المؤلفون: Yokoi, Akira, Villar-Prados, Alejandro, Oliphint, Paul Allen, Zhang, Jianhua, Song, Xingzhi, De Hoff, Peter, Morey, Robert, Liu, Jinsong, Roszik, Jason, Clise-Dwyer, Karen, Burks, Jared K, O'Halloran, Theresa J, Laurent, Louise C, Sood, Anil K

المصدر: Science advances. 5(11)

مصطلحات موضوعية: Cell Line, Tumor, Micronuclei, Chromosome-Defective, Humans, Ovarian Neoplasms, DNA Damage, DNA, Female, Exosomes, DNA Copy Number Variations, Tetraspanins, Biomarkers, Tumor, Cell Line, Tumor, Micronuclei, Chromosome-Defective, Biomarkers, Ovarian Cancer, Cancer, Rare Diseases, Genetics, 2.1 Biological and endogenous factors

الوصف: Exosome cargoes are highly varied and include proteins, small RNAs, and genomic DNA (gDNA). The presence of gDNA suggests that different intracellular compartments contribute to exosome loading, resulting in distinct exosome subpopulations. However, the loading of gDNA and other nuclear contents into exosomes (nExo) remains poorly understood. Here, we identify the relationship between cancer cell micronuclei (MN), which are markers of genomic instability, and nExo formation. Imaging flow cytometry analyses reveal that 10% of exosomes derived from cancer cells and

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/24m1v062Test

المؤلفون: Zhang, Haiyu¹ (AUTHOR), Villar‐Prados, Alejandro² (AUTHOR), Bussel, James B.³ (AUTHOR), Zehnder, James L.⁴ (AUTHOR) zehnder@stanford.edu

المصدر: British Journal of Haematology. Jan2024, Vol. 204 Issue 1, p56-67. 12p.

مصطلحات موضوعية: *PLATELET count, *THROMBOCYTOPENIA, *AUTOIMMUNE diseases, *IDIOPATHIC thrombocytopenic purpura, *THROMBOPOIETIN, *THERAPEUTICS

مستخلص: Summary: Cyclic thrombocytopenia (CTP) is characterized by periodic platelet oscillation with substantial amplitude. Most CTP cases have a thrombocytopenic background and are often misdiagnosed as immune thrombocytopenia with erratically effective treatment choices. CTP also occurs during hydroxyurea treatment in patients with myeloproliferative diseases. While the aetiology of CTP remains uncertain, here we evaluate historical, theoretical and clinical findings to provide a framework for understanding CTP pathophysiology. CTP retains the intrinsic oscillatory factors defined by the homeostatic regulation of platelet count, presenting as reciprocal platelet/thrombopoietin oscillations and stable oscillation periodicity. Moreover, CTP patients possess pathogenic factors destabilizing the platelet homeostatic system thereby creating opportunities for external perturbations to initiate and sustain the exaggerated platelet oscillations. Beyond humoral and cell‐mediated autoimmunity, we propose recently uncovered germline and somatic genetic variants, such as those of MPL, STAT3 or DNMT3A, as pathogenic factors in thrombocytopenia‐related CTP. Likewise, the JAK2 V617F or BCR::ABL1 translocation that drives underlying myeloproliferative diseases may also play a pathogenic role in hydroxyurea‐induced CTP, where hydroxyurea treatment can serve as both a trigger and a pathogenic factor of platelet oscillation. Elucidating the pathogenic landscape of CTP provides an opportunity for targeted therapeutic approaches in the future. [ABSTRACT FROM AUTHOR]

المؤلفون: Ma, Shaolin, Mangala, Lingegowda S., Hu, Wen, Bayaktar, Emine, Yokoi, Akira, Hu, Wei, Pradeep, Sunila, Lee, Sanghoon, Piehowski, Paul D., Villar-Prados, Alejandro, Wu, Sherry Y., McGuire, Michael H., Lara, Olivia D., Rodriguez-Aguayo, Cristian, LaFargue, Christopher J., Jennings, Nicholas B., Rodland, Karin D., Liu, Tao, Kundra, Vikas, Ram, Prahlad T., Ramakrishnan, Sundaram, Lopez-Berestein, Gabriel, Coleman, Robert L., Sood, Anil K.

المصدر: Cell Reports ; volume 36, issue 7, page 109549 ; ISSN 2211-1247

مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology

الإتاحة: https://doi.org/10.1016/j.celrep.2021.109549Test
https://api.elsevier.com/content/article/PII:S2211124721009839?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2211124721009839?httpAccept=text/plainTest

المؤلفون: Ma, Shaolin, McGuire, Michael H., Mangala, Lingegowda S., Lee, Sanghoon, Stur, Elaine, Hu, Wen, Bayraktar, Emine, Villar-Prados, Alejandro, Ivan, Cristina, Wu, Sherry Y., Yokoi, Akira, Dasari, Santosh K., Jennings, Nicholas B., Liu, Jinsong, Lopez-Berestein, Gabriel, Ram, Prahlad, Sood, Anil K.

المساهمون: Cancer Prevention and Research Institute of Texas, National Cancer Institute

المصدر: Cell Reports ; volume 34, issue 6, page 108726 ; ISSN 2211-1247

مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology

الإتاحة: https://doi.org/10.1016/j.celrep.2021.108726Test
https://api.elsevier.com/content/article/PII:S2211124721000395?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2211124721000395?httpAccept=text/plainTest

المؤلفون: Villar‐Prados, Alejandro¹ (AUTHOR), Abdelmonem, Mohamed² (AUTHOR), Duda, Molly¹ (AUTHOR), Chien, May¹ (AUTHOR), Yunce, Muharrem^2,3 (AUTHOR) myunce@stanford.edu

المصدر: Transfusion. Oct2023, Vol. 63 Issue 10, p1969-1977. 9p.

مصطلحات موضوعية: *PAROXYSMAL hemoglobinuria, *AUTOIMMUNE hemolytic anemia, *ANTIBODY titer, *LACTATE dehydrogenase

مستخلص: Background: Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia (AIHA), mainly affecting children. The diagnosis and management are challenging due to similarities to other causes for AIHA and limited availability to Donath‐Landsteiner (DL) testing. Study Design and Methods: In this single‐center retrospective study, we aimed to characterize the clinical presentation and outcomes of PCH patients, defined as having positive Donath‐Landsteiner antibodies, compared to a cohort of AIHA patients. Results: DL‐positive patients were observed to have higher lactate dehydrogenase levels and lower reticulocyte counts compared to DL‐negative patients, although this was not statistically significant. We also observed that using steroids in DL‐positive patients did not significantly impact their recovery. Discussion: Our findings support the limited published data on PCH patients and further prompt larger multicenter studies to further characterize these patients so that they are more readily identified, especially in centers where DL antibody testing is not readily available. [ABSTRACT FROM AUTHOR]

المؤلفون: Zhang, Haiyu, Villar‐Prados, Alejandro, Bussel, James B., Zehnder, James L.

المساهمون: National Institutes of Health

المصدر: British Journal of Haematology ; volume 204, issue 1, page 56-67 ; ISSN 0007-1048 1365-2141

الوصف: Summary Cyclic thrombocytopenia (CTP) is characterized by periodic platelet oscillation with substantial amplitude. Most CTP cases have a thrombocytopenic background and are often misdiagnosed as immune thrombocytopenia with erratically effective treatment choices. CTP also occurs during hydroxyurea treatment in patients with myeloproliferative diseases. While the aetiology of CTP remains uncertain, here we evaluate historical, theoretical and clinical findings to provide a framework for understanding CTP pathophysiology. CTP retains the intrinsic oscillatory factors defined by the homeostatic regulation of platelet count, presenting as reciprocal platelet/thrombopoietin oscillations and stable oscillation periodicity. Moreover, CTP patients possess pathogenic factors destabilizing the platelet homeostatic system thereby creating opportunities for external perturbations to initiate and sustain the exaggerated platelet oscillations. Beyond humoral and cell‐mediated autoimmunity, we propose recently uncovered germline and somatic genetic variants, such as those of MPL , STAT3 or DNMT3A, as pathogenic factors in thrombocytopenia‐related CTP. Likewise, the JAK2 V617F or BCR::ABL1 translocation that drives underlying myeloproliferative diseases may also play a pathogenic role in hydroxyurea‐induced CTP, where hydroxyurea treatment can serve as both a trigger and a pathogenic factor of platelet oscillation. Elucidating the pathogenic landscape of CTP provides an opportunity for targeted therapeutic approaches in the future.

الإتاحة: https://doi.org/10.1111/bjh.19239Test

المؤلفون: Gharpure, Kshipra M., Pradeep, Sunila, Sans, Marta, Rupaimoole, Rajesha, Ivan, Cristina, Wu, Sherry Y., Bayraktar, Emine, Nagaraja, Archana S., Mangala, Lingegowda S., Zhang, Xinna, Haemmerle, Monika, Hu, Wei, Rodriguez-Aguayo, Cristian, McGuire, Michael, Mak, Celia Sze Ling, Chen, Xiuhui, Tran, Michelle A., Villar-Prados, Alejandro, Pena, Guillermo Armaiz, Kondetimmanahalli, Ragini, Nini, Ryan, Koppula, Pranavi, Ram, Prahlad, Liu, Jinsong, Lopez-Berestein, Gabriel, Baggerly, Keith, S. Eberlin, Livia, Sood, Anil K.

المصدر: Nature Communications ; volume 9, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.

الإتاحة: https://doi.org/10.1038/s41467-018-04987-yTest
https://www.nature.com/articles/s41467-018-04987-y.pdfTest
https://www.nature.com/articles/s41467-018-04987-yTest

المؤلفون: Williams, Erin, Villar-Prados, Alejandro, Bowser, Jessica, Broaddus, Russell, Gladden, Andrew B.

المساهمون: Zegers, Mirjam M., U.S. Department of Defense, National Cancer Institute, National Center for Research Resources

المصدر: PLOS ONE ; volume 12, issue 12, page e0189081 ; ISSN 1932-6203

الإتاحة: https://doi.org/10.1371/journal.pone.0189081Test

المؤلفون: Villar-Prados, Alejandro, Wu, Sherry Y., Court, Karem A., Ma, Shaolin, LaFargue, Christopher, Chowdhury, Mamur A., Engelhardt, Margaret I., Ivan, Cristina, Ram, Prahlad T., Wang, Ying, Baggerly, Keith, Rodriguez-Aguayo, Cristian, Lopez-Berestein, Gabriel, Ming-Yang, Shyh, Maloney, David J., Yoshioka, Makoto, Strovel, Jeffrey W., Roszik, Jason, Sood, Anil K.

مصطلحات موضوعية: Potential Therapeutic Target, Ovarian-Cancer, Gene-Expression, Bet, Inhibition, Resistance, Pathway, Chromatin, Enhancer, Cells, 1306 Cancer Research, 2730 Oncology

الوصف: Systematic approaches for accurate repurposing of targeted therapies are needed. We developed and aimed to biologically validate our therapy predicting tool (TPT) for the repurposing of targeted therapies for specific tumor types by testing the role of Bromodomain and Extra-Terminal motif inhibitors (BETi) in inhibiting BRD4 function and downregulating Notch3 signaling in ovarian cancer.Utilizing established ovarian cancer preclinical models, we carried out in vitro and in vivo studies with clinically relevant BETis to determine their therapeutic effect and impact on Notch3 signaling.Treatment with BETis or siRNA-mediated BRD4 knockdown resulted in decreased cell viability, reduced cell proliferation, and increased cell apoptosis in vitro. In vivo studies with orthotopic mouse models demonstrated that treatment with BETi decreased tumor growth. In addition, knockdown of BRD4 with doxycycline-inducible shRNA increased survival up to 50% (P < 0.001). Treatment with either BETis or BRD4 siRNA decreased Notch3 expression both in vitro and in vivo BRD4 inhibition also decreased the expression of NOTCH3 targets, including HES1 Chromatin immunoprecipitation revealed that BRD4 was present at the NOTCH3 promoter.Our findings provide biological validation for the TPT by demonstrating that BETis can be an effective therapeutic agent for ovarian cancer by downregulating Notch3 expression.The TPT could rapidly identify candidate drugs for ovarian or other cancers along with novel companion biomarkers.

العلاقة: orcid:0000-0002-6051-4252; P30 CA016672; UH3TR000943; P50 CA217685; U01 CA213759 P50 CA098258; R35 CA209904; U54CA096300/U54CA096297; Not set; P30CA16672; RP101502; RP140106; RP170067; P50CA098258; P30CA016672; U54CA096297

الإتاحة: https://doi.org/10.1158/1535-7163.MCT-18-0365Test
https://espace.library.uq.edu.au/view/UQ:d0da1e1Test

المؤلفون: Villar-Prados, Alejandro¹ avillarp@stanford.edu, Chang, Julia J.² jchang89@stanford.edu, Stevens, David A.^3,4 stevens@stanford.edu, Schoolnik, Gary K.³ gks007@stanford.edu, Wang, Samantha X. Y.⁵ wangxy@stanford.edu

المصدر: Journal of Fungi. Aug2021, Vol. 7 Issue 8, p1-7. 7p.

مصطلحات موضوعية: *GLUCOCORTICOIDS, *HYDROCORTISONE, *ANTIFUNGAL agents, *IATROGENIC diseases, *HYPOKALEMIA

مستخلص: A 56-year-old Hispanic man with a history of disseminated coccidioidomycosis was diagnosed with persistent glucocorticoid insufficiency and pseudohyperaldosteronism secondary to posaconazole toxicity. This case was notable for unexpected laboratory findings of both pseudohyperaldosteronism and severe glucocorticoid deficiency due to posaconazole's mechanism of action on the adrenal steroid synthesis pathway. Transitioning to fluconazole and starting hydrocortisone resolved the hypokalemia but not his glucocorticoid deficiency. This case highlights the importance of recognizing iatrogenic glucocorticoid deficiency with azole antifungal agents and potential long term sequalae. [ABSTRACT FROM AUTHOR]