bims-tubesc 2021-07-04 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–07–04
seventeen papers selected by

Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment.
Potential Pitfalls in Pre-implantation Genetic Diagnosis in a Patient with Tuberous Sclerosis and Isolated Mosaicism for a TSC2 Variant in Renal Tissue.
HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies.
Amino Acid-Mediated Intracellular Ca2+ Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca2+/Calmodulin.
Quality of life and its predictors in adults with tuberous sclerosis complex (TSC): a multicentre cohort study from Germany.
New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration.
Tuberous sclerosis complex.
Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis: Case Report.
Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations.
Regulation of mTORC1 activity by the Golgi apparatus.
Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration.
Sporadic uterine Lymphangioleiomyomatosis (LAM): Report of a unique case arising in the lower uterine segment with short review.
Renal Epithelioid Angiomyolipoma in Children.
mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex.
Drosophila yakuba - Tsc1.
Fibrous papules on the lips.
Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance.

Int J Mol Sci. 2021 Jun 22. pii: 6677. [Epub ahead of print]22(13):

Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment.

Masashi Mizuguchi, Maki Ohsawa, Hirofumi Kashii, Atsushi Sato.

  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.

Keywords:  TSC; autism; epilepsy; epileptic encephalopathy; intellectual disability; mTOR inhibitor; mTORopathy

DOI:  https://doi.org/10.3390/ijms22136677
Mol Syndromol. 2021 Jun;12(3): 154-158

Potential Pitfalls in Pre-implantation Genetic Diagnosis in a Patient with Tuberous Sclerosis and Isolated Mosaicism for a TSC2 Variant in Renal Tissue.

Kristin M Ikeda, Andrew A House, Dervla M Connaughton, Stephen E Pautler, Victoria Mok Siu, Michelle-Lee Jones.

  Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that displays a wide spectrum of clinical manifestations, often affecting multiple organs including the kidneys, brain, lungs, and skin. A pathogenic mutation in either the TSC1 or TSC2 gene can be detected in almost 85% of the cases, with mosaicism accounting for about half of the remaining cases. We report a case of TSC diagnosed clinically, requesting genetic counselling regarding reproductive risks. No mutation was identified on initial testing of peripheral blood; however, mosaicism for a likely pathogenic frameshift variant in TSC2 was detected at a level of 15% in renal angiomyolipoma tissue. Despite widespread clinical manifestations of TCS, this variant was not detected in skin fibroblasts or saliva, raising the possibility this is an isolated somatic mutation in renal tissue with the underlying germline mutation not yet identified. This case highlights the difficulties when counselling patients with mosaicism regarding their reproductive risks and prenatal diagnostic options.

Keywords:  Genetic counselling; Mosacism; Tuberous sclerosis

DOI:  https://doi.org/10.1159/000513326
Biomolecules. 2021 Jun 11. pii: 871. [Epub ahead of print]11(6):

HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies.

Shun-Yun Cheng, Anneliese Malachi, Joris Cipi, Shan Ma, Richard S Brush, Martin-Paul Agbaga, Claudio Punzo.

  Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1. Here, we confirm our previous findings by deletion of the other complex protein, namely TSC2, in rod photoreceptors. Similar to deletion of Tsc1, mice with deletion of Tsc2 in rods develop AMD-like pathologies, including accumulation of apolipoproteins, migration of microglia, geographic atrophy, and neovascular pathologies. Subtle differences between the two mouse models, such as a significant increase in microglia activation with loss of Tsc2, were seen as well. To investigate the role of altered glucose metabolism in disease pathogenesis, we generated mice with simulation deletions of Tsc2 and hexokinase-2 (Hk2) in rods. Although retinal lactate levels returned to normal in mice with Tsc2-Hk2 deletion, AMD-like pathologies still developed. The data suggest that the metabolic adaptations in PRs that cause AMD-like pathologies are independent of HK2-mediated aerobic glycolysis.

Keywords:  AMD; CNV; GA; aerobic glycolysis; dry AMD; glycolytic metabolism; photoreceptors; wet AMD

DOI:  https://doi.org/10.3390/biom11060871
Int J Mol Sci. 2021 Jun 27. pii: 6897. [Epub ahead of print]22(13):

Amino Acid-Mediated Intracellular Ca2+ Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca2+/Calmodulin.

Yuna Amemiya, Nao Nakamura, Nao Ikeda, Risa Sugiyama, Chiaki Ishii, Masatoshi Maki, Hideki Shibata, Terunao Takahara.

  Mechanistic target of rapamycin complex 1 (mTORC1) is a master growth regulator by controlling protein synthesis and autophagy in response to environmental cues. Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Although amino acids are believed to exclusively regulate lysosomal translocation of mTORC1 by Rag GTPases, how amino acids increase mTORC1 activity besides regulation of mTORC1 subcellular localization remains largely unclear. Here we report that amino acids also converge on regulation of the TSC2-Rheb GTPase axis via Ca2+/calmodulin (CaM). We showed that the amino acid-mediated increase of intracellular Ca2+ is important for mTORC1 activation and thereby contributes to the promotion of nascent protein synthesis. We found that Ca2+/CaM interacted with TSC2 at its GTPase activating protein (GAP) domain and that a CaM inhibitor reduced binding of CaM with TSC2. The inhibitory effect of a CaM inhibitor on mTORC1 activity was prevented by loss of TSC2 or by an active mutant of Rheb GTPase, suggesting that a CaM inhibitor acts through the TSC2-Rheb axis to inhibit mTORC1 activity. Taken together, in response to amino acids, Ca2+/CaM-mediated regulation of the TSC2-Rheb axis contributes to proper mTORC1 activation, in addition to the well-known lysosomal translocation of mTORC1 by Rag GTPases.

Keywords:  Rheb GTPase; TSC; amino acid; calcium; calmodulin; mTOR

DOI:  https://doi.org/10.3390/ijms22136897
Neurol Res Pract. 2021 Jun 28. 3(1): 35

Quality of life and its predictors in adults with tuberous sclerosis complex (TSC): a multicentre cohort study from Germany.

Johann Philipp Zöllner, Nadine Conradi, Matthias Sauter, Markus Knuf, Susanne Knake, Gerhard Kurlemann, Thomas Mayer, Christoph Hertzberg, Astrid Bertsche, Ilka Immisch, Karl Martin Klein, Klaus Marquard, Sascha Meyer, Anna H Noda, Felix von Podewils, Hannah Schäfer, Charlotte Thiels, Bianca Zukunft, Susanne Schubert-Bast, Janina Grau, Laurent M Willems, Felix Rosenow, Jens-Peter Reese, Adam Strzelczyk.

   BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC.
METHODS: We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders.
RESULTS: We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18-61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p < 0.001), active epilepsy (large effect, p < 0.001), and neuropsychiatric manifestations (medium effect, p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p < 0.001). The HRQoL among patients with active TSC-associated epilepsy was worse than that among patients with drug-refractory mesial temporal lobe epilepsy (p < 0.001), and the generic QoL among patients with more than three TSC organ manifestations was similar to those of patients with severe migraine and uncontrolled asthma.
CONCLUSIONS: Active epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity.
TRIAL REGISTRATION: DRKS, DRKS00016045 . Registered 01 March 2019.

Keywords:  EQ-5D; Epilepsy; Organ manifestations; QOLIE-31; Quality of life; Rare disease; Seizure; TSC; Tuberous sclerosis complex; mTOR inhibitor

DOI:  https://doi.org/10.1186/s42466-021-00130-3
Int J Mol Sci. 2021 Jun 24. pii: 6802. [Epub ahead of print]22(13):

New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration.

Justyna Jakubowska, Bartłomiej Pawlik, Krystyna Wyka, Małgorzata Stolarska, Katarzyna Kotulska, Sergiusz Jóźwiak, Wojciech Młynarski, Joanna Trelińska.

  The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 μM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 μM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.

Keywords:  K562 cells; everolimus; mTOR inhibitor; microcytosis of the red blood cells

DOI:  https://doi.org/10.3390/ijms22136802
Cleve Clin J Med. 2021 Jul 01. 88(7): 367-368

Tuberous sclerosis complex.

Jesica Martín Carmona, Elisabeth Gómez Moyano, Ana Raquel de Castro Almeida, Leandro Martínez Pilar.

DOI: https://doi.org/10.3949/ccjm.88a.20075
Neurologist. 2021 Jul 06. 26(4): 122-124

Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis: Case Report.

Frank J Barbiero, Anita J Huttner, Robert K Fulbright, Joachim M Baehring.

BACKGROUND: We present an uncommon cause of intracranial hemorrhage in a young adult. Tuberous sclerosis complex is a rare genetic disorder characterized by skin changes, benign systemic or central nervous system tumors [subependymal giant cell astrocytoma (SEGA)], mental retardation, or epilepsy. Hemorrhage into SEGA is exceedingly rare.
CASE PRESENTATION: We evaluated a 21-year-old college student with migraine. Biopsy of numerous popular skin lesions on his nose revealed adenoma sebaceum. Magnetic resonance imaging brain showed a subependymal nodule near the foramen of Monro suspected to be SEGA. Genetic analysis identified a tuberous sclerosis complex-1 germ line mutation. Surveillance imaging was recommended for the subependymal tumor. Fourteen months later, he presented with spontaneous hemorrhage into the tumor. Hematoma evacuation and tumor resection revealed SEGA. The college graduate was able to return to full-time work.
CONCLUSIONS: We present an unusual cause of intracranial hemorrhage in a young adult. Thorough work-up and recognition of an underlying genetic predisposition can curtails diagnostic delay when life-threatening complications occur.

DOI: https://doi.org/10.1097/NRL.0000000000000338
Front Oncol. 2021 ;11 644592

Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations.

Elhusseiny Mohamed Mahmoud Abdelwahab, Judit Bovari-Biri, Gabor Smuk, Tunde Harko, Janos Fillinger, Judit Moldvay, Vera P Krymskaya, Judit E Pongracz.

   Background: Mutation in a tuberous sclerosis gene (TSC1 or 2) leads to continuous activation of the mammalian target of rapamycin (mTOR). mTOR activation alters cellular including vitamin A metabolism and retinoic acid receptor beta (RARβ) expression. The goal of the present study was to investigate the molecular connection between vitamin A metabolism and TSC mutation. We also aimed to investigate the effect of the FDA approved drug rapamycin and the vitamin A metabolite retinoic acid (RA) in cell lines with TSC mutation.
Methods: Expression and activity of vitamin A associated metabolic enzymes and RARβ were assessed in human kidney angiomyolipoma derived cell lines, primary lymphangioleiomyomatosis (LAM) tissue derived LAM cell lines. RARβ protein levels were also tested in primary LAM lung tissue sections. TaqMan arrays, enzyme activities, qRT-PCRs, immunohistochemistry, immunofluorescent staining, and western blotting were performed and analysed. The functional effects of retinoic acid (RA) and rapamycin were tested in a scratch and a BrDU assay to assess cell migration and proliferation.
Results: Metabolic enzyme arrays revealed a general deregulation of many enzymes involved in vitamin A metabolism including aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases (ADHs) and Cytochrome P450 2E1 (CYP2E1). Furthermore, RARβ downregulation was a characteristic feature of all TSC-deficient cell lines and primary tissues. Combination of the two FDA approved drugs -RA for acute myeloid leukaemia and rapamycin for TSC mutation- normalised ALDH and ADH expression and activity, restored RARβ expression and reduced cellular proliferation and migration.
Conclusion: Deregulation of vitamin A metabolizing enzymes is a feature of TSC mutation. RA can normalize RARβ levels and limit cell migration but does not have a significant effect on proliferation. Based on our data, translational studies could confirm whether combination of RA with reduced dosage of rapamycin would have more beneficial effects to higher dosage of rapamycin monotherapy meanwhile reducing adverse effects of rapamycin for patients with TSC mutation.

Keywords:  RARβ; rapamycin; retinoic acid; tuberous sclerosis gene mutation; vitamin A metabolism

DOI:  https://doi.org/10.3389/fonc.2021.644592
Fac Rev. 2021 ;10 50

Regulation of mTORC1 activity by the Golgi apparatus.

Christian Makhoul, Paul A Gleeson.

  Mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) is a major signalling kinase in cells that regulates proliferation and metabolism and is controlled by extrinsic and intrinsic signals. The lysosome has received considerable attention as a major hub of mTORC1 activation. However, mTOR has also been located to a variety of other intracellular sites, indicating the possibility of spatial regulation of mTORC1 signalling within cells. In particular, there have been numerous recent reports of mTORC1 activation associated with the Golgi apparatus. Here, we review the evidence for the regulation of mTORC1 signalling at the Golgi in mammalian cells. mTORC1 signalling is closely linked to the morphology of the Golgi architecture; a number of Golgi membrane tethers/scaffolds that influence Golgi architecture in mammalian cells that directly or indirectly regulate mTORC1 activation have been identified. Perturbation of the Golgi mTORC1 pathway arising from fragmentation of the Golgi has been shown to promote oncogenesis. Here, we highlight the potential mechanisms for the activation mTORC1 at the Golgi, which is emerging as a major site for mTORC1 signalling.

Keywords:  Arf1; GAT4; GCC88; GOLPH3; Golgi architecture; Rab1A; actin; mTORC1; signalling; trans-Golgi network

DOI:  https://doi.org/10.12703/r/10-50
Mol Neurodegener. 2021 Jul 02. 16(1): 44

Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration.

Henry Querfurth, Han-Kyu Lee.

  Novel targets to arrest neurodegeneration in several dementing conditions involving misfolded protein accumulations may be found in the diverse signaling pathways of the Mammalian/mechanistic target of rapamycin (mTOR). As a nutrient sensor, mTOR has important homeostatic functions to regulate energy metabolism and support neuronal growth and plasticity. However, in Alzheimer's disease (AD), mTOR alternately plays important pathogenic roles by inhibiting both insulin signaling and autophagic removal of β-amyloid (Aβ) and phospho-tau (ptau) aggregates. It also plays a role in the cerebrovascular dysfunction of AD. mTOR is a serine/threonine kinase residing at the core in either of two multiprotein complexes termed mTORC1 and mTORC2. Recent data suggest that their balanced actions also have implications for Parkinson's disease (PD) and Huntington's disease (HD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Beyond rapamycin; an mTOR inhibitor, there are rapalogs having greater tolerability and micro delivery modes, that hold promise in arresting these age dependent conditions.

Keywords:  Akt; Alzheimer’s; Insulin signaling; Parkinson’s; Rapamycin; mTOR

DOI:  https://doi.org/10.1186/s13024-021-00428-5
Gynecol Oncol Rep. 2021 Aug;37 100812

Sporadic uterine Lymphangioleiomyomatosis (LAM): Report of a unique case arising in the lower uterine segment with short review.

Tip Pongsuvareeyakul, Sara Maleki, Bradley D DeNardo, Don S Dizon, Chanika Phornphutkul, Kamaljeet Singh.

  •Extrapulmonary lymphangioleiomyomatosis is rare and can be associated with tuberous sclerosis.•Recognition of lymphangioleiomyomatosis is important for early disease screening and genetic testing.•Lymphangioleiomyomatosis in lower uterine segment is very rare and can be overlooked.

Keywords:  Lymphangioleiomyomatosis; Tuberous sclerosis; Uterus

DOI:  https://doi.org/10.1016/j.gore.2021.100812
J Kidney Cancer VHL. 2021 ;8(2): 20-26

Renal Epithelioid Angiomyolipoma in Children.

Dhruv Mahajan, Vishesh Jain, Sandeep Agarwala, Manisha Jana, Prashant P Ramteke.

  Renal angiomyolipoma is a rare cause of renal tumor in children. Most are associated with tuberous sclerosis, and the classic type is observed more commonly. Epithelioid angiomyolipoma is even rarer with only limited case reports and series published in literature, most of which are of adult patients. We describe a 12-year-old boy, a diagnosed patient of tuberous sclerosis, who presented with pain in the left flank. On evaluation, it was found to have a left renal mass with the clinical picture suggestive of renal cell carcinoma. Partial nephrectomy was performed and histopathology revealed epithelioid angiomyolipoma. The child was asymptomatic at follow-up after 3 months. Only a few such cases in children are found in literature, which are discussed alongside. Differential diagnosis of this rare tumor must be kept in mind in a renal tumor as surgery is generally curative in this possibly malignant tumor. Metastasis confers a poor prognosis. Chemotherapy is generally not effective, although various regimens have been tried. Tumor recurrence must be kept in mind and a follow-up after apparent complete remission is of paramount importance.

Keywords:  angiomyolipoma; kidney tumor; pediatric cancer; renal epithelioid angiomyolipoma; tuberous sclerosis

DOI:  https://doi.org/10.15586/jkcvhl.v8i2.178
Int J Mol Sci. 2021 Jun 03. pii: 6034. [Epub ahead of print]22(11):

mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex.

Martin Schüle, Tamer Butto, Sri Dewi, Laura Schlichtholz, Susanne Strand, Susanne Gerber, Kristina Endres, Susann Schweiger, Jennifer Winter.

  Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.

Keywords:  NF-Y; SP1; SREBP; cholesterol; mTOR; mTORC1; neurogenesis

DOI:  https://doi.org/10.3390/ijms22116034
MicroPubl Biol. 2021 Jun 24. 2021

Drosophila yakuba - Tsc1.

Bailey Lose, Abigail Myers, Savanah Fondse, Ian Alberts, Joyce Stamm, James J Youngblom, Chinmay P Rele, Laura K Reed.

Gene Model for Tsc1 in the Drosophila yakuba's DyakCAF1 assembly (GCA_000005975.1).

DOI: https://doi.org/10.17912/micropub.biology.000407
Pediatr Dermatol. 2021 Jun 28.

Fibrous papules on the lips.

Xiuyan Shi, Bin Zhang, Lin Ma.

  Multiple angiofibromas are commonly found in patients with tuberous sclerosis complex. We report a rare presentation of multiple congenital fibrous papules occurring only on the lips with no syndromic associations.

Keywords:  angiofibroma; fibrous papule; mucosal lesions

DOI:  https://doi.org/10.1111/pde.14610
Oxid Med Cell Longev. 2021 ;2021 6613151

Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance.

Xiangyu Che, Xiaochen Qi, Yingkun Xu, Qifei Wang, Guangzhen Wu.

The mTOR pathway, a major signaling pathway, regulates cell growth and protein synthesis by activating itself in response to upstream signals. Overactivation of the mTOR pathway may affect the occurrence and development of cancer, but no specific treatment has been proposed for targeting the mTOR pathway. In this study, we explored the expression of mTOR pathway genes in a variety of cancers and the potential compounds that target the mTOR pathway and focused on an abnormal type of cancer, kidney renal clear cell carcinoma (KIRC). Based on the mRNA expression of the mTOR pathway gene, we divided KIRC patient samples into three clusters. We explored possible therapeutic targets of the mTOR pathway in KIRC. We predicted the IC50 of some classical targeted drugs to analyze their correlation with the mTOR pathway. Subsequently, we investigated the correlation of the mTOR pathway with histone modification and immune infiltration, as well as the response to anti-PD-1 and anti-CTLA-4 therapy. Finally, we used a LASSO regression analysis to construct a model to predict the survival of patients with KIRC. This study shows that mTOR scores can be used as tools to study various treatments targeting the mTOR pathway and that we can predict the recovery of KIRC patients through the expression of mTOR pathway genes. These research results can provide a reference for future research on KIRC patient treatment strategies.

DOI: https://doi.org/10.1155/2021/6613151