The Laboratory Diagnosis Of Tuberous Sclerosisatss
Presented at the 2007 ATSS Conference: Advances in Tuberous Sclerosis: From Pathway to Therapy. Michael Buckley presented outcomes from the SEALS laboratoty and described the basic processes being used at the lab.
Intra Cranial Stem Cell Transplant For Npc.Ppt 2Duriya Lakdawala
Finding a treatment for Niemann Pick Type C will provide hope not only to Aaditya Ravi Dasgupta and Tasneem Tankiwala in India but to many others like Addi and Cassi Hempel, Gabrielle Laverde and Peyton and Kayla Hadley in US, Husein Taher in Tanzania, South Africa, Roy Green in UK and so many more kids, teens and adults all over the world and in India that have not been diagnosed yet due to the cost and complexity of the diagnostic process. You can leave a wish for Aaditya (http://addiandcassi.com/guestbook) or for more information go to: www.HopeforAaditya.org
The Laboratory Diagnosis Of Tuberous Sclerosisatss
Presented at the 2007 ATSS Conference: Advances in Tuberous Sclerosis: From Pathway to Therapy. Michael Buckley presented outcomes from the SEALS laboratoty and described the basic processes being used at the lab.
Intra Cranial Stem Cell Transplant For Npc.Ppt 2Duriya Lakdawala
Finding a treatment for Niemann Pick Type C will provide hope not only to Aaditya Ravi Dasgupta and Tasneem Tankiwala in India but to many others like Addi and Cassi Hempel, Gabrielle Laverde and Peyton and Kayla Hadley in US, Husein Taher in Tanzania, South Africa, Roy Green in UK and so many more kids, teens and adults all over the world and in India that have not been diagnosed yet due to the cost and complexity of the diagnostic process. You can leave a wish for Aaditya (http://addiandcassi.com/guestbook) or for more information go to: www.HopeforAaditya.org
Présentation de Michel Pucéat réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
Mitochondrial diseases are characterized by a high clinical and genetic heterogeneity and a growing number of genes of mitochondrial disease has been identified. Mitochondrial diseases follow any mode of inheritance, due to the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). 1 000 to 1 500 nuclear genes encode mitochondrial proteins. Approximately 250 of these genes have been reported as disease causing. These genes not only encode the various subunits of each respiratory chain complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA maintenance. Some of these genes are associated with well defined syndromes but more and more are specific to one patient or family only, hampering to establish genotype-phenotype correlations. The clinical heterogeneity of these disorders makes the diagnosis difficult especially in the first years of the clinical course and other genetic diseases can present an overlapping phenotype. Therefore only the identification of the disease causing mutation allows to certainly establish the diagnosis of mitochondrial disease.
Dr. Rötig (PhD) is the head of the group working on mitochondrial diseases in Necker Hospital (Paris). This group has initially settled and integrated platform of clinic, biochemistry and molecular analysis to investigate patients with OXPHOS disease. The scientific field of this group is the identification of genes involved in mitochondrial disorders and the investigation of their pathophysiology. They have described the first non-neuromuscular presentation of mitochondrial diseases and characterized the very first mutations in nuclear genes resulting in defects of Krebs’s cycle or the respiratory chain.
Présentation de Michel Pucéat réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
Mitochondrial diseases are characterized by a high clinical and genetic heterogeneity and a growing number of genes of mitochondrial disease has been identified. Mitochondrial diseases follow any mode of inheritance, due to the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). 1 000 to 1 500 nuclear genes encode mitochondrial proteins. Approximately 250 of these genes have been reported as disease causing. These genes not only encode the various subunits of each respiratory chain complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA maintenance. Some of these genes are associated with well defined syndromes but more and more are specific to one patient or family only, hampering to establish genotype-phenotype correlations. The clinical heterogeneity of these disorders makes the diagnosis difficult especially in the first years of the clinical course and other genetic diseases can present an overlapping phenotype. Therefore only the identification of the disease causing mutation allows to certainly establish the diagnosis of mitochondrial disease.
Dr. Rötig (PhD) is the head of the group working on mitochondrial diseases in Necker Hospital (Paris). This group has initially settled and integrated platform of clinic, biochemistry and molecular analysis to investigate patients with OXPHOS disease. The scientific field of this group is the identification of genes involved in mitochondrial disorders and the investigation of their pathophysiology. They have described the first non-neuromuscular presentation of mitochondrial diseases and characterized the very first mutations in nuclear genes resulting in defects of Krebs’s cycle or the respiratory chain.
Hippocampus & Recognition Memory by Raghav MattayRaghav Mattay
UPenn study rejects hypothesis that the hippocampus exclusively supports the recollection component of recognition memory and, instead, indicates that this structure is functionally relevant to both processes thought to support recognition.
Tuberous sclerosis dr. amit vatkar, pediatric neurologistDr Amit Vatkar
Tuberous Sclerosis is a genetically inherited neurocutaneous syndrome can affect families in an autosomal dominant.
in this presentaion i will try and give u a review to the case and its management.
it will help u get a n outllook to diagnose a case of tuberous sclerosis
i have shown some images of the lesions present in the case to get a photographic memory.
Dr Chris Kingswood, UK, presented at the 2007 ATSS Conference - Advances in Tuberous Sclerosis: From Pathway to Therapy.
Reviews key clinical manifestations of TSC and recommended treatment and management guidelines.
Provides detailed information and images on kidney involvement in Tuberous Sclerosis.
TSC is neurocutaneous hereditary disorder either AD or sporadic characterized by multiple hamartomatous growths affecting skin, brain, heart, lung & kidney
Open Source Pharma /Genomics and clinical practice / Prof Hosur opensourcepharmafound
Access to Research
Date 11-08-2018
Venue Conference HAll NIAS IISc campus
Conference and workshops for clinical practitioners to introduce them to modern tools and an alternative approach to modern scientific research.
Purpose
1. Build a network of physicians across the country
2 Train physicians to analyse clinical data and restructure it to make it compatible with research standards
3. Introduce modern tools to understand the mechanism of actions of medicine
4. Introduce artificial intelligence and machine learning to clinical practitioners to support decision-making processes
Access to Science
Clinical experience and traditional knowledge are important sources of data that affect decision making processes in modern healthcare systems. This data should be made accessible for scientific evaluation and validation to improve healthcare worldwide. The Open Source Pharma Foundation believes that clinical practitioners from various disciplines should have the right to access research so that they can help identify problems, contribute their scientific knowledge, and support the discovery ecosystem.
Background
The majority of medical practitioners working on the ground level with patients do not take part in open clinical research worldwide. However, the data collected and owned by them plays an important role in establishing better discovery pathways. Through this workshop, we seek to open opportunities to enhance health care systems around the world and to overcome the following challenges faced by medical practitioners.
1. Regulatory limitations
2. Academic limitations
3. Time constraints
4. Lack of access to modern tools
5. Lack of access to research facilities
My Prostate Cancer Story by Paul SchellhammerTony Crispino
With permission of Dr. Schellhammer this slide deck should be interesting to any PCa patient. Dr. Schellhammer is a former president of the American Urological Association and a leading authority on prostate cancer. He has fought i long battle. He and his colleague, Paul Lange operated on each other and had vastly different results.
Mackenzie Cottrell, PharmD
Assistant Professor
Co-Director of the UNC CFAR Clinical Pharmacology and Analytical Chemistry Core
Division of Pharmacotherapy and Experimental Therapeutics
University of North Carolina at Chapel Hill
Mmc1 2 The Lancet - Supplementary appendix 10/15/2014John Redaelli
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem
cell-derived retinal pigment epithelium in patients with age-related macular degeneration
and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet
2014; published online Oct 15. http://dx.doi.org/10.1016/S0140-6736(14)61376-3.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus–associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC.
Sipuleucel_T Immunotherapy for Metastatic Prostate Cancer after Failing Hormo...mjavan2001
This PowerPoint presentation demonstrates findings on a clinical trial of sipuleucel-T in HRPC patients to evaluate overall survival in this group. The FDA approval of Provenge was based on the results of IMPACT study.
Dietary Administration of Diquat for 13 Weeks Does Not Result in a Loss of Do...EPL, Inc.
Dietary Administration of Diquat for 13 Weeks Does Not Result in a Loss of Dopaminergic Neurons in the Substantia Nigra Pars Compacta (SNpc) of C57BL/6J Mice
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
14. mTOR Pathway RTK PIP2 PIP3 AMP Energy Stress Serum Nutrient Hypoxia Actin Organization mTORC1 mTORC2 Translation off 40S Scanning Akt/PKB Translation On Secondary Structure Unwinding VEGF Pathway Akt Signaling PMA PC PA DAG AUG AUG C Rictor 4EBP G β L TSC2 Raptor AMPK DGK ξ PI3K Redd1 eIF4B eIF3 PKC p70S6K mTOR eIF4G eIF4A eIF4E Rheb eIF3 eIF4B eIF4G eIF4A eIF4E eIF4B G β L mTOR eIF4E 4EBP VEGF eIF4G eIF4A eIF4E Growth Factors Insulin Receptor P PDK-1 40S RPS6 TSC1 PP2A FKBP12 Rho HIF1 α PKC Rac PLD PKC α LKB1 Akt Ras RSK MAPK IRS1 Insulin 2009 ProteinLounge.com
15.
16.
17. Distribution of IQ in TSC 20 100 Global Intellectual Ability (‘IQ’) in TSC Normal Distribution (ND) TSC phenotype Profound (P) TSC phenotype 70 Normal distribution in the general population Prather & de Vries, JCN 2004, de Vries & Prather, NEJM, 2007
18.
19.
20. Axial T1 +C Axial T1 +C MRI after treatment MRI prior to treatment
21. Rapamycin Afinitor ® O O O H O O O N O O O O O H O H O O O O H O O O N O O O O O O H O O H Chemical Structure Rapamycin and Everolimus (Afinitor ® )
22.
23.
24.
25.
26.
27.
28.
29.
30. Cellular Abnormalities in Human TSC Vimentin /DAPI Vimentin /DAPI Veronique Ruppe Pelin Dilsiz TUBER PERI-TUBER
31. Altered mTORC1 signaling in human cortical tubers Veronique Ruppe Pelin Dilsiz SMI 311 /pS6 /DAPI Vimentin /pS6 /DAPI
32. Altered mTORC1 signaling in human peri-tuberal cortex Veronique Ruppe Pelin Dilsiz SMI 311 /pS6 /DAPI Vimentin /pS6 /DAPI
33.
34. Seizures Natural history of epilepsy in TSC mouse model P7 P14 1 month 3 months P21 Brain collection Epidural electrode implantation Long term video EEG monitoring Video EEG monitoring at intervals Repeated subcutaneous electrode placements Brain collection Brain collection Brain collection
35. Seizures Early treatment P7 P14 1 month 3 months P21 Epidural electrode implantation Long term video EEG monitoring Brain collection Brain collection Brain collection Daily anti-inflammatory drug treatment
36. Seizures Late treatments of epilepsy P14 1 month 2 months P21 Epidural electrode implantation Long term video EEG monitoring Brain collection Brain collection 2. Anti-inflammatory drug 1.5 month 1. Conventional AED 3. Combination treatment
Orrin Devinsky, MD Tuberous Sclerosis: Update in Diagnosis and Treatment
Review: mTOR (Mammalian Target of Rapamycin) is a 289-kDa serine/threonine protein kinase and a member of the PIKK (Phosphatidylinositol 3-Kinase-related Kinase) family. The protein consists of a Catalytic Kinase domain, an FRB (FKBP12–Rapamycin Binding) domain, a putative Auto-inhibitory domain (Repressor domain) near the C-terminus and up to 20 tandemly repeated HEAT motifs at the Amino terminus, as well as FAT (FRAP-ATM-TRRAP) and FATC (FAT C-terminus) domains. The C-terminus of TOR is highly homologous to the catalytic domain of PI3K (Phosphatidylinositol 3-Kinase). TOR proteins are evolutionarily conserved from yeast to human in the C-domain, with human, mouse, and rat mTOR proteins sharing 95% identity at the amino acid level. The human mTOR gene encodes a protein of 2549 amino acids with 42% and 45% sequence identity to yeast TOR1 and TOR2, respectively. mTOR functions as a central element in a signaling pathway involved in the control of cell growth and proliferation (Ref.1). The mTOR pathway is regulated by a wide variety of cellular signals, including Mitogenic Growth Factors, Hormones such as Insulin, Nutrients (Amino acids, Glucose), Cellular Energy Levels, and Stress conditions. A principal pathway that signals through mTOR is the PI3K/Akt (v-Akt Murine Thymoma Viral Oncogene Homolog-1) signal transduction pathway, which is critically involved in the mediation of cell survival and proliferation. Signaling through the PI3K/Akt pathway is initiated by mitogenic stimuli from Growth factors that bind receptors in the cell membrane. These receptors include IGFR (Insulin-like Growth Factor Receptor), PDGFR (Platelet-Derived Growth Factor Receptor), EGFR (Epidermal Growth Factor Receptor), and the Her family. The signal from the activated receptors is transferred directly to the PI3K/Akt pathway, or, alternatively, it can be activated through activated Growth Factor Receptors that signal through oncogenic Ras. Ras is another central switch for signal transduction and has been shown to be a pivotal activator of the MAPK (Mitogen-Activated Protein Kinase) signal transduction pathway. PI3K/Akt pathway can also be activated by Insulin via IRS1/2 (Insulin Receptor Substrate-1/2). Insulin binding activates the IR (Insulin Receptor) tyrosine kinase, which phosphorylates IRS1 or IRS2. PI3K binds phosphorylated IRS by SH2 (Src-Homology-2) domains in the p85 regulatory subunit. This interaction activates the p110 catalytic subunit. PI3K then catalyzes the conversion of membrane-bound PIP2 (Phosphatidylinositol (4,5)-bisphosphate) to PIP3 (Phosphatidylinositol (3,4,5)-triphosphate). PIP3 then binds the pleckstrin homology domain of Akt, which results in Akt activation through dimerization and exposure of its catalytic site. Akt can also be phosphorylated and activated by PDK-1 (Phospholipid-Dependent Kinase-1). Akt phosphorylates mTOR directly. Akt may also work indirectly on mTOR through the actions of the TSC1/TSC2 (Tuberous Sclerosis Complex). The physical association of the proteins TSC1 (Hamartin) and TSC2 (Tuberin) produces a functional complex that inhibits mTOR. Recent evidence indicates that the inhibitory effect of TSC1/TSC2 is mediated through TSC2 inactivation of a Ras family small GTPase known as RHEB (Ras Homolog Enriched in Brain). TSC2 has GAP (GTPase-Activating Protein) activity toward RHEB, and it has been postulated that the TSC1/TSC2 complex inhibits mTOR signaling by stimulating GTP hydrolysis of RHEB. RHEB-GTP activates mTOR. PMA (Phorbol Myristate Acetate) can also lead to mTOR phosphorylation independently of Akt through inhibition of the TSC1/2 complex via PKC (Protein Kinase-C) and RSK1 (Ribosomal-S6 Kinase-1) as well as through activation of S6K1 by PKC. AMPK (AMP (Adenosine 5'-Monophosphate)-Activated Protein Kinase) can also modulate mTOR. AMPK functions as the key energy-sensing kinase by virtue of its exquisite sensitivity to increases in the cellular AMP (Adenosine 5'-Monophosphate) /ATP (Adenosine Triphosphate) ratio. Increases in this ratio promote AMPK phosphorylation and activation by the upstream kinase LKB1, a human tumor suppressor mutated in Peutz-Jeghers syndrome. Activated AMPK in turn phosphorylates TSC2 (on residues distinct from those phosphorylated by Akt), apparently promoting its activation. This in turn inhibits the action of mTOR activity (Ref.2, 3 & 5). PA (Phosphatidic Acid) can also activate mTOR. Three different enzymes generate PA: PLD (Phospholipase-D), LPAAT (Lysophosphatidic Acid Acyltransferase), and DGK (Diacylglycerol Kinase). PLD is regarded as the main contributor of PA to mTOR signaling. Nonetheless, other PA-generating enzymes can also contribute to mTOR activation; LPAAT is reported to be elevated in some tumors, and its overexpression leads to cell transformation. Serum stimulation leads to PLD activation, which correlates with increased mTOR signaling. Serum, a mixture of mitogenic agents, acts through GPCRs (G-Protein Coupled Receptors) or RTKs (Receptor Tyrosine Kinase). PLD activity increases in response to stimulation of both receptor types. Lipids such as DAG (Diacylglycerol) and PA are generated in membrane domains, where an intimate connection between distinct lipid metabolic pathways is maintained, to produce appropriate spatio-temporal responses. PLD and DGK may operate in parallel pathways, but they may also act as DAG- and PA-generating enzymes in a single pathway. In mammalian cells, the PA generated at internal membranes, such as Golgi, is produced mainly by PLD action on PC (Phosphatidylcholine). This PA can serve either as a messenger, promoting vesicle fission, or as a substrate for Phosphatases that transform PA to DAG. Because PC is the most abundant lipid in mammalian membranes, this pathway serves as a robust supplier of DAG that could then be used as a DGK substrate (Ref.4 & 5). Thus, several mechanisms have been proposed to explain how mTOR is regulated by growth factors and cellular energy levels. However, little is known as to how mTOR is regulated by stress conditions. Two stress-induced proteins, RTP801/Redd1 and RTP801L/Redd2, potently inhibit signaling through mTOR. RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions. Another inhibitor of mTOR is Rapamycin. When complexed with its cellular receptor, FKBP12 (FK506 Binding Protein-12), Rapamycin binds directly to TOR to inhibit downstream signaling (Ref. 6 & 7). Activation of mTOR results in phosphorylation of several downstream targets. For the protein mTOR to activate its signaling cascade, it must form the Ternary complex mTORC1 (mTOR Complex-1) and mTORC2 (mTOR Complex-2). Rapamycin-sensitive mTORC1 controls several pathways that collectively determine the mass (size) of the cell. Rapamycin-insensitive mTORC2 controls the actin cytoskeleton and thereby determines the shape of the cell. mTORC1 (and likely mTORC2) are multimeric, although are drawn as monomers. mTORC1 is a ternary complex containing mTOR, RAPTOR (Regulatory Associated Protein of mTOR) and G-BetaL (G-protein Beta-subunit-like protein). On the other hand mTORC2 complex consist of mTOR, G-BetaL and Rictor. The best-characterized effectors downstream of mTOR are 2 signaling pathways that act in parallel to control mRNA translation. Activated mTOR mediates the phosphorylation of the eIF4EBP1 (Eukaryotic Translation Initiation Factor-4E-Binding Protein-1) and the ribosomal protein p70S6K or S6K1 (S6 Kinase). 4EBP1 (also known as PHAS1 (Phosphorylated Heat-stable and Acid-Stable protein)) is a low molecular weight protein that can repress the activity of the eIF4F (eukaryotic Initiation Factor-4) complex. In its unphosphorylated state, 4EBP1/PHAS1 binds tightly to eIF4E (Eukaryotic Translation Initiation Factor-4E), the mRNA cap binding subunit of the eIF4F complex, which inhibits the activity of eIF4E in the initiation of protein synthesis. Phosphorylation of 4EBP1 by mTOR reduces its affinity for eIF4E, and the 2 proteins dissociate. eIF4E is then able to associate with the other components of eIF4F, which include the large scaffolding protein, eIF4G (Eukaryotic Translation Initiation Factor-4-Gamma), the adenosine triphosphate dependent RNA helicase eIF4A (Eukaryotic Translation Initiation Factor-4A), and eIF4B (Eukaryotic Translation Initiation Factor-4B), to form an active complex. This complex facilitates cap-dependent protein translation. The net effect is an increase in the translation of the subset of mRNAs with 5´ UTRs (Untranslated Regions), which often encode proteins associated with the proliferative response and the transition from G1 to S phase in the cell cycle. Such mRNAs include those that code for c-Myc, CcnD1 (Cyclin-D1), and Ornithine Decarboxylase. Cyclin-D1 binds with CDK4 (Cyclin-Dependent Kinase-4) to form a complex required for the phosphorylation of Rb (Retinoblastoma) protein, which subsequently contributes to progression of the cell cycle and DNA replication. Growth factor deprivation or inhibition of mTOR results in the dephosphorylation of 4EBP1, followed by its reassociation with eIF4E and a subsequent reduction in cap-specific translation. mTOR may also indirectly influence the phosphorylation state of 4EBP1 by modulating the activity of PP2A (Protein Phosphatase-2A). The second principal effector downstream of mTOR is the S6K1 serine/threonine kinase. After receiving a proliferative upstream signal mediated by the PI3K/Akt pathway, mTOR phosphorylates and activates S6K1. In turn, S6K1 phosphorylates and activates the 40S ribosomal S6 protein, facilitating the recruitment of the 40S ribosomal subunit into actively translating polysomes. In particular, the translation of mRNAs with 5´TOP (5´-Terminal Oligopyrimidine) sequence is enhanced. These 5´TOP mRNAs code primarily for ribosomal proteins, elongation factors and IGF-II (Insulin-like Growth Factor-II). Dephosphorylation of S6K1 decreases the synthesis of components of the protein translation system and results in a profound decrease in protein synthesis. mTORC1 also regulates VEGF (Vascular Endothelial Growth Factor) by phosphorylating HIF1Alpha (Hypoxia-Inducible Factor-1-Alpha Subunit) (Ref.8, 9 & 10). In addition to its effects on translation, mTOR also modulates protein synthesis through regulation of RNA Polymerase I and III, which are responsible for the transcription of ribosomal and transfer RNAs. In the presence of appropriate Growth signals such as IGF1, mTOR, together with the PI3K and MAPK pathways, modulates Pol I-directed transcription of ribosomal RNAs. There is also evidence that mTOR may exert its effects on the polymerases through regulation of the phosphorylation status of Rb by influencing the stability and expression of Cyclin-D1 and p27, both of which regulate CDKs upstream of Rb. mTORC2 may signal to the actin cytoskeleton through a small Rho-type GTPase and PKC. Furthermore, mTORC2 controls the formation of activated, GTP-bound Rac1 in a growth-factor-dependent fashion. mTORC2 also controls the phosphorylation and activation of PKC-Alpha (Protein Kinase-C-Alpha). mTOR as a central modulator of proliferative signal transduction is an ideal therapeutic target against cancer. Through extensive clarification of many signal transduction pathways, it has become clear that the mTOR kinase participates in critical events that integrate external signals with internal signals, coordinating cellular growth and proliferation. mTOR receives signals that indicate whether transcription and translational machinery should be upregulated, then efficiently transmits these signals to the appropriate pathways. Multiple components of pathways that signal through mTOR are dysregulated in numerous cancer types. The development of inhibitors of mTOR is a rational therapeutic strategy for malignancies that are characterized by dysregulated pathways that signal through mTOR (Ref.9 & 11). References: 1. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006 Feb 10;124(3):471-84. PubMed ID: 16469695 2. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006 Feb 1;66(3):1500-8. PubMed ID: 16452206 3. Jozwiak J, Jozwiak S, Grzela T, Lazarczyk M. Positive and negative regulation of TSC2 activity and its effects on downstream effectors of the mTOR pathway. Neuromolecular Med. 2005;7(4):287-96. PubMed ID: 16391386 4. Avila-Flores A, Santos T, Rincon E, Merida I. Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. J Biol Chem. 2005 Mar 18;280(11):10091-9. PubMed ID: 15632115 5. Han S, Khuri FR, Roman J. Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. Cancer Res. 2006 Jan 1;66(1):315-23. PubMed ID: 16397245 6. Cortot A, Armand JP, Soria JC. PI3K-AKT-mTOR pathway inhibitors. Bull Cancer. 2006 Jan 1;93(1):19-26. PubMed ID: 16455502 7. Ellisen LW. Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle. 2005 Nov;4(11):1500-02. Epub 2005 Nov 1. PubMed ID: 16258273 8. Fumarola C, La Monica S, Alfieri RR, Borra E, Guidotti GG. Cell size reduction induced by inhibition of the mTOR/S6K-signaling pathway protects Jurkat cells from apoptosis. Cell Death Differ. 2005 Oct;12(10):1344-57. PubMed ID: 15905878 9. Lang CH, Frost RA. Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. J Cell Physiol. 2005 Apr;203(1):144-55. PubMed ID: 15389631 10. Fiano V, Ghimenti C, Imarisio S, Silengo L, Schiffer D. PAkt, cyclin D1 and p27/Kip.1 in glioblastomas with and without EGFR amplification and PTEN mutation. Anticancer Res. 2004 Sep-Oct;24(5A):2643-7. PubMed ID: 15517868 11. Choo AY, Blenis J. TORgeting oncogene addiction for cancer therapy. Cancer Cell. 2006 Feb;9(2):77-9. PubMed ID: 16473275 Orrin Devinsky, MD Tuberous Sclerosis: Update in Diagnosis and Treatment
Orrin Devinsky, MD Tuberous Sclerosis: Update in Diagnosis and Treatment
Orrin Devinsky, MD Tuberous Sclerosis: Update in Diagnosis and Treatment
Orrin Devinsky, MD Tuberous Sclerosis: Update in Diagnosis and Treatment