scholarly journals Expression of an active Gαs mutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance

2017 ◽  
Vol 115 (3) ◽  
pp. E428-E437 ◽  
Author(s):  
Xuefeng Zhao ◽  
Peng Deng ◽  
Ramiro Iglesias-Bartolome ◽  
Panomwat Amornphimoltham ◽  
Dana J. Steffen ◽  
...  
Keyword(s):  
Fibrous Dysplasia ◽  
Treatment Options ◽  
Fibrous Tissue ◽  
Genetic Alterations ◽  
Bone Lesions ◽  
Α Subunit ◽  
Activating Mutations ◽  
Adult Mice ◽  
New Treatment ◽  
Lesion Regression

Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the α-subunit of the Gs stimulatory protein. FD is characterized by the development of areas of abnormal fibroosseous tissue in the bones, resulting in skeletal deformities, fractures, and pain. Despite the well-defined genetic alterations underlying FD, whether GNAS activation is sufficient for FD initiation and the molecular and cellular consequences of GNAS mutations remains largely unresolved, and there are no currently available targeted therapeutic options for FD. Here, we have developed a conditional tetracycline (Tet)-inducible animal model expressing the GαsR201C in the skeletal stem cell (SSC) lineage (Tet–GαsR201C/Prrx1-Cre/LSL-rtTA-IRES-GFP mice), which develops typical FD bone lesions in both embryos and adult mice in less than 2 weeks following doxycycline (Dox) administration. Conditional GαsR201C expression promoted PKA activation and proliferation of SSCs along the osteogenic lineage but halted their differentiation to mature osteoblasts. Rather, as is seen clinically, areas of woven bone admixed with fibrous tissue were formed. GαsR201C caused the concomitant expression of receptor activator of nuclear factor kappa-B ligand (Rankl) that led to marked osteoclastogenesis and bone resorption. GαsR201C expression ablation by Dox withdrawal resulted in FD-like lesion regression, supporting the rationale for Gαs-targeted drugs to attempt FD cure. This model, which develops FD-like lesions that can form rapidly and revert on cessation of mutant Gαs expression, provides an opportunity to identify the molecular mechanism underlying FD initiation and progression and accelerate the development of new treatment options.

scholarly journals Tibial fibrous dysplasia in children treated by Ilizarov technique – a review of treatment options

2021 ◽  
Vol 27 (3) ◽  
pp. 357-360
Author(s):  
M.M. Bari ◽  
◽  
I. Shahidul ◽  
A. Tanvir ◽  
A.M. Shayan R. Bari ◽  
...  
Keyword(s):  
Fibrous Dysplasia ◽  
Operative Treatment ◽  
Pathological Condition ◽  
Treatment Options ◽  
Fibrous Tissue ◽  
Ilizarov Technique ◽  
Medullary Bone

Fibrous dysplasia is a pathological condition, where normal medullary bone is replaced by fibrous tissue and small woven specules of bone. Fibrous dysplasia can occur in epiphysis, metaphysis or diaphysis. Occasionally, biopsy is necessary to establish the diagnosis. We present a review of operative treatment using the Ilizarov technique.

Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: Preliminary data from MyPathway.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 402-402 ◽  
Author(s):  
Milind M. Javle ◽  
John D. Hainsworth ◽  
Charles Swanton ◽  
Howard A. Burris ◽  
Razelle Kurzrock ◽  
...  
Keyword(s):  
Preliminary Data ◽  
Therapeutic Target ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Biliary Cancer ◽  
Her2 Positive ◽  
Open Label ◽  
Activating Mutations ◽  
Tumor Types

402 Background: Biliary cancers have a high mortality rate, with limited treatment options. While HER2 is overexpressed in 9-20% of biliary cancers, it has not been fully explored as a therapeutic target. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. We present preliminary data for patients with HER2-positive metastatic biliary cancer receiving HER2-targeted treatment with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is an open-label, multicenter, phase IIA study. Patients in this subset analysis had refractory metastatic biliary cancer with HER2 amplification/overexpression or putative activating mutations by gene sequencing, FISH, or IHC. Patients received standard doses of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (RECIST v1.1). Results: As of July 31, 2016, 11 patients with HER2-positive biliary cancer (HER2-amplified/overexpressed, n = 8; HER2-mutated, n = 3 [D277Y, S310F, and A775-G776insYVMA]) have been enrolled. At a median follow-up of 4.2 (range 2.0–12.0) months, 4 patients had partial responses (PR) and 3 had stable disease (SD) for > 4 months (Table). Safety was consistent with the package inserts. Conclusions: Preliminary results indicate that pertuzumab + trastuzumab has activity in HER2 amplified/overexpressed/mutated metastatic biliary tumors, suggesting HER2 as a therapeutic target for these rare cancers. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]

scholarly journals Frontal bone fibrous dysplasia in a 6-months-old boy: A distinctive entity

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Kleanthis Anastasiadis ◽  
Vassilis Lambropoulos ◽  
Kalliopi Tsoleka ◽  
Chrysostomos Kepertis ◽  
Vassilis Mouravas ◽  
...  
Keyword(s):  
Fibrous Dysplasia ◽  
Stromal Cells ◽  
Fibrous Tissue ◽  
Activating Mutations ◽  
Normal Bone ◽  
Woven Bone ◽  
Gnas Gene ◽  
Cosmetic Effect ◽  
Differentiation And Proliferation ◽  
Malignant Condition

Fibrous Dysplasia (FD) is a non-malignant condition caused by post-zygotic, activating mutations of the GNAS gene that results in inhibition of the differentiation and proliferation of bone-forming stromal cells and leads to the replacement of normal bone and marrow by fibrous tissue and woven bone. The clinical behavior and progression of FD is variable. The management of this condition is difficult and in every case is strictly individualized. We report a case of frontal fibrous dysplasia in a 6month’s old boy who underwent a successfully resection of the lesion with an excellent cosmetic effect.

scholarly journals Phylostratigraphic analysis of tumor and developmental transcriptomes reveals relationship between oncogenesis, phylogenesis and ontogenesis

2017 ◽  
Author(s):  
Joseph X. Zhou ◽  
Luis Cisneros ◽  
Theo Knijnenburg ◽  
Kalliopi Trachana ◽  
Paul Davies ◽  
...  
Keyword(s):  
Treatment Options ◽  
Age Distribution ◽  
Genetic Alterations ◽  
Cancer Tissue ◽  
Control Mechanisms ◽  
Ancestral State ◽  
Bioinformatics Analyses ◽  
Differentiated Cells ◽  
Ultimate Explanation ◽  
New Treatment

ABSTRACTThe question of the existence of cancer is inadequately answered by invoking somatic mutations or the disruptions of cellular and tissue control mechanisms. As such uniformly random events alone cannot account for the almost inevitable occurrence of an extremely complex process such as cancer. In the different epistemic realm, an ultimate explanation of cancer is that cancer is a reversion of a cell to an ancestral pre-Metazoan state, i.e. a cellular form of atavism. Several studies have suggested that genes involved in cancer have evolved at particular evolutionary time linked to the unicellular-multicellular transition. Here we used a refined phylostratigraphic analysis of evolutionary ages of the known genes/pathways associated with cancer and the genes differentially expressed between normal and cancer tissue as well as between embryonic and mature (differentiated) cells. We found that cancer-specific transcriptomes and cancer-related pathways were enriched for genes that evolved in the pre-Metazoan era and depleted of genes that evolved in the post-Metazoan era. By contrast an opposite relation was found for cell maturation: the age distribution frequency of the genes expressed in differentiated epithelial cells were enriched for post-Metazoan genes and depleted of pre-Metazoan ones. These findings support the atavism theory that cancer cells manifest the reactivation of an ancient ancestral state featuring unicellular modalities. Thus our bioinformatics analyses suggest that not only does oncogenesis recapitulate ontogenesis, and ontogenesis recapitulates phylogenesis, but also oncogenesis recapitulates phylogenesis. This more encompassing perspective may offer a natural organizing framework for genetic alterations in cancers and point to new treatment options that target the genes controlling the atavism transition.One Sentence SummaryTracing cancer gene evolutionary ages revealed that cancer reverts to a pre-existing early Metazoan state.

scholarly journals Tibial fibrous dysplasia in children treated by Ilizarov Technique- A review of treatment options

2021 ◽  
Vol 13 (2) ◽  
pp. 26-29
Author(s):  
Bari MM ◽  
Islam Shahidul ◽  
Ashraf Tanvir ◽  
 Bari AM Shayan R
Keyword(s):  
Fibrous Dysplasia ◽  
Operative Treatment ◽  
Pathological Condition ◽  
Treatment Options ◽  
Fibrous Tissue ◽  
Ilizarov Technique ◽  
Medullary Bone

ibrous dysplasia is a pathological condition, where normal medullary bone is replaced by fibrous tissue and small, woven specules of bone. Fibrous dysplasia can occur in epiphysis, metaphysis or diaphysis. Occationally, biopsy is necessary to establish the diagnosis. We present a review of operative treatment using the Ilizarov technique.

scholarly journals Biological treatment of severe asthma: new objectives and new treatment options

2019 ◽  
pp. 50-61
Author(s):  
N. M. Nenasheva
Keyword(s):  
Monoclonal Antibody ◽  
Atopic Dermatitis ◽  
Severe Asthma ◽  
Biological Treatment ◽  
Treatment Options ◽  
Severe Atopic Dermatitis ◽  
Α Subunit ◽  
Main Emphasis ◽  
New Treatment

This article is devoted to the main characteristics of severe bronchial asthma (SBA) and its heterogeneity, in particular, T2 asthma is characterized and the role of the main cytokines forming T2-inflammation is presented. The main emphasis is made on the role of the IL-4 and IL-13 in the pathogenesis of AD as the key cytokines in the initiation and maintenance of T2-inflammation, as well as on a new biological molecule – monoclonal antibody – dupilumab, directed to the α-subunit of IL-4 receptor, thus blocking the pathways of IL-4 and IL-13. Dupilumab has recently been registered in our country for the treatment of moderate and severe BA, as well as moderate and severe atopic dermatitis. The article presents the clinical efficacy and tolerability of dupillumab in patients with moderate and severe BA.

Management of thoracic aortic lesions - the future is endovascular

VASA ◽  
2012 ◽  
Vol 41 (3) ◽  
pp. 163-176 ◽  
Author(s):  
Weidenhagen ◽  
Bombien ◽  
Meimarakis ◽  
Geisler ◽  
A. Koeppel
Keyword(s):  
Thoracic Aorta ◽  
Clinical Decision Making ◽  
Treatment Options ◽  
Clinical Decision ◽  
Clinical Results ◽  
Treatment Modalities ◽  
Traumatic Rupture ◽  
Descending Thoracic Aorta ◽  
New Treatment ◽  
Aneurysm Dissection

Open surgical repair of lesions of the descending thoracic aorta, such as aneurysm, dissection and traumatic rupture, has been the “state-of-the-art” treatment for many decades. However, in specialized cardiovascular centers, thoracic endovascular aortic repair and hybrid aortic procedures have been implemented as novel treatment options. The current clinical results show that these procedures can be performed with low morbidity and mortality rates. However, due to a lack of randomized trials, the level of reliability of these new treatment modalities remains a matter of discussion. Clinical decision-making is generally based on the experience of the vascular center as well as on individual factors, such as life expectancy, comorbidity, aneurysm aetiology, aortic diameter and morphology. This article will review and discuss recent publications of open surgical, hybrid thoracic aortic (in case of aortic arch involvement) and endovascular repair in complex pathologies of the descending thoracic aorta.

Cystic Bone Lesions in Horses and Humans: A Comparative Review

1998 ◽  
Vol 11 (01) ◽  
pp. 08-18 ◽  
Author(s):  
C. W. McIlwraith ◽  
J. A. Auer ◽  
Brigitte von Rechenberg
Keyword(s):  
Recurrence Rate ◽  
Subchondral Bone ◽  
Fibrous Tissue ◽  
Clinical Signs ◽  
Bone Lesions ◽  
Anatomical Location ◽  
Cystic Lesions ◽  
Bone Cysts ◽  
Biological Behaviour ◽  
Comparative Review

SummaryCases of cystic bone lesions in horses and humans were reviewed in the literature. These lesions are radiolucent areas of bone, recognized as subchondral cystic lesions in the horse (SCL), intra-osseous ganglia (IOG), subchondral bone cysts secondary to osteoarthrosis (OAC), and unicameral bone cysts (UCB) in humans. Their morphology is quite similar, consisting of lesions with a distinct cyst wall, and a cavity filled with fibrous tissue and yellowish mucoid fluid. The lesions are surrounded by sclerotic bone and can be easily diagnosed radiographically. SCL, IOG and OAC occur in the subchondral bone close to the adjacent joint, whereas UCB occur in the metaphysis of long bones. Their aetiology and pathogenesis is still unknown, although primary damage to the subchondral bone, cartilage or local blood supply and growth disturbances are discussed. In this review 703 lesions of SCL in horses, 289 lesions of IOG and 1460 lesions of UCB in humans were compared in their anatomical location and clinical signs. SCL and OAC resembled each other with respect to anatomical location. A correlation of affected bones could not be found for all four groups. Clinical presentation concerning age was most similar for SCL and UCB with both lesions mainly occurring in young individuals. Gender predominance of males was present in SCL, IOG and UCB. Clinical diagnosis was either incidental, or connected with intermittent pain in all lesions except for OAC. Additionally, the lesions were also found in conjunction with degenerative joint disease (SCL, OAC) or pathological fractures (UCB). Cystic bone lesions were either treated conservatively, surgically with curettage alone, curettage in combination with grafting procedures, or intra-lesional application of corticosteroids. SCL and UCB were similar in their biological behaviour concerning their slow response to the therapy and relatively high recurrence rate. None of the cystic bone lesions were comparable, and a common aetiology and pathogenesis could not be found.In a literature review cases of cystic bone lesions in horses and humans were compared with the goal to find a common aetiology and pathogenesis. Cystic bone lesions occur in horses as subchondral cystic lesions (SCL), and in humans as either intra-osseous ganglia (IOG), subchondral cystic lesions secondary to osteoarthrosis (OAC) or unicameral bone cysts (UCB). IOG and OAC compare with SCL mainly in the anatomical location. IOG and SCL resemble each other in size, clinical signs and histology, whereas UCB and SCL show a similar biological behaviour regarding their therapeutic response and recurrence rate. None of the cystic bone lesions in humans were comparable to the SCL in horses in all aspects. A common aetiology and pathogenesis could not be established.

A Genomic Approach to Characterize the Vulnerable Patient – a Clinical Update

2019 ◽  
Vol 4 (3) ◽  
pp. 141-144
Author(s):  
Evelin Szabó ◽  
Zsolt Parajkó ◽  
Diana Opincariu ◽  
Monica Chițu ◽  
Nóra Raț ◽  
...  
Keyword(s):  
Risk Factors ◽  
Myocardial Ischemia ◽  
Treatment Options ◽  
Ischemic Heart ◽  
Pathophysiological Mechanism ◽  
Ischemia And Reperfusion Injury ◽  
Myocardial Ischemia And Reperfusion ◽  
Vulnerable Patient ◽  
Traditional Risk Factors ◽  
New Treatment

Abstract Atherosclerosis is the elemental precondition for any cardiovascular disease and the predominant cause of ischemic heart disease that often leads to myocardial infarction. Systemic risk factors play an important role in the starting and progression of atherosclerosis. The complexity of the disease is caused by its multifactorial origin. Besides the traditional risk factors, genetic predisposition is also a strong risk factor. Many studies have intensively researched cardioprotective drugs, which can relieve myocardial ischemia and reperfusion injury, thereby reducing infarct size. A better understanding of abnormal epigenetic pathways in the myocardial pathology may result in new treatment options. Individualized therapy based on genome sequencing is important for an effective future medical treatment. Studies based on multiomics help to better understand the pathophysiological mechanism of several diseases at a molecular level. Epigenomic, transcriptomic, proteomic, and metabolomic research may be essential in detecting the pathological phenotype of myocardial ischemia and ischemic heart failure.

Proteomic Analysis of the Vitreous Body in Proliferative and Non-Proliferative Diabetic Retinopathy

2020 ◽  
Vol 17 ◽  
Author(s):  
Van-An Duong ◽  
Jeeyun Ahn ◽  
Na-Young Han ◽  
Jong-Moon Park ◽  
Jeong-Hun Mok ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Proliferative Diabetic Retinopathy ◽  
Microvascular Complications ◽  
Treatment Options ◽  
Vitreous Body ◽  
Control Group ◽  
Diabetic Patients ◽  
Protein Protein Interaction ◽  
Alpha Beta ◽  
New Treatment

Background: Diabetic Retinopathy (DR), one of the major microvascular complications commonly occurring in diabetic patients, can be classified into Proliferative Diabetic Retinopathy (PDR) and Non-Proliferative Diabetic Retinopathy (NPDR). Currently available therapies are only targeted for later stages of the disease in which some pathologic changes may be irreversible. Thus, there is a need to develop new treatment options for earlier stages of DR through revealing pathological mechanisms of PDR and NPDR. Objective: The purpose of this study was to characterize proteomes of diabetic through quantitative analysis of PDR and NPDR. Methods: Vitreous body was collected from three groups: control (non-diabetes mellitus), NPDR, and PDR. Vitreous proteins were digested to peptide mixtures and analyzed using LC-MS/MS. MaxQuant was used to search against the database and statistical analyses were performed using Perseus. Gene ontology analysis, related-disease identification, and protein-protein interaction were performed using the differential expressed proteins. Results: Twenty proteins were identified as critical in PDR and NPDR. The NPDR group showed different expressions of kininogen-1, serotransferrin, ribonuclease pancreatic, osteopontin, keratin type II cytoskeletal 2 epidermal, and transthyretin. Also, prothrombin, signal transducer and activator of transcription 4, hemoglobin subunit alpha, beta, and delta were particularly up-regulated proteins for PDR group. The up-regulated proteins related to complement and coagulation cascades. Statherin was down-regulated in PDR and NPDR compared with the control group. Transthyretin was the unique protein that increased its abundance in NPDR compared with the PDR and control group. Conclusion: This study confirmed the different expressions of some proteins in PDR and NPDR. Additionally, we revealed uniquely expressed proteins of PDR and NPDR, which would be differential biomarkers: prothrombin, alpha-2-HS-glycoprotein, hemoglobin subunit alpha, beta, and transthyretin.

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