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BETA
Brodin, Veronika Patcha
Alternative names
Publications (9 of 9) Show all publications
Gnosa, S., Zhang, H., Brodin Patcha, V., Carstensen, J., Adell, G. & Sun, X.-F. (2014). AEG-1 expression is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy: a study in a Swedish clinical trial. British Journal of Cancer, 111(1), 166-173
Open this publication in new window or tab >>AEG-1 expression is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy: a study in a Swedish clinical trial
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2014 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, no 1, p. 166-173Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Preoperative radiotherapy (RT) is widely used to downstage rectal tumours, but the rate of recurrence varies significantly. Therefore, new biomarkers are needed for better treatment and prognosis. It has been shown that astrocyte elevated gene-1 (AEG-1) is a key mediator of migration, invasion, and treatment resistance. Our aim was to analyse the AEG-1 expression in relation to RT in rectal cancer patients and to test its radiosensitising properties.

METHODS:

The AEG-1 expression was examined by immunohistochemistry in 158 patients from the Swedish clinical trial of RT. Furthermore, we inhibited the AEG-1 expression by siRNA in five colon cancer cell lines and measured the survival after irradiation by colony-forming assay.

RESULTS:

The AEG-1 expression was increased in the primary tumours compared with the normal mucosa independently of the RT (P<0.01). High AEG-1 expression in the primary tumour of the patients treated with RT correlated independently with higher risk of distant recurrence (P=0.009) and worse disease-free survival (P=0.007). Downregulation of AEG-1 revealed a decreased survival after radiation in radioresistant colon cancer cell lines.

CONCLUSIONS:

The AEG-1 expression was independently related to distant recurrence and disease-free survival in rectal cancer patients with RT and could therefore be a marker to discriminate patients for distant relapse.

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
Keywords
MTDH; astrocyte elevated gene-1; distant recurrence; disease-free survival
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-109376 (URN)10.1038/bjc.2014.250 (DOI)000339163300020 ()24874474 (PubMedID)
Available from: 2014-08-15 Created: 2014-08-15 Last updated: 2018-01-11Bibliographically approved
Raffetseder, J., Pienaar, E., Blomgran, R., Eklund, D., Brodin Patcha, V., Andersson, H., . . . Lerm, M. (2014). Replication Rates of Mycobacterium tuberculosis in Human Macrophages Do Not Correlate with Mycobacterial Antibiotic Susceptibility. PLoS ONE, 9(11), e112426
Open this publication in new window or tab >>Replication Rates of Mycobacterium tuberculosis in Human Macrophages Do Not Correlate with Mycobacterial Antibiotic Susceptibility
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112426-Article in journal (Refereed) Published
Abstract [en]

The standard treatment of tuberculosis (TB) takes six to nine months to complete and this lengthy therapy contributes to the emergence of drug-resistant TB. TB is caused by Mycobacterium tuberculosis (Mtb) and the ability of this bacterium to switch to a dormant phenotype has been suggested to be responsible for the slow clearance during treatment. A recent study showed that the replication rate of a non-virulent mycobacterium, Mycobacterium smegmatis, did not correlate with antibiotic susceptibility. However, the question whether this observation also holds true for Mtb remains unanswered. Here, in order to mimic physiological conditions of TB infection, we established a protocol based on long-term infection of primary human macrophages, featuring Mtb replicating at different rates inside the cells. During conditions that restricted Mtb replication, the bacterial phenotype was associated with reduced acid-fastness. However, these phenotypically altered bacteria were as sensitive to isoniazid, pyrazinamide and ethambutol as intracellularly replicating Mtb. In support of the recent findings with M. smegmatis, we conclude that replication rates of Mtb do not correlate with antibiotic tolerance.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-113014 (URN)10.1371/journal.pone.0112426 (DOI)000345250400061 ()25386849 (PubMedID)
Note

Funding Agencies|Bill and Melinda Gates Foundation; Swedish Research Council [2009-3821, 2012-3349]; Swedish International Development Cooperation Agency; Swedish Heart-Lung Foundation; King Oscar II Foundation; Carl Trygger Foundation; Clas Groschinsky Foundation

Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2018-01-11
Blomgran, R., Brodin Patcha, V., Verma, D., Bergström, I., Söderkvist, P., Sjöwall, C., . . . Sarndahl, E. (2012). Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils. PLoS ONE, 7(3)
Open this publication in new window or tab >>Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3Article in journal (Refereed) Published
Abstract [en]

Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1 beta production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages. less thanbrgreater than less thanbrgreater thanMethods and Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response. less thanbrgreater than less thanbrgreater thanConclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.

Place, publisher, year, edition, pages
Public Library of Science, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77736 (URN)10.1371/journal.pone.0031326 (DOI)000303017700010 ()
Note
Funding Agencies|Swedish Research Council||Heart-Lung Foundation||King Gustaf V Memorial Foundation||County Council of Ostergotland||Soderberg Foundation||Available from: 2012-05-29 Created: 2012-05-28 Last updated: 2017-12-07
Börgeson, E., Lönn, J., Bergström, I., Brodin Patcha, V., Ramström, S., Nayeri, F., . . . Bengtsson, T. (2011). Lipoxin A(4) Inhibits Porphyromonas gingivalis-Induced Aggregation and Reactive Oxygen Species Production by Modulating Neutrophil-Platelet Interaction and CD11b Expression. INFECTION AND IMMUNITY, 79(4), 1489-1497
Open this publication in new window or tab >>Lipoxin A(4) Inhibits Porphyromonas gingivalis-Induced Aggregation and Reactive Oxygen Species Production by Modulating Neutrophil-Platelet Interaction and CD11b Expression
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2011 (English)In: INFECTION AND IMMUNITY, ISSN 0019-9567, Vol. 79, no 4, p. 1489-1497Article in journal (Refereed) Published
Abstract [en]

Porphyromonas gingivalis is an etiological agent that is strongly associated with periodontal disease, and it correlates with numerous inflammatory disorders, such as cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. Lipoxin A(4) (LXA(4)) is an endogenous anti-inflammatory and proresolving mediator that is protective of inflammatory disorders. The aim of this study was to investigate the effect of LXA(4) on the P. gingivalis-induced activation of neutrophils and platelets and the possible involvement of Rho GTPases and CD11b/CD18 integrins. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry and fluorescence microscopy. Integrin activity was studied by flow cytometry, detecting the surface expression of CD11b/CD18 as well as the exposure of the high-affinity integrin epitope, whereas the activation of Rac2/Cdc42 was examined using a glutathione S-transferase pulldown assay. The study shows that P. gingivalis activates Rac2 and Cdc42 and upregulates CD11b/CD18 and its high-affinity epitope on neutrophils, and that these effects are diminished by LXA(4). Furthermore, we found that LXA(4) significantly inhibits P. gingivalis-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA(4) was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA(4) antagonizes P. gingivalis-induced cell activation in a manner that is dependent on leukocyte-platelet interaction, likely via the inhibition of Rho GTPase signaling and the downregulation of CD11b/CD18. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis.

Place, publisher, year, edition, pages
American Society for Microbiology, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67160 (URN)10.1128/IAI.00777-10 (DOI)000288532300010 ()
Available from: 2011-04-01 Created: 2011-04-01 Last updated: 2015-03-13
Särndahl, E., Bergström, I., Brodin Patcha, V., Nijm, J., Setterud, H. & Jonasson, L. (2007). Activation state of neutrophils in patients with stable coronary artery disease. In: 76th Congress of the European Atherosclerosis Society,2007.
Open this publication in new window or tab >>Activation state of neutrophils in patients with stable coronary artery disease
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2007 (English)In: 76th Congress of the European Atherosclerosis Society,2007, 2007Conference paper, Published paper (Other academic)
Abstract [en]

   

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40760 (URN)54061 (Local ID)54061 (Archive number)54061 (OAI)
Available from: 2009-10-10 Created: 2009-10-10
Lerm, M., Brodin Patcha, V., Ruishalme, I., Stendahl, O. & Särndahl, E. (2007). Inactivation of Cdc42 is nessecary for depolymerization of phagosomal F-actin and subsequent phagosomal maturation. Journal of Immunology, 178(11), 7357-7365
Open this publication in new window or tab >>Inactivation of Cdc42 is nessecary for depolymerization of phagosomal F-actin and subsequent phagosomal maturation
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2007 (English)In: Journal of Immunology, ISSN 0022-1767, Vol. 178, no 11, p. 7357-7365Article in journal (Refereed) Published
Abstract [en]

Phagocytosis is a complex process involving the activation of various signaling pathways, such as the Rho GTPases, and the subsequent reorganization of the actin cytoskeleton. In neutrophils, Rac and Cdc42 are activated during phagocytosis but less is known about the involvement of these GTPases during the different stages of the phagocytic process. The aim of this study was to elucidate the role of Cdc42 in phagocytosis and the subsequent phagosomal maturation. Using a TAT-based protein transduction technique, we introduced dominant negative and constitutively active forms of Cdc42 into neutrophil-like HL60 (human leukemia) cells that were allowed to phagocytose IgG-opsonized yeast particles. Staining of cellular F-actin in cells transduced with constitutively active Cdc42 revealed that the activation of Cdc42 induced sustained accumulation of periphagosomal actin. Moreover, the fusion of azurophilic granules with the phagosomal membrane was prevented by the accumulated F-actin. In contrast, introducing dominant negative Cdc42 impaired the translocation per se of azurophilic granules to the periphagosomal area. These results show that efficient phagosomal maturation and the subsequent eradication of ingested microbes in human neutrophils is dependent on a strictly regulated Cdc42. To induce granule translocation, Cdc42 must be in its active state but has to be inactivated to allow depolymerization of the F-actin cage around the phagosome, a process essential for phagolysosome formation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14632 (URN)
Available from: 2007-09-13 Created: 2007-09-13
Särndahl, E., Bergström, I., Brodin, V. P., Nijm, J., Lundqvist Setterud, H. & Jonasson, L. (2007). Neutrophil activation status in stable coronary artery disease.. PLoS ONE, 2(10), e1056-
Open this publication in new window or tab >>Neutrophil activation status in stable coronary artery disease.
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2007 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 2, no 10, p. e1056-Article in journal (Refereed) Published
Abstract [en]

Background: During the last years, neutrophils have emerged as important players in atherogenesis. They are highly activated in peripheral blood of patients with unstable angina. Moreover, a primed state of circulating neutrophils has been proposed in patients with stable angina. Our aim was to investigate the neutrophil activation status in patients with stable coronary artery disease (CAD) at conventional drug treatment.

Methodology and principal findings: Thirty patients with stable CAD and 30 healthy controls were included using a paired design. The neutrophil expression of CD18 and high-affinity state of CD11b was analysed by flow cytometry before and after stimulation with chemoattractants. Also, the production of reactive oxygen species (ROS) was determined by chemiluminescence. During basal conditions, the neutrophil expression of CD18 or high-affinity state of CD11b did not differ between patients and controls. Chemoattractants (Interleukin-8 and Leukotriene B(4)) did not increase either the expression or the amount of high-affinity CD11b/CD18-integrins in CAD patients compared to controls, and had no effect on the production of ROS. On the other hand, the ROS production in response to C3bi-opsonised yeast particles and the neutrophils' inherent capacity to produce ROS were both significantly decreased in patients.

Conclusion/Significance: We could not find any evidence that neutrophils in patients with stable CAD were primed, i.e. more prone to activation, compared to cells from healthy controls. According to our data, the circulating neutrophils in CAD patients rather showed an impaired activation status. It remains to be elucidated whether the neutrophil dysfunction in CAD is mainly a marker of chronic disease, an atherogenic factor or a consequence of the drug treatment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17246 (URN)10.1371/journal.pone.0001056 (DOI)17957240 (PubMedID)
Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2010-01-14
Brodin Patcha, V. (2007). Pro- and anti-inflammatory regulation of β2 integrin signalling in human neutrophils. (Doctoral dissertation). Linköping: Institutionen för biomedicin och kirurgi
Open this publication in new window or tab >>Pro- and anti-inflammatory regulation of β2 integrin signalling in human neutrophils
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The body is under constant attack from pathogens trying to slip by our immune defence. If the barrier is breached, invading pathogens enter the tissues and cause inflammation. During this process neutrophils, constituting the first line of defence, leave the bloodstream and seek out and kill the invading pathogens. The mechanisms leading to activation of receptors on neutrophils must be closely orchestrated. Pro- and anti-inflammatory substances can influence the outcome of the inflammation process by affecting the involved players. If not well balanced, inflammatory diseases, such as atherosclerosis and rheumatoid arthritis, can be the outcome.

The aim of this thesis was to elucidate the effect of pro- (fMLP, Leukotriene B4, and Interleukin-8) and anti- (lipoxins, aspirin and statins) inflammatory substances on the β2 integrins, mediating adhesion of neutrophils both under “normal” conditions and during coronary artery disease. More specifically, the effect of these substances on the β2 integrins were studied in regard to: i) the activity (i.e. affinity and avidity) of β2 integrins, ii) the signalling capacity of β2 integrins (i.e. detected as release of arachidonic acid, and the production of reactive oxygen species, and iii) the signal transduction mediated by the β2 integrins (i.e. phosphorylation of Pyk2).

The pro-inflammatory substances belong to the family of chemoattractants that induces transmigration and chemotaxis. A hierarchy exists between the different family members; the end-target chemoattractants (e.g. fMLP) being more potent than intermediary chemoattractants (e.g. IL-8 and LTB4). It was found that intermediary chemoattractants regulate β2 integrins by mainly affecting the avidity of β2 integrins. End-target chemoattractants on the other hand, affected the β2 integrins by increasing the avidity and the affinity, as well as their signalling capacity.

The anti-inflammatory substances used in this study were the exogenous aspirin and statins, and the endogenous lipoxins. In the presence of aspirin, stable analogues of lipoxin (i.e. epi-lipoxins) are formed in a trans-cellular process. Lipoxin inhibited the signalling capacity of β2 integrins mediated by intermediary chemoattractants, as well as the signal transduction induced by end-target chemoattractants. Moreover, the signalling capacity of β2 integrins in neutrophils from patients suffering from coronary artery disease (CAD) was impaired. Arachidonic acid, the precursor for both pro- and anti-inflammatory eicosanoid, induced an increase in the β2 integrin activity (both affinity and avidity), but had no effect on the signal transduction.

In conclusion, different “roles” were observed for end-target and intermediary chemoattractants in the regulation of β2 integrins. The inhibitory effects of the anti-inflammatory lipoxins support earlier studies suggesting that these agents function as “stop signals” in inflammation. This is also confirmed by our findings in CAD patients, who have elevated levels of epi-lipoxins due to aspirin treatment. Moreover, Pyk2 was identified as a possible target for the inhibitory effect of anti-inflammatory drugs.

Place, publisher, year, edition, pages
Linköping: Institutionen för biomedicin och kirurgi, 2007. p. 75
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 996
Keywords
inflammation, neutrophils, signalling, integrins
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-9661 (URN)978-91-85715-22-0 (ISBN)
Public defence
2007-05-16, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2010-01-14
Patcha Brodin, V., Wigren, J., Winberg, M. E., Rasmusson, B., Li, J. & Särndahl, E. (2004). Differential inside-out activation of β2 integrins by leukotriene B4 and fMLP in human neutrophils. Experimental Cell Research, 300(2), 308-319
Open this publication in new window or tab >>Differential inside-out activation of β2 integrins by leukotriene B4 and fMLP in human neutrophils
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2004 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 300, no 2, p. 308-319Article in journal (Refereed) Published
Abstract [en]

We have investigated how LTB4, an endogenous chemoattractant encountered early in the inflammatory process, and fMLP, a bacteria-derived chemotactic peptide emanating from the site of infection, mediate inside-out regulation of the β2-integrin. The role of the two chemoattractants on β2-integrin avidity was investigated by measuring their effect on β2-integrin clustering and surface mobility, whereas their effect on β2-integrin affinity was measured by the expression of a high affinity epitope, a ligand-binding domain on β2-integrins, and by integrin binding to s-ICAM. We find that the two chemoattractants modulate the β2-integrin differently. LTB4 induces an increase in integrin clustering and surface mobility, but only a modest increase in integrin affinity. fMLP evokes a large increase in β2-integrin affinity as well as in clustering and mobility. Lipoxin, which acts as a stop signal for the functions mediated by pro-inflammatory agents, was used as a tool for further examining the inside-out mechanisms. While LTB4-induced integrin clustering and mobility were inhibited by lipoxin, only a minor inhibition of fMLP-induced β2-integrin avidity and no inhibition of integrin affinity were detected. The different modes of the inside-out regulation of β2-integrins suggest that distinct mechanisms are involved in the β2-integrin modulation induced by various chemoattractants.

Keywords
β2-Integrins, Cell adhesion, Chemotactic factors, Eicosanoids, Inflammation, Leukotriene B4, Lipoxins, Human Neutrophils, Signal transduction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14629 (URN)10.1016/j.yexcr.2004.07.015 (DOI)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2017-12-13Bibliographically approved
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