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The control of exosome release is associated with numerous physiological and pathological activities, and that release is often indicative of health, disease, and environmental nutrient stress. Tuberous sclerosis complex (TSC) regulates the cell viability via the negative regulation of the mammalian target of rapamycin complex (mTORC1) during glucose deprivation. However, the mechanism by which viability of TSC-null cells is regulated by mTORC1 inhibition under glucose deprivation remains unclear. Here, we demonstrated that exosome release regulates cell death induced by glucose deprivation in TSC-null cells. The mTORC1 inhibition by rapamycin significantly increased the exosome biogenesis, exosome secretion, and cell viability in TSC-null cells. In addition, the increase in cell viability by mTORC1 inhibition was attenuated by two different types of inhibitors of exosome release under glucose deprivation. Taken together, we suggest that exosome release inhibition might be a novel way for regression of cell growth in TSC-null cells showing lack of cell death by mTORC1 inhibition. [ABSTRACT FROM AUTHOR]

Hsp90 is a ubiquitous molecular chaperone involved in many cell signaling pathways, and its interactions with specific chaperones and cochaperones determines which client proteins to fold. Hsp90 has been shown to be involved in the promotion and maintenance of proper protein complex assembly either alone or in association with other chaperones such as the R2TP chaperone complex. Hsp90-R2TP acts through several mechanisms, such as by controlling the transcription of protein complex subunits, stabilizing protein subcomplexes before their incorporation into the entire complex, and by recruiting adaptors that facilitate complex assembly. Despite its many roles in protein complex assembly, detailed mechanisms of how Hsp90-R2TP assembles protein complexes have yet to be determined, with most findings restricted to proteomic analyses and in vitro interactions. This review will discuss our current understanding of the function of Hsp90-R2TP in the assembly, stabilization, and activity of the following seven classes of protein complexes: L7Ae snoRNPs, spliceosome snRNPs, RNA polymerases, PIKKs, MRN, TSC, and axonemal dynein arms. [ABSTRACT FROM AUTHOR]

In this study, assessing the microbial quality and safety of the market raw milk and pasteurized milk is the basal objective of this study. One hundred and twenty (120) milk samples (60 of each) were collected randomly from different supermarkets and retailer shops in Dakahlia governorate, Egypt. Samples were analyzed for Total bacterial count (TBC), total coliforms (TCC), Total Staphylococcus count (TSC), and Total yeast and mould count. All market milk samples, and pasteurized milk were found to be contaminated and judged poor. Listeria spp. were isolated on Oxford agar and then subjected to biochemical and molecular identification. The overall isolation rate of Listeria spp. from the market raw milk was 28.33%. The prevalence rates of Listeria monocytogenes were 13.33% in raw market milk. The prevalence of Listeria innocula and other Listeria species were 3.33% and 11.67%, respectively. Polymerase chain reaction (PCR) was used to detect the virulence genes (16SrRNA, hylA, and prfA) of 8 biochemically identified L. monocytogenes strains recovered from raw market milk using specific primers. 16SrRNA, hylA, and prfA genes are considered the best indicator for virulence determination of L. monocytogenes isolated from market raw milk. A high microbial load of market milk and pasteurized milk may present a public health hazard to the consumers and emphasizes the need for improved hygienic standards. [ABSTRACT FROM AUTHOR]

What is known and objective: Patients with tuberous sclerosis complex (TSC) demonstrate disrupted lipid homeostasis before and during treatment with mammalian target of rapamycin (mTOR) inhibitor. However, few previous reports focused on if the serum lipid status at baseline would influence lipid metabolic side‐effects of mTOR inhibitors for TSC associated renal angiomyolipomas (TSC‐AML). The present study was designed to evaluate the predictive function of serum lipid status at baseline for hyperlipidaemia by mTOR inhibitor treatment in TSC‐AML patients. Methods: The clinical data of TSC‐AML patients who took mTOR inhibitors in Department of Urology of Peking Union Medical College Hospital (PUMCH) from 1 January 2014 to 1 January 2021, were retrospectively analysed. The record of lipid parameters at baseline and the highest levels of total cholesterol (TC) and triglyceride (TG) after treatment at least ≥3 months were collected. The correlation of serum lipid parameters at baseline with incidence of hyperlipidaemia during mTOR inhibitor treatment was analysed. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of the serum lipid parameters in predicting hyperlipidaemia. Results and discussion: 19 patients experienced hyperlipidaemia and 13 patients still had normal TC and TG levels during mTOR inhibitor treatment. The levels of high‐density lipoprotein cholesterol (HDL‐C) (0.98 ± 0.30 mmol/L vs. 1.23 ± 0.31 mmol/L, p = 0.030), low‐density lipoprotein cholesterol (LDL‐C) (2.47 ± 0.69 mmol/L vs. 1.95 ± 0.53 mmol/L, p = 0.029) and apolipoprotein B (ApoB) (0.82 ± 0.21 g/L vs. 0.65 ± 0.16 g/L, p = 0.019) are higher in the patients who experienced hyperlipidaemia during mTOR inhibition therapy. TC, TG, LDL‐C, ApoB and high‐sensitivity C‐reactive protein (hsCRP) at baseline had positive correlation with TC after treatment; ApoB at baseline had positive correlation, while HDL‐C and free fat acid (FFA) at baseline had negative correlation with TG after treatment. Therefore, ApoB concentration at baseline has statistically significant correlation with both TC (p < 0.001) and TG (p = 0.012) levels after mTOR inhibitor treatment. ROC curve and AUC revealed that ApoB with a cut‐off value of 0.640g/L may be the best parameter for predicting hyperlipidaemia during mTOR inhibitor treatment in TSC‐AML patients. The incidence rates of hyperlipidaemia were 27.3% and 76.2% among the patients with ApoB level ≤0.640 g/L and >0.640 g/L respectively. What is new and conclusion: Some baseline serum lipid parameters could be used for predicting incidence of hyperlipidaemia during mTOR inhibition therapy in TSC‐AML patients, and ApoB with 0.640 g/L as a cut‐off value may be a potentially optimal indicator, which could help for diagnosis and treatment decision‐making. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct disorders typically associated with pathogenic variants in TSC1 and TSC2 for the former and PKD1 and PKD2 for the latter. TSC2 and PKD1 lie adjacent to each other, and large deletions comprising both genes lead to TSC2/PKD1 contiguous gene deletion syndrome (CGS). In this study, we describe a young female patient exhibiting symptoms of TSC2/PKD1 CGS in which genetic analysis disclosed two noncontiguous partial gene deletions in TSC2 and PKD1 that putatively are responsible for the manifestations of the syndrome. Further analysis revealed that both deletions appear to be de novo on the maternal chromosome, presumably with a germline origin. Despite extensive analysis, no maternal chromosomal rearrangement triggering these pathogenic variants was detected. This case elucidates a unique pathogenesis for TSC2/PKD1 CGS, diverging from the common contiguous deletions typically observed, marking the first reported instance of TSC2/PKD1 CGS caused by independent, functionally significant partial gene deletions., (© 2024 Wiley Periodicals LLC.)

A 33-year-old patient presented with a chief complaint of patent ductus arteriosus (PDA) persisting for over 30 years. Physical examination revealed bilateral facial angiofibromas, multiple nail fibromas, intraoral fibromas, and a 'shagreen patch' on the left lumbar region. Genetic testing was performed using a peripheral venous blood sample, which confirmed the diagnosis of Tuberous Sclerosis Type 2 (TSC2). Subsequently, the patient underwent cardiac color Doppler ultrasound and chest computed tomography angiography, which confirmed the presence of PDA. Tuberous sclerosis complex (TSC) is associated with cardiovascular diseases. The initial clinical manifestation of TSC is usually cardiac rhabdomyoma in children, and it is rarely reported in adults with PDA. In this case, the patient was diagnosed with PDA when he was young, and the genetic test showed heterozygous variation of TSC2 gene. The purpose of this article is to explore the correlation between TSC and PDA at the gene level through literature review., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Chen, Wu and Wang.)

The Mammalian Target of Rapamycin Complex 1 (mTORC1) is a serine threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However recent studies have indicated that mTORC1 may be active towards its canonical substrates, 4EBP1 and S6K, involved in mRNA translation and protein synthesis, and inactive towards TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt Hogg Dube (BHD) and recently, Tuberous Sclerosis Complex (TSC). Furthermore, TFEB and TFE3 hyperactivation in these syndromes, and in translocation Renal Cell Carcinomas (tRCC), drives mTORC1 activity towards the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity towards 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies". Currently, there no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.

Background: Aberrant activation of mTORC1 is clearly defined in TSC, causing uncontrolled cell growth. While mTORC1 inhibitors show efficacy to stabilise tumour growth in TSC, they are not fully curative. Disease facets of TSC that are not restored with mTOR inhibitors might involve NF-κB. The study aimed to characterise NF-κB in the context of TSC., Results: Enrichment of NF-κB-regulated genes was observed in TSC patient tumours, SEN/SEGAs, cortical tubers and a TSC tumour-derived cell line (621 - 101). Highlighting an inflammatory component of TSC, TSC cell models showed an elevated level of NF-κB and STAT3 activation. Herein, we report a dysregulated inflammatory phenotype of TSC2 -deficient cells where NF-κB promotes autocrine signalling involving IL-6. Of importance, mTORC1 inhibition does not block this inflammatory signal to promote STAT3, while NF-κB inhibition was much more effective. Combined mTORC1 and NF-κB inhibition was potent at preventing anchorage-independent growth of TSC2 -deficient cells, and unlike mTORC1 inhibition alone was sufficient to prevent colony regrowth after cessation of treatment., Conclusion: This study reveals autocrine signalling crosstalk between NF-κB and STAT3 in TSC cell models. Furthermore, the data presented indicate that NF-κB pathway inhibitors could be a viable adjunct therapy with the current mTOR inhibitors to treat TSC., Competing Interests: Declarations Competing interests The authors declare that they have no competing interests. While this study is funded in part by Health and Care Research Wales, the views expressed are those of the authors and not necessarily those of Health and Care Research Wales or the Welsh Government.

Renal angiomyolipoma is a benign mesenchymal tumor that can be divided into classical and other subtypes. Angiomyolipoma with epithelial cysts (AMLEC) is an extremely rare non classical subtype. AMLEC without fat component is even rarer. We report a case of AMLEC without fat in a 29-year-old man who was provisionally diagnosed with cystic renal carcinoma by ultrasonography, abdominal enhanced CT and MRI. He had no complaints, or personal or family history of TSC, or other malignancies. Based on imaging findings, robot-assisted laparoscopic nephron-sparing partial nephrectomy through a retroperitoneal approach was performed for the purpose of both diagnosis and treatment. We diagnosed AMLEC after considering the differential diagnosis of other cystic renal neoplasms, such as cystic renal carcinoma, multilocular cystic renal cell neoplasm of low malignant potential, adult cystic nephroma and mixed epithelium and stromal tumor. Meanwhile, the whole-exon sequencing (WES) results showed insert-splicing mutation in the 21st exon and 20th exon of the TSC1 gene. No treatments were performed after the operation and no evidence of recurrence or metastasis at regular follow-up., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Abstract Background Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients. Methods TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2). Results Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals

Chordoma associated with tuberous sclerosis complex (TSC) is an extremely rare tumor that was described only in 13 cases since 1975. Сhordoma itself is a malignant slow-growing bone tumor thought to arise from vestigial or ectopic notochordal tissue. Chordoma associated with TSC differs from chordoma in the general pediatric population in the median age, where the diagnosis of TSC-associated chordoma is 6.2 months, whereas for chordoma in the general pediatric population it is set to 12 years. The majority of TSC-associated chordomas are localized in skull-based and sacrum regions, and rare in the spine. Chordomas are genetically heterogeneous tumors characterized by chromosomal instability (CIN), and alterations involving PI3K-AKT signaling pathway genes and chromatin remodeling genes. Here we present the 14th case of chordoma associated with TSC in a 1-year-old pediatric patient. Alongside biallelic inactivation of the TSC1 gene, molecular genetic analysis revealed CIN and involvement of epigenetic regulation genes. In addition, we found the engagement of CBX7 and apolipoprotein B editing complex (APOBEC3) genes that were not yet seen in chordomas before. Amplification of CBX7 may epigenetically silence the CDKN2A gene, whereas amplification of APOBEC3 genes can explain the frequent occurrence of CIN in chordomas. We also found that KRAS gene is located in the region with gain status, which may suggest the ineffectiveness of potential EGFR monotherapy. Thus, molecular genetic analysis carried out in this study broadens the horizons of possible approaches for targeted therapies with potential applications for personalized medicine.

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.

The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function.

Teaching Point: Multiple micronodular pneumocyte hyperplasia (MMPH) is a less-known presentation of tuberous sclerosis complex (TSC) associated lung disease that usually requires no treatment or follow-up imaging.

Background: Epilepsy is a neurological disease that is mostly caused by genetic factors. The genetic diagnosis of patients in a pediatric epilepsy cohort was provided. Methods: After phenotypic characterization, a 48-gene Next Generation Sequencing panel was performed in 110 Turkish children with epilepsy. The variants were called and annotated using the QIAGEN Ingenuity® Variant Analysis software. Results: Of those carrying pathogenic mutations, two patients had mutations in the SCN1A gene and two patients in the TSC2 gene; other patients had mutations in the SCN1B, GRIN2B, KCNQ2, PCDH19, CHRNA2, and MECP2 genes. In total, nine out of 10 patients had pathogenic variants that were not previously reported. Conclusions: The genotype-phenotype correlations of these variants were discussed by comparing the clinical findings with the literature. [ABSTRACT FROM AUTHOR]

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is an emerging entity in renal neoplasia with distinctive histopathological findings and a generally favorable prognosis. The presence of melanin pigment in a renal tumor typically prompts the observer to consider the microphthalmia-associated transcription family translocation renal cell carcinomas. We present a renal tumor occurring in a 19-year-old male patient which had the typical morphology of ESC-RCC but showed the additional finding of focal melanin pigment. This tumor showed strong and diffuse positive immunolabeling with paired box gene 8 and cytokeratin 20, and was negative with epithelial membrane antigen, carbonic anhydrase 9, CD117, cytokeratin 7, and transcription factor E3. Human melanoma black-45 showed focal positivity, but Melan-A was negative. Next-generation sequencing revealed a mutation in the TSC2 gene (c.4490C > G, p.[Pro1497Arg] and c.1257 + 1del) and break apart fluorescence in-situ hybridization with TFE3 and TFEB probes was negative. In this case report, we present the novel finding of melanin pigment occurring in a genetically proven and otherwise typical ESC-RCC, and briefly discuss the differential diagnostic considerations. [ABSTRACT FROM AUTHOR]

Low-grade oncocytic tumor (LOT) has recently been described as a distinct renal tumor. LOT shows consistent morphologic features and a CK7-positive/CD117-negative immunophenotype. To examine the clinicopathological, immunohistochemical, and molecular features of LOT, we searched our institutional archives and identified seven cases of LOT. All patients were female, with a mean age of 66 years (range 44–79 years). The average tumor size was 3.2 cm (range 1.6–5.5 cm). Macroscopically, the tumors showed tan-brown and solid cut surfaces. Microscopically, the tumors showed compact nested to solid growth pattern, three cases with areas of edematous stroma containing loosely connected small clusters, cords or dispersed single tumor cells. The tumor cells had uniformly round to oval nuclei with eosinophilic cytoplasm, and showed perinuclear halos. Two cases focally had nuclear irregularities and binucleated cells were occasionally seen in three cases. Immunohistochemically, diffuse positivity for CK7 and lack of CD117 expression were present in all cases. All of the tumors were negative for CD10, CK20, vimentin, CA9, TFE3, TFEB, HMB45, and Melan-A. All tumors were positive for MTOR and negative for Cathepsin-K. FH and SDHB were retained. Next generation sequencing identified genetic variations in the MTOR pathway related genes: TSC1 (4/7), TSC2 (5/7), and MTOR (1/7). All patients were alive and without disease progression, after a mean follow-up of 43 months (range 6–89 months). LOT is an uncommon eosinophilic renal neoplasm with unique morphological and characteristic immunophenotypic features, and may represent an emerging separate renal entity characterized by mutations in the TSC/MTOR pathway. [ABSTRACT FROM AUTHOR]

Abstract Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. Methods A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). Results We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533–7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780–1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503–3840) among working-age individuals (

Abstract 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

In power system, the study of optimal power flow (OPF) with transient stability constrained (TSC) of the mixed AC/DC networks is a big and celebrated challenging optimization problem. Because, of its effort and high complexity in its solution, this paper presents an efficient method to resolve its problem. The goal of standard OPF is to minimize the objective function necessary for a good service of network, under normal operation with respects the number of equality and inequality constraints. But the main objective function of transient stability constrained optimal power flow (TSC-OPF) is minimization of fuel cost for all generators with preserving the rotor angle deviation within acceptable limits after credible contingencies (fault). The integration of static var compensator (SVC), and high-voltage direct current (HVDC) link and transient stability problem in the OPF will be the major defy. The simulations are carried out in Matlab environment, the effectiveness and robustness of the proposed method is verified on the standard IEEE 14-bus test system with different objectives.

Abstract Background The tuberous sclerosis-associated neuropsychiatric disorders (TAND) have not previously been studied in China. We aimed to assess the psychiatric level of individuals with TAND using the Mini International Neuropsychiatric Interview for Children (MINI-KID) in China. Results A total of 83.16% of individuals (79/95) had at least one TAND, and 70.53% (67/95) had an intellectual disability. The MINI-KID tool diagnosed 16 neuropsychiatric diseases, the most common of which were attention-deficit/hyperactivity disorder (ADHD) (51.58%, 49/95) and social anxiety disorder (30.53%, 29/95). The number of children with psychiatric diseases in the tuberous sclerosis complex (TSC) group was significantly greater than the number in the typically developing group (P

Abstract Background Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. Methods At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). Results Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). Conclusions These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

Identification of trap centers in semiconductors takes great importance for improving the performance of electronic and optoelectronic devices. In the present study, we employed the thermally stimulated current (TSC) method within a temperature range of 10–280 K to explore trap centers in InSe crystal—a material with promising applications in next-generation devices. Our findings revealed the existence of two distinct hole trap centers within the InSe crystal lattice located at 0.06 and 0.14 eV. Through the leveraging the T stop method, we offered trap distribution parameters of revealed centers. The results obtained from the experimental methodology employed to investigate the distribution of trap centers indicated that one of the peaks extended between 0.06 and 0.13 eV, while the other spanned from 0.14 to 0.31 eV. Notably, our research uncovers a remarkable variation in trap density, spanning one order of magnitude, for every 10 and 88 meV of energy variation. The results of our research present the characteristics of shallow trap centers in InSe, providing important information for the design and optimization of InSe-based optoelectronic devices. • TSC measurements were performed on InSe crystal in the below room temperature. • The presence of two hole traps at 0.06 and 0.14 eV was revealed. • The distribution of trap centers was investigated by applying T stop - T m method. • The results provide important information for design of InSe-based optoelectronic devices. [ABSTRACT FROM AUTHOR]

Teaching Point: Multiple micronodular pneumocyte hyperplasia (MMPH) is a lessknown presentation of tuberous sclerosis complex (TSC) associated lung disease that usually requires no treatment or follow-up imaging. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is an inherited genetic disorder characterized by mutations in TSC1 or TSC2 class of tumor suppressers which impact several organs including the kidney. The renal manifestations are usually in the form of angiomyolipoma (AML, in 80% of the cases) and cystadenomas. mTOR inhibitors such as rapamycin and everolimus have shown efficacy in reducing the renal tumor burden. Early treatment prevents the progression of AML; however, the tumors regrow upon cessation of therapy implying a lifelong need for monitoring and management of this morbid disease. There is a critical need for development of imaging strategies to monitor response to therapy and progression of disease which will also facilitate development of newer targeted therapy. In this study we evaluated the potential of multiparametric 1H magnetic resonance imaging (mpMRI) to monitor tumor response to therapy in a preclinical model of TSC, the transgenic mouse A/J Tsc2+/-. We found 2-dimensional T2-weighted sequence with 0.5 mm slice thickness to be optimal for detecting renal lesions as small as 0.016 mm3. Baseline characterization of lesions with MRI to assess physiological parameters such as cellularity and perfusion is critical for distinguishing between cystic and solid lesions. Everolimus treatment for three weeks maintained tumor growth at 36% from baseline, while control tumors displayed steady growth and were 70% larger than baseline at the end of therapy. Apparent diffusion coefficient, T1 values and normalized T2 intensity changes were also indictive of response to treatment. Our results indicate that standardization and implementation of improved MR imaging protocols will significantly enhance the utility of mpMRI in determining the severity and composition of renal lesions for better treatment planning.

Subependymal giant cell astrocytomas (SEGAs) are the most common intracranial tumors in Tuberous Sclerosis Complex (TSC). Very few cases of solitary SEGA without a diagnosis of TSC have been described. Most of these previously reported solitary SEGAs were located near the caudothalamic groove or in close proximity to the lateral ventricles. Here, we describe a unique case of solitary extraventricular SEGA in a 17-year-old boy who presented with new-onset seizures in the absence of the clinical and genetic diagnosis of TSC. This extraventricular SEGA was involving white matter and cortex of the occipital lobe and was predominantly hypointense on T1 and T2-weighted images with a markedly hypointense signal on susceptibility-weighted images likely secondary to dense internal calcifications. Solitary SEGA can occur in the extraventricular location in patients without TSC and should be included in the differential diagnosis of a densely calcified supratentorial intra-axial tumor in children, especially during the second decade of life.

In this work, the effects of 60Co γ -ray irradiation on high resistivity p -type diodes have been investigated. The diodes were exposed to dose values of 0.1, 0.2, 1, and 2 MGy. Both macroscopic (I – V , C – V) and microscopic investigations, by means of Thermally Stimulated Current (TSC) and Deep Level Transient Spectroscopy (DLTS) techniques, were conducted to characterize the radiation-induced changes. The investigated diodes were manufactured on high resistivity p -type Float Zone (FZ) silicon and were further classified into two types based on the isolation technique between the pad and guard ring: p -stop and p -spray. After irradiation, the macroscopic results of current–voltage and capacitance–voltage measurements were obtained and compared with existing literature data. Additionally, the microscopic measurements focused on the development of the concentration of different radiation-induced defects, including the Boron interstitial-Oxygen interstitial (B i O i) complex, the Carbon interstitial-Oxygen interstitial (C i O i) defect, the H40K, and the so-called I P ∗. To investigate the thermal stability of induced defects in the bulk, isochronal annealing studies were performed in the temperature range of 100 °C to 300 °C. These annealing processes were carried out on diodes irradiated with doses of 1 and 2 MGy. Furthermore, in order to investigate the unexpected results observed in the C – V measurements after irradiation with high dose values, the surface conductance between the pad and guard ring was measured as a function of both dose and annealing temperature. [ABSTRACT FROM AUTHOR]

Aims: To explore the impact of the use of intracardiac echocardiography (ICE) in the ablation of supraventricular arrhythmias requiring transseptal catheterization (TSC), whilst analyzing the reduction in periprocedural complications and complications specifically related to TSC. Methods: A retrospective multicenter study collecting data from consecutive atrial fibrillation (AF) and supraventricular ablation procedures that required TSC was performed in five Italian centers. Based on physician discretion, TSC was performed with or without ICE. Periprocedural complications, separating all complications from complications directly related to TSC, were collected. Independent predictors of periprocedural complications and TSC-related complications were investigated. Results: A total of 2181 TSCs were performed on 1862 patients at five Italian centers from 2006 to 2021, in 76% of cases by AF ablation and in 24% by ablation of other arrhythmias with a circuit in the left atrium. Overall, 1134 (52%) procedures were performed with ICE support and 1047 (48%) without ICE. A total of 67 (3.1%) complications were detected, 19 (1.7%) in the ICE group and 48 (4.6%) in the no ICE group, p < 0.001. A total of 42 (1.5%) complications directly related to TSC: 0.9% in the ICE group and 3.1% in the no ICE group (p < 0.001). The independent predictors of all complications were age (OR 1,02 95% C.I 1.00–1.05; p = 0.036), TSC with the use of ICE (OR 0.27 95% C.I 0.15–0.46; p < 0.001) and AF ablation (OR 2,25 95%C.I 1.05–4.83; p = 0.037). The independent predictors for TSC complications were age (OR 1.03 95% C.I 1.01–1.06; p = 0.013) and TSC with the use of ICE (OR 0.24 95% C.I 0.11–0.49; p < 0.001). Conclusions: ICE reduced periprocedural and TSC-related complications during electrophysiological procedures for ablation of left atrial arrhythmias.

Tuberous sclerosis complex (TSC) is caused by mutations in Tsc1 or Tsc2, whose gene products inhibit the small G-protein Rheb1. Rheb1 activates mTORC1, which may cause refractory epilepsy, intellectual disability, and autism. The mTORC1 inhibitors have been used for TSC patients with intractable epilepsy. However, its effectiveness for cognitive symptoms remains unclear. We found a new signaling pathway for synapse formation through Rheb1 activation, but not mTORC1. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib increased unfarnesylated (inactive) Rheb1 levels and restored synaptic abnormalities in cultured Tsc2+/- neurons, whereas rapamycin did not enhance spine synapse formation. Lonafarnib treatment also restored the plasticityrelated Arc (activity-regulated cytoskeleton-associated protein) expression in cultured Tsc2+/- neurons. Lonafarnib action was partly dependent on the Rheb1 reduction with syntenin. Oral administration of lonafarnib increased unfarnesylated protein levels without affecting mTORC1 and MAP (mitogen-activated protein (MAP)) kinase signaling, and restored dendritic spine morphology in the hippocampi of male Tsc2+/- mice. In addition, lonafarnib treatment ameliorated contextual memory impairments and restored memory-related Arc expression in male Tsc2+/- mice in vivo. Heterozygous Rheb1 knockout in male Tsc2+/- mice reproduced the results observed with pharmacological treatment. These results suggest that the Rheb1 activation may be responsible for synaptic abnormalities and memory impairments in Tsc2+/- mice, and its inhibition by lonafarnib could provide insight into potential treatment options for TSC-associated neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Objective: Tuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI). Methods: A total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers. Results: The TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC. Conclusion: The disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage. [ABSTRACT FROM AUTHOR]

Von Hippel-Lindau disease and tuberous sclerosis are rare genetic disorders, which belong to the group of phacomatoses. They involve an increased risk of development of multiple cancers, mostly benign ones, which may undergo malignant transformation. Genetic diagnostic including identification of the pathogenic variant of the VHL and TSC1 and TSC2 genes enables optimisation of patient care and identification of relatives who carry the mutation. [ABSTRACT FROM AUTHOR]

Transpired solar collectors (TSC) are one of the most popular solar thermal technologies for building façades. TSC use solar energy to heat the absorber surface, which transmits thermal energy to the ambient air. A variant of TSC, namely, a double skin transpired solar collector (DSTSC), has been analyzed in this paper, thus providing guide values and a technical point of view for engineers, architects, and constructors when designing such transpired solar collectors. Three important parameters were addressed in this study through numerical simulation: the influence of a separation plate introduced in a TSC, turning it into a DSTSC; the air layer thickness influence on the performance of the collector; and the influence of the used absorber materials for the separation plate material. Greater heat exchange efficiency was noticed for the DSTSC at every imposed airflow rate compared with the TSC. Regarding the thickness of the collector, the efficiency gradually increased when increasing the solar collector thickness until it reached a value of 20 cm, though not varying significantly at a thickness of 30 cm. [ABSTRACT FROM AUTHOR]

ObjectiveTuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI).MethodsA total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers.ResultsThe TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC.ConclusionThe disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

The ability of cells to sense diverse environmental signals, including nutrient availability and conditions of stress, is critical for both prokaryotes and eukaryotes to mount an appropriate physiological response. While there is a great deal known about the different biochemical pathways that can detect and relay information from the environment, how these signals are integrated to control progression through the cell cycle is still an expanding area of research. Over the past three decades the proteins Tuberin, Hamartin and TBC1D7 have emerged as a large protein complex called the Tuberous Sclerosis Complex. This complex can integrate a wide variety of environmental signals to control a host of cell biology events including protein synthesis, cell cycle, protein transport, cell adhesion, autophagy, and cell growth. Worldwide efforts have revealed many molecular pathways which alter Tuberin post-translationally to convey messages to these important pathways, with most of the focus being on the regulation over protein synthesis. Herein we review the literature supporting that the Tuberous Sclerosis Complex plays a critical role in integrating environmental signals with the core cell cycle machinery.

Aim: We aimed to describe the experience of a large single-center cohort for the clinical, radiological, and genetic characteristics, as well as to determine the efficacy of different anti-epileptic strategies in children and adults with tuberous sclerosis complex (TSC). Methods: We carried out a historical cohort study on 91 TSC patients treated in a single center between 2008 and 2018. Results: Our cohort comprised 46 males and 45 females, with a median age of 15.6 years at the last follow-up. Mean follow-up time was 2.5 ± 0.75–5.5 years (range 0–9.5 years). Of those tested, a disease-causing mutation was identified in 90% of patients, 53% in TSC2, and 37% in TSC1. Epilepsy prevalence was similar among TSC1 and TSC2 mutated patients. The most common radiological finding were cortical tubers in 95% of patients, while subependymal giant cell astrocytoma (SEGA) were detected in 36% of patients. Notably, infantile spasms (IS) were diagnosed in 29%, with SEGA representing the only finding significantly different in prevalence between those with and without IS (62% vs. 28%, respectively, p = 0.009). Lastly, we did not find any difference in efficacy between three anti-epileptic treatments: Vagus nerve stimulation (VNS), CBD-based products, and the ketogenic diet, all showing approximately 30%–40% response rates. Significance: Altogether, we provide a comprehensive description of our experience in treating TSC, which could serve to expand current knowledge of the disease and its treatments. [ABSTRACT FROM AUTHOR]

The current pandemic forced us to introspect and revisit our armamentarium of medicinal agents which could be life‐saving in emergency situations. Oxygen diffusion‐enhancing compounds represent one such class of potential therapeutic agents, particularly in ischemic conditions. As rewarding as the name suggests, these agents, represented by the most advanced and first‐in‐class molecule, trans‐sodium crocetinate (TSC), are the subject of intense clinical investigation, including Phase 1b/2b clinical trials for COVID‐19. Being a successor of a natural product, crocetin, TSC is being investigated for various cancers as a radiosensitizer owing to its oxygen diffusion enhancement capability. The unique properties of TSC make it a promising therapeutic agent for various ailments such as hemorrhagic shock, stroke, heart attack, among others. The present review outlines various (bio)synthetic strategies, pharmacological aspects, clinical overview and potential therapeutic benefits of crocetin and related compounds including TSC. The recent literature focusing on the delivery aspects of these compounds is covered as well to paint the complete picture to the curious reader. Given the potential TSC holds as a first‐in‐class agent, small‐ and/or macromolecular therapeutics based on the core concept of improved oxygen diffusion from blood to the surrounding tissues where it is needed the most, will be developed in future and satisfy the unmet medical need for many diseases and disorders. [ABSTRACT FROM AUTHOR]

This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers. Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4–18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation. The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers. Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers. DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045. • Multicenter study in 184 children with TSC as well as their caregivers • Children with TSC have significantly lower HRQOL than the normal population • Adolescence, drug-related adverse events and the severity of TSC manifestation impact HRQOL • Caregivers have lower QOL and more depressive symptoms than the normal population • TSC2 variants were predictive of lower QOL and increased depressive symptoms in caregivers [ABSTRACT FROM AUTHOR]

Objective To explore the characteristic of gene mutation and surgical treatment of refractory epilepsy patients related to m TOR pathway. Methods The clinical data of 3 patients with refractory genetic epilepsy with DEPDC5、RELN、TSC mutations were analyzed retrospectively. The method and effect of the surgical operation were analyzed combined with the literature reviewe. Results The three patients were seizure free after surgery. It was found that DEPDC5, RELN and TSC mutations were related to m TOR pathway and may cause cortical dysplasia through disturbing neuronal migration. Conclusion The m TOR pathway related refractory patients indicates surgical treatment. Studying genetic variations in patients with refractory epilepsy could help guide the selection of surgical candidates. [ABSTRACT FROM AUTHOR]

Aims: Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA‐34a (miR‐34a) among the most upregulated miRs in tubers. Here, we characterised miR‐34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR‐34a. Methods: We analysed the expression of miR‐34a in resected cortical tubers (n = 37) compared with autopsy‐derived control tissue (n = 27). The effect of miR‐34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH‐SY5Y cells following miR‐34a transfection. Results: The peak of miR‐34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR‐34a was also strongly expressed in foetal TSC cortex. Overexpression of miR‐34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR‐34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. Conclusions: MicroRNA‐34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR‐34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC. [ABSTRACT FROM AUTHOR]

Objective: To describe the first large population (n = 297) with tuberous sclerosis complex (TSC) in China and to examine the relationship between variants (type and location) and epilepsy.Methods: All exons and intron-exon boundaries of TSC1/TSC2 were sequenced with next-generation sequencing, and the distribution of several variants and associations between variant types and epilepsy were investigated.Results: Epilepsy occurred in 83.5% (248/297) of the individuals. The TSC1/TSC2 gene variant detection rate was 89.6% (266/297). The rate of epilepsy was significantly higher in the TSC2 group than in the TSC1 (p = 0.02) and no mutation identified (NMI) groups (p = 0.0005). TSC2 individuals are more likely to have spasms than TSC1 individuals (p =0.03). The age at epilepsy onset of individuals in the TSC2 group was younger than that of individuals in the TSC1 group (p = 0.008) and NMI group (p = 0.01). The age at epilepsy onset with truncated variants in the TSC1 group was significantly younger than that of individuals with nontruncated variants (p = 0.0001). The rate of epilepsy was significantly higher if variants occurred in the functional domain than in the nonfunctional domain in TSC2 individuals (p = 0.02).Conclusion: This was the first large cohort study of the Chinese TSC population in which a comparative analysis of genotype and epilepsy was conducted. Individuals with TSC2 variants appeared to have more severe epileptic phenotypes, such as younger age at epilepsy onset, than those with TSC1 variants and NMI, and individuals with variants that occurred in TSC2 functional domains were more prone to epilepsy and had a younger age at epilepsy onset. [ABSTRACT FROM AUTHOR]

Abstract Background Tuberous Sclerosis Complex (TSC) and Neurofibromatosis type 1 (NF1) are neurocutaneous disorders commonly characterized by neuropsychiatric comorbidities. The TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist is currently used to quickly screen for behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations in patients with TSC. We administered the authorized Italian version of the TAND Checklist to the parents of 42 TSC patients and 42 age- and sex-matched NF1 patients, for a total of 84 individuals, aged 4–20 years. Aims of this study: - to test the overall usability of the TAND Checklist in NF1, −to compare the results between children and adolescents with TSC and NF1, and -to examine the association between neuropsychiatric manifestations and severity of the phenotype in terms of epilepsy severity in the TSC cohort and disease severity according to the modified version of the Riccardi severity scale in the NF1 cohort. Results TSC cohort: 35.6% had Intellectual Disability (ID), 11.9% Specific Learning Disorders (SLD), 50.0% Attention Deficit Hyperactivity Disorder (ADHD) and 16.6% anxious/mood disorder. 33.3% had a formal diagnosis of Autism Spectrum Disorder (ASD). Paying attention and concentrating (61.9%), impulsivity (54.8%), temper tantrums (54.8%), anxiety (45.2%), overactivity/hyperactivity (40.5%), aggressive outburst (40.5%), absent or delayed onset of language (40.5%), repetitive behaviors (35.7%), academic difficulties (> 40%), deficits in attention (61.9%) and executive skills (50.0%) were the most commonly reported problems. NF1 cohort: 9.5% had ID, 21.4% SLD, 46.6% ADHD, and 33.3% anxious/mood disorder. No one had a diagnosis of ASD. Commonly reported issues were paying attention and concentrating (59.5%), impulsivity (52.4%), anxiety (50.0%), overactivity/hyperactivity (38.1%), temper tantrums (38.1%), academic difficulties (> 40%), deficits in attention (59.5%), and executive skills (38.1%). Neuropsychiatric features in TSC vs NF1: Aggressive outburst and ASD features were reported significantly more frequently in TSC than in NF1. Neuropsychiatric manifestations and phenotype severity: Depressed mood, absent or delayed onset of language, repetitive language, difficulties in relationship with peers, repetitive behaviors, spelling, mathematics, dual-tasking, visuo-spatial tasks, executive skills, and getting disoriented were significantly different among TSC patients with different epilepsy severity. No statistically significant differences in the NF1 subgroups were noted for any of the items in the checklist. Conclusion The TAND Checklist used for TSC is acceptable and feasible to complete in a clinical setting, and is able to detect the complexity of neuropsychiatric involvement in NF1 as well. NF1 is mainly characterized by an ADHD profile, anxiety problems and SLD, while ASD features are strongly associated with TSC. In conclusion, the TAND Checklist is a useful and feasible screening tool, in both TSC and NF1.

Therapies with the mechanistic target of rapamycin complex 1 (mTORC1) inhibitors are not fully curative for tuberous sclerosis complex (TSC) patients. Here, we propose that some mTORC1-independent disease facets of TSC involve signaling through redox factor-1 (Ref-1). Ref-1 possesses a redox signaling activity that stimulates the transcriptional activity of STAT3, NF-kB, and HIF-1α, which are involved in inflammation, proliferation, angiogenesis, and hypoxia, respectively. Here, we demonstrate that redox signaling through Ref-1 contributes to metabolic transformation and tumor growth in TSC cell model systems. In TSC2-deficient cells, the clinically viable Ref-1 inhibitor APX3330 was effective at blocking the hyperactivity of STAT3, NF-kB, and HIF-1α. While Ref-1 inhibitors do not inhibit mTORC1, they potently block cell invasion and vasculature mimicry. Of interest, we show that cell invasion and vasculature mimicry linked to Ref-1 redox signaling are not blocked by mTORC1 inhibitors. Metabolic profiling revealed that Ref-1 inhibitors alter metabolites associated with the glutathione antioxidant pathway as well as metabolites that are heavily dysregulated in TSC2-deficient cells involved in redox homeostasis. Therefore, this work presents Ref-1 and associated redox-regulated transcription factors such as STAT3, NF-kB, and HIF-1α as potential therapeutic targets to treat TSC, where targeting these components would likely have additional benefits compared to using mTORC1 inhibitors alone.

Tuberous sclerosis complex (TSC) is a multisystem developmental disorder characterized by hamartomas in various organs, such as the brain, lungs, and kidneys. Epilepsy, along with autism and intellectual disability, is one of the neurologic impairments associated with TSC that has an intimate relationship with developmental outcomes and quality of life. Sustained activation of the mammalian target of rapamycin (mTOR) via TSC1 or TSC2 mutations is known to be involved in the onset of epilepsy in TSC. However, the mechanism by which mTOR causes seizures remains unknown. In this study, we showed that, human induced pluripotent stem cell-derived TSC2-deficient (TSC2-/-) neurons exhibited elevated neuronal activity with highly synchronized Ca2+ spikes. Notably, TSC2-/- neurons presented enhanced Ca2+ influx via L-type Ca2+ channels (LTCCs), which contributed to the abnormal neurite extension and sustained activation of cAMP response element binding protein (CREB), a critical mediator of synaptic plasticity. Expression of Cav1.3, a subtype of LTCCs, was increased in TSC2-/- neurons, but long-term rapamycin treatment suppressed this increase and reversed the altered neuronal activity and neurite extensions. Thus, we identified Cav1.3 LTCC as a critical downstream component of TSC-mTOR signaling that would trigger enhanced neuronal network activity of TSC2-/- neurons. We suggest that LTCCs could be potential novel targets for the treatment of epilepsy in TSC. [ABSTRACT FROM AUTHOR]

Uncontrolled cell proliferation associated with cancer depends on the functional abrogation of at least one of tumor suppressor. In response to nutrient cue, tuberous sclerosis complex (TSC) works as a tumor suppressor which inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). However, the regulation mechanism of nutrient-dependent cell proliferation in TSC-null cells remains unclear. Here, we demonstrate that leucine is required for cell proliferation through the activation of leucyl-tRNA synthetase (LARS1)-mTORC1 pathway in TSC-null cells. Cell proliferation and survival were attenuated by LARS1 knock-down or inhibitors in TSC-null cells. In addition, either rapamycin or LARS1 inhibitors significantly decreased colony formation ability while their combined treatment drastically attenuated it. Taken together, we suggest that LARS1 inhibitors might considered as novel tools for the regression of tumor growth and proliferation in TSC-null tumor cells which regrow upon discontinuation of the mTORC1 inhibition. • Leucine supplement in TSC-null cells is required for cell viability and proliferation. • Inhibition of LARS1 attenuates the proliferation of WT, TSC1 (−/−), or TSC2 (−/−) MEF cells. • LARS1-dependent mTORC1 activity controls anchorage-independent growth. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is the most common neurological manifestation in individuals with tuberous sclerosis complex (TSC). However, real-world evidence on diagnosis and treatment patterns is limited. Here, we present data from TuberOus Sclerosis registry to increase disease Awareness (TOSCA) on changes in patterns of epilepsy diagnosis, treatments, and outcomes over time, and detailed epilepsy characteristics from the epilepsy substudy. Methods: TuberOus Sclerosis registry to increase disease Awareness (TOSCA) was a multicentre, international disease registry, consisting of a main study that collected data on overall diagnostic characteristics and associated clinical features, and six substudies focusing on specific TSC manifestations. The epilepsy substudy investigated detailed epilepsy characteristics and their correlation to genotype and intelligence quotient (IQ). Results: Epilepsy was reported in 85% of participants, more commonly in younger individuals (67.8% in 1970s to 91.8% in last decade), while rate of treatments was similar across ages (>93% for both infantile spasms and focal seizures, except prior to 1960). Vigabatrin (VGB) was the most commonly used antiepileptic drugs (AEDs). Individuals with infantile spasms showed a higher treatment response over time with lower usage of steroids. Individuals with focal seizures reported similar rates of drug resistance (32.5–43.3%). Use of vagus nerve stimulation (VNS), ketogenic diet, and surgery remained low. Discussion: The epilepsy substudy included 162 individuals from nine countries. At epilepsy onset, most individuals with infantile spasms (73.2%) and focal seizures (74.5%) received monotherapies. Vigabatrin was first-line treatment in 45% of individuals with infantile spasms. Changes in initial AEDs were commonly reported due to inadequate efficacy. TSC1 mutations were associated with less severe epilepsy phenotypes and more individuals with normal IQ. In individuals with TSC diagnosis before seizure onset, electroencephalogram (EEG) was performed prior to seizures in only 12.5 and 25% of subsequent infantile spasms and focal seizures, respectively. Conclusions: Our study confirms the high prevalence of epilepsy in TSC individuals and less severe phenotypes with TSC1 mutations. Vigabatrin improved the outcome of infantile spasms and should be used as first-line treatment. There is, however, still a need for improving therapies in focal seizures. Electroencephalogram follow-up prior to seizure-onset should be promoted for all infants with TSC in order to facilitate preventive or early treatment. [ABSTRACT FROM AUTHOR]

Background: Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients.Methods: TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2).Results: Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%).Conclusion: Rare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common. [ABSTRACT FROM AUTHOR]