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Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multi-drug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density.

Our preliminary studies identified a small population side population (SP) cells in pancreatic cancer cells with stem cell-like properties, which were able to induce fast and aggressive tumor formation in nude mice. Gene expression analysis showed a significant difference in the expression of more than 1,300 genes in SP cells, among which a highly significant difference in microRNA expression of miR-21 and miR-221 between SP and NSP cells was identified. SP cells were identified and characterized by flow cytometry using Hoechst 33342 dye staining from a highly metastatic human pancreatic cancer cell line (L3.6pl). Antagomir transfection was performed using miRNA-21 and miRNA-221 antisense oligonucleotides (ASOs) and followed by detection of cell apoptosis, cell cycle progression, chemosensitivity, and invasion. Sorted SP cells from gemcitabine-resistant L3.6pl cells (L3.6pl Gres -SP) cells were orthotopically implanted in nude mice with or without miRNA-21 and miRNA-221 ASOs mono- and combination therapy. The administration of antagomir-21 and antagomir-221 significantly reduced the SP cell fraction, decreased SP cell differentiation, and downstream gene regulation, and thereby induced reduction of L3.6pl cell proliferation, invasion, and chemoresistance against gemcitabine and 5-Fluorouracil. Combination of ASOs therapy against miRNA-21 and miRNA-221 significantly inhibited primary tumor growth and metastasis compared to single antagomir treatment, especially, in L3.6pl Gres -SP-induced pancreatic tumor growth in vivo. These findings further indicate that the inhibition of miR-21 and miR-221 appear particularly suitable to target stem-like subpopulations and address their specific biological function to promote tumor progression in pancreatic cancer.

Inhalation errors frequently occur in patients receiving inhalation treatment, which can significantly impair treatment success. While this underscores the importance of inhalation training, the role of modern web-based instructional videos has not yet been investigated. A randomized controlled trial using standardized checklists (10 items: preparation, N = 3, inhalation routine, N = 6, and closure of inhalation, N = 1) was carried out to determine the relative effects of web-based, device-specific videos versus standard personal instruction on reducing multiple (≥2) inhalation errors in severe COPD patients requiring hospitalisation. Investigators assessing inhalation errors were blinded to the intervention. Multiple handling errors were recorded at baseline in 152 out of 159 patients (95.6%). Each teaching method led to a similar reduction in errors (videos: from 4.2±1.6 to 1.5±1.5 errors; personal instruction: from 3.8±1.5 to 1.3±1.6; p<0.0001), although non-inferiority of web-based video teaching could not be confirmed statistically due to an unpredictably high number of patients in both groups still making multiple handling errors (44.0% versus 40.3%, mean difference 3.7%; 95%CI [-12.0-19.4%]). Multiple inhalation errors regularly occur in severe COPD patients requiring hospitalisation. Web-based video teaching is capable of reducing inhalation errors. However, compared to personal instruction non-inferiority could not be established. This was due to an unexpectedly high number of patients with persisting inhalation errors despite training. Clinical trial Registration: German Clinical Trial Register, DRKS 00004320.

Background Long-term non-invasive ventilation (NIV) is as an established treatment option for chronic hypercapnic COPD patients. Beneficial effects have also been shown during exercise, but this is restricted to rehabilitation programs. New portable NIV (pNIV) devices may now enable NIV application during walking at home. Study design and methods In two randomized crossover trials, the impact of pNIV on dyspnea and endurance capacity was investigated in patients with moderate to severe COPD. Participants performed a standardized 6-min walking test, with and without pNIV, using a pre-set inspiratory/expiratory positive airway pressure of 18/8 cmH 2 O. The first study was performed in NIV-naïve patients (Study I), while the second study was performed in those already established on long-term NIV (Study II). Results 38 patients (66.9 ± 7.4 years, mean FEV 1 : 30.3 ± 8%pred) and 23 patients (67.6 ± 8.7 years, mean FEV 1 : 29.8 ± 10.4%pred) participated in Study I and II, respectively. In Study I, the mean difference in the Borg Dyspnea Scale (BDS, primary outcome) score following walking was 3.2 (IQR 2–4) without pNIV, compared to 2.6 (IQR 1–4) with pNIV (ΔBDS 0.65, P  = 0.04), while walking distance increased from 311.8 m (95%CI 276.9–346.6 m) to 326.3 m (95%CI 291.5–361.2 m) ( P  = 0.044) when pNIV was used. Accordingly, in Study II, the mean difference in BDS was 4.4 (IQR 3–6) without pNIV, compared to 4.5 (IQR 3–6) with pNIV (ΔBDS 0.09, P  = 0.54), while walking distance decreased from 291.5 m (95%CI 246.1–336.9 m) to 258.4 m (95%CI 213–303.8 m) ( P  ≤ 0.001). Interpretation The use of a pNIV device during walking can improve dyspnea and walking distance in patients with moderate to severe COPD. Patients who do not already receive long-term NIV therapy are more likely to benefit compared to those undergoing long-term NIV. Careful patient selection is mandatory. Clinical Trial Register : DRKS00013203; DRKS00012913 registered October 20th 2017 and October 16th 2017; https://www.drks.de/drks_web/

Background Research on health-related quality of life (HRQL) has become increasingly important in recent decades. However, the impact of both living conditions and the level of autonomy impairments on HRQL in COPD patients receiving non-invasive ventilation (NIV) is still unclear. Methods The Severe Respiratory Insufficiency Questionnaire (SRI) was used to measure HRQL in a prospective cohort of COPD patients in whom home NIV was already established. Data on sociodemographics, clinical characteristics and standardized levels of autonomy impairment were evaluated. A multiple linear regression analysis was performed to identify the factors associated with a reduced HRQL. Results A total of 137 patients (67.0 ± 7.8 years, 45% female) were assessed. The mean SRI Summary Score was 54.1 ± 16.9 (95%CI: 51.1–57.1; N = 127). Regular ambulatory care was provided in 76% of patients, but only 37% underwent pulmonary rehabilitation. Overall, 69% of patients lived with family members, while 31% lived alone (family situation). Autonomy impairment levels were most serious in 3%, serious in 14%, and significant in 29% of patients, while 54% had no impairments at all. Of note, higher levels of autonomy impairment were markedly associated with lower SRI scores (regression coefficient − 6.5 ± 1.1 per level; P  < 0.001). In contrast, family situation (0.2 ± 3.0; P  = 0.959), ambulatory care by a respiratory specialist (1.7 ± 3.6; P  = 0.638), and pulmonary rehabilitation (− 0.8 ± 3.1; P  = 0.802) did not appear to influence HRQL. Possible subgroup effects were evident for the factors “impaired autonomy” and “living in a nursing home” ( P  = 0.016). Conclusion A higher level of autonomy impairment has been identified as the major determinant of reduced HRQL in COPD-patients receiving long-term NIV, particularly in those living in a nursing home. Trial Registration German Clinical Trials Register (DRKS00008759).

The original text in the manuscript published in the American Heart Journal (2012;163:938-45) reads as follows:\"Because most of the patients will not be able to provide full informed consent before randomization, an individualized informed consent process covering 4 different scenarios has been validated and approved by the central ethical committee at the University of Leipzig, Germany, and also all local ethical committees.

To investigate dynamic contrast-enhanced computed tomography for monitoring the effects of regorafenib on experimental colon carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation. Colon carcinoma xenografts (HT-29) implanted subcutaneously in female athymic rats (n = 15) were imaged at baseline and after a one-week treatment with regorafenib by dynamic contrast-enhanced computed tomography (128-slice dual-source computed tomography). The therapy group (n = 7) received regorafenib daily (10 mg/kg bodyweight). Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. Dynamic contrast-enhanced computed tomography parameters were validated with immunohistochemical assessments of tumor microvascular density (CD-31), tumor cell apoptosis (TUNEL), and proliferation (Ki-67). Regorafenib suppressed tumor vascularity (15.7±5.3 to 5.5±3.5%; p<0.05) and tumor perfusion (12.8±2.3 to 8.8±2.9 mL/100 mL/min; p = 0.063). Significantly lower microvascular density was observed in the therapy group (CD-31; 48±10 vs. 113±25, p<0.05). In regorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 11844±2927 vs. 5097±3463, p<0.05) were observed. Dynamic contrast-enhanced computed tomography tumor perfusion and tumor vascularity correlated significantly (p<0.05) with microvascular density (CD-31; r = 0.84 and 0.66) and inversely with apoptosis (TUNEL; r = -0.66 and -0.71). Regorafenib significantly suppressed tumor vascularity (plasma volume) quantified by dynamic contrast-enhanced computed tomography in experimental colon carcinomas in rats with good-to-moderate correlations to an immunohistochemical gold standard. Tumor response biomarkers assessed by dynamic contrast-enhanced computed tomography may be a promising future approach to a more personalized and targeted cancer therapy.

Background: Long-term non-invasive ventilation (NIV) is an established and increasingly used treatment option for patients with chronic hypercapnic chronic obstructive pulmonary disease (COPD). Following inpatient NIV establishment, inpatient control visits regularly occur thereafter. However, it remains unclear whether such control visits can also be performed in an outpatient setting, which, in turn, would reduce costs, patient burden and the complications related to hospitalization. Objectives: To investigate an outpatient setting with predefined criteria for hospitalization for patients with chronic hypercapnic COPD. Methods: An outpatient clinic located within the hospital in the vicinity of the respiratory care unit provided predefined criteria for hospitalization of COPD patients receiving long-term NIV therapy. The results of this setting were retrospectively analysed. Results: A total of 130 outpatient visits (80 patients) were analysed. In 93 cases (71.5%), hospital admission was not necessary, while hospitalization was performed in 37 cases (28.5%). Out of these, 7 cases with acute conditions required prompt hospitalization. Patients without hospitalization had better PaCO 2 values (45.40 ± 5.27 vs. 50.05 ± 8.04, p = 0.002) and Severe Respiratory Insufficiency Questionnaire Summary scores (55.54 ± 19.74 vs. 41.82 ± 19.59, p = 0.012). Conclusion: Outpatient control of long-term NIV in a hospital setting is feasible and has the capacity to identify stable COPD patients in whom NIV therapy is sufficient according to predefined criteria. These patients may not require hospitalization and may account for more than two thirds of cases.

Background Patients who require a prolonged weaning process comprise a highly heterogeneous group of patients amongst whom the outcome differs significantly. The present study aimed to identify the factors that predict whether the outcome for prolonged weaning will be successful or unsuccessful. Methods Data from tracheotomised patients who underwent prolonged weaning on a specialised weaning unit were assessed retrospectively via an electronic and paper-bound patient chart. Factors for weaning success were analysed by univariate and multivariate analyses. Results Out of the 124 patients examined, 48.4% were successfully weaned ( n  = 60). Univariate analysis revealed that long-term home mechanical ventilation prior to current weaning episode; time between intubation and the first spontaneous breathing trial (SBT); time between intubation and the first SBT of less than 30 days; lower PaCO 2 prior to, and at the end of, the first SBT; and lower pH values at the end of the first SBT were predictors for successful weaning. Following multivariate analysis, the absence of home mechanical ventilation prior to admission, a maximum time period of 30 days between intubation and the first SBT, and a non-hypercapnic PaCO 2 value at the end of the first SBT were predictive of successful weaning. Conclusions The current analysis demonstrates that the evidence for respiratory insufficiency type II provided by clinical findings serves as a predictor of weaning failure.

In patients with ST-segment elevation myocardial infarction, immediate multivessel PCI was noninferior to staged multivessel PCI with respect to the risk of death and adverse cardiovascular events at 1 year.