21 research outputs found
The role of the angiotensin II receptor type I on proliferation and invasion of the gastric cancer cell line MKN28
Das Magenkarzinom ist weltweit der vierthäufigste bösartige Tumor des
Menschen. Trotz rückläufiger Inzidenz ist die Letalitätsrate unverändert hoch.
Um die schlechte Prognose zu verbessern, benötigt es dringend eine frühere
Diagnose und ein größeres Spektrum an therapeutischen Optionen. Zahlreiche
epidemiologische Studien sowie in vitro und in vivo Experimente zeigen, dass
das lokale Angiotensin II System, das aus ANG I, ANG II, ACE und den beiden
Rezeptoren AT1R und AT2R besteht, in der Pathogenese maligner Tumoren eine
entscheidende Rolle spielt und medikamentös beeinflussbar ist. Neueste Studien
belegen die Beteiligung des lokalen Angiotensin II Systems auch in der
Tumorbiologie des Magens. Ziel der vorliegenden Arbeit war es, im
Zellkulturmodell die pathophysiologischen Mechanismen, mit denen das lokale
Angiotensin II System in die Biologie des Magenkarzinoms eingreift, zu
identifizieren und zu charakterisieren. Mittels stabilen Gentransfers wurde
eine Magenkarzinomzelllinie etabliert, die den AT1R verschieden stark
überexprimiert. Anschließend wurde der Einfluss der unterschiedlichen AT1R
Expression auf das Proliferations- und Invasionsverhalten dieser Zellen
untersucht. Die Zellkulturexperimente konnten zeigen, dass der AT1R das
Tumorwachstum von Magenkarzinomzellen beeinflusst. Die Ãœberexpression des
AT1R-Gens in der Magenkarzinomzelllinie MKN28 bewirkte eine signifikant
gesteigerte Proliferation und Invasion. Die Ergebnisse weisen daraufhin, dass
das lokale Angiotensin II System die Tumorprogression und -metastasierung
nicht nur durch eine allgemein anerkannte Induktion der Angiogenese fördert,
sondern dass die Expression des AT1R direkt das Wachstum der Tumorzellen
stimuliert und die Invasion erleichtert. Allerdings ist festzuhalten, dass
keine lineare Gen-Dosis-Wirkung vorliegt. Zusätzliche Faktoren scheinen die
Wirkung des AT1R zu modulieren. Die in vitro Experimente an
Magenkarzinomzellen belegen die tumorbiologische Relevanz des lokalen
Angiotensin II Systems und kennzeichnen dieses System als potentielle
Zielstruktur für die Behandlung des Magenkarzinoms. Zusätzliche in vivo
Untersuchungen müssen klären, ob sich die Hemmung des lokalen Angiotensin II
Systems als neue therapeutische Strategie in der Behandlung des Magenkarzinoms
eignet.Gastric cancer is one of the most common cancers worldwide, ranking fourth in
overall frequency. While the incidence of gastric cancer has decreased,
mortality from gastric cancer is second only to lung cancer. In view of the
extremely poor prognosis of gastric cancer, it is becoming imperative to
improve early identification of gastric cancer and develop new therapeutic
options. Recent studies have shown that local angiotensin II systems,
including ANG I, ANG II, ACE, AT1R and AT2R, play an important role in cancer
progression and provide strong evidence that drugs that inhibit this system
have the potential to reduce cancer risk or retard tumour growth and
metastasis. Studies suggest involvement of a lokal angiotensin II system in
gastric cancer progression too. The focus of this study was to investigate the
mechanisms by which the local angiotensin II system might mediate its
pathological function in gastric cancer. Gastric cancer cells, different
overexpressing the AT1R, were established by stable gene transfer and the
possible influence of the angiotensin II system on in vitro proliferation and
invasive ability of these gastric cancer cells were examined. The in vitro
experiments showed that the AT1R promote the growth of gastric cancer cells.
Overexpressing AT1R gene in the gastric cancer cell line MKN28 significantly
increased proliferation and invasive potential. The results suggest that the
involvement of local angiotensin II systems in tumour growth and metastasis is
not limited to the generally accepted promotion of angiogenesis, but the
expression of AT1R by the tumour cells directly facilitates proliferation and
invasion. Though there is no linear gene dose reponse, other factors might
effect AT1R actions. These results provide abundant evidence for the
biological significance of the local angiotensin II system in gastric cancer
and identify this system as a novel therapeutic target for gastric carcinoma.
Further in vivo studies are required to evaluate the clinical potential of
manipulation and blockade of the local angiotensin II system as a novel and
promising strategy for the treatment of gastric cancer
Value of Different Comorbidity Indices for Predicting Outcome in Patients with Acute Myeloid Leukemia
<div><p>Age is a dominant predictor of outcome in acute myeloid leukemia (AML). However, it is not clear to which extent comorbidities contribute to this effect. The objective of this study was to determine the impact of pretreatment comorbidities on survival of AML patients. In a single-center retrospective study 194 adult AML patients were included. The Hematopoietic cell transplantation comorbidity index (HCT-CI), the Adult Comorbidity Evaluation-27 (ACE-27) score and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) as well as data on demographics, cytogenetics, treatment and outcome were evaluated at the time of initial diagnosis by univariate and multivariate analysis. The study included 102 male and 92 female (median age 60.9 years) of which 173 (89.2%) received intensive chemotherapy. Median overall survival (OS) was 17 months. In univariate analysis, cardiovascular disease (26 vs 12 months, <i>p</i> = .005), severe hepatic disease (19 vs 4 months, <i>p</i> = .013) and renal impairment (17 vs 7 months, <i>p</i> = .016) was associated with inferior OS. For each index, the highest comorbidity burden was associated with reduced OS. However, in multivariate analysis only the ACE-27 score was associated with outcome. Besides ECOG ≥ 2 and poor cytogenetics only the ACE-27 score but not higher age was associated with OS in the group of patients receiving intensive therapy. Adjusted hazard ratios were 3.1, 3.5 and 4.0 for mild, moderate and severe ACE-27-assessed comorbidities, respectively (<i>p</i> = .012). Our study confirms that comorbidities significantly impact survival of AML patients and a pretreatment assessment of comorbidities may help to identify patients with poor outcome.</p></div
Overall survival for the entire patient cohort and for different treatment strategies.
<p>Kaplan-Meier analysis was performed and the effect of treatment on OS was tested using the long-rank test. <b>(A)</b> OS in the entire patient cohort. The median OS was 17 months. <b>(B)</b> OS in the patient groups according to treatment strategy. The median OS of the 173 patients treated intensively was 18 months (blue line) while the 21 patients who received palliative treatment, had a median OS of one month (green line).</p
Cox proportional hazard regression model with factors predicting overall survival for the entire cohort.
<p>Cox proportional hazard regression model with factors predicting overall survival for the entire cohort.</p
Distribution of ACE-27 categories in different age groups.
<p>Distribution of ACE-27 score of none, mild, moderate and severe comorbidities among four age groups in all 194 AML patients. 22 patients were younger than 41 years, 53 patients were between 41 and 59 years old, 119 patients were more than 60 and 58 patients more than 70 years old. Increasing age was significantly associated with higher ACE-27 score as analyzed by x<sup>2</sup> test (<i>p</i> < .000).</p
Distribution of individual comorbidities.
<p>Individual comorbidities among 194 AML patients as assessed by the three indices, respectively. Hepatic diseases are not assessed by the ACE-27 score, and infections are only assessed by the HCT-CI.</p
Survival curves according to the 3 comorbidity indices HCT-CI, ACE-27 and CIRS-G.
<p>Risk groups based on comorbidity were stratified by HCT-CI, ACE-27 score and CIRS-G in all 194 patients and differences in survival between groups were tested using the long-rank test.</p