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Article: Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia.

Darvish-Damavandi, Mahnaz / Ho, Han Kiat / Kang, Tse Siang

Molecular genetics and metabolism reports

2016 Volume 8, Page(s) 51–60

Abstract: Propionic acidemia (PA) is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). This enzyme is responsible for degrading the metabolic intermediate, propionyl ... ...

Abstract	Propionic acidemia (PA) is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). This enzyme is responsible for degrading the metabolic intermediate, propionyl coenzyme-A (PP-CoA), derived from multiple metabolic pathways. Currently, except for drastic surgical and dietary intervention that can only provide partial symptomatic relief, no other form of therapeutic option is available for this genetic disorder. Here, we examine a novel approach in protein delivery by specifically targeting and localizing our protein candidate of interest into the mitochondrial matrix of the cells. In order to test this concept of delivery, we have utilized cell penetrating peptides (CPPs) and mitochondria targeting sequences (MTS) to form specific fusion PCC protein, capable of translocating and localizing across cell membranes. In vitro delivery of our candidate fusion proteins, evaluated by confocal images and enzymatic activity assay, indicated effectiveness of this strategy. Therefore, it holds immense potential in creating a new paradigm in site-specific protein delivery and enzyme replacement therapeutic for PA.
Language	English
Publishing date	2016-07-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2821908-9
ISSN	2214-4269
ISSN	2214-4269
DOI	10.1016/j.ymgmr.2016.06.009
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An analysis of SARS-CoV-2 cell entry genes identifies the intestine and colorectal cancer as susceptible tissues.

Darvish-Damavandi, Mahnaz / Laycock, James / Ward, Christopher / van Driel, Milou S / Goldgraben, Mae A / Buczacki, Simon Ja

The British journal of surgery

2020 Volume 107, Issue 11, Page(s) e452–e454

MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; COVID-19/metabolism ; Colorectal Neoplasms/metabolism ; Disease Susceptibility ; Humans ; Intestinal Mucosa/metabolism ; Receptors, Virus/metabolism ; SARS-CoV-2/physiology ; Serine Endopeptidases/metabolism ; Tissue Donors ; Virus Internalization
Chemical Substances	Receptors, Virus ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Keywords	covid19
Language	English
Publishing date	2020-08-10
Publishing country	England
Document type	Letter
ZDB-ID	2985-3
ISSN	1365-2168 ; 0263-1202 ; 0007-1323 ; 1355-7688
ISSN (online)	1365-2168
ISSN	0263-1202 ; 0007-1323 ; 1355-7688
DOI	10.1002/bjs.11911
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Article: An analysis of SARS-CoV-2 cell entry genes identifies the intestine and colorectal cancer as susceptible tissues

Darvish-Damavandi, Mahnaz / Laycock, James / Ward, Christopher / van Driel, Milou S / Goldgraben, Mae A / Buczacki, Simon Ja

Br. j. surg

Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #702766
Database	COVID19

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Article ; Online: An analysis of SARS-CoV-2 cell entry genes identifies the intestine and colorectal cancer as susceptible tissues ; An analysis of SARS-CoV-2 cell entry genes

Darvish-Damavandi, Mahnaz / Laycock, James / Ward, Christopher / van Driel, Milou S / Goldgraben, Mae A / Buczacki, Simon JA

British Journal of Surgery ; ISSN 0007-1323

2020

Keywords	Surgery ; covid19
Language	English
Publisher	Wiley
Publishing country	us
Document type	Article ; Online
DOI	10.1002/bjs.11911
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia

Mahnaz Darvish-Damavandi / Han Kiat Ho / Tse Siang Kang

Molecular Genetics and Metabolism Reports, Vol 8, Iss C, Pp 51-

2016 Volume 60

Abstract	Propionic acidemia (PA) is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). This enzyme is responsible for degrading the metabolic intermediate, propionyl coenzyme-A (PP-CoA), derived from multiple metabolic pathways. Currently, except for drastic surgical and dietary intervention that can only provide partial symptomatic relief, no other form of therapeutic option is available for this genetic disorder. Here, we examine a novel approach in protein delivery by specifically targeting and localizing our protein candidate of interest into the mitochondrial matrix of the cells. In order to test this concept of delivery, we have utilized cell penetrating peptides (CPPs) and mitochondria targeting sequences (MTS) to form specific fusion PCC protein, capable of translocating and localizing across cell membranes. In vitro delivery of our candidate fusion proteins, evaluated by confocal images and enzymatic activity assay, indicated effectiveness of this strategy. Therefore, it holds immense potential in creating a new paradigm in site-specific protein delivery and enzyme replacement therapeutic for PA.
Keywords	Propionic acidemia ; Enzyme replacement therapy ; Protein transduction domains ; Mitochondrial targeting sequences ; Propionyl coenzyme-A carboxylase ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2016-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer.

Clifford, Rachael E / Govindarajah, Naren / Bowden, David / Sutton, Paul / Glenn, Mark / Darvish-Damavandi, Mahnaz / Buczacki, Simon / McDermott, Ultan / Szulc, Zdzislaw / Ogretmen, Besim / Parsons, Jason L / Vimalachandran, Dale

Cells

2020 Volume 9, Issue 12

Abstract: Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the ... ...

Abstract	Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer.
MeSH term(s)	Acid Ceramidase/metabolism ; Apoptosis/radiation effects ; CRISPR-Cas Systems/genetics ; Cell Line, Tumor ; Cell Survival/radiation effects ; Gene Editing ; Humans ; Models, Biological ; Organoids/pathology ; Organoids/radiation effects ; Radiation Tolerance ; Rectal Neoplasms/enzymology ; Rectal Neoplasms/radiotherapy ; Tumor Suppressor Protein p53/metabolism ; X-Rays
Chemical Substances	Tumor Suppressor Protein p53 ; Acid Ceramidase (EC 3.5.1.23)
Language	English
Publishing date	2020-12-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9122693
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Article ; Online: Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

Beach, Callum / MacLean, David / Majorova, Dominika / Melemenidis, Stavros / Nambiar, Dhanya K / Kim, Ryan K / Valbuena, Gabriel N / Guglietta, Silvia / Krieg, Carsten / Darvish-Damavandi, Mahnaz / Suwa, Tatsuya / Easton, Alistair / Hillson, Lily Vs / McCulloch, Ashley K / McMahon, Ross K / Pennel, Kathryn / Edwards, Joanne / O'Cathail, Sean M / Roxburgh, Campbell S /

Domingo, Enric / Moon, Eui Jung / Jiang, Dadi / Jiang, Yanyan / Zhang, Qingyang / Koong, Albert C / Woodruff, Trent M / Graves, Edward E / Maughan, Tim / Buczacki, Simon Ja / Stucki, Manuel / Le, Quynh-Thu / Leedham, Simon J / Giaccia, Amato J / Olcina, Monica M

The Journal of clinical investigation

2023 Volume 133, Issue 23

Abstract: An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated ... ...

Abstract	An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.
MeSH term(s)	Humans ; Complement C5a/genetics ; Receptors, Complement/genetics
Chemical Substances	Complement C5a (80295-54-1) ; Receptors, Complement ; C5AR1 protein, human
Language	English
Publishing date	2023-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI168277
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Article ; Online: An analysis of SARS-CoV-2 cell entry genes identifies the intestine and colorectal cancer as susceptible tissues.

Darvish-Damavandi, Mahnaz / Laycock, James / Ward, Christopher / van Driel, Milou S / Goldgraben, Mae / Buczacki, Simon

2020

Abstract: SARS-CoV-2 is the causative agent for the COVID-19 pandemic. COVID-19 has necessitated rapid changes in surgical practice and organisation through both the initial peak and ongoing recovery period 1. SARS-CoV-2 infects cells by interacting with the host ... ...

Abstract	SARS-CoV-2 is the causative agent for the COVID-19 pandemic. COVID-19 has necessitated rapid changes in surgical practice and organisation through both the initial peak and ongoing recovery period 1. SARS-CoV-2 infects cells by interacting with the host cell surface protein ACE2 and utilises TMPRSS2 in viral spike protein priming to facilitate cell entry (Fig. 1a) 2. Whilst COVID-19 is predominantly a respiratory disease approximately 15% of patients have concurrent gastrointestinal symptoms 3. SARS-CoV-2 RNA and live virus have been identified in stool from COVID-19 patients and SARS-CoV-2 readily infects intestinal organoids 4-6. Despite these circumstantial data, gastrointestinal transmission has not yet been formally confirmed. Cancers commonly express different genes from the tissue of origin and it is largely unexplored whether tumours can be infected with SARS-CoV-2. We sought to explore the expression of ACE2 and TMPRSS2 in large publicly available normal tissue and pan-cancer expression data sets to understand whether levels of these genes identify susceptible tissues. SJAB is supported by an Advanced Clinician Scientist Fellowship grant from Cancer Research UK C14094/A27178; and core funding from Wellcome and MRC to the Wellcome-MRC Cambridge Stem Cell Institute.
Keywords	covid19
Language	English
Publishing date	2020-08-10
Publisher	Wiley-Blackwell
Publishing country	uk
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome.

Darvish-Damavandi, Mahnaz / Nikfar, Shekoufeh / Abdollahi, Mohammad

World journal of gastroenterology

2010 Volume 16, Issue 5, Page(s) 547–553

Abstract: We evaluated the efficacy and tolerability of mebeverine, a musculotropic antispasmodic agent, in irritable bowel syndrome (IBS) and compared its usual dosages by meta-analysis. Medical databases and all relevant literature were searched from 1965 to ... ...

Abstract	We evaluated the efficacy and tolerability of mebeverine, a musculotropic antispasmodic agent, in irritable bowel syndrome (IBS) and compared its usual dosages by meta-analysis. Medical databases and all relevant literature were searched from 1965 to June 2009 for any placebo-controlled clinical trials of mebeverine, using search terms such as mebeverine, clinical trials, and IBS. Eight randomized trials met our criteria, including six trials that compared mebeverine with placebo and two that compared mebeverine tablets with capsules. These eight trials included 555 patients randomized to receive either mebeverine or placebo with 352 (63%) women and 203 (37%) men in all subtypes of IBS. The pooled relative risk (RR) for clinical improvement of mebeverine was 1.13 (95% CI: 0.59-2.16, P = 0.7056) and 1.33 (95% CI: 0.92-1.93, P = 0.129) for relief of abdominal pain. The efficacy of mebeverine 200 mg compared to mebeverine 135 mg indicated RRs of 1.12 (95% CI: 0.96-1.3, P = 0.168) for clinical or global improvement and 1.08 (95% CI: 0.87-1.34, P = 0.463) for relief of abdominal pain. Thus, mebeverine is mostly well tolerated with no significant adverse effects; however, its efficacy in global improvement of IBS is not statistically significant.
MeSH term(s)	Anticonvulsants/therapeutic use ; Databases, Factual ; Female ; Humans ; Irritable Bowel Syndrome/drug therapy ; Irritable Bowel Syndrome/physiopathology ; Male ; Parasympatholytics/therapeutic use ; Phenethylamines/therapeutic use ; Placebos/therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome
Chemical Substances	Anticonvulsants ; Parasympatholytics ; Phenethylamines ; Placebos ; mebeverine (7F80CC3NNV)
Language	English
Publishing date	2010-02-01
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Review ; Systematic Review
ZDB-ID	2185929-2
ISSN	2219-2840 ; 1007-9327
ISSN (online)	2219-2840
ISSN	1007-9327
DOI	10.3748/wjg.v16.i5.547
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Article ; Online: Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer

Rachael E. Clifford / Naren Govindarajah / David Bowden / Paul Sutton / Mark Glenn / Mahnaz Darvish-Damavandi / Simon Buczacki / Ultan McDermott / Zdzislaw Szulc / Besim Ogretmen / Jason L. Parsons / Dale Vimalachandran

Cells, Vol 9, Iss 2693, p

2020 Volume 2693

Abstract	Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer.
Keywords	acid ceramidase ; ionizing radiation ; LCL521 ; rectal cancer ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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