Category Archives: Stell Cell Genetics

International Myeloma Working Group, Member

American College of Physicians, Fellow

American Federation for Clinical Research, 1993-94 Eastern Section, Hematology/Oncology Session Chairman

American Society for Blood and Marrow Transplantation

American Society of Clinical Oncology, 1995-96 Member, ASCO Program Committee 1995-96 Member, Bone Marrow Transplantation, High Dose Chemotherapy and Cytokines Subcommittee 2004-present Member, Editorial Board Journal of Clinical Oncology

American Society of Hematology, 2001,2004,2008, 2010 Abstract Reviewer/Session Moderator, Clinical Bone Marrow Transplantation

Autologous Bone Marrow Transplant Registry (ABMTR/CIBMTR), 2000-2006 Member, ABMTR Advisory Board 2004-2006 Member, ABMTR Executive Committee 2004-2006 Chairman, ABMTR Nominating Committee 2006-2008 Member, CIBMTR Nominating Committee 2006-2008 Member, CIBMTR Advisory Committee 2008-Present Co-Chair, CIBMTR Solid Tumor Working Committee 2006-present Member, CIBMTR Clinical Trials Advisory Committee

Bone Marrow Transplant Clinical Trials Network, 2001-Principal Investigator, University of Pennsylvania 2001-2005 Chairman, Administration/Operations Committee 2001-2005 Member, Executive Committee 2001-Present Member, Steering Committee 2001-Present Member, Member, Publications Committee, Chair 2007-2011 2005-Present Member, BMT-CTN Myeloma Intergroup Working Committee, Chair 2012-Present 2006-Present, Chair, Publications Committee

Eastern Cooperative Oncology Group, 1990-Member, Bone Marrow Transplant Core Committee 1993-Co-chairman, Bone Marrow Transplant Committee 1991-Member, Leukemia Core Committee 1992-Member, Myeloma Core Committee 1998-Member, Lymphoma Core Committee

Foundation for the Accreditation of Hematopoietic Cell Therapy, 1999-Inspection Team, Member 1999-Team Leader, Clinical Program Inspector 2000-Stem Cell Collection Facility Inspector 2004-Member, Accrediation Committee

Membership in National Scientific Review Panels, 2002, Ad hoc Member, NIH Clinical Oncology Study Section 2005-present, Ad hoc Member, NHLBI Program Project Reviews 2006-present, Member, Leukemia and Lyumphoma Society, Clinical Development Program, Grant Review Subcommittee

NIAID Hematopoietic Stem Cell Transplantation Data Safety Monitoring Board (HSCT DSMB), 2005-present, Member

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Edward A. Stadtmauer, MD profile | PennMedicine.org

Bruce Alberts Former Editor in Chief at Science, former President of the National Academy of Sciences, USA

Tony Hyman Research Group Leader and Director, The Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)

Arne Johansson Professor in Mechanics, Vice President,the Royal Institute of Technology (KTH)

Catriona MacCallum Senior Advocacy Manager PLOS, and Consulting Editor at PLOS ONE

Tommy Ohlsson Professor in Theoretical Physics at the Royal Institute of Technology (KTH)

Brandon Stell Research Associate, CNRS, Co-Team Leader, Laboratoire de Physiologie Crbrale Universit Paris Descartes

09.30 Coffee

10.00 Welcome!

10.10 How can a nation support excellence in scientific research and teaching? Bruce Alberts

11.00 Publication assessment and university governance Arne Johansson

11.30 Encouraging innovation through peer review and evaluation Tony Hyman

12.00 Lunch

12.45 Scientific Communication on Trial Catriona MacCallum

13.15 Open Access Publishing with arXiv Tommy Ohlsson

13.45 Coffee

14.15 Introducing PubPeer Brandon Stell

14.45 Panel discussion 15.30 End

This year marks the 350th anniversary of the longest running scientific journal: The Philosophical Transactions of the Royal Society (London). Already at its inception, it had the fundamental functions usually associated with scientific publishing such as registration of submission and publication dates, peer review, and means for dissemination and archiving. Today scientific publishing is more important than ever, with the number of journals rapidly growing, and the perceived success of a scientist to an increasing degree defined by scientific publications, with particular pressure to publish in so-called high-impact journals. In parallel these trends appear to put in question the value of the traditional scientific peer review, both in the publication process where newsworthiness, impact and potential for citations may trump scientific rigor, and in evaluation for tenured positions, where bibliometric indices and impact assessment tools risk reducing a young scientists work to a number.

At the seminar we will discuss the rapidly changing scientific publishing landscape and its implications. How does the increasing number of journals and the increasing focus on journal impact change how science is carried out and how young scientist choose their topics and plan their research? What is the impact of entirely open and non-reviewed pre-publication online archives are they promising new solutions to effective dissemination and open science, or of little value to young scientists when evaluations put a premium on journal impact? Is the pre-publication peer review model faltering under the increasing volume of peer review and the shrinking time and effort available for peer review? Can post-publication peer review offer a more sustainable solution? Are universities over-relying on bibliometric tools when assessing the value of their tenured researchers and when hiring new researchers?

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Publish and perish? - Sveriges Unga Akademi

Our Board of Directors is a group of volunteers committed to the Foundations mission to find a cure for retinitis pigmentosa, macular degeneration and related diseases of the retina. The Board includes representatives from the corporate and medical worlds, as well as individuals affected by vision loss.

Andrew Burke, Chair Partner, Stewart McKelvey Halifax, Nova Scotia

JoeGrech, Vice-Chair Vancouver, British Columbia

Rahn Dodick, Treasurer President, Dodick Landau Inc. Toronto, Ontario

Malcolm Hunter, Corporate Secretary President, Fred Deeley ImportsLtd. Vancouver, British Columbia

John Breen, Executive Officer SeniorExecutive Investment Officer, Sanabil Al-Saudia Investments

Catherine Tillmann, Executive Officer Director of Brand Image, Corporate Marketing, Four Seasons Hotels and Resorts(retired) Toronto, Ontario

Donna Green, Past Chair Principal, Greenrock Investments / Chief Executive Officer, Glittering Investments Limited Toronto, Ontario

Michel Cayouette, PhD Research Unit Director, Institut de recherches cliniques de Montreal (IRCM) Research Associate Professor, University of Montreal Montreal, Quebec

David Drury General Manager, IBM Canada Ltd. Toronto, Ontario

Sherif El-Defrawy, MD, PhD, FRCSC Chief of Ophthalmology, University of Toronto Toronto, Ontario

Peter FarmerDirector, Strategic Partnerships, Rogers CommunicationsToronto, Ontario

Jane Humphreys Toronto, Ontario

Peter J. Kertes, MD, FRCSC Vitreoretinal Surgeon/Ophthalmologist-in-Chief, Sunnybrook Health Sciences Centre Professor of Ophthalmology & Vision Sciences, University of Toronto Toronto, Ontario

Gary Mandel President, CEO, Independent Financial Concepts Group Ltd. Toronto, Ontario

Michael Ovens Process Analyst, Change Management, Bank of Montreal Toronto, Ontario

Lorna L. Rosenstein General Manager, Lotus Canada(retired) Toronto, Ontario

George Sheen Partner, PwC (retired) Toronto, Ontario

Raymond M. Stein, MD, FRCSC Medical Director, Bochner Eye Institute Toronto, Ontario

David D. Sweeny Director, RBC Capital Markets Toronto, Ontario

Deborah Tennant Toronto, Ontario

The Foundation Fighting Blindness Scientific Advisory Board (SAB) is a group of highly qualified and committed volunteers. These scientists bring a wide range of expertise to the FFBs scientific decision-making in genetics, molecular genetics, molecular biology, biochemistry and cell biology. All are actively engaged in sight-saving research.

The SAB is responsible for evaluating research applications submitted to the FFBs annual grant competition(s).

SAB members also aid in promoting retinal disease research amongst the scientific community and support the quality and accuracy of our educational programs and materials. Rigorous review for scientific merit by the SAB ensures that dollars donated to the FFB are used to fund the most productive and promising research projects, addressing crucial questions about the causes and treatment of retinal degenerative diseases. Thanks to the guidance of our scientific advisory boards, past and present, scientists funded by the FFB have consistently accomplished their research goals and have been responsible for major research breakthroughs.

Dr. Rod Bremner, PhD (Interim Chair) Senior Investigator, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Professor of Ophthalmology; Laboratory Medicine & Pathobiology, University of Toronto

Dr. Seth Blackshaw, PhD Associate Professor in the Department of Neuroscience at the Johns Hopkins University School of Medicine, Baltimore

Dr. Sylvain Chemtob Sylvain Chemtob, MD, PhD Professor, Departments of Pediatrics, Ophthalmology and Pharmacology, University of Montreal

Dr. Brian Link Brian A. Link, PhD Associate Professor of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin

Dr. Orson Moritz Orson Moritz, PhD Associate Professor of Ophthalmology and Visual Science, University of British Columbia

Dr. Bill Stell Bill Stell, PhD (non-voting member) Expert Scientific Advisor for the Foundation Fighting Blindness Professor of Cell Biology and Anatomy; Ophthalmology; Neurosciences, University of Calgary

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The Foundation Fighting Blindness Leadership

Summary

The transport of calcium ions (Ca2+) to the cytosol is essential for immunoreceptor signaling, regulating lymphocyte differentiation, activation, and effector function. Increases in cytosolic-free Ca2+ concentrations are thought to be mediated through two interconnected and complementary mechanisms: the release of endoplasmic reticulum Ca2+ stores and store-operated Ca2+ entry via plasma membrane channels. However, the identity of molecular components conducting Ca2+ currents within developing and mature Tcells is unclear. Here, we have demonstrated that the L-type voltage-dependent Ca2+ channel CaV1.4 plays a cell-intrinsic role in the function, development, and survival of naive Tcells. Plasma membrane CaV1.4 was found to be essential for modulation of intracellular Ca2+ stores and Tcell receptor (TCR)-induced rises in cytosolic-free Ca2+, impacting activation of Ras-extracellular signal-regulated kinase (ERK) and nuclear factor of activated Tcells (NFAT) pathways. Collectively, these studies revealed that CaV1.4 functions in controlling naive Tcell homeostasis and antigen-driven Tcell immune responses.

CaV1.4 is required for store-operated calcium entry by naive CD4+ and CD8+ Tcells CaV1.4 regulates TCR-induced Ras-ERK and NFAT signaling CaV1.4 modulates the survival of naive CD4+ and CD8+ Tcells Cav1.4 is critical for pathogen-specific CD4+ and CD8+ Tcell responses

Calcium (Ca2+) ions act as universal second messengers in virtually all cell types, including cells of the immune system. In lymphocytes, Ca2+ signals modulate the activation of calcineurin-nuclear factor of activated Tcells (NFAT) and Ras-Mitogen-activated protein kinases (MAPK) pathways, serving to regulate cell activation, proliferation, differentiation, and apoptosis (Oh-hora, 2009andVig and Kinet, 2009). Tcell receptor (TCR) stimulation invokes rises in cytosolic Ca2+ through the activation of phospholipase C-1 (PLC1) and the associated hydrolysis of phosphatidylinositol-3,4-bisphosphate (PIP2) into inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Subsequently, IP3 binds IP3 receptors in the endoplasmic reticulum (ER) and induces Ca2+ release from ER storesthus triggering store-operated Ca2+ entry (SOCE) from outside the cell via plasma membrane channels (Oh-hora, 2009andVig and Kinet, 2009). For Ca2+ signaling to affect Tcell fate or effector functions, sustained Ca2+ influx via plasma membrane channels is probably necessary for a number of hours, maintaining cytoplasmic Ca2+ concentrations higher than resting baseline (Oh-hora, 2009).

The identity and number of plasma membrane channels mediating sustained Ca2+ entry into Tcells is unclear (Kotturi etal., 2006). One well-characterized mechanism of entry is through Ca2+ release-activated calcium (CRAC) channels (Oh-hora, 2009). In the CRAC pathway, the Ca2+ sensor STIM1 responds to decreases in ER Ca2+ stores by associating with the CRAC channel pore subunit ORAI1 and activating SOCE. However, loss of ORAI1 in naive Tcells has been found to have minimal effects on their ability to flux Ca2+ or proliferate upon TCR stimulation (Gwack etal., 2008andVig etal., 2008). Other candidate plasma membrane Ca2+ channels operating in lymphocytes include the P2X receptor, transient receptor potential (TRP) cation channels, TRP vanilloid channels, TRP melastatin channels, and voltage-dependent Ca2+ channels (VDCC). It is unknown whether the repertoire of Ca2+ channels operating in Tcells remains constant or changes during various stages of development or differentiation.

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The CaV1.4 Calcium Channel Is a Critical Regulator of T ...

Dr. Meyer has been passionately involved with the CEREC (CAD/CAM) system for the past ten years. She specializes in front crowns and veneers (smile makeovers), and full mouth rehabilitations as well as teeth whitening. She understands the high aesthetic demands of her patients very well, and can meet them with her expertise and has a highly specialized dental practice. The most modern updated equipment includes CEREC 3D computers, milling units, lasers, baking ovens and the absolute state of the art X-ray Galileos CT unit. For more info on our services follow the links below: Teeth Whitening CEREC Crowns CEREC Veneers Dental Implants Stem Cell Harvesting

Dentistry, Full Mouth Rehabilitations, Gum Surgery Cosmetic Dentistry, CEREC Crowns, CEREC Veneers, Dental Implants, Gum Surgery, Tooth Whitening, Stem Cell Harvesting, Botox Tooth Decay, Broken/missing teeth, Old silver/amalgam fillings,Antibiotic stained, Chipped or mild crooked teeth,Yellow teeth,Loss of a tooth,Loose and/or ill fitting dentures,Severe grinding,Bad breath and/or periodontal (gum) disease CAD/CAM (computer aided design/computer aided milling) system, CEREC Cosmetic Dentist, Crowns, Veneers, Dental Implants, Dentist, Tooth Whitening, Tooth decay Most procedures can be done in +/- 1 hour in the dental chair, All procedures are fully computerized, Our practice is fitted and equipped with the latest state of the art technology and equipment that is available in the world today.

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Dr Ad Meyer | Cosmetic and Reconstructive Dentist ...

Description of Research Expertise:

I am a hematologist-oncologist with a specific research and clinical interest in plasma cell disorders and related dysproteinemias: multiple myeloma, immunoglobulin light chain (AL) amyloidosis, and Waldenstroms macroglobulinemia.

I also lead the multi-disciplinary Penn Amyloidosis Program. This is a cross-disciplinary program involving clinicians with expertise in amyloidosis from cardiology, nephrology, pathology and other disciplines.

I am involved in clinical, translational and epidemiologic research throughout the spectrum of plasma cell disorders. My primary research focus is on the myeloma precursor states: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). I have previously established that both multiple myeloma (Weiss Blood 2009) and AL amyloidosis (Weiss J Clin Oncol 2014) have precursor states that are detectable for many years prior to diagnosis. I have also validated biomarkers for ultra-high risk SMM (Waxman Leukemia 2014) that have contributed to changing the diagnostic criteria for multiple myeloma requiring treatment (Rajkumar Lancet Oncol 2014).

I am currently performing trials to develop and test novel biomarkers for progression in the myeloma precursor states (MGUS and SMM). I am also participating in trials of early intervention in high risk SMM.

I am also conducting trials of novel agents for AL amyloidosis and relapsed and refractory multiple myeloma.

Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritits E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jaganath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Laheurta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BGM, San Miguel JF: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 15 : e538-48,2014.

Weiss BM, Hebreo J, Cordaro DV, Roschewski MJ, Baker TP, Abbott KC, Olson SW: Increased Serum Free Light Chains Precede the Presentation of Immunoglobulin Light Chain Amyloidosis J Clin Oncol 32 (25): 2699-704,2014.

Waxman AJ, Mick R, Garfall AL, Cohen A, Vogl DT, Stadtmauer EA, Weiss BM: Classifying ultra-high risk smoldering myeloma Leukemia : 2014.

Weiss BM: Multiethnic myeloma Blood 121 (16): 3062-4,2013.

Fermand JP, Bridoux F, Kyle RA, Kastritis E, Weiss BM, Cook MA, Drayson MT, Dispenzieri A, Leung N; International Kidney and Monoclonal Gammopathy Research Group.: How I treat monoclonal gammopathy of renal significance (MGRS) Blood 122 (22): 3583-90,2013.

Minter AR, Simpson H, Weiss BM, Landgren O: Bone Disease From Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: Pathogenesis, Interventions, and Future Opportunities. Seminars in Hematology 48 (1): 55-65,2011.

Weiss BM, Minter A, Abadie J, Howard R, Ascencao J, Schechter GP, Kuehl M, Landgren O: Patterns of Monoclonal Immunoglobulins and Serum Free Light Chains Are Significantly Different in African-American Compared to Caucasian MGUS Patients. American Journal of Hematology 86 (6): 475-8,2011.

Waxman AJ, Mink PJ, Devesa SS, Anderson WF, Weiss BM, Kristinsson SY, McGlynn KA, Landgren O: Racial disparities in incidence and outcome in multiple myeloma: a population-based study. Blood 116 (25): 5501-5506,2010.

Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113 (22): 5418-5422,2009.

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Brendan M. Weiss, MD profile| PennMedicine.org

Dominant Demyelinating CMT1A PMP-22 17p11.2-12 (duplication/point mutations) myelination, cell growth, differentiation progressive distal muscle weakness and atrophy, mostly at lower extremities, peroneal gait, areflexia MNCV< 38 m/s, median MNCV 15-30m/s, no conduction block CMT1B MPZ/P0 1q22 adhesion proteins onset in first decade, variable degree of progressive distal muscle weakness MNCV < 20 m/s (in patients with early onset) > 38 m/s (in patients with late onset) CMT1C LITAF/SIMPLE 16p13 protein degradation typical CMT1 MNCV 1625 m/s CMT1D EGR2/Krox20 10q21-22 transcription factor upregulation of myelin genes cranial nerve involvement progressive scoliosis MNCV 942 m/s CMT1F NEFL 8q21 neurofilaments organization, axonal transport onset in early childhood, delayed motor development, severe CMT1 phenotype, similar to DSS MNCV 1538 m/s Special forms: HNPP PMP-22 17p11.2-12 deletion/point mutations) episodes of painless weakness, calf hypertrophy, asymmetrical, CNS demyelination, dystonia rarely, corticosteroid efficient in some patients normal, or mild decreasing, conduction block at pressure site, prolonged distal latencies Neuropathy with hearing impairment connexin -31 (GJB3) 1p35.1 ion channel formation predominantly sensory neuropathy, variable disease severity, asymmetrical hearing loss MNCV and SNCV mildly reduced SNAPs and CMAPs mildly decreased Hypomyelinating neuropathy without clinical symptoms ARGHEF 10 8p23 development of peripheral nerve myelination clinically asymptomatic MNCV 2742 m/s, CMAPs and SNAPs normal Dominant:Axonal CMT2A MFN2 1p33-36 GTP-ase, axonal transport of mitochondria severe, early onset, hearing loss, CNS and pyramidal tract involvement very low CMAPs and SNAPs normal or slightly reduced NCV KIF1B 1p33-36 synaptic vesicle transport CMT2B RAB7 3q13-q22, intracellular membrane traffic sensory loss, feet ulcerations distal motor weakness, hyperkeratosis Normal MNCV CMT2C unknown 12q23-q24 diaphragmal and vocal cord paresis, death normal MNCV CMT2D GARS 7p15 translation process, motor neuron integrity small hand muscles atrophy normal MNCV CMT2E NEFL 8p21 axonal transport, neurofilament organization sensory loss of all modalities MNCV 13-38 m/s CMT2F HSPB1 (HSP27) 7q11-q21 protection of the structure of cell proteins sensory loss, motor impairment of different severity, small hand muscles atrophy later in the course of disease reduced or absent CMAPs CMT2G unknown 12q12-13.3 slowly progressive walking difficulties, preserved knee jerks, absent triceps surae jerks MNCV normal or mildly reduced CMT2H/K GDAP1 8q13-21.1 mitochondrial protein expressed mostly in neurons, regulation of mitochondrial dynamics mild clinical phenotype, vocal cord paralysis, slowly progressive course MNCV slightly decreased or in intermediate range CMT 2I/J MPZ 1q22-23 deafness, Adie pupils MNCV <38 m/s, progress to reduced MNCV CMT2L HSPB8/HSP22 12q24.3 mild sensory loss, scoliosis normal MNCV Dominant:Intermediate DI-CMTA unknown 10q24.1-q25.1 CMT phenotype of moderate severity MNCV 25-45 m/s DI-CMTB dynamin 2 19q12-q13.2 vesicular traffic, endocytosis protein synthesis normal or increased tendon reflexes neutropenia DI-CMTC YARS 1p34-p35 CMT phenotype of moderate severity DI-CMTD MPZ 1q22 variable and moderate severity Dominant: X-linked CMTX1 GJB1 Xq13.1 encodes connexin32, transfer of low weight material between cells hand/thenar muscles, CNS involvement, deafness, visual impairment, white matter lesion conduction block, temporal dispersion MNCV 30-40 m/s in males, MNCV 10-37 m/s in severely affected males MNCV 3050 m/s in females, low CMAPs CMT 3A (DSS) PMP22 17p11.2-12 onset<3y,palpable nerves, ataxia, progressive weakness, severe disability, increased CSF protein content, short stature NCV <10 m/s, fibrillation, positive denervation waves CMT 3B MPZ 1q22-23 onset in infancy, hypotonia, respiratory insufficiency and early deaths occasionally MNCV < 15 m/s CMT 3C unknown 8q23-q24 Charcot joints decreased MNCV DSS-EGR EGR2 10q21-22 phenotype consistent with DSS, cranial nerve involvement, respiratory difficulties MNCV < 8 m/s CMT 3D or CMT 4F periaxin 19q13.1 q13.2 maintenance of the peripheral nerve myelin extracelular matrix signaling unusual facies, deafness very slow MNCV Recessive:demyelinating CMT 4A GDAP1 8q13-21.1 early onset, severe motor retardation, progressive scoliosis MNCV 2535 m/s CMT 4B-1 MTMR2 11q22 transcription and cell proliferation cranial nerves affection, blindness, glaucoma, severe disability MNCV 922m/s CMT 4B-2 MTMR13/SBF2 11p15 onset at 5 years, early onset glaucoma, similar to CMT4B1 phenotype MNCV 1530 m/s CMT 4C KIAA1985 5q23-33 unknown function early onset, severe motor retardation, scoliosis respiratory insufficiency MNCV 1034 m/s CMT 4D (HSMN-Lom) NDRG1 8q24.3 cell growth arrest and differentiation deafness, tongue atrophy Roma population MNCV 920 m/s CMT 4E EGR2 10q 21.1-22 17p onset presented at birth, generalized hypotonia, arthrogryposis, cranial nerves involvement MNCV< 8m/s CMT 4F periaxin 19q13.1-q13.3 maintenance of peripheral nerve myelin, extracellular matrix signaling severe DSS or CMT1 phenotype, curvilinear inclusions in nerves MNCV <15 m/s, CMAPs absent or very low CMT 4G (Russe) unknown 10q23.2 severe distal muscle weakness, prominent sensory loss, frequently in Roma population MNCV 3035 m/s CMT 4H unknown 12p11.21 delay in motor development, scoliosis MNCV < 15 m/s low amplitudes CMT 4J FIG4 6q21 phosphoinositides content vesicular trafficking early onset, coordination disorder, severe disability MNCV 27 m/s CMAPs reduced CCFDN CTDP1 18q23 regulation of proteins involved in transcription and mRNA processing congenital cataract, mental retardation, facial dysmorphism, growth retardation, chorea, tremor, rhabdomyolisis, more frequently in Roma population MNCV 1933 m/s Recessive:Axonal CMT4C1 or AR CMT 2B1 lamin A/C 1q21.2-q21.3 nuclear lamina component, gene transcription rapid evolution involvement of proximal muscles reduced CMAPs, normal MNCV CMT4C2 or AR-CMT 2C or AR CMT 2H unknown 8q21.3 brisk patellar and upper limbs reflexes, ankle reflexes absent, plantar anattainable normal or mildly reduced MNCV, reduced CMAPs amplitude CMT4C3 Or AR CMT2B2 ARC 92/ACID1 (MED 25) 19q13.3 mediator complex associated with RNA polymerase II typical CMT2 phenotype reduced CMAPs mild decrease of MNCV CMT4C4 Or AR CMT 2K GDAP1 8q13-21.1 early onset, hypotonia, kyphoscoliosis, progressive course, hoarse voice, vocal cord paralysis, respiratory insufficiency MNCV> 40 m/s, absent CMAPs Recessive-X-linked CMTX2 unknown Xq 22.2 areflexia, pes cavus, mental retardation, unaffected females decreased NCV, low CMAPs CMTX3 unknown Xq26.3-q27.1 onset 313 years, progressive muscle weakness, normal mental development low CMAPs and median MNCV 2557 m/s CMTX4 Chowchock syndrome unknown X q24-q26.1 onset in infancy, deafness, mental retardation in 60% MNCV 3356 m/s, decreased sensory NCV CMTX5 unknown Xq21.32-q24 hearing loss, optic neuropathy, females unaffected low or absent CMAPs, mild decreasing of MNCV (4351 m/s) Dominant:axonal CMT (AD) with pyramidal features (HMSN V) mitofusin 2 (MFN2) 1p36.2 mitochondrial GTP-ase regulator of mitochondrial fussion and transport ankle jerk absent, tendon jerks present or increased MNCV decreased, low SNAPs and CMAPs amplitudes CMT with optic atrophy (HMSN VI or CMT 6) MFN2 1p36.2 early onset, optic atrophy MNCV slightly decreased Dominant:distal motor Distal HMN I unknown early onset 220 years, reflexes present or increased, ankle jerks absent, distal weakness and wasting MNCV normal or mildly decreased, SNAPs mildly reduced Distal HMN II HSP22, HSP27 12q24.3, 7q11-21 development of thermotolerance onset 1520 years, rapid progression, exstensor muscle weakness MNCV normal, CMAPs normal or reduced, SNCV normal Distal HMN V (HMN 5A) GARS 7p15 protein biosynthesis, role in translation phase pronounced hand muscles wasting and weakness, spasticity on lower extremities MNCV and CMAPs, normal or mildly reduced Distal HMN V- Silver's syndrome (HMN 5B) BSCL2, seipin 11q12q14 involved in RNA transport and glycosylation pronounced hand muscles wasting and weakness, mild lower extremities spasticity, no sensory/autonomic dysfunction reduced CMAPs, normal or mild reduction of MNCV Distal HMN VII B dynactin 2p13 role in prevention of neurodegeneration adult onset, bilateral vocal cord paralysis, progressive facial weakness and atrophy of hand muscles and distal legs normal MNCV, low CMAPs distally Distal HMN VII A unknown 2q14 onset in second decade, unilateral or bilateral vocal cord paralysis, breathing difficulties, weakness and atrophy of, hands and distal legs muscles Dist. HMN ALS4 SETX 9q34 possible role in RNA processing early onset, pyramidal tract involvement MNCV normal, CMAPs reduced Recessive:distal HMN Distal HMN III unknown telomeric to IGHMBP2 11q13 infantile onset, diaphragmal hypomobility CMAPs low, MNCV normal or mildly reduced Distal HMN IV unknown 11q13 mild neuropathy of late onset in third decade CMAPs low, MNCV normal or mildly reduced Distal HMN VI (SMARD1) IGHMBP2 11q13.2-13.4 RNA processing diaphragmal paresis, IURG, infantile onset, respiratory insufficiency, death low/absent CMAPs, mild decreased MNCV Distal HMN-J unknown 9p21.1-p12 onset between 610 years, first brisk reflexes and Babinski sign followed by areflexia and absent Babinski sign MNCV normal to mildly reduced, CMAP reduced amplitudes SNAP normal Cong. distal SMA unknown 12q23-q24 antenatal onset, arthrogryposis, severe course, paraplegia, scoliosis, trunk weakness MNCV normal X-linked distal HMN unknown Xq13-q21 juvenile onset, mild distal weakness and wasting CMAP amplitudes reduced, MNCV mildly reduced, and SNCV normal HSAN:Autosomal dominant HSAN I SPTLC1 9q22.1-q22.3 sphingolipid synthesis common features of all HSAN types: arthropathy, mutilating, paronychia, ulcers of fingers, pathological fractures, prolonged QT, syncopes, convulsions decreased SNCV HSAN 1B associated with cough and gastroesophageal reflux (GER) unknown 3p22-p24 cough, hoarse voice, syncopes, retinal detachment, hearing loss, GER, rarely ulcers, sensory loss decreased SNCV HSAN:Recessive HSAN II HSN 2 12p13.33 loss of pain, touch and temperature sensation, finger ulcerations, loss of tendon reflexes, mild muscle weakness SNCV decreased, SNAPs absent HSAN III or Riley-Day syndrome IKBKAP 9q31 transcription process onset at birth, hypotonia, defect in lacrimation, thermal dysregulation, postural hypotension, prominent autonomic dysfunction, gastrooesophageal reflux, chronic lung disease, ataxia, convulsions SNCV decreased, SNAPs absent or reduced HSAN IV TRKA/NGF NTRK1 1q21-q22 NGF signaling, thermal regulation via sweating, nociceptive system development pain insensitivity, anhydrosis normal reflexes, mild mental retardation normal MNCV and CMAPs, SNAPs and SNCV mildly reduced HSAN V TRKA/NGF NGF 1q21-q22 1p13.2-11.2 NGF signaling, CNS and peripheral pain pathways development onset at birth, pain insensitivity, bone/joint fractures, episodes of hyperpyrexia, anhydrosis less pronounced than in HSAN IV, hyperkeratosis, normal mental development NCV normal HSAN with deafness and global delay unknown unknown hypotonia, areflexia, developmental delay, hearing loss, dysmorphic features, renal tubular acidosis sensory neuropathy HSAN with spastic paraplegia unknown 5q15.31-14.1 severe sensory neuropathy, trophic ulcers and mutilation, MRI spinal cord atrophy axonal sensory neuropathy, SNAPs amplitudes reduced or absent, MNCV normal or mildly reduced X-linked HSAN associated with deafness (AUNX1) unknown AUNX1 locus Xq23-27.3 progressive auditory neuropathy, decreased otoacustic emission, progressive sensory neuropathy SNAPs reduced or absent, mildly reduced sensory NCV, normal MNCV

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Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation

Biological processes are all ultimately how chemical processes react with their surroundings. The more detail that is known about a process, the greater our ability to modify it. Myopia is a complex interplay of many factors that result in an eyeball being too long for the focal plane of light entering the eye. Why this happens will ultimately be understood as the interplay of many molecular processes and the study of the very basic parts of this process will eventually allow us to greatly modify, if not control, myopia.

These references are mostly, but not exclusively, related to the lower levels of juvenile myopia. More references can be found by searching for your own articles using the PubMed (National Library of Medicine) database. Just enter some terms such as "myopia gene". There were 629 such articles listed on 04 October 2011.

MyopiaPrevention.org comment: Subtitled Myopia Control with Atropine 0.01% Eyedrops. From the conclusions: "Over 5 years, atropine 0.01% eyedrops were more effective in slowing myopia progression with less visual side effects compared with higher doses of atropine."

Read the commentary by Jeffrey Cooper: Practice Update. Eye Care. Expert Comment. August 25, 2015. "This study completes a series of clinical trials demonstrating the efficacy of atropine in slowing the progression of myopia and makes a strong case for clinical use of atropine in young patients."

MyopiaPrevention.org comment: The data is now five years old, but it shows that atropine use increased over the years while the concentration of the drop used decreased. In 2007, approximately 50% of children diagnosed with myopia were prescribed atropine, 40% of those getting .1% atropine. Among 9-10 year olds with myopia, 60% were prescribed atropine. Over the seven year period, atropine use increased 34%.

MyopiaPrevention.org comment: This ATOM2 followup of the ATOM1 study sought to determine if concentrations weaker than the previously studied 1% would have a similar effect. A dose as low as .01% was shown to slow myopia clinically at the same rate as 1% with "negligible effect on accommodation and pupil size, and no effect on near visual acuity." There were no reports of allergic conjunctivitis or dermatitis. This is a significant finding that could change how myopia is treated.

MyopiaPrevention.org comment: The abstract talks about the gene mutation identified in a specific population: "Bedouin Israeli consanguineous kindred." In other words, a very small, specific population. Such studies allow researchers to more easily determine the actions of a specific gene. Further research is then needed to determine if this action is somehow impaired in myopic individuals who do not have the specific mutation.

MyopiaPrevention.org comment: A retrospective study of controlled clinical trials. Atropine slowed myopic progression by .773D/yr compared to placebo. Effects of .5% and 1% were similar.

MyopiaPrevention.org comment: While atropine (a muscarinic antagonist) has been shown to reduce myopic progression, the specific receptor that mediates the effect has not been identified. This study indicates that "muscarinic antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina."

This is important in that, if proven true, it would permit the development of a more targeted drug for myopia control than the more broad acting atropine.

MyopiaPrevention.org comment: This study of 22 subjects aged 13 to 25 found that myopes had slightly lower levels of Vitamin D in their blood compared to non-myopes when adjusted for age and diet, but the results were questioned because the study did not find that outdoor time was related to myopia.

MyopiaPrevention.org comment: A comprehensive review of the drugs used to study myopia progression involving various receptor targets within the eye. Various models for myopia progression are discussed. "...new bioengineering approaches for drug delivery" are called for.

MyopiaPrevention.org comment: Not yet read. The abstract states that "The findings that have resulted from this study have not only provided greater insight into the role of genes and other factors involved in myopia but have also gone some way to uncovering the aetiology of other refractive errors."

MyopiaPrevention.org comment: This is a study that looked at varying the dosage of atropine based on the season, with the idea of increasing the dose when the sun exposure is the least. It was found to be effective and tolerable to the students.

MyopiaPrevention.org comment: Insulin-like growth factor-1 (IGF-1) "may play a role in control of eye growth" and this study found a "genetic association between IGF-1 and high-grade myopia."

MyopiaPrevention.org comment: The study shows the type of work needed to identify a genetic component to myopia progression. A single gene was studied and was found to be associated with both hyperopia and myopia. No attempt is made to identify how the gene might create its influence.

MyopiaPrevention.org comment: Just like the title says. This is different than has been found in other populations.

MyopiaPrevention.org comment: In simplified terms, glucose levels in the body are regulated by insulin (lowers glucose) and glucagon (raises glucose). Chick eyes were studied for the effect of these two hormones and their ability to control ocular elongation and choroidal thickness, both responsible for emetropization and myopic development. The relationship is complicated. "the simplest view of how glucagon and insulin might control emmetropization would be that insulin stimulates the eye to elongate and the choroid to thin, thus acting like a negative lens, whereas glucagon does the reverse, slowing the elongation and causing the choroid to thicken, thus acting like a positive lens. We conclude the situation is considerably more complex." It appears that this more simplistic action is maintained if the eye is compensating for defocus during which time the eye is less responsive to the drug that would be expected to slow the process in either direction.

MyopiaPrevention.org comment: Pirenzepine was shown to slow myopia to .58 diopters over two years vs. .99 diopters for the placebo group, thus cutting the progression approximately in half. An editorial in the same edition (How should we try to affect myopic progression?) by Sherwin J. Isenberg notes that although atropine and pirenzepine have the best results "in properly conducted clinical trials" for myopia control, the former is an "off-label" use and the later is not available in the United States.

MyopiaPrevention.org comment: "The experiments reported here demonstrate that both unselective blocking of potassium channels and selective inhibition of the sodium-potassium-chloride symporter can produce dramatic interference with refractive compensation to optically induced blur." "The action of bumetanide appears to combine a defocus-sensitve inhibition of refractive compensation under conditions that would normally lead to myopia"

MyopiaPrevention.org comment: This adenosine antagonist (in tablet form) was tested in a study of 68 children of average age 11 for three years. The first year half the students received the tablets, the second year all students were given the choice of once a day or twice a day tablets and the third year all medication was stopped. The authors conclude that 7-mx is efficient in retarding myopia, but I don't see that from their results and study design.

MyopiaPrevention.org comment: Paired box gene 6 (PAX6) showed no association with myopia. COL2A1 (a collagen gene) was indicated as possibly associated with myopia.

MyopiaPrevention.org comment: In the chick eye, the perception of blur does not drive emmetropization but rather the energy at high spatial frequencies in an image, leading them to conclude that amacrine cells within the retina may be sufficient to drive emmetropization.

MyopiaPrevention.org comment: The title says it all.

MyopiaPrevention.org comment: Melatonin is a hormone that "transmits daily and seasonal timing information to a variety of tissues in essentially all vertebrate species." Application of systemic melatonin altered the growth of various ocular tissues where receptors have been identified. Further study is called for to elicit more specific data.

MyopiaPrevention.org comment: A pdf of the slides presented at a lecture for ARVO's (Association for Research in Vision and Ophthalmology) symposium. A discussion of the biochemical signals controlling growth that are operating within the retina.

MyopiaPrevention.org comment: Abstract in Polish translated into English on Pubmed.com. The abstract is perhaps most interesting for the listing of potential chemicals for myopia prevention.

MyopiaPrevention.org comment: Glucagon, a chemical messenger in the body, was investigated to see whether it is involved with signaling the eye to change its growth in response to plus lenses. It was shown to thicken the choroid and may contribute to myopia prevention by reducing sclera growth.

MyopiaPrevention.org comment: "That the combination of apomorphine and atropine were not additive suggests that combining dopaminergic and muscarinic agents is not a useful strategy for improving the efficacy of these antimyopia drug treatments."

MyopiaPrevention.org comment: A study of genes within a region previously identified as associated with high myopia. No significant gene was found. Includes a good summary of the incidence of eye problems associated with increased myopia in the section "Ocular Morbidity" including such facts as the lifetime risk of retinal detachment is 9.3% for those with myopia over 5.00 D. A necessary read for anyone thinking that identifying the genetic component of myopia should be easy.

MyopiaPrevention.org comment: Pirenzepine appeared to be safe to use in children but the study did not attempt to determine if it was effective in myopia prevention.

MyopiaPrevention.org comment: 331 children aged 6-12 studied over two years showed that myopia progressed 1.20 diopters in the control (placebo drops) group and .25 diopters in the group given 1% atropine drops daily. Results for axial elongation (another measure of myopia progression) were similar.

MyopiaPrevention.org comment: A summary of many of the issues in myopia research.

MyopiaPrevention.org comment: The concern is that long term atropine use might cause either toxic problems or lead to increased light damage to the eye due to atropine dilating pupils. This study did multifocal electroretinograms (mfERG) to determine if such damage was detectable for those who had used atropine for two years. The results showed slight changes of unknown significance in the atropine group. The author states "The clinical implications of these findings need to be further explored."

MyopiaPrevention.org comment: A review of the molecular techniques being used to study myopia.

MyopiaPrevention.org comment: Pirenzepine (a selective muscarinic antagonist) studied in 353 Asian children ages 6-12. 2% drops twice a day (progressed -.47 D), once a day (progressed -.70 D) and placebo(progressed -.84 D), thus showing a 43% drop in myopic progression for 2% pirenzepine drops given twice a day. Side effects included follicles and papillae (bumps on the inner lids) that were stated to be usually symptom free with overall "minimal anti-muscarinic safety issues."

MyopiaPrevention.org comment: An extensive review of the pharmacology of myopia presented at the 9th International Myopia Conference. You must be able to read .ppt files. From Dr. Wildsoet's web site.

MyopiaPrevention.org comment: Three groups (total 188 students age 6-13): Atropine + multifocal glasses, multifocal glasses, and single vision glasses. Followed for 18 months. Progression was least for atropine+multifocals (.40 D), and more for multifocals (1.19 D) and single vision lenses (1.40 D). Although the two glasses group did differ from each other, it was not felt the difference was strong enough to say multifocals were better at prevention than single vision glasses.

MyopiaPrevention.org comment: Amacrine cells within the retina "respond differentially" depending on whether the eye is myopic or hyperopic and thus may be important in emmetropization.

MyopiaPrevention.org comment: 168 children, age 6-13 were treated with either of .5%, .25% or .1% atropine drops nightly for up to two years. Myopic progression rates were .04, .45 and .47 Diopters/year respectively compared to a control of 1.06 Diopters/year. The .5% was the most effective.

MyopiaPrevention.org comment: A study of 214 students in Olmsted County, Minnesota (USA) received atropine for various lengths of time, from 18 weeks to 11.5 years. Photophobia and blurred vision were frequently reported, but the author did not classify those as "serious side effects". The atropine group had very little myopic change (.05 units/year) vs the "no-drug" group (.36 units/year). The article has a fairly extensive discussion of atropine in various myopia control studies and background data on myopia in general. Forty five pages.

The same article appears as Kennedy RH, Dyer JA, Kennedy MA, Parulkar S, Kurland LT, Herman DC, McIntire D, Jacobs D, Luepker RV.(2000) Reducing the progression of myopia with atropine: a long term cohort study of Olmsted County students. (ABSTRACT) Binocul Vis Strabismus Q. 2000;15(3 Suppl):281-304.

MyopiaPrevention.org comment: Injected atropine in chick eyes dramatically slowed myopic progression but did not reduce accommodation. Atropine eye drops would not stop myopic progression by affecting accommodation, further proof that accommodation or reading does not by itself cause myopia.

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Myopia Medications and Genetics - MYOPIA * Prevention

INTRODUCTION

Squamous cell carcinogenesis in the mucosa of the head and neck involves the progressive accumulation of a large series of genetic abnormalities in genes regulating cell cycle progression, mitogenic and differentiative signaling pathways, angiogenesis, and cell death. This mutagenic progression, called multistep carcinogenesis, parallels the genetic model of colorectal carcinogenesis [1,2]. (See "Molecular genetics of colorectal cancer".)

Evidence for a mutational progression in tumorigenesis of head and neck squamous cell carcinoma (HNSCC) first derived from cytogenetic studies that demonstrated nonrandom clonal losses, duplications, and rearrangements of chromosome segments in head and neck tumors [3-5]. Within many of these regions of recurring chromosomal abnormality, candidate oncogenes or tumor suppressors have since been identified, some of which appear to play critical roles in carcinogenic transformation. Subsequent detailed progression models for carcinogenesis of the head and neck have been based upon mutational models and differential gene expression [6,7]. More recently, we have a better understanding of the mutational landscape in HNSCC from newer sequencing technologies [8-10].

Identification of some of the critical genetic events leading to head and neck cancer has clarified the molecular basis for epidemiologic observations regarding risk factors (eg, tobacco), identified previously unknown risk factors (eg, human papillomavirus infection), and is yielding information that may be critical for risk stratification. (See "Epidemiology and risk factors for head and neck cancer" and "Human papillomavirus associated head and neck cancer".)

In addition, these studies have unveiled a new series of targets for chemotherapeutic and chemopreventive intervention, which ultimately may result in more rational and successful therapies for this disease. (See "Chemoprevention and screening in oral dysplasia and squamous cell head and neck cancer".)

FIELD CANCERIZATION

The term field cancerization was first used to describe observations from microscopic examination of 738 lip, oral cavity, and pharyngeal carcinomas [11]. The grossly normal epithelium adjacent to the cancer in this study frequently contained dysplasia, carcinoma in situ, or invasive carcinoma, as though the entire mucosal field had been damaged and preconditioned by a carcinogen.

Literature review current through: Mar 2016. | This topic last updated: Tue Nov 24 00:00:00 GMT 2015.

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Head and neck squamous cell carcinogenesis: Molecular and ...

Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the bodys hereditary material and can make copies of themselves.

Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order:

Within cells, the cytoplasm is made up of a jelly-like fluid (called the cytosol) and other structures that surround the nucleus.

The cytoskeleton is a network of long fibers that make up the cells structural framework. The cytoskeleton has several critical functions, including determining cell shape, participating in cell division, and allowing cells to move. It also provides a track-like system that directs the movement of organelles and other substances within cells.

This organelle helps process molecules created by the cell. The endoplasmic reticulum also transports these molecules to their specific destinations either inside or outside the cell.

The Golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.

These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.

Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.

The nucleus serves as the cells command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cells hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.

The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.

Ribosomes are organelles that process the cells genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum (see above).

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What is a cell? - Genetics Home Reference