Alexander Arlt - Academia.edu (original) (raw)

Papers by Alexander Arlt

Innate Immun, 2013

Appendicitis represents a common and severe gastrointestinal illness in younger individuals world... more Appendicitis represents a common and severe gastrointestinal illness in younger individuals worldwide. The disease is characterized by an excessive inflammatory response and it is believed that bacterial overgrowth due to blockage of the appendix lumen might be involved. Despite the high incidence, only limited data on the pathophysiological changes exist; in particular, the innate immune responses involved are largely unknown. Real-time PCR analysis of tissue samples from inflamed and normal appendices demonstrated differentially regulated expression patterns of epithelial-derived antimicrobial peptides (AMP). The α-defensins human neutrophil peptides 1-3, HD5 and HD6, as well as the two β-defensins, human β-defensins (hBD)-2 and hBD-3, were up-regulated, whereas hBD-1 was down-regulated in acute appendicitis. Expression of upstream regulators of AMP expression, NOD-2 and TLRs 1, 2, 4, 5, 7, 8 and 10 was significantly increased as detected by real-time PCR. Finally, we confirmed the involvement of the pro-inflammatory cytokines IL-1β and IL-8, and detected characteristic changes in microbial community composition in appendicitis tissue specimens by 16S rDNA based detection techniques. In this study, we demonstrate a differential regulation of the innate immune system along with an altered bacterial diversity in acute appendicitis.

e.Curriculum Innere Medizin, 2016

Der Gastroenterologe, 2011

Cme Premium Fortbildung Für Die Medizinische Praxis, Jul 1, 2014

American Journal of Respiratory and Critical Care Medicine, Jan 15, 2015

Der Gastroenterologe, 2013

Oncogene, 2003

Loss of growth control and a marked resistance to apoptosis are considered major mechanisms drivi... more Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumour progression. Protein kinases C (PKC) have been shown to be important in the regulation of proliferation and apoptosis. In this report, we investigated the role of the PKC-like kinase PKCμ in the control of these processes in pancreatic adenocarcinoma cells. We demonstrate that in

Cancer Research, Mar 1, 2004

Pancreatic ductal carcinoma is characterized by a profound chemoresistance. As we have shown prev... more Pancreatic ductal carcinoma is characterized by a profound chemoresistance. As we have shown previously, these tumor cells can develop chemoresistance by interleukin (IL)-1␤ in an autocrine and nuclear factor-B-dependent fashion. Because pancreatic ductal carcinoma contains many mesenchymal stromal cells, we further investigated how tumorstroma interactions contribute to chemoresistance by using a transwell coculture model, including murine pancreatic fibroblasts and the chemosensitive human pancreatic carcinoma cell lines T3M4 and PT45-P1. If cultured with fibroblast-conditioned medium or kept in coculture with fibroblasts, both cell lines became much less sensitive toward treatment with etoposide than cells cultured under standard conditions. Furthermore, the secretion of IL-1␤ in T3M4 and PT45-P1 cells was increased by the fibroblasts, and IL-1␤-receptor blockade abolished the resistanceinducing effect during cocultivation. This stimulated IL-1␤ secretion could be attributed to nitric oxide (NO) released by the fibroblasts as an

Bmc Immunol, 2009

Background: Candida albicans resides on epithelial surfaces as part of the physiological microflo... more Background: Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions it may cause life-threatening infections like Candida sepsis. Human β-defensins (hBDs) are critical components of host defense at mucosal surfaces and we have recently shown that hBD-2 and hBD-3 are upregulated in Candida esophagitis. We therefore studied the role of Candidate signalling pathways in order to understand the mechanisms involved in regulation of hBD-expression by C. albicans. We used the esophageal cell line OE21 and analysed the role of paracrine signals from polymorphonuclear leukocytes (PMN) in an in vitro model of esophageal candidiasis.

Nature medicine, Jan 4, 2016

Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute ... more Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associat...

Journal of Cell Science, Aug 1, 2001

Oncogene, 2001

is a putative NF-kB target gene implicated in the regulation of cellular viability. Here, we show... more is a putative NF-kB target gene implicated in the regulation of cellular viability. Here, we show that in HeLa cells TNFa induces expression of p22 PRG1/IEX-1 in an NF-kB dependent fashion. Blockade of NF-kB activation by various NF-kB inhibitors abolished TNFa-induced p22 PRG1/IEX-1 expression and increased the sensitivity to apoptosis induced by TNFa, an activating Fas-antibody or the anti-cancer drug etoposide. Surprisingly, ectopic expression of p22 PRG1/IEX-1 in HeLa cells transfected with an inducible p22 PRG1/IEX-1 -expression vector augments the susceptibility to apoptosis initiated by death-receptor ligands or by etoposide. In addition, p22 PRG1/IEX-1 expressing HeLa cells exhibit an accelerated progression through the cell cycle. Transfection of an antisense hammerhead ribozyme targeted to p22 PRG1/IEX-1 reduced the speed in cell cycle progression and decreased the apoptotic response to death ligands. Our data demonstrate that p22 PRG1/IEX-1 is speci®cally induced during NF-kB activation, but this seems not to be related to the anti-apoptotic actions of NF-kB. Instead, NF-kB dependent recruitment of p22 PRG1/ IEX-1 might be related to a modulation in the cell cycle, and hereby, p22 PRG1/IEX-1 may accelerate cell growth on the one hand, but may trigger apoptosis on the other. Oncogene (2001) 20, 69 ± 76.

International Journal of Cancer, Apr 20, 2003

Sulfasalazine is commonly used as an anti inflammatory agent and is known as a potent inhibitor o... more Sulfasalazine is commonly used as an anti inflammatory agent and is known as a potent inhibitor of NF-κB. Some pancreatic carcinomas are characterized by a constitutively elevated NF-κB activity accounting for chemoresistance. To elucidate whether blockade of NF-κB activity ...

Background: Candida albicans resides on epithelial surfaces as part of the physiological microflo... more Background: Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions it may cause life-threatening infections like Candida sepsis. Human β-defensins (hBDs) are critical components of host defense at mucosal surfaces and we have recently shown that hBD-2 and hBD-3 are upregulated in Candida esophagitis. We therefore studied the role of Candidate signalling pathways in order to understand the mechanisms involved in regulation of hBD-expression by C. albicans. We used the esophageal cell line OE21 and analysed the role of paracrine signals from polymorphonuclear leukocytes (PMN) in an in vitro model of esophageal candidiasis.

Data Revues 00165107 V75i4ss S0016510712014848, Apr 1, 2012

following criteria: 1) no changes, 2) unclear, 3) multiple echo-free spots, 4) budding sign, 5) i... more following criteria: 1) no changes, 2) unclear, 3) multiple echo-free spots, 4) budding sign, 5) irregular narrowing (2). 88% (nϭ58) patients underwent endoscopic treatment and 12% (nϭ9) patients -surgery. Diagnostic accuracy of EUS for T staging of the EGC was determined by comparing preoperative EUS with subsequent postoperative histopathology findings. Results: Depending on the growth of EGC within the mucosal layer diagnostic accuracy of EUS was 93%, within submucosal layer -66%, within muscular layer -66%. The overall diagnostic accuracy of EUS in preoperative determination of EGC depth of invasion was 75%. Depending on the type of the EGC accuracy of EUS was varying: type 0-Ips -78%, type 0-IIa -87,5%, type 0-IIa/c -78%, type 0-IIb -0, type 0-IIc -75%, type 0-IIc/IIa -75%. Predominant location and distribution of the EGC in the stomach were in the antrum -50%, corpus (lower part -16,5%, middle part -9%, upper part -9%), angle of stomach -10,6%, cardia -5%. The rates for overstaging and understaging were 20% and 5%, respectively. Conclusion: EUS is a useful diagnostic method for preoperative staging of EGC for T criteria. However, EUS tended to overstage T criteria, and misdiagnosis increases with depth of tumor invasion. The least accurate EUS was at type 0-IIc and type 0-IIc/IIa. The main reasons of misdiagnosis were biopsy effect, wrong interpretation of the submucosal layer, peristaltic movements and perifocal inflammatory changes.

Oncogene, 2003

Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to b... more Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to be the only clinically active drug but, because of pre-existing or acquired chemoresistance of most of the tumor cells, it failed to significantly improve the outcome of pancreatic ...

Innate Immun, 2013

Appendicitis represents a common and severe gastrointestinal illness in younger individuals world... more Appendicitis represents a common and severe gastrointestinal illness in younger individuals worldwide. The disease is characterized by an excessive inflammatory response and it is believed that bacterial overgrowth due to blockage of the appendix lumen might be involved. Despite the high incidence, only limited data on the pathophysiological changes exist; in particular, the innate immune responses involved are largely unknown. Real-time PCR analysis of tissue samples from inflamed and normal appendices demonstrated differentially regulated expression patterns of epithelial-derived antimicrobial peptides (AMP). The α-defensins human neutrophil peptides 1-3, HD5 and HD6, as well as the two β-defensins, human β-defensins (hBD)-2 and hBD-3, were up-regulated, whereas hBD-1 was down-regulated in acute appendicitis. Expression of upstream regulators of AMP expression, NOD-2 and TLRs 1, 2, 4, 5, 7, 8 and 10 was significantly increased as detected by real-time PCR. Finally, we confirmed the involvement of the pro-inflammatory cytokines IL-1β and IL-8, and detected characteristic changes in microbial community composition in appendicitis tissue specimens by 16S rDNA based detection techniques. In this study, we demonstrate a differential regulation of the innate immune system along with an altered bacterial diversity in acute appendicitis.

e.Curriculum Innere Medizin, 2016

Der Gastroenterologe, 2011

Cme Premium Fortbildung Für Die Medizinische Praxis, Jul 1, 2014

American Journal of Respiratory and Critical Care Medicine, Jan 15, 2015

Der Gastroenterologe, 2013

Oncogene, 2003

Loss of growth control and a marked resistance to apoptosis are considered major mechanisms drivi... more Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumour progression. Protein kinases C (PKC) have been shown to be important in the regulation of proliferation and apoptosis. In this report, we investigated the role of the PKC-like kinase PKCμ in the control of these processes in pancreatic adenocarcinoma cells. We demonstrate that in

Cancer Research, Mar 1, 2004

Pancreatic ductal carcinoma is characterized by a profound chemoresistance. As we have shown prev... more Pancreatic ductal carcinoma is characterized by a profound chemoresistance. As we have shown previously, these tumor cells can develop chemoresistance by interleukin (IL)-1␤ in an autocrine and nuclear factor-B-dependent fashion. Because pancreatic ductal carcinoma contains many mesenchymal stromal cells, we further investigated how tumorstroma interactions contribute to chemoresistance by using a transwell coculture model, including murine pancreatic fibroblasts and the chemosensitive human pancreatic carcinoma cell lines T3M4 and PT45-P1. If cultured with fibroblast-conditioned medium or kept in coculture with fibroblasts, both cell lines became much less sensitive toward treatment with etoposide than cells cultured under standard conditions. Furthermore, the secretion of IL-1␤ in T3M4 and PT45-P1 cells was increased by the fibroblasts, and IL-1␤-receptor blockade abolished the resistanceinducing effect during cocultivation. This stimulated IL-1␤ secretion could be attributed to nitric oxide (NO) released by the fibroblasts as an

Bmc Immunol, 2009

Background: Candida albicans resides on epithelial surfaces as part of the physiological microflo... more Background: Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions it may cause life-threatening infections like Candida sepsis. Human β-defensins (hBDs) are critical components of host defense at mucosal surfaces and we have recently shown that hBD-2 and hBD-3 are upregulated in Candida esophagitis. We therefore studied the role of Candidate signalling pathways in order to understand the mechanisms involved in regulation of hBD-expression by C. albicans. We used the esophageal cell line OE21 and analysed the role of paracrine signals from polymorphonuclear leukocytes (PMN) in an in vitro model of esophageal candidiasis.

Nature medicine, Jan 4, 2016

Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute ... more Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associat...

Journal of Cell Science, Aug 1, 2001

Oncogene, 2001

is a putative NF-kB target gene implicated in the regulation of cellular viability. Here, we show... more is a putative NF-kB target gene implicated in the regulation of cellular viability. Here, we show that in HeLa cells TNFa induces expression of p22 PRG1/IEX-1 in an NF-kB dependent fashion. Blockade of NF-kB activation by various NF-kB inhibitors abolished TNFa-induced p22 PRG1/IEX-1 expression and increased the sensitivity to apoptosis induced by TNFa, an activating Fas-antibody or the anti-cancer drug etoposide. Surprisingly, ectopic expression of p22 PRG1/IEX-1 in HeLa cells transfected with an inducible p22 PRG1/IEX-1 -expression vector augments the susceptibility to apoptosis initiated by death-receptor ligands or by etoposide. In addition, p22 PRG1/IEX-1 expressing HeLa cells exhibit an accelerated progression through the cell cycle. Transfection of an antisense hammerhead ribozyme targeted to p22 PRG1/IEX-1 reduced the speed in cell cycle progression and decreased the apoptotic response to death ligands. Our data demonstrate that p22 PRG1/IEX-1 is speci®cally induced during NF-kB activation, but this seems not to be related to the anti-apoptotic actions of NF-kB. Instead, NF-kB dependent recruitment of p22 PRG1/ IEX-1 might be related to a modulation in the cell cycle, and hereby, p22 PRG1/IEX-1 may accelerate cell growth on the one hand, but may trigger apoptosis on the other. Oncogene (2001) 20, 69 ± 76.

International Journal of Cancer, Apr 20, 2003

Sulfasalazine is commonly used as an anti inflammatory agent and is known as a potent inhibitor o... more Sulfasalazine is commonly used as an anti inflammatory agent and is known as a potent inhibitor of NF-κB. Some pancreatic carcinomas are characterized by a constitutively elevated NF-κB activity accounting for chemoresistance. To elucidate whether blockade of NF-κB activity ...

Background: Candida albicans resides on epithelial surfaces as part of the physiological microflo... more Background: Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions it may cause life-threatening infections like Candida sepsis. Human β-defensins (hBDs) are critical components of host defense at mucosal surfaces and we have recently shown that hBD-2 and hBD-3 are upregulated in Candida esophagitis. We therefore studied the role of Candidate signalling pathways in order to understand the mechanisms involved in regulation of hBD-expression by C. albicans. We used the esophageal cell line OE21 and analysed the role of paracrine signals from polymorphonuclear leukocytes (PMN) in an in vitro model of esophageal candidiasis.

Data Revues 00165107 V75i4ss S0016510712014848, Apr 1, 2012

following criteria: 1) no changes, 2) unclear, 3) multiple echo-free spots, 4) budding sign, 5) i... more following criteria: 1) no changes, 2) unclear, 3) multiple echo-free spots, 4) budding sign, 5) irregular narrowing (2). 88% (nϭ58) patients underwent endoscopic treatment and 12% (nϭ9) patients -surgery. Diagnostic accuracy of EUS for T staging of the EGC was determined by comparing preoperative EUS with subsequent postoperative histopathology findings. Results: Depending on the growth of EGC within the mucosal layer diagnostic accuracy of EUS was 93%, within submucosal layer -66%, within muscular layer -66%. The overall diagnostic accuracy of EUS in preoperative determination of EGC depth of invasion was 75%. Depending on the type of the EGC accuracy of EUS was varying: type 0-Ips -78%, type 0-IIa -87,5%, type 0-IIa/c -78%, type 0-IIb -0, type 0-IIc -75%, type 0-IIc/IIa -75%. Predominant location and distribution of the EGC in the stomach were in the antrum -50%, corpus (lower part -16,5%, middle part -9%, upper part -9%), angle of stomach -10,6%, cardia -5%. The rates for overstaging and understaging were 20% and 5%, respectively. Conclusion: EUS is a useful diagnostic method for preoperative staging of EGC for T criteria. However, EUS tended to overstage T criteria, and misdiagnosis increases with depth of tumor invasion. The least accurate EUS was at type 0-IIc and type 0-IIc/IIa. The main reasons of misdiagnosis were biopsy effect, wrong interpretation of the submucosal layer, peristaltic movements and perifocal inflammatory changes.

Oncogene, 2003

Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to b... more Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to be the only clinically active drug but, because of pre-existing or acquired chemoresistance of most of the tumor cells, it failed to significantly improve the outcome of pancreatic ...