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Article ; Online: Tumor Immunity and Immunotherapy for HPV-Related Cancers.

Shamseddine, Achraf A / Burman, Bharat / Lee, Nancy Y / Zamarin, Dmitriy / Riaz, Nadeem

2021 Volume 11, Issue 8, Page(s) 1896–1912

Abstract: Human papillomavirus (HPV) infection drives tumorigenesis in the majority of cervical, oropharyngeal, anal, and vulvar cancers. Genetic and epidemiologic evidence has highlighted the role of immunosuppression in the oncogenesis of HPV-related ... ...

Abstract	Human papillomavirus (HPV) infection drives tumorigenesis in the majority of cervical, oropharyngeal, anal, and vulvar cancers. Genetic and epidemiologic evidence has highlighted the role of immunosuppression in the oncogenesis of HPV-related malignancies. Here we review how HPV modulates the immune microenvironment and subsequent therapeutic implications. We describe the landscape of immunotherapies for these cancers with a focus on findings from early-phase studies exploring antigen-specific treatments, and discuss future directions. Although responses across these studies have been modest to date, a deeper understanding of HPV-related tumor biology and immunology may prove instrumental for the development of more efficacious immunotherapeutic approaches. SIGNIFICANCE: HPV modulates the microenvironment to create a protumorigenic state of immune suppression and evasion. Our understanding of these mechanisms has led to the development of immunomodulatory treatments that have shown early clinical promise in patients with HPV-related malignancies. This review summarizes our current understanding of the interactions of HPV and its microenvironment and provides insight into the progress and challenges of developing immunotherapies for HPV-related malignancies.
MeSH term(s)	Female ; Humans ; Immunotherapy ; Oropharyngeal Neoplasms/immunology ; Papillomaviridae/immunology ; Papillomavirus Infections/immunology ; Papillomavirus Vaccines ; Uterine Cervical Neoplasms/immunology
Chemical Substances	Papillomavirus Vaccines
Language	English
Publishing date	2021-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-20-1760
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Article ; Online: Automatic segmentation of brain metastases using T1 magnetic resonance and computed tomography images.

Hsu, Dylan G / Ballangrud, Åse / Shamseddine, Achraf / Deasy, Joseph O / Veeraraghavan, Harini / Cervino, Laura / Beal, Kathryn / Aristophanous, Michalis

Physics in medicine and biology

2021 Volume 66, Issue 17

Abstract: An increasing number of patients with multiple brain metastases are being treated with stereotactic radiosurgery (SRS). Manually identifying and contouring all metastatic lesions is difficult and time-consuming, and a potential source of variability. ... ...

Abstract	An increasing number of patients with multiple brain metastases are being treated with stereotactic radiosurgery (SRS). Manually identifying and contouring all metastatic lesions is difficult and time-consuming, and a potential source of variability. Hence, we developed a 3D deep learning approach for segmenting brain metastases on MR and CT images. Five-hundred eleven patients treated with SRS were retrospectively identified for this study. Prior to radiotherapy, the patients were imaged with 3D T1 spoiled-gradient MR post-Gd (T1 + C) and contrast-enhanced CT (CECT), which were co-registered by a treatment planner. The gross tumor volume contours, authored by the attending radiation oncologist, were taken as the ground truth. There were 3 ± 4 metastases per patient, with volume up to 57 ml. We produced a multi-stage model that automatically performs brain extraction, followed by detection and segmentation of brain metastases using co-registered T1 + C and CECT. Augmented data from 80% of these patients were used to train modified 3D V-Net convolutional neural networks for this task. We combined a normalized boundary loss function with soft Dice loss to improve the model optimization, and employed gradient accumulation to stabilize the training. The average Dice similarity coefficient (DSC) for brain extraction was 0.975 ± 0.002 (95% CI). The detection sensitivity per metastasis was 90% (329/367), with moderate dependence on metastasis size. Averaged across 102 test patients, our approach had metastasis detection sensitivity 95 ± 3%, 2.4 ± 0.5 false positives, DSC of 0.76 ± 0.03, and 95th-percentile Hausdorff distance of 2.5 ± 0.3 mm (95% CIs). The volumes of automatic and manual segmentations were strongly correlated for metastases of volume up to 20 ml (r=0.97,p<0.001). This work expounds a fully 3D deep learning approach capable of automatically detecting and segmenting brain metastases using co-registered T1 + C and CECT.
MeSH term(s)	Automation ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/secondary ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Radiosurgery ; Retrospective Studies ; Tomography, X-Ray Computed
Language	English
Publishing date	2021-08-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ac1835
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Article: A role for caspase‐2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells – implications for the CHK1‐suppressed pathway

Carroll, Brittany L. / Bonica, Joseph / Shamseddine, Achraf A. / Hannun, Yusuf A. / Obeid, Lina M.

FEBS Open Bio. 2018 Jan., v. 8, no. 1

2018

Abstract: Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1‐phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have ... ...

Abstract	Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1‐phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have demonstrated that SK1 proteolysis occurs downstream of the tumor suppressor p53 in response to several DNA‐damaging agents. Moreover, loss of SK1 in p53‐knockout mice resulted in complete protection from thymic lymphoma, providing evidence that regulation of SK1 constitutes a major tumor suppressor function of p53. Given this profound phenotype, this study aimed to investigate the mechanism by which wild‐type p53 regulates proteolysis of SK1 in response to the DNA‐damaging agent doxorubicin in breast cancer cells. We find that p53‐mediated activation of caspase‐2 was required for SK1 proteolysis and that caspase‐2 activity significantly alters the levels of endogenous sphingolipids. As p53 is mutated in 50% of all cancers, we extended our studies to investigate whether SK1 is deregulated in the context of triple‐negative breast cancer cells (TNBC) harboring a mutation in p53. Indeed, caspase‐2 was not activated in these cells and SK1 was not degraded. Moreover, caspase‐2 activation was recently shown to be downstream of the CHK1‐suppressed pathway in p53‐mutant cells, whereby inhibition of the cell cycle kinase CHK1 leads to caspase‐2 activation and apoptosis. Indeed, knockdown and inhibition of CHK1 led to the loss of SK1 in p53‐mutant TNBC cells, providing evidence that SK1 may be the first identified effector of the CHK1‐suppressed pathway.
Keywords	angiogenesis ; apoptosis ; breast neoplasms ; caspase-2 ; cell cycle ; doxorubicin ; lymphoma ; mutation ; phenotype ; proteolysis ; sphingolipids ; sphingosine
Language	English
Dates of publication	2018-01
Size	p. 27-40.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2651702-4
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.12344
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Article ; Online: Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer.

Han, James / Zakeri, Kaveh / Raab, Gabriel / Hesse, Jennifer / Shamseddine, Achraf / Chen, Linda / Yu, Yao / Kang, Jung Julie / McBride, Sean M / Riaz, Nadeem / Tsai, C Jillian / Gelblum, Daphna / Sherman, Eric J / Wong, Richard J / Michel, Loren / Lee, Nancy Y

Head & neck

2023 Volume 45, Issue 9, Page(s) 2207–2216

Abstract: Background: We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel.: Materials and methods: We included consecutive HNSCC patients treated from 2013 to 2021 that ... ...

Abstract	Background: We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel. Materials and methods: We included consecutive HNSCC patients treated from 2013 to 2021 that received definitive chemoradiation with carboplatin and paclitaxel. Locoregional recurrences (LRR) and distant metastases (DM) were estimated using cumulative incidence functions. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. Results: Sixty-five patients were identified with median age of 71 years (range 44-85). Median radiation dose was 70 Gy and the median doses of carboplatin and paclitaxel were AUC 1 and 40 mg/m Conclusions: Chemoradiation with carboplatin and paclitaxel is an excellent option for cisplatin-ineligible HNSCC patients.
MeSH term(s)	Humans ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Carboplatin/therapeutic use ; Paclitaxel ; Cisplatin/therapeutic use ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Neoplasm Recurrence, Local/drug therapy ; Head and Neck Neoplasms/drug therapy ; Chemoradiotherapy/adverse effects
Chemical Substances	Carboplatin (BG3F62OND5) ; Paclitaxel (P88XT4IS4D) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2023-07-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	645165-2
ISSN	1097-0347 ; 0148-6403 ; 1043-3074
ISSN (online)	1097-0347
ISSN	0148-6403 ; 1043-3074
DOI	10.1002/hed.27456
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Zs.A 1493: Show issues

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Article: Early Detection of Leptomeningeal Metastases Among Patients Undergoing Spinal Stereotactic Radiosurgery.

Freret, Morgan E / Wijetunga, N Ari / Shamseddine, Achraf A / Higginson, Daniel S / Schmitt, Adam M / Yamada, Yoshiya / Lis, Eric / Boire, Adrienne / Yang, Jonathan T / Xu, Amy J

Advances in radiation oncology

2022 Volume 8, Issue 2, Page(s) 101154

Abstract: Purpose: The management of patients with advanced solid malignancies increasingly uses stereotactic body radiation therapy (SBRT). Advanced cancer patients are at risk for developing leptomeningeal metastasis (LM), a fatal complication of metastatic ... ...

Abstract	Purpose: The management of patients with advanced solid malignancies increasingly uses stereotactic body radiation therapy (SBRT). Advanced cancer patients are at risk for developing leptomeningeal metastasis (LM), a fatal complication of metastatic cancer. Cerebrospinal fluid (CSF) is routinely collected during computed tomography (CT) myelography for spinal SBRT planning, offering an opportunity for early LM detection by CSF cytology in the absence of radiographic LM or LM symptoms (subclinical LM). This study tested the hypothesis that early detection of tumor cells in CSF in patients undergoing spine SBRT portends a similarly poor prognosis compared with clinically overt LM. Methods and materials: We retrospectively analyzed clinical records for 495 patients with metastatic solid tumors who underwent CT myelography for spinal SBRT planning at a single institution from 2014 to 2019. Results: Among patients planned for SBRT, 51 (10.3%) developed LM. Eight patients (1.6%) had subclinical LM. Median survival with LM was similar between patients with subclinical versus clinically evident LM (3.6 vs 3.0 months, Conclusions: LM remains a fatal complication of metastatic cancer. Subclinical LM detected by CSF cytology in spine SBRT patients has a similarly poor prognosis compared with standardly detected LM and warrants consideration of central nervous system-directed therapies. As aggressive local therapies are increasingly used for metastatic patients, more sensitive CSF evaluation may further identify patients with subclinical LM and should be evaluated prospectively.
Language	English
Publishing date	2022-12-26
Publishing country	United States
Document type	Journal Article
ISSN	2452-1094
ISSN	2452-1094
DOI	10.1016/j.adro.2022.101154
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Article ; Online: Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes.

Shamseddine, Achraf A / Airola, Michael V / Hannun, Yusuf A

Advances in biological regulation

2015 Volume 57, Page(s) 24–41

Abstract: Our understanding of the functions of ceramide signaling has advanced tremendously over the past decade. In this review, we focus on the roles and regulation of neutral sphingomyelinase 2 (nSMase2), an enzyme that generates the bioactive lipid ceramide ... ...

Abstract	Our understanding of the functions of ceramide signaling has advanced tremendously over the past decade. In this review, we focus on the roles and regulation of neutral sphingomyelinase 2 (nSMase2), an enzyme that generates the bioactive lipid ceramide through the hydrolysis of the membrane lipid sphingomyelin. A large body of work has now implicated nSMase2 in a diverse set of cellular functions, physiological processes, and disease pathologies. We discuss different aspects of this enzyme's regulation from transcriptional, post-translational, and biochemical. Furthermore, we highlight nSMase2 involvement in cellular processes including inflammatory signaling, exosome generation, cell growth, and apoptosis, which in turn play important roles in pathologies such as cancer metastasis, Alzheimer's disease, and other organ systems disorders. Lastly, we examine avenues where targeted nSMase2-inhibition may be clinically beneficial in disease scenarios.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Animals ; Apoptosis ; Ceramides/genetics ; Ceramides/metabolism ; Exosomes/genetics ; Exosomes/metabolism ; Humans ; Neoplasm Metastasis ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Processing, Post-Translational/genetics ; Signal Transduction ; Sphingomyelin Phosphodiesterase/genetics ; Sphingomyelin Phosphodiesterase/metabolism ; Sphingomyelins/genetics ; Sphingomyelins/metabolism ; Transcription, Genetic/genetics
Chemical Substances	Ceramides ; Neoplasm Proteins ; Sphingomyelins ; SMPD3 protein, human (EC 3.1.4.12) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12)
Language	English
Publishing date	2015-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2667413-0
ISSN	2212-4934 ; 2212-4926
ISSN (online)	2212-4934
ISSN	2212-4926
DOI	10.1016/j.jbior.2014.10.002
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Uc I Zs.364: Show issues

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Article ; Online: Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases.

Mohammed, Samia / Shamseddine, Achraf A / Newcomb, Benjamin / Chavez, Ronald S / Panzner, Tyler D / Lee, Allen H / Canals, Daniel / Okeoma, Chioma M / Clarke, Christopher J / Hannun, Yusuf A

Breast cancer research : BCR

2021 Volume 23, Issue 1, Page(s) 76

Abstract: Background: Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in ... ...

Abstract	Background: Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in survival rate in patients receiving low doses of Dox. To effectively mitigate this, a better understanding of the adverse effects of suboptimal Dox doses is needed. Methods: Effects of sublethal dose of Dox on phenotypic changes were assessed with light and confocal microscopy. Migratory and invasive behavior were assessed by wound healing and transwell migration assays. MTT and LDH release assays were used to analyze cell growth and cytotoxicity. Flow cytometry was employed to detect cell surface markers of cancer stem cell population. Expression and activity of matrix metalloproteinases were probed with qRT-PCR and zymogen assay. To identify pathways affected by sublethal dose of Dox, exploratory RNAseq was performed and results were verified by qRT-PCR in multiple cell lines (MCF7, ZR75-1 and U-2OS). Regulation of Src Family kinases (SFK) by key players in DNA damage response was assessed by siRNA knockdown along with western blot and qRT-PCR. Dasatinib and siRNA for Fyn and Yes was employed to inhibit SFKs and verify their role in increased migration and invasion in MCF7 cells treated with sublethal doses of Dox. Results: The results show that sublethal Dox treatment leads to increased migration and invasion in otherwise non-invasive MCF7 breast cancer cells. Mechanistically, these effects were independent of the epithelial mesenchymal transition, were not due to increased cancer stem cell population, and were not observed with other chemotherapies. Instead, sublethal Dox induces expression of multiple SFK-including Fyn, Yes, and Src-partly in a p53 and ATR-dependent manner. These effects were validated in multiple cell lines. Functionally, inhibiting SFKs with Dasatinib and specific downregulation of Fyn suppressed Dox-induced migration and invasion of MCF7 cells. Conclusions: Overall, this study demonstrates that sublethal doses of Dox activate a pro-invasive, pro-migration program in cancer cells. Furthermore, by identifying SFKs as key mediators of these effects, our results define a potential therapeutic strategy to mitigate local invasion through co-treatment with Dasatinib.
MeSH term(s)	Ataxia Telangiectasia Mutated Proteins/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Adhesion/drug effects ; Cell Adhesion/genetics ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Movement/genetics ; Dose-Response Relationship, Drug ; Doxorubicin/pharmacology ; Female ; Humans ; Protein Kinase Inhibitors/pharmacology ; Tumor Suppressor Protein p53/metabolism ; src-Family Kinases/antagonists & inhibitors ; src-Family Kinases/metabolism
Chemical Substances	Protein Kinase Inhibitors ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Doxorubicin (80168379AG) ; src-Family Kinases (EC 2.7.10.2) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
Language	English
Publishing date	2021-07-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-021-01452-5
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Article: A role for caspase-2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells - implications for the CHK1-suppressed pathway.

Carroll, Brittany L / Bonica, Joseph / Shamseddine, Achraf A / Hannun, Yusuf A / Obeid, Lina M

FEBS open bio

2017 Volume 8, Issue 1, Page(s) 27–40

Abstract: Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1-phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have ... ...

Abstract	Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1-phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have demonstrated that SK1 proteolysis occurs downstream of the tumor suppressor p53 in response to several DNA-damaging agents. Moreover, loss of SK1 in p53-knockout mice resulted in complete protection from thymic lymphoma, providing evidence that regulation of SK1 constitutes a major tumor suppressor function of p53. Given this profound phenotype, this study aimed to investigate the mechanism by which wild-type p53 regulates proteolysis of SK1 in response to the DNA-damaging agent doxorubicin in breast cancer cells. We find that p53-mediated activation of caspase-2 was required for SK1 proteolysis and that caspase-2 activity significantly alters the levels of endogenous sphingolipids. As p53 is mutated in 50% of all cancers, we extended our studies to investigate whether SK1 is deregulated in the context of triple-negative breast cancer cells (TNBC) harboring a mutation in p53. Indeed, caspase-2 was not activated in these cells and SK1 was not degraded. Moreover, caspase-2 activation was recently shown to be downstream of the CHK1-suppressed pathway in p53-mutant cells, whereby inhibition of the cell cycle kinase CHK1 leads to caspase-2 activation and apoptosis. Indeed, knockdown and inhibition of CHK1 led to the loss of SK1 in p53-mutant TNBC cells, providing evidence that SK1 may be the first identified effector of the CHK1-suppressed pathway.
Language	English
Publishing date	2017-12-08
Publishing country	England
Document type	Journal Article
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.12344
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Article ; Online: Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies.

Shamseddine, Achraf / Patel, Suchit H / Chavez, Valery / Moore, Zachary R / Adnan, Mutayyaba / Di Bona, Melody / Li, Jun / Dang, Chau T / Ramanathan, Lakshmi V / Oeffinger, Kevin C / Liu, Jennifer E / Steingart, Richard M / Piersigilli, Alessandra / Socci, Nicholas D / Chan, Angel T / Yu, Anthony F / Bakhoum, Samuel F / Schmitt, Adam M

The Journal of experimental medicine

2022 Volume 220, Issue 3

Abstract: Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies ... ...

Abstract	Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies inducing delayed cardiac inflammation following therapy due to activation of cGAS- and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING signaling in mice inhibits DNA damage-induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA-damaging therapies and effectively mitigates cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.
MeSH term(s)	Animals ; Mice ; Cardiotoxicity ; Immunity, Innate ; Inflammation ; Neoplasms/drug therapy ; Nucleotidyltransferases/genetics ; DNA Damage ; Antineoplastic Agents/adverse effects
Chemical Substances	Nucleotidyltransferases (EC 2.7.7.-) ; Antineoplastic Agents
Language	English
Publishing date	2022-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20220809
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Article ; Online: ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation.

Clarke, Christopher J / Shamseddine, Achraf A / Jacob, Joseph J / Khalife, Gabrielle / Burns, Tara A / Hannun, Yusuf A

Journal of lipid research

2016 Volume 57, Issue 5, Page(s) 868–881

Abstract: Neutral sphingomyelinase-2 (nSMase2) is a key ceramide-producing enzyme in cellular stress responses. While many posttranslational regulators of nSMase2 are known, emerging evidence suggests a more protracted regulation of nSMase2 at the transcriptional ... ...

Abstract	Neutral sphingomyelinase-2 (nSMase2) is a key ceramide-producing enzyme in cellular stress responses. While many posttranslational regulators of nSMase2 are known, emerging evidence suggests a more protracted regulation of nSMase2 at the transcriptional level. Previously, we reported that nSMase2 is induced by all-trans retinoic acid (ATRA) in MCF7 cells and implicated nSMase2 in ATRA-induced growth arrest. Here, we further investigated how ATRA regulates nSMase2. We find that ATRA regulates nSMase2 transcriptionally through the retinoic acid receptor-α, but this is independent of previously identified transcriptional regulators of nSMase2 (Sp1, Sp3, Runx2) and is not through increased promoter activity. Epigenetically, the nSMase2 gene is not repressively methylated in MCF7 cells. However, inhibition of histone deacetylases (HDACs) with trichostatin A (TSA) induced nSMase2 comparably to ATRA; furthermore, combined ATRA and TSA treatment was not additive, suggesting ATRA regulates nSMase2 through direct modulation of histone acetylation. Confirming this, the histone acetyltransferases CREB-binding protein and p300 were required for ATRA induction of nSMase2. Finally, use of class-specific HDAC inhibitors suggested that HDAC4 and/or HDAC5 are negative regulators of nSMase2 expression. Collectively, these results identify a novel pathway of nSMase2 regulation and suggest that physiological or pharmacological modulation of histone acetylation can directly affect nSMase2 levels.
MeSH term(s)	Acetylation ; DNA Methylation ; Enzyme Induction ; Gene Expression Regulation, Neoplastic ; Histone Deacetylases/metabolism ; Histones/metabolism ; Humans ; Hydroxamic Acids/pharmacology ; MCF-7 Cells ; Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism ; Promoter Regions, Genetic ; Protein Processing, Post-Translational ; Sphingomyelin Phosphodiesterase/genetics ; Sphingomyelin Phosphodiesterase/metabolism ; Transcription, Genetic ; Transcriptional Activation ; Tretinoin/physiology ; Up-Regulation ; p300-CBP Transcription Factors/metabolism
Chemical Substances	Histones ; Hydroxamic Acids ; Nuclear Receptor Subfamily 1, Group F, Member 1 ; RORA protein, human ; trichostatin A (3X2S926L3Z) ; Tretinoin (5688UTC01R) ; p300-CBP Transcription Factors (EC 2.3.1.48) ; SMPD3 protein, human (EC 3.1.4.12) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2016-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.M067447
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Order via subito

Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

Order via subito