Hits, No Outs, and the Eker Rat is up to Bat." Epilepsy Currents 5, no. 4 (July 2005): 136–38. http://dx.doi.org/10.1111/j.1535-7511.2005.00045.x.
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Abnormal Cortical Cells and Astrocytomas in the Eker Rat Model of Tuberous Sclerosis Complex Takahashi DK, Dinday MT, Barbaro NM, Baraban SC Epilepsia 2004;45:1525–1530 Purpose In patients with tuberous sclerosis complex (TSC), a wide range of neurologic abnormalities develop, including mental retardation and seizures. Brains from TSC patients are characterized by the presence of cortical tubers, large dysmorphic neurons, and abnormal cytomegalic cells. Although analysis of human TSC brain samples led to the identification of these abnormal cell types, very little is known about how these cells function. In an effort to model TSC-associated CNS abnormalities (and ultimately to analyze the electrophysiologic properties of abnormal cells), we examined Eker rats carrying a Tsc2 mutation. Anatomic studies, including standard histologic stains and immunocytochemistry, were performed on young Eker rats exposed to a carcinogen in utero or on aged untreated Eker rats (18–24 months old). Methods Pregnant TSC2+/– females were injected once a day with hydroquinone, and offspring were killed at postnatal day P14 or P28. Coronal tissue sections throughout the CNS were prepared and stained for cresyl violet. In separate studies, brains of old untreated Eker rats were sectioned for anatomic analysis by using standard immunohistochemical techniques. Results Tissue sections stained with cresyl violet did not reveal any gross differences between hydroquinonetreated Eker ( Tsc2 Ek/+) rats and siblings ( Tsc2+/+). However, two classes of abnormal giant cells were observed in brain sections from untreated aged Eker rats: 1) large dysmorphic pyramid-like cells immunoreactive for NeuN, tuberin, and EAAC-1 in layers IV to VI; and 2) abnormal cytomegalic cells immunoreactive for glial fibrillary acidic protein, vimentin, and nestin in deep cortical layers or along the white matter. In addition, large subependymal astrocytomas were observed in four animals. Conclusions Our data suggest that cortical tuber formation in Eker rats is a rare event and that prenatal exposure to a nongenotoxic carcinogen such as hydroquinone is not sufficient to induce tuber formation. However, with advanced age, an increased likelihood of astrocytoma formation and the emergence of dysmorphic neurons and cytomegalic cells in the Eker rat brain might exist; each of these abnormalities mimics those seen clinically and could contribute to neurologic problems associated with TSC. Further analysis of this rodent model may be warranted. Morphology of Cerebral Lesions in the Eker Rat Model of Tuberous Sclerosis Wenzel HJ, Patel LS, Robbins CA, Emmi A, Yeung RS, Schwartzkroin PA Acta Neuropathol (Berl) 2004;108:97–108 Tuberous sclerosis (TSC) is an autosomal dominant disorder, caused by mutations of either the TSC1 or TSC2 gene. Characteristic brain pathologies (including cortical tubers and subependymal hamartomas/giant astrocytomas) are thought to cause epilepsy, as well as other neurologic dysfunction. The Eker rat, which carries a spontaneous germline mutation of the TSC2 gene ( Tsc2+/+), provides a unique animal model in which to study the relation between TSC cortical pathologies and epilepsy. In the present study, we analyzed the seizure propensity and histopathologic features of a modified Eker rat preparation, in which early postnatal irradiation was used as a “second hit” stimulus in an attempt to exacerbate cortical malformations and increase seizure propensity. Irradiated Eker rats had a tendency toward lower seizure thresholds (latencies to flurothyl-induced seizures) than seen in nonirradiated Eker rats (significant difference) or irradiated wild-type rats (nonsignificant difference). The majority of irradiated Eker rats exhibited dysplastic cytomegalic neurons and giant astrocyte-like cells, similar to cytopathologies observed in TSC lesions of patients. The most prominent features in these brains were hamartoma-like lesions involving large eosinophilic cells, similar to giant tuber cells in human TSC. In some cells from these hamartomas, immunocytochemistry revealed features of both neuronal and glial phenotypes, suggesting an undifferentiated or immature cell population. Both normal-appearing and dysmorphic neurons, as well as cells in the hamartomas, exhibited immunopositivity for tuberin, the protein product of the TSC2 gene.
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Zeng, L. H., N. R. Rensing, B. Zhang, D. H. Gutmann, M. J. Gambello, and M. Wong. "Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of Tuberous Sclerosis Complex." Human Molecular Genetics 20, no. 3 (November 9, 2010): 445–54. http://dx.doi.org/10.1093/hmg/ddq491.
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Mizuguchi, Masashi, Maki Ohsawa, Hirofumi Kashii, and Atsushi Sato. "Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment." International Journal of Molecular Sciences 22, no. 13 (June 22, 2021): 6677. http://dx.doi.org/10.3390/ijms22136677.
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The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure/function, and excessive epileptic discharges, further worsening epilepsy and intellectual/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders.
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Beirowski, Bogdan, Keit Men Wong, Elisabetta Babetto, and Jeffrey Milbrandt. "mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells." Proceedings of the National Academy of Sciences 114, no. 21 (May 8, 2017): E4261—E4270. http://dx.doi.org/10.1073/pnas.1620761114.
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The myelination of axons in peripheral nerves requires precisely coordinated proliferation and differentiation of Schwann cells (SCs). We found that the activity of the mechanistic target of rapamycin complex 1 (mTORC1), a key signaling hub for the regulation of cellular growth and proliferation, is progressively extinguished as SCs differentiate during nerve development. To study the effects of different levels of sustained mTORC1 hyperactivity in the SC lineage, we disrupted negative regulators of mTORC1, including TSC2 or TSC1, in developing SCs of mutant mice. Surprisingly, the phenotypes ranged from arrested myelination in nerve development to focal hypermyelination in adulthood, depending on the level and timing of mTORC1 hyperactivity. For example, mice lacking TSC2 in developing SCs displayed hyperproliferation of undifferentiated SCs incompatible with normal myelination. However, these defects and myelination could be rescued by pharmacological mTORC1 inhibition. The subsequent reconstitution of SC mTORC1 hyperactivity in adult animals resulted in focal hypermyelination. Together our data suggest a model in which high mTORC1 activity promotes proliferation of immature SCs and antagonizes SC differentiation during nerve development. Down-regulation of mTORC1 activity is required for terminal SC differentiation and subsequent initiation of myelination. In distinction to this developmental role, excessive SC mTORC1 activity stimulates myelin growth, even overgrowth, in adulthood. Thus, our work delineates two distinct functions of mTORC1 in the SC lineage essential for proper nerve development and myelination. Moreover, our studies show that SCs retain their plasticity to myelinate and remodel myelin via mTORC1 throughout life.
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Malloy, Dillon C., Maria Knikou, and Marie-Pascale Côté. "Adapting Human-Based Transcutaneous Spinal Cord Stimulation to Develop a Clinically Relevant Animal Model." Journal of Clinical Medicine 11, no. 7 (April 5, 2022): 2023. http://dx.doi.org/10.3390/jcm11072023.
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Transcutaneous spinal cord stimulation (tSCS) as a neuromodulatory strategy has received great attention as a method to promote functional recovery after spinal cord injury (SCI). However, due to the noninvasive nature of tSCS, investigations have primarily focused on human applications. This leaves a critical need for the development of a suitable animal model to further our understanding of this therapeutic intervention in terms of functional and neuroanatomical plasticity and to optimize stimulation protocols. The objective of this study is to establish a new animal model of thoracolumbar tSCS that (1) can accurately recapitulate studies in healthy humans and (2) can receive a repeated and stable tSCS treatment after SCI with minimal restraint, while the electrode remains consistently positioned. We show that our model displays bilateral evoked potentials in multisegmental leg muscles characteristically comparable to humans. Our data also suggest that tSCS mainly activates dorsal root structures like in humans, thereby accounting for the different electrode-to-body-size ratio between the two species. Finally, a repeated tSCS treatment protocol in the awake rat after a complete spinal cord transection is feasible, tolerable, and safe, even with minimal body restraint. Additionally, repeated tSCS was capable of modulating motor output after SCI, providing an avenue to further investigate stimulation-based neuroplasticity and optimize treatment.
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Atochina-Vasserman, Elena N., Elena Abramova, Melane L. James, Ryan Rue, Amy Y. Liu, Nathan Tessema Ersumo, Chang-Jiang Guo, Andrew J. Gow, and Vera P. Krymskaya. "Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 12 (December 15, 2015): L1447—L1454. http://dx.doi.org/10.1152/ajplung.00262.2015.
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Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 ( Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.
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Chen, Luyao, Ang Ke, Peng Zhang, Zhaolong Gao, Xuecheng Zou, and Jiping He. "Bioheat transfer model of transcutaneous spinal cord stimulation-induced temperature changes." PeerJ 6 (June 4, 2018): e4921. http://dx.doi.org/10.7717/peerj.4921.
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Transcutaneous spinal cord stimulation (tSCS) has been extensively studied due to its promising application in motor function restoration. Many previous studies have explored both the essential mechanism of action and the methods for determining optimal stimulation parameters. In contrast, the bioheat transfer analysis of tSCS therapy has not been investigated to the same extent, despite widely existing, and being of great significance in assuring a stable and thermally safe treatment. In this paper, we concentrated on the thermal effects of tSCS using a finite element-based method. By coupling the electric field and bioheat field, systematic finite element simulations were performed on a human spinal cord model to survey the influence of anatomical structures, blood perfusion, and stimulation parameters on temperature changes for the first time. The results show that tSCS-induced temperature rise mainly occurs in the skin and fat layers and varies due to individual differences. The current density distribution along with the interactions of multiple biothermal effects synthetically determines the thermal status of the whole spinal cord model. Smaller stimulation electrodes have a higher risk of thermal damage when compared with larger electrodes. Increasing the stimulation intensity will result in more joule heat accumulation, hence an increase in the temperature. Among all configurations in this study that simulated the clinical tSCS protocols, the temperature rise could reach up to 9.4 °C on the skin surface depending on the stimulation parameters and tissue blood perfusion.
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Tao, Xu, Junpeng Liu, Lei Chen, You Zhou, and Kanglai Tang. "EGR1 Induces Tenogenic Differentiation of Tendon Stem Cells and Promotes Rabbit Rotator Cuff Repair." Cellular Physiology and Biochemistry 35, no. 2 (2015): 699–709. http://dx.doi.org/10.1159/000369730.
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Background/Aims: The rate of healing failure after surgical repair of chronic rotator cuff tears is considerably high. The aim of this study was to investigate the function of the zinc finger transcription factor early growth response 1 (EGR1) in the differentiation of tendon stem cells (TSCs) and in tendon formation, healing, and tendon tear repair using an animal model of rotator cuff repair. Methods: Tenocyte, adipocyte, osteocyte, and chondrocyte differentiation as well as the expression of related genes were determined in EGR1-overexpressing TSCs (EGR1-TSCs) using tissue-specific staining, immunofluorescence staining, quantitative PCR, and western blotting. A rabbit rotator cuff repair model was established, and TSCs and EGR1-TSCs in a fibrin glue carrier were applied onto repair sites. The rabbits were sacrificed 8 weeks after repair operation, and tissues were histologically evaluated and tenocyte-related gene expression was determined. Results: EGR1 induced tenogenic differentiation of TSCs and inhibited non-tenocyte differentiation of TSCs. Furthermore, EGR1 promoted tendon repair in a rabbit model of rotator cuff injury. The BMP12/Smad1/5/8 signaling pathway was involved in EGR1-induced tenogenic differentiation and rotator cuff tendon repair. Conclusion: EGR1 plays a key role in tendon formation, healing, and repair through BMP12/Smad1/5/8 pathway. EGR1-TSCs is a promising treatment for rotator cuff tendon repair surgeries.
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Lan, ZiLian, Ziyao Jia, Hengyuan Guo, Zhaoshou Yang, Zifan Yang, and Xuan Pan. "Model of Human Tongue Squamous Cell Lines Stably Transfected with Human Papillomavirus (HPV)16 E6 and E7 Genes and Biological Characteristic Analysis." BioMed Research International 2021 (June 17, 2021): 1–12. http://dx.doi.org/10.1155/2021/9968691.
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Background. Human tongue squamous cell carcinoma (TSCC) is the most common oral cancer with the highest human papillomavirus (HPV) infection rate in oral cancer. The purpose of this study was to research the correlation between HPV and TSCC. Method. Plasmid pEGFP/HPV16 E6E7 and plasmid pEGFP/no HPV16 E6E7 were constructed. TSCC cell lines SCC9 and SCC15 were infected by liposome transfection and would be highly selected by antibiotic. Fluorescence imaging, PCR, and Western blot were used to detect the expression of HPV16 E6E7 in cells. The biological characteristics were detected by CCK-8, wound healing assay, qRT-PCR, and Western blot. Result. TSCC cell lines transfected with HPV16 E6E7 gene were successfully established and identified. And the proliferation and migration ability of the TSCC cell lines infected with HPV16 E6E7 gene were significantly stronger than that of the blank group. Conclusion. TSCC cell lines infected with HPV16 E6E7 with significantly higher ability of proliferation and migration were more malignant than those not infected with HPV16 E6E7.
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M A, Sureshkumar, Caroline R. Delma, Krishnan Manickam, Sumathy Mohan, Samy L. Habib, and Mohan Natarajan. "Heterozygous Tsc2 (Tsc2+/–) mouse model to study induced renal cancer in response to ionizing radiation at low doses." Carcinogenesis 40, no. 6 (December 2, 2018): 782–90. http://dx.doi.org/10.1093/carcin/bgy172.
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Abstract Kidneys are one of the main dose-limiting organs in radiotherapeutic procedures of lower abdomen. Likewise, the threat of exposure of radiosensitive organs such as kidneys in warfare or radiation accidents among military personal or due to terrorist activities in general public is of increasing concern. These events warrant the need for appropriate animal models to study the acute and chronic effects of low- and high-dose rate radiation exposures. In this study, for the first time, we validated Tsc2+/– mouse model to study whether radiation accelerates carcinogenesis in kidneys. Tsc2+/– mice at increasing age groups at 8 and 10 months were exposed to repeated doses of gamma radiation (0.4 Gy × 5) and assessed for aggravated kidney tumor formation at 2 months post-irradiation. Animals from irradiated group showed a significant increase in numbers of bilateral, multifocal tumors compared with mock-irradiated animals. Intra-glomerular reactive oxygen species (ROS) levels measured by dihydroethidium florescence showed significant increases in ROS production in irradiated Tsc2+/– mice compared with non-irradiated animals. Similarly, selective hematological parameters and glomerular filtration rate were further reduced significantly in irradiated Tsc2+/– mice. Tsc2 protein, tuberin in irradiated mice, however, remains at the same reduced levels as that of the mock-irradiated heterozygous Tsc2 mice. The results indicate that radiation alters kidney homeostatic function and influences high spontaneous incidence of renal cell carcinoma in this rodent model. Repurposing of Tsc2+/– mice model will, therefore, provide a unique opportunity to study acute and delayed effects of radiation in the development of kidney cancers.
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Yang, Meng, Changyu Zeng, Zhongcheng Gong, Bo Shao, Gaocheng Liu, Xuying Bao, and Bin Nie. "Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma." Open Life Sciences 17, no. 1 (January 1, 2022): 1657–68. http://dx.doi.org/10.1515/biol-2022-0469.
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Abstract The present study involved building a model of immune-related genes (IRGs) that can predict the survival outcomes of tongue squamous cell carcinoma (TSCC). Using the TCGA database, we collected the gene expression profiles of patients with TSCC and analyzed the differences in IRGs obtained from the ImmPort database. Subsequently, we constructed a predictive model. Transcription factors and differentially expressed IRGs can be used to construct TSCC regulatory network. CIBERSORT tool was used to analyze the relative proportion of 22 tumor-infiltrating immune cells in TSCC samples. Finally, a prognostic model is constructed. We established an IRG model formed by seven genes. The receiver operating characteristic value of the prognostic model based on IRGs is 0.739. After the analysis of the correlation between IRGs and clinical and pathological conditions, we found that Gast was related to grade, IRF9, LTB, and T stage. Among the 22 tumor-infiltrating immune cells, the resting natural killer (NK) cells were found to be related to the 5-year survival rate. This study constructed a prognostic model formed by seven IRGs and discussed the tumor-infiltrating immune cells, which are related to the survival outcome, reflecting the potential regulatory role of TSCC tumor immune microenvironment that could potentially promote individualized treatment.
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Men, Zhongxian, Adam W. Kolkiewicz, and Tony S. Wirjanto. "Threshold Stochastic Conditional Duration Model for Financial Transaction Data." Journal of Risk and Financial Management 12, no. 2 (May 14, 2019): 88. http://dx.doi.org/10.3390/jrfm12020088.
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This paper proposes a variant of a threshold stochastic conditional duration (TSCD) model for financial data at the transaction level. It assumes that the innovations of the duration process follow a threshold distribution with a positive support. In addition, it also assumes that the latent first-order autoregressive process of the log conditional durations switches between two regimes. The regimes are determined by the levels of the observed durations and the TSCD model is specified to be self-excited. A novel Markov-Chain Monte Carlo method (MCMC) is developed for parameter estimation of the model. For model discrimination, we employ deviance information criteria, which does not depend on the number of model parameters directly. Duration forecasting is constructed by using an auxiliary particle filter based on the fitted models. Simulation studies demonstrate that the proposed TSCD model and MCMC method work well in terms of parameter estimation and duration forecasting. Lastly, the proposed model and method are applied to two classic data sets that have been studied in the literature, namely IBM and Boeing transaction data.
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Nunney, Leonard, and Kevin Thai. "Determining cancer risk: the evolutionary multistage model or total stem cell divisions?" Proceedings of the Royal Society B: Biological Sciences 287, no. 1941 (December 16, 2020): 20202291. http://dx.doi.org/10.1098/rspb.2020.2291.
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A recent hypothesis proposed that the total number of stem cell divisions in a tissue (TSCD model) determine its intrinsic cancer risk; however, a different model—the multistage model—has long been used to understand how cancer originates. Identifying the correct model has important implications for interpreting the frequency of cancers. Using worldwide cancer incidence data, we applied three tests to the TSCD model and an evolutionary multistage model of carcinogenesis (EMMC), a model in which cancer suppression is recognized as an evolving trait, with natural selection acting to suppress cancers causing a significant mean loss of Darwinian fitness. Each test supported the EMMC but contradicted the TSCD model. This outcome undermines results based on the TSCD model quantifying the relative importance of ‘bad luck' (the random accumulation of somatic mutations) versus environmental and genetic factors in determining cancer incidence. Our testing supported the EMMC prediction that cancers of large rapidly dividing tissues predominate late in life. Another important prediction is that an indicator of recent oncogenic environmental change is an unusually high mean fitness loss due to cancer, rather than a high lifetime incidence. The evolutionary model also predicts that large and/or long-lived animals have evolved mechanisms of cancer suppression that may be of value in preventing or controlling human cancers.
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Buzoianu-Anguiano, Vinnitsa, Sandra Orozco-Suárez, Elisa García-Vences, Sara Caballero-Chacón, Gabriel Guizar-Sahagún, Luis Chavez-Sanchez, and Israel Grijalva. "The Morphofunctional Effect of the Transplantation of Bone Marrow Stromal Cells and Predegenerated Peripheral Nerve in Chronic Paraplegic Rat Model via Spinal Cord Transection." Neural Plasticity 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/389520.
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Functional recovery following spinal cord injury (SCI) is limited by poor axonal and cellular regeneration as well as the failure to replace damaged myelin. Employed separately, both the transplantation of the predegenerated peripheral nerve (PPN) and the transplantation of bone marrow stromal cells (BMSCs) have been shown to promote the regrowth and remyelination of the damaged central axons in SCI models of hemisection, transection, and contusion injury. With the aim to test the effects of the combined transplantation of PPN and BMSC on regrowth, remyelination, and locomotor function in an adult rat model of spinal cord (SC) transection, 39 Fischer 344 rats underwent SC transection at T9 level. Four weeks later they were randomly assigned to traumatic spinal cord injury (TSCI) without treatment, TSCI + Fibrin Glue (FG), TSCI + FG + PPN, and TSCI + FG + PPN + BMSCs. Eight weeks after, transplantation was carried out on immunofluorescence and electron microscope studies. The results showed greater axonal regrowth and remyelination in experimental groups TSCI + FG + PPN and TSCI + FG + PPN + BMSCs analyzed with GAP-43, neuritin, and myelin basic protein. It is concluded that the combined treatment of PPN and BMSCs is a favorable strategy for axonal regrowth and remyelination in a chronic SC transection model.
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Gui, Yu, Gordon H. He, Michael P. Walsh, and Xi-Long Zheng. "Predisposition to tetraploidy in pulmonary vascular smooth muscle cells derived from the Eker rats." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 3 (September 2007): L702—L711. http://dx.doi.org/10.1152/ajplung.00016.2007.
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Somatic mutations in the tuberous sclerosis complex-2 (TSC2) gene are associated with pulmonary lymphangioleiomyomatosis (LAM), a disorder characterized by benign lesions of smooth muscle and/or smooth muscle-like cells in the lung. However, the cellular mechanisms underlying LAM disease are largely unknown. Given that the TSC2 gene product tuberin is involved in the regulation of cell growth and proliferation, the present study was designed to investigate the potential roles of TSC2 in regulation of the cell cycle. We studied cell cycle profiles of pulmonary vascular smooth muscle cells (SMCs) derived from Eker rats (Tsc2+/EK), a genetic model carrying a germline insertional deletion in one copy of the Tsc2 gene, and the wild-type rats (Tsc2+/+), a noncarrier counterpart. We found that Tsc2+/EK, but not Tsc2+/+, SMCs displayed increases in cells with ≥4N DNA content (≥4N cells) and in the bromodeoxyuridine (BrdU) incorporation of ≥4N cells. Centrosome number was also increased in Tsc2+/EK SMCs, but the mitotic index was comparable between Tsc2+/+ and Tsc2+/EK SMCs. Furthermore, Tsc2+/EK SMCs showed elevated phosphorylation of p70S6K and increased expression of cell cycle regulatory proteins Cdk1, cyclin B, Cdk2, and cyclin E. Inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin not only inhibited the phosphorylation of p70S6K and the expression of cell cycle regulatory proteins but also reduced accumulation of ≥4N cells and BrdU incorporation of >4N cells. Therefore, our results demonstrate that Tsc2+/EK SMCs are predisposed to undergo tetraploidization, involving activation of the mTOR pathway. These findings suggest an important role of Tsc2 in regulation of the cell cycle.
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Shen, Xiao Yang, Zhi Jun Zheng, and Ping Wang. "Optimum Design on Screw Parameters of the Twin Screw Pulping Extruder Based on the Extrusion Model." Advanced Materials Research 139-141 (October 2010): 1411–14. http://dx.doi.org/10.4028/www.scientific.net/amr.139-141.1411.
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In order to enhance design reliability of a co-rotating twin screw pulping extruder (TSPE), optimum design on screw parameters of the TSPE was studied based on the extrusion model. The maximum shear flux or the minimum power consumption, or the two synchronous optimizations were taken as objective functions, and constraint conditions, such as thread lead, depth of thread, screw rotational speed, number of reverse thread lead, actual top width of the flight, torsional strength and stiffness of the screw mandrel, and so on were confirmed base on actual requirements of the TSPE manufacture and application. The optimizing results show that two-objective optimum design results split the difference of the two single-objective optimum design, and it is the most economical in reducing manufacture cost of the equipment and pulping expenses.
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Tkachev, Victor, Scott N. Furlan, Benjamin K. Watkins, Angela Panoskaltsis-Mortari, Bruce R. Blazar, and Leslie S. Kean. "Biological role of T Memory Stem Cells as a Cellular Reservoir for Graft-versus-Host Disease." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 140.8. http://dx.doi.org/10.4049/jimmunol.196.supp.140.8.
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Abstract T memory stem cells (Tscm) are a subset of antigen-experienced, long-lived, self-renewing and multipotent T cells, which reconstitute immunity following hematopoietic cell transplantation (HCT). Here we investigated the biological role of Tscm in acute Graft-versus-Host Disease (GVHD) using a translational non-human primate model. Tscm cells were tracked longitudinally following autologous or allogeneic HCT under different immunoprophylaxis regimens, resulting either in fulminant Th1-dependent ‘Primary GVHD’, late-onset Th17-driven ‘Breakthrough GVHD’, or GVHD-free immune tolerance. Following HCT, Tscm acquired an activated phenotype (Ki67+, CD69+, PD-1+ and CCR5+), but produced low amounts of IFNγ, IL-2, IL-17A, TNFα and Granzyme B. Tscm were a minor population in donor grafts but expanded in peripheral blood (with a reciprocal decline of naïve T cells) early after HCT and then contracted (with a concomitant increase of effector T cells) when recipients developed clinical GVHD. The kinetics of Tscm expansion/contraction correlated closely with clinical disease: Tscm expanded slower and contracted later in animals progressing to Breakthrough compared to Primary GVHD, and Tscm numbers remained stable under tolerizing conditions. At necropsy, animals with GVHD had increased numbers of Tscm in both lymphoid organs (blood, lymph nodes, spleen) and non-lymphoid GVHD-target organs (colon, lungs, liver) compared to GVHD-free animals. Our data demonstrates that Tscm dynamics correlate with GVHD-free survival and suggest that pathogenic T cells infiltrating both lymphoid and non-lymphoid organs transition from the naïve into the effector state via Tscm. Thus Tscm may play a key role as a cellular reservoir for GVHD.
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Li, Qiang, and Liyang Xie. "Analysis and Optimization of Tooth Surface Contact Stress of Gears with Tooth Profile Deviations, Meshing Errors and Lead Crowning Modifications Based on Finite Element Method and Taguchi Method." Metals 10, no. 10 (October 14, 2020): 1370. http://dx.doi.org/10.3390/met10101370.
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Based on the three-dimensional (3D) finite element method (FEM) and Taguchi method (TM), this paper analyzes the tooth surface contact stress (TSCS) of spur gears with three different influence factors: tooth profile deviations (TPD), meshing errors (ME) and lead crowning modifications (LCM), especially researching and analyzing the interactions between TPD, ME and LCM and their degree of influence on the TSCS. In this paper, firstly, a 3D FEM model of one pair of engaged teeth is modeled and the mesh of the contact area is refined by FEM software. In the model, the refined area mesh and the non-refined area mesh are connected by multi-point constraint (MPC); at the same time, in order to save the time of the FEM solution on the premise of ensuring the solution’s accuracy, the reasonable size of the refined area is studied and confirmed. Secondly, the TSCS analyses of gears with one single influence factor (other factors are all ideal) are carried out. By inputting the values of different levels of one single factor into the FEM model, especially using the real measurement data of TPD, and conducting the TSCS analysis under different torques, the influence degree of one single factor on TSCS is discussed by comparing the ideal model, and it is found that when the influence factors exist alone, each factor has a great influence on the TSCS. Finally, through TM, an orthogonal test is designed for the three influence factors. According to the test results, the interactions between the influence factors and the influence degree of the factors on the TSCS are analyzed when the three factors exist on the gear at the same time, and it is found that the TPD has the greatest influence on the TSCS, followed by the lead crowning modified quantity. The ME is relatively much small, and there is obvious interaction between ME and LCM. In addition, the optimal combination of factor levels is determined, and compared with the original combination of a gear factory, we see that the contact fatigue performance of the gear with the optimal combination is much better. The research of this paper has a certain reference significance for the control of TPD, ME and LCM when machining and assembling the gears.
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Prabhakar, Shilpa, June Goto, Xuan Zuang, Miguel Sena-Esteves, Roderick Bronson, Jillian Brockmann, Davide Gianni, et al. "Stochastic Model of Tsc1 Lesions in Mouse Brain." PLoS ONE 8, no. 5 (May 16, 2013): e64224. http://dx.doi.org/10.1371/journal.pone.0064224.
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Vilajosana, Xavier, Qin Wang, Fabien Chraim, Thomas Watteyne, Tengfei Chang, and Kristofer S. J. Pister. "A Realistic Energy Consumption Model for TSCH Networks." IEEE Sensors Journal 14, no. 2 (February 2014): 482–89. http://dx.doi.org/10.1109/jsen.2013.2285411.
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