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  1. Article ; Online: Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.

    Welch, Carrie L / Aldred, Micheala A / Balachandar, Srimmitha / Dooijes, Dennis / Eichstaedt, Christina A / Gräf, Stefan / Houweling, Arjan C / Machado, Rajiv D / Pandya, Divya / Prapa, Matina / Shaukat, Memoona / Southgate, Laura / Tenorio-Castano, Jair / Chung, Wendy K

    Genetics in medicine : official journal of the American College of Medical Genetics

    2023  Volume 25, Issue 11, Page(s) 100925

    Abstract: Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, ... ...

    Abstract Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing.
    Methods: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence.
    Results: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time.
    Conclusion: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.
    MeSH term(s) Adult ; Child ; Humans ; Pulmonary Arterial Hypertension/genetics ; Mutation ; Hypertension, Pulmonary/diagnosis ; Hypertension, Pulmonary/genetics ; Genetic Predisposition to Disease ; Genetic Testing ; Bone Morphogenetic Protein Receptors, Type II/genetics ; Bone Morphogenetic Protein Receptors, Type II/metabolism ; Adenosine Triphosphatases/genetics ; Membrane Transport Proteins/genetics ; Activin Receptors, Type II/genetics ; Protein Serine-Threonine Kinases/genetics ; Bone Morphogenetic Proteins/genetics
    Chemical Substances Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30) ; ATP13A3 protein, human (EC 3.6.1.-) ; Adenosine Triphosphatases (EC 3.6.1.-) ; Membrane Transport Proteins ; ACVRL1 protein, human (EC 2.7.11.30) ; Activin Receptors, Type II (EC 2.7.11.30) ; EIF2AK4 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; BMP10 protein, human ; Bone Morphogenetic Proteins
    Language English
    Publishing date 2023-07-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1455352-1
    ISSN 1530-0366 ; 1098-3600
    ISSN (online) 1530-0366
    ISSN 1098-3600
    DOI 10.1016/j.gim.2023.100925
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells.

    Kumar, Sandeep / Inigo, Joseph R / Kumar, Rahul / Chaudhary, Ajay K / O'Malley, Jordan / Balachandar, Srimmitha / Wang, Jianmin / Attwood, Kristopher / Yadav, Neelu / Hochwald, Steven / Wang, Xinjiang / Chandra, Dhyan

    Cancer letters

    2017  Volume 413, Page(s) 82–93

    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive disease and current treatment regimens fail to effectively cure PDAC. Development of resistance to current therapy is one of the key reasons for this outcome. Nimbolide (NL), a triterpenoid ... ...

    Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive disease and current treatment regimens fail to effectively cure PDAC. Development of resistance to current therapy is one of the key reasons for this outcome. Nimbolide (NL), a triterpenoid obtained from Azadirachta indica, exhibits anticancer properties in various cancer including PDAC cells. However, the underlying mechanism of this anticancer agent in PDAC cells remains undefined. We show that NL exerts a higher level of apoptotic cell death compared to the first-line agent gemcitabine for PDAC, as well as other anticancer agents including sorafenib and curcumin. The anticancer efficacy of NL was further evidenced by a reduction in the CD44
    MeSH term(s) Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Caspase Inhibitors/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Dose-Response Relationship, Drug ; Humans ; Hyaluronan Receptors/metabolism ; Limonins/pharmacology ; Mitochondria/drug effects ; Mitochondria/metabolism ; Mitochondria/pathology ; Mutation ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Reactive Oxygen Species/metabolism ; Time Factors ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Antineoplastic Agents, Phytogenic ; CD44 protein, human ; Caspase Inhibitors ; Hyaluronan Receptors ; Limonins ; Reactive Oxygen Species ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Deoxycytidine (0W860991D6) ; nimbolide (25990-37-8) ; gemcitabine (B76N6SBZ8R)
    Language English
    Publishing date 2017-10-26
    Publishing country Ireland
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2017.10.029
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1177: Show issues Location:
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  3. Article ; Online: Lipid quantification by Raman microspectroscopy as a potential biomarker in prostate cancer.

    O'Malley, Jordan / Kumar, Rahul / Kuzmin, Andrey N / Pliss, Artem / Yadav, Neelu / Balachandar, Srimmitha / Wang, Jianmin / Attwood, Kristopher / Prasad, Paras N / Chandra, Dhyan

    Cancer letters

    2017  Volume 397, Page(s) 52–60

    Abstract: Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and is one of the leading causes of cancer-related death among American men. Therefore, detection of prostate cancer (PCa) at early stages may reduce PCa-related mortality in men. ... ...

    Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and is one of the leading causes of cancer-related death among American men. Therefore, detection of prostate cancer (PCa) at early stages may reduce PCa-related mortality in men. We show that lipid quantification by vibrational Raman Microspectroscopy and Biomolecular Component Analysis may serve as a potential biomarker in PCa. Transcript levels of lipogenic genes including sterol regulatory element-binding protein-1 (SREBP-1) and its downstream effector fatty acid synthase (FASN), and rate-limiting enzyme acetyl CoA carboxylase (ACACA) were upregulated corresponding to both Gleason score and pathologic T stage in the PRAD TCGA cohort. Increased lipid accumulation in late-stage transgenic adenocarcinoma of mouse prostate (TRAMP) tumors compared to early-stage TRAMP and normal prostate tissues were observed. FASN along with other lipogenesis enzymes, and SREBP-1 proteins were upregulated in TRAMP tumors compared to wild-type prostatic tissues. Genetic alterations of key lipogenic genes predicted the overall patient survival using TCGA PRAD cohort. Correlation between lipid accumulation and tumor stage provides quantitative marker for PCa diagnosis. Thus, Raman spectroscopy-based lipid quantification could be a sensitive and reliable tool for PCa diagnosis and staging.
    MeSH term(s) Adenocarcinoma/enzymology ; Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma/secondary ; Animals ; Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; Computational Biology ; Databases, Genetic ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Humans ; Lipogenesis/genetics ; Male ; Mice ; Mice, Transgenic ; Neoplasm Grading ; Neoplasm Staging ; Phenotype ; Predictive Value of Tests ; Prostatic Neoplasms, Castration-Resistant/enzymology ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/metabolism ; Prostatic Neoplasms, Castration-Resistant/pathology ; RNA, Messenger/genetics ; Spectrum Analysis, Raman
    Chemical Substances Biomarkers, Tumor ; RNA, Messenger
    Language English
    Publishing date 2017--01
    Publishing country Ireland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2017.03.025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1177: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  4. Article ; Online: Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations.

    Balachandar, Srimmitha / Graves, Tamara J / Shimonty, Anika / Kerr, Katie / Kilner, Jill / Xiao, Sihao / Slade, Richard / Sroya, Manveer / Alikian, Mary / Curetean, Emanuel / Thomas, Ellen / McConnell, Vivienne P M / McKee, Shane / Boardman-Pretty, Freya / Devereau, Andrew / Fowler, Tom A / Caulfield, Mark J / Alton, Eric W / Ferguson, Teena /
    Redhead, Julian / McKnight, Amy J / Thomas, Geraldine A / Aldred, Micheala A / Shovlin, Claire L

    American journal of medical genetics. Part A

    2021  Volume 188, Issue 3, Page(s) 959–964

    Abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ...

    Abstract Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.
    MeSH term(s) Activin Receptors, Type II/genetics ; Arteriovenous Fistula ; Arteriovenous Malformations/diagnosis ; Arteriovenous Malformations/genetics ; Child ; Endoglin/genetics ; Endoglin/metabolism ; Epistaxis ; Growth Differentiation Factor 2/genetics ; Humans ; Mutation ; Pulmonary Artery/abnormalities ; Pulmonary Veins/abnormalities ; Telangiectasia, Hereditary Hemorrhagic/diagnosis ; Telangiectasia, Hereditary Hemorrhagic/genetics ; Telangiectasia, Hereditary Hemorrhagic/pathology
    Chemical Substances Endoglin ; GDF2 protein, human ; Growth Differentiation Factor 2 ; ACVRL1 protein, human (EC 2.7.11.30) ; Activin Receptors, Type II (EC 2.7.11.30)
    Language English
    Publishing date 2021-12-13
    Publishing country United States
    Document type Case Reports ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.62584
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

    Welch, Carrie L. / Aldred, Micheala A. / Balachandar, Srimmitha / Dooijes, Dennis / Eichstaedt, Christina A. / Gräf, Stefan / Houweling, Arjan C. / Machado, Rajiv D. / Pandya, Divya / Prapa, Matina / Shaukat, Memoona / Southgate, Laura / Tenorio-Castano, Jair / Chung, Wendy K. / Callejo, Emily P. / Day, Kristina M. / Macaya, Daniela / Maldonado-Velez, Gabriel / Archer, Stephen L. /
    Auckland, Kathryn / Austin, Eric D. / Badagliacca, Roberto / Barberá, J. A. / Belge, Catharina / Bogaard, Harm Jan / Bonnet, Sébastien / Boomars, Karin A. / Boucherat, Olivier / Chakinala, Murali M. / Condliffe, Robin / Damico, Rachel Lynn / Delcroix, Marion / Desai, Ankit A. / Doboszyńska, Anna / Elliott, C. Greg / Eyries, Melanie / Escribano Subías, Maria Pilar / Gall, Henning / Ghio, Stefano / Ghofrani, Ardeschir-Hossein / Grünig, Ekkehard / Hamid, Rizwan / Harbaum, Lars / Hassoun, Paul M. / Hemnes, Anna R. / Hinderhofer, Katrin / Howard, Luke S. / Humbert, Marc / Kiely, D. G. / Langleben, David / Lawrie, Allan / Loyd, Jim E. / Moledina, Shahin / Montani, David / Morrell, Nichols W. / Nichols, William C. / Olschewski, Andrea / Olschewski, Horst / Papa, Silvia / Pauciulo, Mike W. / Provencher, Steve / Quarck, Rozenn / Rhodes, Christopher J. / Scelsi, Laura / Seeger, Werner / Stewart, Duncan J. / Sweatt, Andrew / Swietlik, Emilia M. / Treacy, Carmen / Trembath, Richard C. / Tura-Ceide, Olga / Vizza, Carmine Dario / Noordegraaf, Anton Vonk / Wilkins, Martin R. / Zamanian, Roham T. / Zateyshchikov, Dmitry

    American College of Medical Genetics and Genomics Genetics in Medicine. 2023 Nov., v. 25, no. 11 p.100925-

    2023  

    Abstract: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary ... ...

    Institution ClinGen PH VCEP
    International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI)
    Abstract Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia–, and congenital heart disease–associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.
    Keywords genome ; heart ; hypertension ; medicine ; mortality ; pulmonary artery ; Genetics ; Genomic medicine ; Molecular diagnosis ; Pulmonary arterial hypertension ; AD ; APAH ; ClinGen ; HPAH ; IPAH ; LOF ; PAECs ; PASMCs ; PAH ; pLOF ; RV ; RVSP ; SPS
    Language English
    Dates of publication 2023-11
    Publishing place Elsevier Inc.
    Document type Article ; Online
    ZDB-ID 1455352-1
    ISSN 1530-0366 ; 1098-3600
    ISSN (online) 1530-0366
    ISSN 1098-3600
    DOI 10.1016/j.gim.2023.100925
    Database NAL-Catalogue (AGRICOLA)

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