ORCID Profile
0000-0003-3245-5360
Current Organisations
RWTH Aachen University
,
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 24-07-2014
DOI: 10.1007/S00280-014-2519-4
Abstract: Diarrhoea caused by treatment with receptor tyrosine kinase inhibitors (TKI) targeting Epidermal Growth Factor Receptors (EGFR) is an important clinical toxicity in oncology that remains poorly understood. This study aimed to identify histological and molecular changes within the intestine following lapatinib to elucidate mechanisms of diarrhoea related to treatment with this dual EGFR TKI. Male albino Wistar rats were orally gavaged lapatinib at 100, 240 or 500 mg/kg daily for 4 weeks and assessed for indicators of gastrointestinal injury at the end of each week. Lapatinib in combination with weekly paclitaxel (9 mg/kg i.p.) was also assessed for cumulative injury. At each time point, blood was collected for biochemical analysis. Sections or jejunum and colon were also collected and underwent immunohistochemistry and RT-PCR to detect markers of EGFR pathway signalling, and morphometric analysis to assess changes in mucosal architecture. Lapatinib (with or without paclitaxel co-treatment) caused dose-dependent changes in crypt length, mitotic rate and goblet cell morphology. Jejunal crypt expression of EGFR and ErbB2 were decreased, whilst no changes in Erk1/2 were observed. Markers of apoptosis (caspase-3) and proliferation (Ki-67) were only significantly altered in rats treated with both lapatinib and paclitaxel. In our novel rat model of lapatinib-induced diarrhoea we have shown that changes in small intestinal morphometry and expression of EGFR are associated with diarrhoea. Further research is required to test intervention agents for the prevention of diarrhoea.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2015
Publisher: Copernicus GmbH
Date: 04-08-2023
DOI: 10.5194/EGQSJ-72-163-2023
Abstract: Abstract. The study of geological archives of dust is of great relevance as they are directly linked to past atmospheric circulation and bear the potential to reconstruct dust provenance and flux relative to climate changes. Among the dust sinks, loess–palaeosol sequences (LPSs) represent the only continental and non-aquatic archives that are predominantly built up by dust deposits close to source areas, providing detailed information on Quaternary climatic and terrestrial environmental changes. Upper Pleistocene LPSs of western central Europe have been investigated in great detail showing their linkage to millennial-scale northern hemispheric climate oscillations, but comprehensive data on dust composition and potential source–sink relationships as well as inferred past atmospheric circulation patterns for this region are still fragmentary. Here, we present an integrative approach that systematically combines sedimentological, rock magnetic, and bulk geochemical data, as well as information on Sr and Nd isotope composition, enabling a synthetic interpretation of LPS formation. We focus on the Schwalbenberg RP1 profile in the Middle Rhine Valley in Germany and integrate our data into a robust age model that has recently been established based on high-resolution radiocarbon dating of earthworm calcite granules. We show that Schwalbenberg RP1 is sub ided into a lower section corresponding to late oxygen isotope stage 3 (OIS ∼ 40–30 ka) and an upper section dating into the Last Glacial Maximum (LGM ∼ 24–22 ka), separated by a major stratigraphic unconformity. Sedimentological proxies of wind dynamics (U ratio) and pedogenesis (finest clay) of the lower section attest to comparable and largely synchronous patterns of northern hemispheric climatic changes supporting the overall synchronicity of climatic changes in and around the North Atlantic region. The anisotropy of magnetic susceptibility (AMS) reveals a clear correlation between finer grain size and increasing AMS foliation within interstadials, possibly owing to continuous accumulation of dust during pedogenic phases. Such a clear negative correlation has so far not been described for any LPS on stadial–interstadial scales. Distinct shifts in several proxy data supported by changes in isotope composition (87Sr/86Sr and εNd) within the lower section are interpreted as changes in provenance and decreasing weathering simultaneously with an overall cooling and aridification towards the end of OIS 3 (after ∼ 35 ka) and enhanced wind activity with significant input of coarse-grained material recycled from local sources related to increased landscape instability (after ∼ 31.5 ka). We find that environmental conditions within the upper section, most likely dominated by local to regional environmental signals, significantly differ from those in the lower section. In addition, AMS-based reconstructions of near-surface wind trends may indicate the influence of north-easterly winds beside the overall dominance of westerlies. The integrative approach contributes to a more comprehensive understanding of LPS formation including changes in dust composition and associated circulation patterns during Quaternary climate changes.
Publisher: MDPI AG
Date: 22-07-2020
DOI: 10.3390/NU12082172
Abstract: Patients undergoing radiotherapy to treat pelvic-organ cancer are commonly advised to follow a restricted fiber diet. However, reducing dietary fiber may promote gastrointestinal inflammation, eventually leading to deteriorated intestinal health. The goal of this study was to evaluate the influence of dietary fiber on radiation-induced inflammation. C57BL/6J male mice were fed a High-oat bran diet (15% fiber) or a No-fiber diet (0% fiber) and were either irradiated (32 Gy delivered in four fractions) to the colorectal region or only sedated (controls). The dietary intervention started at 2 weeks before irradiation and lasted for 1, 6, and 18 weeks after irradiation, at which time points mice were sacrificed and their serum s les were assayed for 23 cytokines and chemokines. Our analyses show that irradiation increased the serum cytokine levels at all the time points analyzed. The No-fiber irradiated mice had significantly higher levels of pro-inflammatory cytokines than the High-oat irradiated mice at all time points. The results indicate that a fiber-rich oat bran diet reduces the intensity of radiation-induced inflammation, both at an early and late stage. Based on the results, it seems that the advice to follow a low-fiber diet during radiotherapy may increase the risk of decreased intestinal health in cancer survivors.
Publisher: Wiley
Date: 25-02-2014
DOI: 10.1111/ODI.12224
Abstract: Oral mucositis in patients undergoing cancer therapy is a significant problem. Its prevalence ranges between 20 and 100%, depending on treatment type and protocols and patient-based variables. Mucositis is self-limiting when uncomplicated by infection. Unfortunately, the incidence of developing a local or systemic infection during the course of the treatment is very high. At this stage, it is unclear which role oral microbiota play in the onset, duration, and severity of oral mucositis. Nevertheless, there is growing interest in this underexplored topic, and new studies are being undertaken to unravel their impact on the pathogenesis of mucositis.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.NEURO.2013.06.007
Abstract: Alimentary mucositis is a severe, dose-limiting, toxic side effect of cytotoxic chemotherapy and radiotherapy. Patients with mucositis often have reductions or breaks imposed on cytotoxic therapy, which may lead to reduced survival. Furthermore, there is an increased risk of infection and hospitalization, compounding the cost of treatment. There are currently limited therapeutic options for mucositis, and no effective prevention available. Mucin expression and secretion have been shown to be associated with mucositis. Furthermore, mucins exhibit protective effects on the alimentary tract through reducing mechanical and chemical stress, preventing bacterial overgrowth and penetration, and digestion of the mucosa. Additionally, a number of studies have implicated some key neurotransmitters in both mucositis and mucin secretion, suggesting that the enteric nervous system may also play a key role in the development of mucositis.
Publisher: MDPI AG
Date: 30-09-2013
DOI: 10.3390/NU5103948
Publisher: Springer Science and Business Media LLC
Date: 08-07-2019
DOI: 10.1007/S00520-019-04893-Z
Abstract: Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. The MASCC/ISOO Mucositis Study Group regularly assesses available literature relating to pathogenesis, mechanisms, and novel therapeutic approaches and distils this to summary perspectives and recommendations. Reviewers assessed 164 articles published between January 2011 and June 2016 to identify progress made since the last review and highlight new targets for further investigation. Findings were organized into sections including established and emerging mediators of toxicity, potential insights from technological advances in mucositis research, and perspective. Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 27-02-2019
DOI: 10.1007/S00280-019-03787-5
Abstract: Irinotecan-induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric neural cells and goblet cells are altered following irinotecan treatment. Tumour-bearing Dark Agouti rats were administered a single dose of 175 mg/kg of irinotecan intraperitoneally and 0.01 mg/kg atropine subcutaneously. Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120 h after treatment. Jejunum and colon s les were formalin fixed. Haematoxylin and eosin staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (neural cell marker) were carried out. Statistical analyses were carried out using Kruskal-Wallis test with Dunns post test, Mann Whitney U test, and nonlinear regression. Total goblet cells decreased at 72 h compared with controls in the colon (p < 0.05). The percentage of cavitated goblet cells decreased compared to all other time points at 120 h in the colon. The number of S-100-positive cells in the submucosal plexus decreased in the colon (p = 0.0046) and in the myenteric plexus of the jejunum and colon (p = 0.0058 and p = 0.0022, respectively), on comparing treated with control. Enteric ganglia in the myenteric plexus of the jejunum decreased at 24 h and 96 h. Irinotecan-induced mucositis is associated with increases in mucus secretion and enteric neural cell change. These changes may contribute to the pathophysiology of mucositis through the dysregulation of neural signalling.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.NEURO.2018.02.013
Abstract: While people are often aware of the motor symptoms in Parkinson's disease (PD), few know of the many non-motor symptoms, which patients report have a greater impact on their quality of life. Gastrointestinal (GI) dysfunction is one of the most common non-motor symptoms, which can occur at any stage of PD, even years prior to diagnosis, and can affect all sections along the GI tract causing a range of symptoms including drooling, gastroparesis and constipation. We have investigated whether a neurotoxin model of PD induced by rotenone, a mitochondrial complex I inhibitor, is capable of reproducing the GI dysfunction seen clinically. Sprague-Dawley rats were administered 2.75 mg/kg rotenone, 5 days/week for 4 weeks, via intraperitoneal injection. Rats underwent behavioural testing, including the one-hour stool and gastric emptying tests before GI contents and tissues were collected for microbiota and histological analysis. Rats exposed to rotenone had more days with evidence of diarrhoea and significantly delayed gastric emptying, reproducing the clinical symptom of gastroparesis. Microbiota analysis revealed alterations in the small intestine and colon of rotenone-treated rats, relatively consistent with changes described in PD patients. Histological analysis demonstrated mucosal thickening and goblet cell hyperplasia in the colon of rotenone rats, which may be an adaptive response to the toxin or changes in GI microbiota. Our results indicate that rotenone may be a good model for investigating the mechanisms involved with Parkinson's GI symptoms and for screening potential therapeutic options as it is capable of recapitulating some key GI changes that occur during PD progression.
Publisher: Informa UK Limited
Date: 12-2008
Abstract: Chemotherapy-induced diarrhea (CID) is a well recognized side effect of cancer treatment. However, the pathophysiology behind this debilitating side effect remains unclear. Irinotecan causes cholinergic and delayed onset diarrhea in patients, in which beta-glucuronidase produced by gut bacteria is thought to be involved. Diarrhea occurred, as expected, following irinotecan treatment. beta-glucuronidase expression increased in the jejunum and colon. Faecal flora changed quantitatively after treatment also, with increases in E. coli, Staphylococcus spp. and Clostridium spp. (all beta-glucuronidase producing) and decreases in Lactobacillus spp., Bifidobacterium spp. (both beneficial bacteria), and Bacteroides spp. (beta-glucuronidase producing, major component of intestinal flora). Rats were treated with 200 mg/kg irinotecan and killed at various time points up to 72 h. Rats were monitored for diarrhea. Sections were stained for beta-glucuronidase expression, and faecal DNA was analysed using real time PCR. Irinotecan-induced diarrhea may be caused by an increase in beta-glucuronidase producing bacteria. However, the increase in bacteria may also be caused by irinotecan, further exaggerating the toxicity of the drug and emphasising the need for these specific bacteria to be therapeutically targeted for successful treatment regimens to be accomplished.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2018
DOI: 10.1007/S00520-018-4255-5
Abstract: Radiotherapy-induced gut toxicity (RIGT) is associated with significant diarrhoea, pain and rectal bleeding. Matrix metalloproteinases (MMPs) have been reported to be involved in chemotherapy-induced gut toxicity and RIGT following single-dose irradiation in vivo. We therefore proposed MMPs would be involved in the pathobiology of RIGT following fractionated irradiation. Dark Agouti rats were treated with fractionated radiation (3 × 2.5 Gy/week for 6 weeks). Rats were killed at 3, 6 and 15 weeks to represent acute and chronic toxicities. Sections of jejunum and colon were immunostained for MMP-1, MMP-2, MMP-9 and MMP-14. Relative mRNA expression in jejunum and colon was quantified by RT-PCR for MMP-1, MMP-2, MMP-9 and MMP-14. Western blotting was also conducted on jejunum and colon tissue collected at week 6 to determine protein levels of pro- and active MMP-2. MMP-2 total protein levels, determined by western blotting, significantly increased in both the jejunum (p = 0.0359) and the colon (p = 0.0134) 6 weeks into the fractionated radiation schedule. MMP-1, MMP-2, and MMP-14 mRNA expression significantly increased in the jejunum. MMP-2 mRNA expression was also significantly increased in the colon. Immunostaining of MMP-2 was observed to be increased in both crypt enterocytes and the lamina propria. MMP-2 plays a role in the pathobiology of gastrointestinal toxicities following fractionated irradiation. Whilst MMP-1 and MMP-14 mRNA expression was increased, this occurred only in the jejunum, suggesting MMPs are differentially involved in RIGT depending on the intestinal region. Further studies are needed to elucidate the role these mediators play in the development and potentiation of RIGT.
Publisher: Copernicus GmbH
Date: 28-03-2022
DOI: 10.5194/EGUSPHERE-EGU22-12498
Abstract: & & Loess-Palaeosol-Sequences (LPS) are the most widespread aeolian sedimentary deposits providing climatic- and environmental records across continents. As dust sinks, they may archive information on dust source dynamics, if targeted source signals survived processes operating during production, transport, and syn- and post-depositional alteration of particles and sediments. Yet, our knowledge about such dynamics through palaeoenvironmental changes during the Upper Pleistocene remains vague. This limits our understanding of thresholds that may have (de-) activated dust sources causing major environmental changes in prevalent areas. We thus combine results of isotope- (& sup& /86& /sup& Sr, & sup& /144& /sup& Nd) and major element (Si/Al) provenance proxies that react differently to pre-, syn- and post depositional alteration processes, with granulometry (U-ratio) and the anisotropy of magnetic susceptibility (AMS). Granulometry is recognised as an indicator for wind strengths and the primary magnetic fabric of loess deposits has been successfully used to reconstruct surface near wind directions. We apply our approach on the RP1 profile of the Schwalbenberg LPS that covers the late OIS 3 and the OIS 2 in centennial-scale resolution. The site is embedded in the Middle Rhine Valley (Germany) iding the Rhenish Massif in its western and eastern part. Consequently, the Schwalbenberg seems appropriate to trace provenance shifts as it is linked to a distal dust source via the Rhine and as it is surrounded by potential local dust sources of the Rhenish Massif. Our results indicate shifts in source areas NNE-SSW off the site, contemporary with increasing frost dynamics and aridification. Both factors seem to enhance dust inputs from the Rhine system up to a threshold where the Rhenish Massif gets activated as a dominant source. Geochemical fingerprinting and AMS at the Schwalbenberg RP1 LPS reveal insights into dust source dynamics that allow for estimating their emission potential during Upper Pleistocene palaeoenvironmental changes. & & &
Publisher: Springer Science and Business Media LLC
Date: 24-09-2019
DOI: 10.1038/S41598-019-50023-4
Abstract: Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8 Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed radiotherapy, could promote bowel health in pelvic cancer survivors.
Publisher: Oxford University Press (OUP)
Date: 16-11-2021
DOI: 10.1093/JPP/RGAB156
Abstract: To circumvent cisplatin (CDDP) toxic effects and improve the antitumoural effect, our research group developed long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP). This study aimed to evaluate whether SpHL-CDDP is associated with intestinal protection under in-vitro conditions in the presence of host–microbiota, compared with free CDDP. The cytotoxicity of CDDP and SpHL-CDDP were evaluated by colorimetric MTT and sulforhodamine B (SRB) assays. Epithelial proliferation was assessed by using an in-vitro wounding model in the presence of host–microbiota with intestinal epithelial cell line 6 (IEC-6) monolayers. Cytokines were determined by ELISA. Reduced cytotoxicity of SpHL-CDDP in IEC-6 cells (minimum of 1.3-fold according to the IC50 values) was observed when compared with CDDP. The presence of microbiota or CDDP reduced the wound healing. The association of microbiota and SpHL-CDDP improved the wound healing and cell number in IEC-6 cells when compared with control. These beneficial results can be associated with increased IL-6 and IL-10 levels induced by SpHL-CDDP which were affected by the presence of microbiota. These results indicate that the presence of microbiota associated with SpHL-CDDP provided less intestinal cellular damages compared with CDDP and constitutes a promising candidate for clinical use.
Publisher: Elsevier BV
Date: 2004
Publisher: Elsevier BV
Date: 2024
Publisher: Springer Science and Business Media LLC
Date: 28-03-2020
DOI: 10.1007/S12253-019-00644-X
Abstract: Irinotecan-induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric neural cells and goblet cells are altered following irinotecan treatment. Tumour-bearing Dark Agouti rats were administered a single dose of 175 mg/kg of irinotecan intraperitoneally and 0.01 mg/kg atropine subcutaneously. Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120 h after treatment. Jejunum and colon s les were formalin fixed. Haematoxylin and eosin staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (neural cell marker) were carried out. Statistical analyses were carried out using Kruskal-Wallis test with Dunns post test, Mann Whitney U test and nonlinear regression. Total goblet cells decreased at 72 h compared with controls in the colon (p < 0.05). The percentage of cavitated goblet cells decreased compared to all other time points at 120 h in the colon. The number of S-100 positive cells in the submucosal plexus decreased in the colon (p = 0.0046) and in the myenteric plexus of the jejunum and colon (p = 0.0058 and p = 0.0022, respectively), when comparing treated with control. Enteric ganglia in the myenteric plexus of the jejunum decreased at 24 h and 96 h. Irinotecan-induced mucositis is associated with increases in mucus secretion, and enteric neural cell change. These changes may contribute to the pathophysiology of mucositis through the dysregulation of neural signalling.
Publisher: SAGE Publications
Date: 31-07-2019
Abstract: Vitamin D activity is associated with the modulation of a wide variety of biological systems, in addition to its roles in calcium homeostatic mechanisms. While vitamin D is well known to promote gastrointestinal calcium absorption, vitamin D also plays a role in attenuating and/or preventing the progression of several gastrointestinal diseases including Crohn’s disease, ulcerative colitis, and colorectal cancer, and may also play a role in chemotherapy-induced intestinal mucositis. The pro-differentiation, immunomodulatory, and anti-inflammatory effects of vitamin D, which has been reported in numerous circumstances, are key potential mechanisms of action in the prevention of gastrointestinal disorders. While the debate of the effectiveness of vitamin D to treat bone pathologies continues, the clinical importance of vitamin D therapy to prevent gastrointestinal disorders should be investigated given current evidence, using both nutritional and pharmaceutical intervention approaches. The non-skeletal functions of vitamin D play an important role in health and disease. The anti-inflammatory properties and maintenance of intestinal function fulfilled by vitamin D impact other systems in the body though downstream processing. This review provides insight into the mechanisms underpinning the potential benefits of vitamin D in both maintaining intestinal homeostasis and associated diseased states.
Publisher: Informa UK Limited
Date: 07-07-2023
Publisher: MDPI AG
Date: 31-12-2021
DOI: 10.3390/IJMS23010439
Abstract: Dietary fiber is considered a strong intestinal protector, but we do not know whether dietary fiber protects against the long-lasting mucosal damage caused by ionizing radiation. To evaluate whether a fiber-rich diet can ameliorate the long-lasting pathophysiological hallmarks of the irradiated mucosa, C57BL/6J mice on a fiber-rich bioprocessed oat bran diet or a fiber-free diet received 32 Gray in four fractions to the distal colorectum using a linear accelerator and continued on the diets for one, six or 18 weeks. We quantified degenerating crypts, crypt fission, cell proliferation, crypt survival, macrophage density and bacterial infiltration. Crypt loss through crypt degeneration only occurred in the irradiated mice. Initially, it was most frequent in the fiber-deprived group but declined to levels similar to the fiber-consuming group by 18 weeks. The fiber-consuming group had a fast response to irradiation, with crypt fission for growth or healing peaking already at one week post-irradiation, while crypt fission in the fiber-deprived group peaked at six weeks. A fiber-rich diet allowed for a more intense crypt cell proliferation, but the recovery of crypts was eventually lost by 18 weeks. Bacterial infiltration was a late phenomenon, evident in the fiber-deprived animals and intensified manyfold after irradiation. Bacterial infiltration also coincided with a specific pro-inflammatory serum cytokine profile. In contrast, mice on a fiber-rich diet were completely protected from irradiation-induced bacterial infiltration and exhibited a similar serum cytokine profile as sham-irradiated mice on a fiber-rich diet. Our findings provide le evidence that dietary fiber consumption modifies the onset, timing and intensity of radiation-induced pathophysiological processes in the intestinal mucosa. However, we need more knowledge, not least from clinical studies, before this finding can be introduced to a new and refined clinical practice.
Publisher: Bentham Science Publishers Ltd.
Date: 13-07-2018
DOI: 10.2174/1381612824666180409093918
Abstract: Mucositis is a side effect associated with the use of chemotherapy, and has a significant impact on the quality of life. Mucositis, by definition, refers to the inflammation of the mucosa and occurs throughout the alimentary tract from the mouth to anus. Nuclear Factor kappa B (NFκB) encompasses a family of transcription factors, which upregulate pro-inflammatory cytokines. These are recognized as key targets in developing therapeutic interventions for chemotherapy-induced mucositis, and cyclooxygenase (COX)-2 inhibition may also be beneficial in reducing the severity and duration. This review focuses on the pathobiology of chemotherapy-induced oral and gastrointestinal mucositis and recent research examining the role of agents with anti-inflammatory activity in treatment and prevention of the condition. We consider agents in clinical use as well as some others under current investigation including plant-derived and other natural medicines.
Publisher: Copernicus GmbH
Date: 23-03-2020
DOI: 10.5194/EGUSPHERE-EGU2020-11167
Abstract: & & Over the last interglacial/glacial cycle climate variability and forcing in the northern hemisphere is best documented in high resolution from marine and ice core records. The response of land surface processes to climate over this period, however, remains poorly defined. Understanding landscape response to climate change is nevertheless of critical importance not only because as humans we live on and interact with the land, but also in order to identify potential feedbacks and forcings between land and atmosphere which cannot be ascertained from marine and ice core records. In this context, Loess-Palaeosol-Sequences (LPS) are outstanding terrestrial archives allowing detailed reconstruction of palaeoclimate and palaeo& #173 environ& #173 mental changes. However, regarding their complexity, LPS represent polygenetic and multiphase archives over different spatial and temporal scales. Consequently, a solid understanding of geomorphological and pedogenic processes involved in LPS formation, and the interplay with changes in ecological conditions, must be considered before LPS can be correlated with other archives.& & & & Against this background, extensive fieldwork has been carried out at the Schwalbenberg site near Remagen (Middle Rhine valley, Germany) combining geophysical exploration with Direct Push borehole geophysical measurements and sediment coring. We will present a first comprehensive data set for the Schwalbenberg key area based on a transect from up- to downslope. The integration of grain size, organic carbon and weathering indices from long sediment cores (up to 30 m) and profile sections contribute to a better understanding of processes involved in the Schwalbenberg LPS formation. These data combined with age constraints based on radiocarbon and luminescence dating lead to a first robust chronostratigraphic model of the Last Interglacial/Glacial Cycle suggesting the Schwalbenberg LPS to be a terrestrial archive of palaeoclimate variations in phase with northern hemispheric ice and marine records.& &
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
Publisher: Springer Science and Business Media LLC
Date: 21-02-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2010
Publisher: Copernicus GmbH
Date: 04-03-2021
DOI: 10.5194/EGUSPHERE-EGU21-10532
Abstract: & & The Schwalbenberg Loess-Palaeosol-Sequences (LPS) in the Middle Rhine Valley, Germany, comprise unprecedented complete records of Upper Pleistocene terrestrial ecosystem response to global climate changes. However, direct correlation of the Schwalbenberg geochemical signals with climate archives of supra-regional northern hemispheric relevance remains complicated. This is due to the complex interplay of pre-, syn-, or post-depositional processes that left their traces in the terrestrial record. In particular, the use of different element ratios to derive weathering indices may be complicated as dust sources change through time, and as ecosystems respond to changing conditions. In this study, we decode interfering geochemical signatures and re-evaluate proxies, commonly applied, regarding their suitability and meaning for understanding the evolution of the Schwalbenberg LPS. We undertake a systematic approach, firstly iding the 30 m long Schwalbenberg REM3 LPS according to our core description. In a second step, we integrate LOG-ratios indicative of provenance shifts, sediment reworking dynamics and weathering into multivariate analysis. We apply Principle Component Analyses (PCA) and Linear Discriminant Analysis (LDA) to datasets comprising sediments deposited under similar environmental conditions. In doing so, we sensitively quantify subordinate processes and conditions, such as the impact of varying source- and weathering-signals in all proxies. Our results show that in particularly K/Rb and Mg/Ca ratios contain a strong provenance signal in loess deposits, whereas the Ca/Al& sub& d& /sub& ratio (Al& sub& d& /sub& : dithionite extractable)& & sub& & /sub& best indicates the maturity state of Gelic Gleysols. Integration of our filtered datasets with a high-resolution age model enables direct correlation of the variability of principal components on sub-millennial scales with Atlantic-driven climate oscillations. More specifically, PC2 appears to reflect changes in mineral dust accumulation and indicates increasing dust input in response to climate cooling towards the end of interstadials, highlighting the accretionary nature of the Schwalbenberg LPS during transitional periods from interstadial to stadial depositional modes.& & & & & & &
Publisher: Informa UK Limited
Date: 16-08-2012
DOI: 10.4161/CBT.21783
Publisher: Hindawi Limited
Date: 02-09-2012
DOI: 10.1155/2012/490804
Abstract: “Mucositis” is the clinical term used to describe ulceration and damage of the mucous membranes of the entire gastrointestinal tract (GIT) following cytotoxic cancer chemotherapy and radiation therapy common symptoms include abdominal pain, bloating, diarrhoea, vomiting, and constipation resulting in both a significant clinical and financial burden. Chemotherapeutic drugs cause upregulation of stress response genes including NF κ B, that in turn upregulate the production of proinflammatory cytokines such as interleukin-1 β (IL-1 β ), Interleukin-6 (IL-6), and tumour necrosis factor- α (TNF- α ). These proinflammatory cytokines are responsible for initiating inflammation in response to tissue injury. Anti-inflammatory cytokines and specific cytokine inhibitors are also released to limit the sustained or excessive inflammatory reactions. In the past decade, intensive research has determined the role of proinflammatory cytokines in development of mucositis. However, a large gap remains in the knowledge of the role of anti-inflammatory cytokines in the setting of chemotherapy-induced mucositis. This critical paper will highlight current literature available relating to what is known regarding the development of mucositis, including the molecular mechanisms involved in inducing inflammation particularly with respect to the role of proinflammatory cytokines, as well as provide a detailed discussion of why it is essential to consider extensive research in the role of anti-inflammatory cytokines in chemotherapy-induced mucositis so that effective targeted treatment strategies can be developed.
Publisher: Public Library of Science (PLoS)
Date: 02-01-2019
Publisher: Springer Science and Business Media LLC
Date: 21-10-2016
DOI: 10.1007/S00280-016-3165-9
Abstract: A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients' regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2006
DOI: 10.1007/S00520-006-0052-7
Abstract: Growth factors and cytokines may be useful in preventing chemotherapy (CT)- and radiotherapy (RT)-induced oral and gastrointestinal mucositis. Two systematic reviews of the medical literature on growth factors and cytokines for the amelioration of CT- and RT-induced mucositis throughout the alimentary tract were performed by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology. The aim of these evidence-based scientific reviews was to critically evaluate the literature and create evidence-based guidelines for the use of growth factors and cytokines in the prevention or treatment of CT- and RT-induced mucositis. The two reviews covered articles on clinical trials from January 1966 through May 2002 and preclinical studies from June 2002 through May 2005, respectively. The systematic review process was based on a well-established method for evaluating scientific literature. The number of articles in the first review was 29. In the second review, 23 articles were evaluated, 14 preclinical and 9 clinical studies. It was concluded from the first review that there was no sufficient evidence to provide any recommendations for clinical practice guidelines regarding growth factors and cytokines. From the second review, a guideline could be presented recommending the use of recombinant human keratinocyte growth factor-1 (palifermin) to prevent oral mucositis in patients receiving high-dose CT and total body irradiation followed by stem cell transplantation for haematological malignancies. A guideline could also be provided suggesting that granulocyte macrophage colony-stimulating factor mouthwash not be used for the prevention of oral mucositis in the transplant setting with high-dose CT and autologous or allogeneic stem cell transplantation. These systematic reviews have provided clarity and shown exciting new results. Further studies will provide new options for this debilitating side-effect of cancer therapy.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2019
DOI: 10.1007/S00520-019-04892-0
Abstract: The aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM). A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible. A total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged. Of the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2020
Publisher: Informa UK Limited
Date: 31-05-2018
DOI: 10.1080/09553002.2018.1483588
Abstract: Radiotherapy-induced gut toxicity (RIGT) is a debilitating effect of radiotherapy for cancer, often resulting in significant diarrhea and pain. Previous studies have highlighted roles of the intestinal microvasculature and matrix metalloproteinases (MMPs) in the development of RIGT. We hypothesized vascular mediators would be significantly altered in a dark agouti (DA) rat model of RIGT. Additionally, we aimed to assess the effect of MMP-2 and -9 inhibition on the response of tumor-associated microvascular endothelial cells (TAMECs) to radiation. DA rats were administered 2.5 Gy abdominal irradiation (3 times/week over 6 weeks). Vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFβ), von Willebrand factor (VWF), angiostatin, and endostatin expression was assessed at 3, 6, and 15 weeks. Additionally, DA rat mammary adenocarcinoma tumor-associated microvascular endothelial cells (TAMECs) were used to assess the effects of radiation (12 Gy) and the MMP inhibitor SB-3CT on MMP, VEGF, and TGFβ expression, and cell viability. VEGF mRNA expression was significantly increased in the colon at week 15 (p = .0012), and TGFβ mRNA expression was significantly increased in both the jejunum and colon at week 3 (p = .0280 and p = .0310, respectively). Endostatin immunostaining was significantly increased at week 3 (p = .0046), and angiostatin at 3 and 6 weeks (p = .0022 and p = .0135, respectively). MMP-2 and -9 mRNA and total protein levels were significantly increased following irradiation of TAMECs. Although this increase was significantly attenuated by SB-3CT, it did not significantly alter endothelial cell viability or VEGF and TGFβ mRNA expression. Findings of this study support the involvement of VEGF, TGFβ, angiostatin, endostatin, and MMP-2 in the pathobiology of RIGT. However, the relationship between these mediators is complex and needs further investigation to improve understanding of their therapeutic potential in RIGT.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
Publisher: MDPI AG
Date: 08-07-2022
DOI: 10.3390/BIOM12070960
Abstract: The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10−7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.
Publisher: Informa UK Limited
Date: 07-2008
DOI: 10.4161/CBT.7.7.6207
Abstract: Alimentary tract (AT) mucositis is a serious complication of cancer treatment. Determining changes that occur in the AT can be difficult as invasive procedures are usually contraindicated in these patients. Changes in tissue levels of the transcription factor NFkappaB and pro-inflammatory cytokines have been demonstrated. The aims of this study were to determine whether changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 following administration of different drugs predicted histological evidence of tissue damage. Changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 were observed following administration of each drug. These changes differed according to the drug administered. In most instances, peaks in serum levels occurred following initial histological changes, Although following MTX administration, serum IL-1beta peaked before histological changes and following 5-FU administration, serum NFkappaB, TNF, IL-1beta and IL-6 all peaked before histological evidence of tissue damage. Female DA rats (n = 243) were given a single dose of irinotecan (200 mg/kg intraperitoneally), methotrexate (1.5 mg/kg intramuscularly) or 5-fluorouracil (150 mg/kg intraperitoneally) and killed 30, 60, 90 minutes, 2, 6, 12, 24, 48 or 72 hours later. Control rats received no treatment. Blood s les were taken via cardiac puncture and centrifuged at 5000 rpm to collect serum. Serum levels of NFkappaB, and pro-inflammatory cytokines were measured by ELISA. Although changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 preceded histological changes in tissues, it was concluded that measurement of these factors was not useful in predicting mucosal damage because of the critical time constraints between detectable serun changes and the histological damage. This study highlighted the systemic effects of the drugs. Further studies are required to determine the possible relationships between different toxicities and determine how, once these links are known, patient management can be improved.
Publisher: MDPI AG
Date: 29-04-2013
DOI: 10.3390/NU5051488
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2022
Publisher: Wiley
Date: 04-02-2014
DOI: 10.1111/JOP.12152
Abstract: Chemotherapy-induced mucositis is considered to be a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy. In the last 10 years, there have been significant advances in the understanding of mucositis pathobiology. At the basic level, it is now well-understood that it is not just an epithelial process, but rather a complex interaction between epithelial and connective tissue compartments. There is also potential interaction between the oral microenvironment and the development of mucositis. Changes occur in the resident oral flora (commensal) throughout cancer treatment, and it is conceivable that these organisms and changes that occur may have an influence on the development of mucosal toxicity associated with cancer treatment. The aim of this review was to examine the potential contributions of oral microflora in the pathobiology of mucositis and identify pathways and interactions that could be targeted for therapeutic management of mucositis.
No related grants have been discovered for Andrea Stringer.