scholarly journals Genetic Alterations of Malignant Pleural Mesothelima

Mesothelioma ◽  
2020 ◽  
Author(s):  
Benjamin Wadowski ◽  
David T. Severson ◽  
Raphael Bueno ◽  
Assunta De Rienzo
Keyword(s):  
Medical Diagnosis ◽  
Molecular Mechanisms ◽  
Asbestos Exposure ◽  
Mesothelial Cell ◽  
Latency Period ◽  
Genetic Alterations ◽  
Long Latency ◽  
History Of ◽  
Aggressive Tumor ◽  
Generation Sequencing

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that arises from the mesothelial cells lining the pleural cavity. Asbestos is considered the major factor in the pathogenesis of this malignancy, with more than 80% of patients with a history of asbestos exposure. MPM is characterized by a long latency period, typically 20–40 years from the time of asbestos exposure to diagnosis, suggesting that multiple somatic genetic alterations are required for the tumorigenic conversion of a mesothelial cell. In the last few years, advancements in next-generation sequencing and “–omics” technologies have revolutionized the field of genomics and medical diagnosis. The focus of this chapter is to summarize recent studies which explore the molecular mechanisms underlying this disease and identify potential therapeutic targets in MPM.

“Re-Emergence” of Silicosis and Coal Workers Pneumoconiosis in Australia

2020 ◽  
Vol 119 (1) ◽  
pp. 65-92
Author(s):  
Beris Penrose
Keyword(s):  
Data Collection ◽  
Coal Mining ◽  
Disease Onset ◽  
Latency Period ◽  
Dust Exposure ◽  
Long Latency ◽  
History Of ◽  
Coal Workers Pneumoconiosis ◽  
Coal Workers

Some reporters, politicians, and doctors have described current cases as a “re-emergence” of these diseases, based on the notion that they had been eliminated. However, silicosis persisted in centuries-old industries like sandblasting and stonemasonry and coal workers pneumoconiosis (CWP) continued in coal mining. Until recently, their presence was obscured by a combination of factors such as misdiagnosis, especially if there was a history of smoking; the failure to follow up workers thought to have silicosis or CWP; the long latency period between dust exposure and disease onset that can conceal the link between the two; and the lack of data collection that may have revealed their presence. As the recent Queensland government inquiry into CWP noted, current cases are more accurately a reidentification.

The Activated K-RAS Protein Accelerates Human Derived-MLL/AF4 Induced Leukemo-Lymphomogenicity In Transgenic Mice Model

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 61-61
Author(s):  
Hayato Tamai ◽  
Koichi Miyake ◽  
Miyuki Takatori ◽  
Noriko Miyake ◽  
Hiroki Yamaguchi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Latency Period ◽  
Histopathological Analysis ◽  
Murine Models ◽  
Lymphoma Cells ◽  
Ras Mutation ◽  
Long Latency

Abstract Abstract 61 Acute lymphoblastic leukemia (ALL) with MLL/AF4 fusion is a common infant leukemia associated with a poor prognosis. Research into the molecular mechanisms underlying ALL with MLL/AF4 has been hampered by the absence of a good animal model: there is a large discrepancy between the time to disease onset in infants and the long latency seen in previously established murine models (human derived-AF4 knock-in and inverter model). We speculated that the absence of associated K-RAS mutations could explain the long latency seen in murine models of ALL with MLL/AF4. To establish a model combining MLL/AF4 fusion and activated K-RAS, we first established MLL/AF4+ transgenic (Tg) mice through overexpression of human MLL/AF4 fusion protein. These MLL/AF4+ Tg mice exhibited splenomegaly and lung tumors at 8–12 months of age (median, 12 months), and histopathological analysis showed disruption of the spleen structure and infiltration of the liver, lung and spleen by lymphoma cells consisted of pro B-cells (CD45R/B220+CD43+). Western blot analysis showed expression of both MLL/AF4 and HoxA9 was upregulated in all of the tissues tested. Infiltration of tumor cells into the peripheral blood was observed after a long latency period in MLL/AF4+ Tg mice (median, 14 months), at which time abnormal lymphocytes accounted for 7.2±1.2% (n=5) of white blood cells. FACS analysis showed these abnormal lymphocytes to be CD45R/B220+CD43+CD19+ cells, which is the same phenotype as the lymphoma cells. To develop a more aggressive oncogenic model mouse, we generated MLL/AF4+K-RAS mutation+ Tg mice by crossing MLL/AF4+ Tg mice and K-RAS mutation (G12D)+ Tg mice. The resultant mice developed lymphoma significantly earlier (median, 6 months) than MLL/AF4+ Tg mice (median LFS: 5.5 months vs. 12 months, P=0.001). Infiltration of tumor cells into the peripheral blood was observed after a short latency period in MLL/AF4+K-RAS mutation+ Tg mice (median age, 6 months), at which time leukemia cells accounted for 3.2±0.9% of WBCs, suggesting the collaborative acceleration of leukemo-lymphomogenicity through overexpression of MLL/AF4 and mutant K-RAS. We anticipate that the MLL/AF4+K-RAS mutation+ Tg mouse model will be useful for studying the molecular mechanisms of MLL/AF4 leukemogenesis and for developing new therapies against MLL-related malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Limb regeneration in salamanders: the plethodontid tale

2020 ◽  
Vol 52 ◽  
Author(s):  
Claudia M. Arenas Gómez ◽  
Jean P. Delgado
Keyword(s):  
Limb Development ◽  
Molecular Mechanisms ◽  
Limb Regeneration ◽  
Ambystoma Mexicanum ◽  
South American ◽  
Plethodontid Salamanders ◽  
History Of ◽  
Salamander Species ◽  
Generation Sequencing ◽  
Recent Sequencing

Salamanders are the only vertebrates that can regenerate limbs as adults. This makes them ideal models to investigate cellular and molecular mechanisms of tissue regeneration. Ambystoma mexicanum and Nothopthalmus viridescens have long served as primary salamander models of limb regeneration, and the recent sequencing of the axolotl genome now provides a blueprint to mine regeneration insights from other salamander species. In particular, there is a need to study South American plethodontid salamanders that present different patterns of limb development and regeneration. A broader sampling of species using next-generation sequencing approaches is needed to reveal shared and unique mechanisms of regeneration, and more generally, the evolutionary history of salamander limb regeneration.

scholarly journals Meta-Analysis of the Association between Asbestos Exposure and Esophageal Cancer

2021 ◽  
Vol 18 (21) ◽  
pp. 11088
Author(s):  
Chih-Wei Wu ◽  
Hung-Yi Chuang ◽  
Dong-Lin Tsai ◽  
Tzu-Yu Kuo ◽  
Chen-Cheng Yang ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Subgroup Analysis ◽  
Textile Industry ◽  
Meta Analysis ◽  
Asbestos Exposure ◽  
Latency Period ◽  
High Dose ◽  
Long Latency ◽  
Standardized Mortality Rate

Background: We conducted a meta-analysis to quantitatively assess the association between asbestos exposure and esophageal cancer. Methods: We systematically collected articles from three electronic databases and calculated the pooled standardized mortality rate (SMR) from the meta-analysis. Subgroup analysis according to the type of asbestos exposure, follow-up years, sample size, industry classification, sex, and high-dose exposure was conducted. Results: From 242 studies, 34 cohort studies were included in our meta-analysis. Pooled SMR was positively associated with asbestos exposure and esophageal cancer (pooled SMR = 1.28; 95% confidence interval (CI) 1.19–1.38, p < 0.00001). In the subgroup analysis, (1) chrysolite, (2) four groups with follow-up over ten years, (3) the textile industry and shipyard, (4) both male and female, and (5) eight studies on highest asbestos exposure, all the subgroups showed significantly increased pooled SMRs. Conclusion: Asbestos exposure was significantly and positively associated with esophageal cancer, especially chrysolite. Considering the long latency period, we suggest that patients should be followed up for cancer, including esophageal cancer, for over ten years.

scholarly journals Pre-Clinical Research Advancements Relating to Improving the Diagnosis and Treatment of Malignant Pleural Mesothelioma: A Review

Onco ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 49-82
Author(s):  
Ben Johnson ◽  
Kenneth Lee ◽  
Yuen Yee Cheng
Keyword(s):  
Clinical Research ◽  
Malignant Pleural Mesothelioma ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Latency Period ◽  
Pleural Mesothelioma ◽  
Diagnostic Biomarkers ◽  
Disease Biology ◽  
Long Latency

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the lung lining that is predominantly associated with occupational exposure to asbestos. MPM is responsible for thousands of deaths worldwide every year, with the median survival of MPM of 8–14 months. There are limited biomarkers available in the clinic to effectively diagnose MPM, an invasive biopsy procedure is usually required to provide a definitive diagnosis. Due to the long latency period associated with MPM disease presentation, the cancer is usually at an advanced stage at the time of diagnosis where treatment options are largely ineffective at controlling disease progression. Previous MPM-based pre-clinical studies have made significant strides in determining the exact molecular mechanisms associated with asbestos carcinogenesis. Exploring less invasive blood-based biomarkers and treatment strategies involving targeted therapy, immunotherapy, and virotherapy is particularly important. Research in these areas is of crucial importance in relation to improving the rate of novel diagnostic biomarkers and treatment strategies progressing through to clinical trials and ultimately into the clinical setting. This review comprehensively summarises both previous and current pre-clinical research developments that have specifically contributed to an improved understanding of MPM disease biology, and the development of novel diagnostic biomarkers and treatment strategies.

scholarly journals A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations

2018 ◽  
Vol 36 (35) ◽  
pp. 3485-3494 ◽  
Author(s):  
Sandra Pastorino ◽  
Yoshie Yoshikawa ◽  
Harvey I. Pass ◽  
Mitsuru Emi ◽  
Masaki Nasu ◽  
...  
Keyword(s):  
Median Survival ◽  
Sanger Sequencing ◽  
Asbestos Exposure ◽  
Germline Mutations ◽  
Age At Diagnosis ◽  
Deleterious Mutations ◽  
Targeted Next Generation Sequencing ◽  
History Of ◽  
I 11 ◽  
Generation Sequencing

Purpose We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years. Patients and Methods Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing. Results Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001). Conclusion We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

scholarly journals Next Generation Sequencing for the Prediction of the Antibiotic Resistance in Helicobacter pylori: A Literature Review

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 437
Author(s):  
Ilaria Maria Saracino ◽  
Matteo Pavoni ◽  
Angelo Zullo ◽  
Giulia Fiorini ◽  
Tiziana Lazzarotto ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Next Generation Sequencing ◽  
Literature Review ◽  
Molecular Mechanisms ◽  
World Health ◽  
Next Generation ◽  
Culture Methods ◽  
Phenotypic Resistance ◽  
H Pylori ◽  
Generation Sequencing

Background and aims: Only a few antimicrobials are effective against H. pylori, and antibiotic resistance is an increasing problem for eradication therapies. In 2017, the World Health Organization categorized clarithromycin resistant H. pylori as a “high-priority” bacterium. Standard antimicrobial susceptibility testing can be used to prescribe appropriate therapies but is currently recommended only after the second therapeutic failure. H. pylori is, in fact, a “fastidious” microorganism; culture methods are time-consuming and technically challenging. The advent of molecular biology techniques has enabled the identification of molecular mechanisms underlying the observed phenotypic resistance to antibiotics in H. pylori. The aim of this literature review is to summarize the results of original articles published in the last ten years, regarding the use of Next Generation Sequencing, in particular of the whole genome, to predict the antibiotic resistance in H. pylori.Methods: a literature research was made on PubMed. The research was focused on II and III generation sequencing of the whole H. pylori genome. Results: Next Generation Sequencing enabled the detection of novel, rare and complex resistance mechanisms. The prediction of resistance to clarithromycin, levofloxacin and amoxicillin is accurate; for other antimicrobials, such as metronidazole, rifabutin and tetracycline, potential genetic determinants of the resistant status need further investigation.

scholarly journals Metastatic Extraskeletal Mesenchymal Chondrosarcoma of the Pancreas: Report of an Unusual Case with Review of Literature

2021 ◽  
Author(s):  
Saloni Naresh Shah ◽  
Ashok Parameswaran ◽  
Prasanna Kumar Reddy
Keyword(s):  
Unusual Case ◽  
English Literature ◽  
Latency Period ◽  
Sudden Onset ◽  
Mesenchymal Chondrosarcoma ◽  
Pancreatic Tumors ◽  
Good Survival ◽  
Review Of Literature ◽  
Long Latency ◽  
Extraskeletal Mesenchymal Chondrosarcoma

AbstractExtraskeletal mesenchymal chondrosarcoma (ESMC) metastasizing to the pancreas in isolation is a rare occurrence. We report a 49-year-old gentleman who had undergone excision of an ESMC of the thigh in 2009 and presented with sudden onset abdominal pain and icterus in 2019. Radiological imaging revealed calcified mass of the pancreas with multiple nodules with extension into the adipose tissue. Distal pancreatectomy was performed and the pathology revealed a bimorphic tumor composed of undifferentiated round blue cells with abrupt transition to hyaline cartilage, typical of mesenchymal chondrosarcoma. To the best of our knowledge, there are only seven prior cases of metastatic ESMC of the pancreas in the English literature. Surgical intervention appears to be the preferred modality of treatment for metastatic pancreatic tumors. These patients may have long latency period before metastasizing and seem to have a good survival period post excision.

scholarly journals Paracoccidioidomycosis Diagnosed in Europe—A Systematic Literature Review

2021 ◽  
Vol 7 (2) ◽  
pp. 157
Author(s):  
Gernot Wagner ◽  
Deddo Moertl ◽  
Anna Glechner ◽  
Verena Mayr ◽  
Irma Klerings ◽  
...  
Keyword(s):  
Latency Period ◽  
European Countries ◽  
Systemic Mycosis ◽  
Endemic Region ◽  
Travel History ◽  
Long Latency ◽  
Geographical Regions ◽  
The World ◽  
First Occurrence ◽  
Full Text Screening

Paracoccidioidomycosis is a systemic mycosis that is endemic in geographical regions of Central and South America. Cases that occur in nonendemic regions of the world are imported through migration and travel. Due to the limited number of cases in Europe, most physicians are not familiar with paracoccidioidomycosis and its close clinical and histopathological resemblance to other infectious and noninfectious disease. To increase awareness of this insidious mycosis, we conducted a systematic review to summarize the evidence on cases diagnosed and reported in Europe. We searched PubMed and Embase to identify cases of paracoccidioidomycosis diagnosed in European countries. In addition, we used Scopus for citation tracking and manually screened bibliographies of relevant articles. We conducted dual abstract and full-text screening of references yielded by our searches. To identify publications published prior to 1985, we used the previously published review by Ajello et al. Overall, we identified 83 cases of paracoccidioidomycosis diagnosed in 11 European countries, published in 68 articles. Age of patients ranged from 24 to 77 years; the majority were male. Time from leaving the endemic region and first occurrence of symptoms considerably varied. Our review illustrates the challenges of considering systemic mycosis in the differential diagnosis of people returning or immigrating to Europe from endemic areas. Travel history is important for diagnostic-workup, though it might be difficult to obtain due to possible long latency period of the disease.

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