The ubiquitin-mediated proteolytic pathway as a therapeutic area

1997 ◽  
Vol 75 (1) ◽  
pp. 5-17 ◽  
Author(s):  
Mark Rolfe ◽  
M. Isabel Chiu ◽  
M. Pagano
Keyword(s):  
Therapeutic Area ◽  
Proteolytic Pathway

scholarly journals A Screen for Genes Involved in the Anaphase Proteolytic Pathway Identifies tsm1+, a Novel Schizosaccharomyces pombe Gene Important for Microtubule Integrity

Genetics ◽  
1998 ◽  
Vol 149 (3) ◽  
pp. 1251-1264
Author(s):  
Ekaterina L Grishchuk ◽  
James L Howe ◽  
J Richard McIntosh
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Nuclear Division ◽  
Mitotic Division ◽  
Temperature Sensitive ◽  
Permissive Temperature ◽  
Anaphase Promoting Complex ◽  
Chloromethyl Ketone ◽  
Proteolytic Pathway ◽  
Functional Involvement ◽  
Spindle Elongation

Abstract The growth of several mitotic mutants of Schizosaccharomyces pombe, including nuc2-663, is inhibited by the protease inhibitor N-Tosyl-L-Phenylalanine Chloromethyl Ketone (TPCK). Because nuc2+ encodes a presumptive component of the Anaphase Promoting Complex, which is required for the ubiquitin-dependent proteolysis of certain proteins during exit from mitosis, we have used sensitivity to TPCK as a criterion by which to search for novel S. pombe mutants defective in the anaphase-promoting pathway. In a genetic screen for temperature-sensitive mitotic mutants that were also sensitive to TPCK at a permissive temperature, we isolated three tsm (TPCK-sensitive mitotic) strains. Two of these are alleles of cut1+, but tsm1-512 maps to a novel genetic location. The tsm1-512 mutation leads to delayed nuclear division at restrictive temperatures, apparently as a result of an impaired ability to form a metaphase spindle. After shift of early G2 cells to 36°, tsm1-512 arrests transiently in the second mitotic division and then exits mitosis, as judged by spindle elongation and septation. The chromosomes, however, often fail to segregate properly. Genetic interactions between tsm1-512 and components of the anaphase proteolytic pathway suggest a functional involvement of the Tsm1 protein in this pathway.

scholarly journals Development and content validity of the Barth Syndrome Symptom Assessment (BTHS-SA) for adolescents and adults

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Chad Gwaltney ◽  
Jonathan Stokes ◽  
Anthony Aiudi ◽  
Iyar Mazar ◽  
Sarah Ollis ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Genetic Disorder ◽  
Signs And Symptoms ◽  
Symptom Assessment ◽  
Barth Syndrome ◽  
Therapeutic Area ◽  
Symptom Experience ◽  
Patient Reported ◽  
Adolescents And Adults ◽  
Syndrome Symptom

Abstract Background Barth Syndrome (BTHS) is a rare genetic disorder that presents as a complex of debilitating symptoms and reduced life expectancy. Well-developed, BTHS-specific assessments measuring primary signs and symptoms of BTHS are not currently available, making it difficult to evaluate treatment effects in BTHS clinical studies. The objective of this research was to develop symptom-focused patient-reported outcome (PRO) measures for use in clinical studies with adolescents and adults with BTHS. Methods Concept elicitation interviews (CEIs) with pediatric (n = 18, age < 16 years) and adult (n = 15, age ≥ 16 years) individuals with BTHS and/or their caregivers were conducted to identify signs and symptoms relevant to BTHS and important to individuals with the condition. Based on CEI results, questionnaire construction activities were conducted to create unique adolescent and adult versions of the Barth Syndrome-Symptom Assessment (BTHS-SA). The questionnaires were evaluated in cognitive debriefing interviews (CDIs) with adolescents (n = 12; age 12- < 16 years) and adults (n = 12; age ≥ 16 years) with BTHS to assess relevance and readability of the tools. Results During the CEIs, a total of 48 and 40 signs and symptoms were reported by the pediatric and adult groups, respectively; 31 were reported by both age groups. Fatigue/tiredness and muscle weakness were the symptoms most frequently reported by both pediatric and adult patients with BTHS as important to improve with an effective treatment. The CEI results informed construction of a nine-item version of the BTHS-SA for adolescents and an eight-item version for adults. Developed for daily administration, each version asks respondents to rate symptom severity “at its worst” over the 24 h prior to administration. CDIs with both adolescents and adults with BTHS demonstrated that each BTHS-SA version was reflective of the disease experience and that respondents could interpret the questionnaire as intended and provide responses that accurately reflected their symptom experience. Conclusions The BTHS-SA adolescent and adult versions are content-valid PRO measures that can be used to evaluate severity of disease-specific symptoms in future clinical trials. Given the lack of available and well-developed assessments in this underserved therapeutic area, these tools fulfill a need for clinical researchers developing treatments for individuals with BTHS.

scholarly journals 15-Lipoxygenase is a component of the mammalian sperm cytoplasmic droplet

Reproduction ◽  
2005 ◽  
Vol 130 (2) ◽  
pp. 213-222 ◽  
Author(s):  
K A Fischer ◽  
K Van Leyen ◽  
K W Lovercamp ◽  
G Manandhar ◽  
M Sutovsky ◽  
...  
Keyword(s):  
Semen Quality ◽  
Mammalian Species ◽  
Immune Serum ◽  
Residual Body ◽  
Cytoplasmic Droplet ◽  
Mammalian Sperm ◽  
Proteolytic Pathway ◽  
Cellular Debris ◽  
Ubiquitin Conjugating Enzyme ◽  
Boar Spermatozoa

Lipoxygenases (LOXs) are a family of enzymes capable of peroxidizing phospholipids. A member of the LOX family of enzymes, 15-LOX, participates in the degradation of mitochondria and other organelles within differentiating red blood cells, the reticulocytes. The present study provides biochemical and immunocytochemical evidence for the presence of 15-LOX in the sperm cytoplasmic droplet (CD). Testicular, epididymal and ejaculated spermatozoa were evaluated for the presence of 15-LOX using an affinity-purified immune serum raised against a synthetic peptide corresponding to the C-terminal sequence of rabbit reticulocyte 15-LOX. Western blotting revealed an appropriate single band of ~81 kDa in boar spermatozoa but not in boar seminal plasma. When ejaculated boar spermatozoa were subjected to separation on a 45/90% Percoll gradient, 15-LOX co-migrated with the immotile sperm and cellular debris/CD fractions, but not with the motile sperm fraction containing morphologically normal spermatozoa without CDs. Varied levels of 15-LOX were expressed in ejaculated sperm samples from boars with varied semen quality. By immunofluorescence, prominent 15-LOX immunoreactivity was found within the residual body in the testis and within the CDs from caput, corpus and cauda epididymal and ejaculated spermatozoa. Components of the ubiquitin-dependent proteolytic pathway, which is thought to facilitate both spermiogenesis and reticulocyte organelle degradation, were also detected in the sperm CD. These included ubiquitin, the ubiquitin-conjugating enzyme E2, the ubiquitin C-terminal hydrolase PGP 9.5, and various 20S proteasomal core subunits of the α- and β-type. The 15-LOX and various components of the ubiquitin–proteasome pathway were also detected in sperm CDs of other mammalian species, including the human, mouse, stallion and wild babirusa boar. We conclude that 15-LOX is prominently present in the mammalian sperm CD and thus may contribute to spermiogenesis, CD function or CD removal.

scholarly journals Comparing Medications in a Therapeutic Area Using an NNT Model

2004 ◽  
Vol 7 (5) ◽  
pp. 585-594 ◽  
Author(s):  
J. Jaime Caro ◽  
K. Jack Ishak ◽  
Ingrid Caro ◽  
Kristen Migliaccio-Walle ◽  
Wendy S. Klittich
Keyword(s):  
Therapeutic Area

Orphan Drugs in Surgery

2013 ◽  
Vol 13 (1) ◽  
pp. 57-62 ◽  
Author(s):  
Konstantins Logviss ◽  
Dainis Krievins ◽  
Santa Purvina
Keyword(s):  
Genetic Disorders ◽  
Specific Area ◽  
Orphan Drugs ◽  
Acoustic Trauma ◽  
State Agency ◽  
Therapeutic Area ◽  
Glaucoma Filtration Surgery ◽  
Post Surgery ◽  
Orphan Medicinal Products ◽  
Using Data

Summary Introduction. Rare diseases, also called orphan diseases, are life-threatening or chronically debilitating conditions of different origin. Majority of them are genetic disorders, others being rare cancers, congenital malformations, autoimmune, toxic and infectious diseases. Rare conditions may also be related to surgery, e.g. acute sensorineural hearing loss after surgery induced acoustic trauma, scarring post glaucoma filtration surgery, and short bowel syndrome following intestinal surgery. Besides, surgery as a specific area for orphan drugs, has not been studied yet in Latvia. Aim of the study. This study aims to determine orphan drugs associated with surgery (used pre-, during or post-surgery) and their availability and access in Latvia. Materials and methods. European register of designated orphan medicinal products and EMA approved Summary of Product Characteristics were analyzed, to find orphan drugs with approved labeled indications related to surgery. Drug availability and access in Latvia were determined, by using data available from State Agency of Medicines of Latvia and National Health Service. A literature review was performed to compare Latvian situation in field of orphan medicines with other European countries. Results. 15 orphan drugs were identified, 8 of them (53.3%) indicated for different kinds of tumors. 6 drugs (40%) are available in Latvia, including one drug (6.7%) included in the reimbursement list. Conclusions. Oncology is the biggest therapeutic area of orphan drugs. Majority of orphan drugs are not available in Latvia, moreover those drugs that are available are often not accessible.

Article Commentary: Stem Cell Research in Cell Transplantation: An Analysis of Geopolitical Influence by Publications

2007 ◽  
Vol 16 (8) ◽  
pp. 867-873 ◽  
Author(s):  
David J. Eve ◽  
Paul R. Sanberg
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Adult Stem Cells ◽  
Adult Stem Cell ◽  
Therapeutic Area ◽  
Fetal Stem Cells ◽  
Major Player ◽  
The Us ◽  
Restricted Use

One of the fastest growing fields in researching treatments for neurodegenerative and other disorders is the use of stem cells. These cells are naturally occurring and can be obtained from three different stages of an organism's life: embryonic, fetal, and adult. In the US, political doctrine has restricted use of federal funds for stem cells, enhancing research towards an adult source. In order to determine how this legislation may be represented by the stem cell field, a retrospective analysis of stem cell articles published in the journal Cell Transplantation over a 2-year period was performed. Cell Transplantation is considered a translational journal from preclinical to clinical, so it was of interest to determine the publication outcome of stem cell articles 6 years after the US regulations. The distribution of the source of stem cells was found to be biased towards the adult stage, but relatively similar over the embryonic and fetal stages. The fetal stem cell reports were primarily neural in origin, whereas the adult stem cell ones were predominantly mesenchymal and used mainly in neural studies. The majority of stem cell studies published in Cell Transplantation were found to fall under the umbrella of neuroscience research. American scientists published the most articles using stem cells with a bias towards adult stem cells, supporting the effect of the legislation, whereas Europe was the leading continent with a bias towards embryonic and fetal stem cells, where research is “controlled” but not restricted. Japan was also a major player in the use of stem cells. Allogeneic transplants (where donor and recipient are the same species) were the most common transplants recorded, although the transplantation of human-derived stem cells into rodents was the most common specific transplantation performed. This demonstrates that the use of stem cells is an increasingly important field (with a doubling of papers between 2005 and 2006), which is likely to develop into a major therapeutic area over the next few decades and that funding restrictions can affect the type of research being performed.

scholarly journals An analysis of characteristics of post-authorisation studies registered on the ENCePP EU PAS Register

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1447 ◽  
Author(s):  
Robert Carroll ◽  
Sreeram V. Ramagopalan ◽  
Javier Cid-Ruzafa ◽  
Dimitra Lambrelli ◽  
Laura McDonald
Keyword(s):  
Risk Assessment ◽  
Chart Review ◽  
Drug Utilisation ◽  
Data Capture ◽  
Primary Data ◽  
European Medicines Agency ◽  
Therapeutic Area ◽  
The European Union ◽  
Study Designs ◽  
The Eu

Background: The objective of this study was to investigate the study design characteristics of Post-Authorisation Studies (PAS) requested by the European Medicines Agency which were recorded on the European Union (EU) PAS Register held by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Methods: We undertook a cross-sectional descriptive analysis of all studies registered on the EU PAS Register as of 18th October 2016. Results: We identified a total of 314 studies on the EU PAS Register, including 81 (26%) finalised, 160 (51%) ongoing and 73 (23%) planned. Of those studies identified, 205 (65%) included risk assessment in their scope, 133 (42%) included drug utilisation and 94 (30%) included effectiveness evaluation. Just over half of the studies (175; 56%) used primary data capture, 135 (43%) used secondary data and 4 (1%) used a hybrid design combining both approaches. Risk assessment and effectiveness studies were more likely to use primary data capture (60% and 85% respectively as compared to 39% and 14% respectively for secondary). The converse was true for drug utilisation studies where 59% were secondary vs. 39% for primary. For type 2 diabetes mellitus, database studies were more commonly used (80% vs 3% chart review, 3% hybrid and 13% primary data capture study designs) whereas for studies in oncology, primary data capture were more likely to be used (85% vs 4% chart review, and 11% database study designs). Conclusions: Results of this analysis show that study objectives and therapeutic area influence PAS design in terms of type of data capture used.

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