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PLoS Genetics Dec 2020Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities,... (Review)
Review
Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities, stillbirth, and early mortality. The genetic basis for RBS is linked to autosomal recessive loss-of-function mutation of the establishment of cohesion (ESCO) 2 acetyltransferase. ESCO2 is an essential gene that targets the DNA-binding cohesin complex. ESCO2 acetylates alternate subunits of cohesin to orchestrate vital cellular processes that include sister chromatid cohesion, chromosome condensation, transcription, and DNA repair. Although significant advances were made over the last 20 years in our understanding of ESCO2 and cohesin biology, the molecular etiology of RBS remains ambiguous. In this review, we highlight current models of RBS and reflect on data that suggests a novel role for macromolecular damage in the molecular etiology of RBS.
Topics: Acetyltransferases; Animals; Chromosomal Proteins, Non-Histone; Craniofacial Abnormalities; DNA Damage; Ectromelia; Genomic Instability; Humans; Hypertelorism
PubMed: 33382686
DOI: 10.1371/journal.pgen.1009219 -
Journal of Virology Sep 2021Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in antiviral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control...
Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in antiviral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control ectromelia virus (ECTV) infection. How viral infections induce CD4-CTL responses remains incompletely understood. We demonstrate here that not only ECTV but also vaccinia virus and lymphocytic choriomeningitis virus induce CD4-CTL, though the response to ECTV is stronger. Using ECTV, we also demonstrate that in contrast to CD8-CTL, CD4-CTL differentiation requires constant virus replication and ceases once the virus is controlled. We also show that major histocompatibility complex class II molecules on CD11c cells are required for CD4-CTL differentiation and for mousepox resistance. Transcriptional analysis indicated that antiviral CD4-CTL and noncytolytic T helper 1 (Th1) CD4 T cells have similar transcriptional profiles, suggesting that CD4-CTL are terminally differentiated classical Th1 cells. Interestingly, CD4-CTL and classical Th1 cells expressed similar mRNA levels of the transcription factors ThPOK and GATA-3, necessary for CD4 T cell linage commitment, and Runx3, required for CD8 T cell development and effector function. However, at the protein level, CD4-CTL had higher levels of the three transcription factors, suggesting that further posttranscriptional regulation is required for CD4-CTL differentiation. Finally, CRISPR/Cas9-mediated deletion of in CD4 T cells inhibited CD4-CTL but not classical Th1 cell differentiation in response to ECTV infection. These results further our understanding of the mechanisms of CD4-CTL differentiation during viral infection and the role of posttranscriptionally regulated Runx3 in this process. While it is well established that cytotoxic CD4 T cells (CD4-CTLs) directly contribute to viral clearance, it remains unclear how CD4-CTL are induced. We now show that CD4-CTLs require sustained antigen presentation and are induced by CD11c-expressing antigen-presenting cells. Moreover, we show that CD4-CTLs are derived from the terminal differentiation of classical T helper 1 (Th1) subset of CD4 cells. Compared to Th1 cells, CD4-CTLs upregulate protein levels of the transcription factors ThPOK, Runx3, and GATA-3 posttranscriptionally. Deletion of Runx3 in differentiated CD4 T cells prevents induction of CD4-CTLs but not classical Th1 cells. These results advance our knowledge of how CD4-CTLs are induced during viral infection.
Topics: Animals; Antigen-Presenting Cells; CD11 Antigens; CD4-Positive T-Lymphocytes; Cell Differentiation; Core Binding Factor Alpha 3 Subunit; Cytotoxicity, Immunologic; Ectromelia virus; Ectromelia, Infectious; Histocompatibility Antigens Class II; Liver; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Spleen; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th1 Cells; Transcriptome; Virus Diseases; Virus Replication
PubMed: 34260270
DOI: 10.1128/JVI.00566-21 -
Proceedings of the National Academy of... Feb 2022Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are...
Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1β, IL-12p40, TGF-β, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Cell Line; Chlorocebus aethiops; Cidofovir; Cytokines; Drug Evaluation, Preclinical; Drug Therapy, Combination; Ectromelia virus; Etanercept; Female; Lung; Mice, Inbred C57BL; NF-kappa B; Pneumonia, Viral; STAT3 Transcription Factor; Signal Transduction; Tumor Necrosis Factor-alpha; Viral Load; Mice
PubMed: 35177474
DOI: 10.1073/pnas.2112725119 -
ChemMedChem Jun 2022In this work, a library of (+)-camphor and (-)-fenchone based N-acylhydrazones, amides, and esters, including para-substituted aromatic/hetaromatic/cyclohexane ring was...
In this work, a library of (+)-camphor and (-)-fenchone based N-acylhydrazones, amides, and esters, including para-substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure-activity relationship revealed the significance of the substituent at the para-position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p-Cl, p-Br, p-CF and p-NO substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time-of-addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.
Topics: Antiviral Agents; Camphanes; Camphor; Cyclohexanes; Molecular Docking Simulation; Norbornanes; Orthopoxvirus
PubMed: 35388614
DOI: 10.1002/cmdc.202100771 -
Translational Pediatrics Apr 2021Poland's syndrome (PS) is a rare musculoskeletal congenital anomaly with a wide spectrum of presentations. It is typically characterized by hypoplasia or aplasia of... (Review)
Review
Poland's syndrome (PS) is a rare musculoskeletal congenital anomaly with a wide spectrum of presentations. It is typically characterized by hypoplasia or aplasia of pectoral muscles, mammary hypoplasia and variably associated ipsilateral limb anomalies. Limb defects can vary in severity, ranging from syndactyly to phocomelia. Most cases are sporadic but familial cases with intrafamilial variability have been reported. Several theories have been proposed regarding the genesis of PS. Vascular disruption theory, "the subclavian artery supply disruption sequence" (SASDS) remains the most accepted pathogenic mechanism. Clinical presentations can vary in severity from syndactyly to phocomelia in the limbs and in the thorax, rib defects to severe chest wall anomalies with impaired lung function. Most patients have subtle presentation at birth and milder forms in childhood. Functional limitations due to PS are usually minimal. Surgical treatment aims to improve pulmonary functions arising from severe thoracic deformities but is more often done to enhance the cosmesis. The use of adipose-derived mesenchymal stem cells and fat transfer have shown promising results in recent times for correction of chest defects and breast augmentation. Gaining deeper insights into the etiopathogenesis and clinical presentation of PS will improve the clinical recognition and management of this rare condition. In this review article, we aim to outline the details of this syndrome including its etiopathogenesis, evolution, spectrum of clinical manifestations, other systemic associations, diagnostic modalities, and recent advances in treatment.
PubMed: 34012849
DOI: 10.21037/tp-20-320 -
Therapeutic Innovation & Regulatory... Nov 2021Thalidomide (α-phthalimidoglutaride) was marketed in the 1950s and early 1960s; it was promoted as a sedative-hypnotic agent with minimal hangover. It was available in... (Review)
Review
Implementation of a Pregnancy Prevention Programme (PPP) with a Controlled Distribution System (CDS) for the Generic Teratogenic Phthalimides Thalidomide, Lenalidomide and Pomalidomide.
Thalidomide (α-phthalimidoglutaride) was marketed in the 1950s and early 1960s; it was promoted as a sedative-hypnotic agent with minimal hangover. It was available in some countries as an over-the-counter medicine. Publications reporting profound teratogenic effects with thalidomide brought about major revisions to the monitoring of the safety of medicines. As a consequence of previously unrecognised teratogenic effects, it has been estimated that over 12,000 children were born with a range of defects and disabilities, including severe congenital anomalies. Notably, it has been hypothesised that around 40% of babies with thalidomide-induced malformations born during the 1950s and 1960s died in the neonatal period. The commonest causes of death were atresia of the small bowel, cardiac or renal malformations. Nevertheless, phocomelia (as a typical manifestation of thalidomide´s teratogenic effects) has been reported once again after thalidomide was approved for use in areas where leprosy is endemic. As a result, thalidomide embryopathy remains an important topic in countries such as Brazil. Nowadays thalidomide is approved around the world for the treatment of a wide range of conditions, including leprosy, Crohn's disease, multiple myeloma, and certain malignant solid tumours. Second-generation immunmodulatory drugs including lenalidomide and pomalidomide have received approval for use in the management of various forms of neoplastic disease. Based on clinical experience with thalidomide and its derivatives, learnings have been transferred to further research on a subset of substituted phthalimides each of which has a high risk of causing teratogenic effects. This group of phthalimides is classified within regulatory science as human teratogens. In order to gain approval, a Pregnancy Prevention Programme (PPP), along with a Controlled Distribution System (CDS) is required. The challenges of PPPs in particular for a generic manufacturer have been described, including Raising of awareness, and education; Special aspects of data collection and evaluation; Ethically and socially relevant aspects, and Utilising existing information technology and infrastructure. This paper highlights the risks of unplanned pregnancies, provides information on the regulatory background, and regulatory expectations. Our aim is to provide insights and practical learnings that have impacted operational risk management with the teratogenic phthalimides. Opportunities are presented that may support the implementation of harmonised approaches for PPP and CDS using existing IT-systems across countries and companies.
Topics: Child; Female; Humans; Infant, Newborn; Lenalidomide; Phthalimides; Pregnancy; Teratogens; Thalidomide
PubMed: 34331266
DOI: 10.1007/s43441-021-00327-3 -
Journal of Virological Methods May 2020The aim of the work was to create a sensitive and fast immunochemical test for the detection of orthopoxviruses (OPXV) in the "point of care" format. This work presents... (Comparative Study)
Comparative Study
The aim of the work was to create a sensitive and fast immunochemical test for the detection of orthopoxviruses (OPXV) in the "point of care" format. This work presents the results of the comparative evaluation of a single-stage (rapid version) and two-stage protocol of dot-immunoassay based on plane protein array for detection of vaccinia virus (VACV), cowpoxvirus (CPXV) and ectromelia virus (ECTV) in viral culture materials with different degrees of purification. It has been established that rabbit polyclonal VACV-antibodies can be used in a one-stage dot-analysis, both as a capture agent immobilized on a substrate and as a detection reagent bound with colloidal gold particles. It is shown that the sensitivity of detection of OPXV is inversely related to the degree of purification of viruses. The one-stage variant of the dot-immunoassay allows reducing the analysis time to 39 min and increasing the detection sensitivity of all the studied orthopoxviruses in crude viral samples to a range of 10-10 PFU/mL. The increase in sensitivity in the rapid version of the analysis, presumably, occurs due to binding of capture antibodies to subviral structures that form large aggregates of gold particles. Ultrasonic treatment of culture virus reduces the detection sensitivity, presumably due to both the destruction of conformational epitopes located on the surface of subvirus structures, as well as the increase in the dispersion of cell debris, which limits diffusion and contacts of viral antigens with capture antibodies on the substrate. Both versions of the analysis are specific and do not detect interactions both with preparations of non-infected cell culture and with heterogeneous controls of the causative agents of erythematous infections. The rapid protocol of dot-immunnoassay described above can be used to detect, or help to exclude, the presence of threat viruses in samples and could be useful in a variety of biodefense applications. Ready-to-use setup, ease of analysis and the ability to visually accounting for results allow the test to be used outside of laboratories.
Topics: Animals; Antibodies, Viral; Antigens, Viral; Cell Line; Epitopes; Immunoassay; Limit of Detection; Orthopoxvirus; Protein Array Analysis; Rabbits; Sensitivity and Specificity; Vaccinia virus; Viral Proteins
PubMed: 32209339
DOI: 10.1016/j.jviromet.2020.113859 -
Archiv Der Pharmazie Jun 2021Although the World Health Organisation had announced that smallpox was eradicated over 40 years ago, the disease and other related pathogenic poxviruses such as...
Although the World Health Organisation had announced that smallpox was eradicated over 40 years ago, the disease and other related pathogenic poxviruses such as monkeypox remain potential bioterrorist weapons and could also re-emerge as natural infections. We have previously reported (+)-camphor and (-)-borneol derivatives with an antiviral activity against the vaccinia virus. This virus is similar to the variola virus (VARV), the causative agent of smallpox, but can be studied at BSL-2 facilities. In the present study, we evaluated the antiviral activity of the most potent compounds against VARV, cowpox virus, and ectromelia virus (ECTV). Among the compounds tested, 4-bromo-N'-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)benzohydrazide 18 is the most effective compound against various orthopoxviruses, including VARV, with an EC value of 13.9 μM and a selectivity index of 206. Also, (+)-camphor thiosemicarbazone 9 was found to be active against VARV and ECTV.
Topics: Animals; Antiviral Agents; Camphanes; Camphor; Cells, Cultured; Humans; Isoindoles; Orthopoxvirus; Poxviridae Infections; Thiosemicarbazones
PubMed: 33605479
DOI: 10.1002/ardp.202100038 -
Molecular Genetics & Genomic Medicine Jun 2023Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene....
OBJECTIVE
Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene. Cardinal clinical manifestations are pre- and postnatal growth retardation and craniofacial and limb malformations. Here, we report RBS in a Chinese adolescent with novel biallelic ESCO2 variations and complex cerebrovascular diseases.
METHODS
Medical history, neurological examinations, neuroimaging, and pathology were collected in the proband and the family. Whole exome sequencing (WES) with copy number variation analysis was performed to screen for genetic variations.
RESULTS
The clinical features of the proband were craniofacial and limb malformations together with complex cerebrovascular diseases. She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old. Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts. Brain histopathology revealed angiomatous changes and perivascular cysts suggesting chronic small cerebral vasculopathy. Whole exome sequencing (WES) identified novel biallelic variations in the ESCO2 gene (c.1220A>T, p.H407L and c.1562delC, p.A521fs).
CONCLUSIONS
We describe complex cerebrovascular diseases in Roberts syndrome caused by novel ESCO2 biallelic variations. This case expands not only the cerebral involvement in Roberts syndrome but also the disease spectrum of the neuroimaging triad with leukoencephalopathy, calcifications, and cysts.
Topics: Craniofacial Abnormalities; Humans; Female; Adolescent; Acetyltransferases; Chromosomal Proteins, Non-Histone; East Asian People; Cerebrovascular Disorders
PubMed: 37002187
DOI: 10.1002/mgg3.2177 -
SAGE Open Medical Case Reports 2023The treatment of osteoarthritis in patients with phocomelia with total knee arthroplasty is challenging due to the unusual anatomy and severe deformities. The authors...
The treatment of osteoarthritis in patients with phocomelia with total knee arthroplasty is challenging due to the unusual anatomy and severe deformities. The authors present a case of phocomelia caused by thalidomide with end-stage osteoarthritis and grossly medialized patella. The patient was treated with a cemented constrained non-hinged prosthesis and patelloplasty. Six months later, the patient had complete relief of pain and was able to walk without walking assistance. To our knowledge, total knee replacement in a patient with phocomelia caused by thalidomide has not been described in literature.
PubMed: 36798679
DOI: 10.1177/2050313X231154635