RepoMed (Medizinische Hochschule Hannover)
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Effectiveness of hypofractionated and normofractionated radiotherapy in a triple-negative breast cancer model
Get PDFBreast cancer (BC) is one of the most diagnosed malignant carcinomas in women with a triple-negative breast cancer (TNBC) phenotype being correlated with poorer prognosis. Fractionated radiotherapy (RT) is a central component of breast cancer management, especially after breast conserving surgery and is increasingly important for TNBC subtype prognosis. In recent years, moderately hypofractionated radiation schedules are established as a standard of care, but many professionals remain skeptical and are concerned about their efficiency and side effects. In the present study, two different triple-negative breast cancer cell lines, a non-malignant breast epithelial cell line and fibroblasts, were irradiated daily under normofractionated and hypofractionated schedules to evaluate the impact of different irradiation regimens on radiation-induced cell-biological effects. During the series of radiotherapy, proliferation, growth rate, double-strand DNA break-repair (DDR), cellular senescence, and cell survival were measured. Investigated normal and cancer cells differed in their responses and receptivity to different irradiation regimens, indicating cell line/cell type specificity of the effect. At the end of both therapy concepts, normal and malignant cells reach almost the same endpoint of cell count and proliferation inhibition, confirming the clinical observations in the follow-up at the cellular level. These result in cell lines closely replicating the irradiation schedules in clinical practice and, to some extent, contributing to the understanding of growth rate or remission of tumors and the development of fibrosis
Behavioral pathway to a broken heart: The link between adverse childhood experiences, depression, physical exercise and cardiovascular health
Get PDFBackground and aim Adverse childhood experiences (ACEs) are a major risk factor for unfavorable behavioral, mental and health outcomes later in life. However, the precise pathway via which ACEs convey these risks, in particular regarding health outcomes such as cardiovascular disease, remains unknown. Here, we combined psychiatric and cardiac methods to investigate the pathway via which childhood adversities may lead to adult adverse cardiovascular health, with a focus on epicardial adipose tissue (EAT) as a risk marker. Methods 210 adult congenital heart disease outpatients (mean age 35.5 y, 43% female) completed a thorough cardiac and psychiatric evaluation. Psychiatric measurements included an expert interview, the childhood trauma questionnaire (CTQ), Beck's depression inventory II (BDI-II), quality of life and the global scale of functioning, amongst others. All patients completed a full cardiac workup including EAT assessment using echocardiography. We then computed bootstrapping mediation models using ACEs as a predictor, depression and physical activity as mediators and EAT as dependent variable in PROCESS. Results CTQ scores had a significant indirect effect on EAT via a serial mediation of BDI and physical activity [a*b2*d = 0.0260, 95% BCa CI [0.0047, 0.0619]]. Conclusion Using mediation analyses, we show that adverse childhood events are linked to increased depressive symptoms, which are linked to decreased physical activity, which in turn are linked to a higher amount of epicardial adipose tissue. While other pathways most certainly exist and replication is needed, this suggests a meaningful pathway via which ACEs lead to adverse cardiovascular health, with several potential targets for health interventions across time
Elucidating the mechanism behind and investigating the efficacy of Traditional Chinese Medicine and Traditional Tibetan Medicine in combination with standard therapeutics in hepatocellular carcinoma and cholangiocarcinoma in vitro.
Get PDFIn this study, we investigated compounds of plant and mushroom origin belonging to Traditional Chinese Medicine (TCM) and to Traditional Tibetan Medicine (TTM): a sandy beige mushroom Trametes robiniophila Murr, commonly known as Huaier/TCM as well as Ershiwuwei Songshi Wan and Qiwei Honghua Shusheng Wan, which both belong to TTM. We aimed to study the efficacy of TTM and TCM in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) in vitro. TCM and TTM were tested either as a monotherapy, or in combination with standard therapeutics: sorafenib for HCC treatment and gemcitabine for CCA. We also discovered a protective mechanism behind the most successful therapeutic combinations. The results demonstrated that TCM and TTM inhibited the proliferation of cancer cells in a time- and dose-dependent manner. The results were compared to classical chemotherapeutics currently used in the clinic: sorafenib for HCC and gemcitabine for CCA. In HCC settings, a combination of Huaier (16 mg/ml) with half of the human plasma concentration of sorafenib, Qiwei Honghua Shusheng Wan (1 mg/ml) monotherapy as well as its combination with half or even a quarter dose of the human plasma concentration of sorafenib represented the most efficient treatments, inhibiting the growth of HCC cells more effectively than the standard therapy. The inhibitory mechanism relied on a strong induction of apoptosis. In CCA settings, Ershiwuwei Songshi Wan and Qiwei Honghua Shusheng Wan as monotherapies or in combination with very low doses of gemcitabine inhibited the growth of CCA cells more efficiently than the standard therapy. Importantly, Ershiwuwei Songshi Wan at the 8 and 16 mg/ml concentrations and Qiwei Honghua Shusheng Wan at the 4 mg/ml concentration were efficacious with gemcitabine applied at massively reduced concentrations. The protective mechanism in CCA relied on a strong induction of early and late apoptosis. Cellular senescence and necroptosis were not associated with protection against HCC/CCA. Combination therapy with TCM or TTM allowed for a dose reduction of standard chemotherapeutics. This is especially important as both chemotherapeutic drugs show strong side effects in patients. The reduction of chemotherapeutics and the synergistic effect observed while applying them in combination with TCM and TTM has strong perspectives for the clinic and patients suffering from HCC and CCA
Valve-sparing David procedure via minimally invasive access does not compromise outcome.
Get PDFObjectives Aortic valve sparing-aortic root replacement (David procedure) has not been routinely performed via minimally invasive access due to its complexity. We compared our results of elective David procedure via minimally invasive access to those via a full sternotomy. Methods Between 1993 and 2019, a total of 732 patients underwent a valve sparing root replacement (David) procedure. Out of these, 220 patients underwent elective David-I procedure (isolated) without any other concomitant procedures at our center. Patients were assigned to either group A (n = 42, mini-access) or group B (n = 178, full sternotomy). Results Cardiopulmonary bypass time were 188.5 ± 35.4 min in group A and 149.0 (135.5-167.5) in group B (p < 0.001). Aortic cross-clamp time were 126.2 ± 27.2 min in group A and 110.0 (97.0-126.0) in group B (p < 0.001). Post-operative echocardiography showed aortic insufficiency ≤ I° in 41 (100%) patients of group A and 155 (95%) of group B. In-hospital mortality was 2.4% (n = 1) in group A and 0% (n = 0) in group B (p = 0.191). Perioperative stroke occurred in 1 (2.4%) patient of group A and 2 (1.1%) patients of group B (p = 0.483). Reexploration for bleeding was necessary in 4 (9.5%) patients of group A and 7 (3.9%) of group B (p = 0.232). Follow-up was complete for 98% of all patients. The 1-, 2-, 4-, and 6-year survival rates were: 97, 97, 97, and 97%, in group A (mini-access) and 99, 96, 95, and 92% in group B (full sternotomy), respectively. The rates for freedom from valve-related re-operation at 1, 2, 4, and 6 years after initial surgery were: 97, 95, 95, and 84% in group A and 97, 95, 91, and 90% in group B, respectively. Conclusion Early post-operative results after David procedure via minimally invasive access are comparable to conventional full sternotomy. Meticulous attention to hemostasis is a critical factor during minimally access David procedures. Long-term outcome including the durability of the reimplanted aortic valve seems to be comparable, too
The etiology of revision total hip arthroplasty: current trends in a retrospective survey of 3450 cases
Get PDFImpact of electrically assisted bicycles on physical activity and traffic accident risk: a prospective observational study.
Get PDFBackground Electrically assisted bicycles (e-bikes) have become increasingly popular and may facilitate active commuting and recreational cycling. Objective To evaluate the physical activity levels and usage characteristics of e-bikers and conventional cyclists under real-world conditions. Methods We conducted a prospective observational study in Germany to examine the effects of e-biking compared with conventional cycling on reaching the World Health Organization (WHO) target for physical activity-at least 150 min of moderate-to-vigorous physical activity (MVPA) per week. Study participants (1250 e-bikers and 629 conventional bike users) were equipped with activity trackers to assess the time, distance and heart rate during cycling over four consecutive weeks. Questionnaires were used to assess any traffic accidents incurred over 12 months. Results The proportion of participants reaching 150 min of MVPA per week was higher for conventional bike users than for e-bike users (35.0% vs 22.4%, p<0.001). In a multiple regression model, the odds of reaching the physical activity target were lower for e-biking than for conventional biking (OR=0.56; 95% CI 0.43 to 0.72) with age, sex, comorbidities and bike usage patterns as confounding factors. No significant differences were observed between bike groups for traffic accidents, yet when controlled for cycling time and frequency of cycling e-bikers had a higher risk of a traffic accident (OR=1.63; 95% CI 1.02 to 2.58). Conclusion E-bikes are associated with a lower probability of reaching WHO targets for MVPA due to reduced duration and a reduced cardiovascular effort during riding. However, e-bikes might facilitate active transportation, particularly in older individuals or those with pre-existing conditions
The ACE Inhibitor Lisinopril Stimulates Melanoma Cell Invasiveness by Inducing MMP2 Secretion
Get PDFBackground/aims Hypertension is treated primarily with angiotensin II (ATII) receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors (ACEIs). Both ATII and ACEIs can trigger signal transduction via ACE, and a possible correlation between ARB/ACEI therapy and an increased risk of cancer is highly controversial. The question of whether or not ACE as a potential signal transducer affects human melanoma (MV3) cell behavior prompted the present study. Methods Expression of ACE, ATII receptor types 1, 2 (AT1R, AT2R), COX2 and MMP2 in MV3 cells was examined by qPCR. AT1R, AT2R and ACE were inhibited with losartan, EMA401 and lisinopril, respectively. Adhesion, migration and invasiveness of MV3 cells seeded on a hepatocyte (Huh7) monolayer or a reconstituted collagen type I matrix were analyzed using video microscopy and Boyden chambers. Integrity of the Huh7 cell layer was confirmed by measuring transepithelial electrical resistance (TEER). ERK1/2 phosphorylation and MMP2 secretion were evaluated by Western blotting. MMP2 activity was inhibited with ARP-100. Results Losartan, EMA401 and lisinopril stimulated MV3 melanoma cell migration and invasion in a coculture model with Huh7 cells while leaving proliferation and adhesion largely unaffected. The drugs did not interfere with TEER of the hepatocyte monolayer nor with MV3 cell proliferation, but tended to increase the phosphorylation of ERK1/2 and the expression of both COX2 and MMP2. Lisinopril caused a significant increase in MV3 cells' MMP2 secretion and an accelerated MV3 cell-mediated TEER breakdown. The MMP2 inhibitor ARP-100 could antagonize the lisinopril-stimulated invasion of the hepatocyte layer. Conclusion Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2
