74 research outputs found

    Разработка технологии изготовления детали «Седло»

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    Выпускная квалификационная работа включает в себя проектирование технологического процесса обработки детали "Седло" и содержит: анализ чертежа и технологичности детали; способ получения заготовки; расчет припусков на обработку; разработку технологического процесса, выбор и расчет режимов резания; размерный анализ технологического процесса.Final qualifying work includes the design of the technological process of processing details in the "Saddle" and contains: an analysis of drawing and technology details; method of harvesting; calculation of allowances for processing; the design process, the selection and calculation of cutting conditions; dimensional analysis process

    A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

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    Purpose: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. Experimental design: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. Results: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. Conclusions: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation

    Transcript and metabolite profiling of the adaptive response to mild decreases in oxygen concentration in the roots of arabidopsis plants

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    Oxygen can fall to low concentrations within plant tissues, either because of environmental factors that decrease the external oxygen concentration or because the movement of oxygen through the plant tissues cannot keep pace with the rate of oxygen consumption. Recent studies document that plants can decrease their oxygen consumption in response to relatively small changes in oxygen concentrations to avoid internal anoxia. The molecular mechanisms underlying this response have not been identified yet. The aim of this study was to use transcript and metabolite profiling to investigate the genomic response of arabidopsis roots to a mild decrease in oxygen concentrations. Arabidopsis seedlings were grown on vertical agar plates at 21, 8, 4 and 1 % (v/v) external oxygen for 0.5, 2 and 48 h. Roots were analysed for changes in transcript levels using Affymetrix whole genome DNA microarrays, and for changes in metabolite levels using routine GC-MS based metabolite profiling. Root extension rates were monitored in parallel to investigate adaptive changes in growth. The results show that root growth was inhibited and transcript and metabolite profiles were significantly altered in response to a moderate decrease in oxygen concentrations. Low oxygen leads to a preferential up-regulation of genes that might be important to trigger adaptive responses in the plant. A small but highly specific set of genes is induced very early in response to a moderate decrease in oxygen concentrations. Genes that were down-regulated mainly encoded proteins involved in energy-consuming processes. In line with this, root extension growth was significantly decreased which will ultimately save ATP and decrease oxygen consumption. This was accompanied by a differential regulation of metabolite levels at short- and long-term incubation at low oxygen. The results show that there are adaptive changes in root extension involving large-scale reprogramming of gene expression and metabolism when oxygen concentration is decreased in a very narrow range

    Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer

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    Background Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. Objectives We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. Methods We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50–61, > 61 g/m2; men, < 60, 60–74, > 74 g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24 kg/m2 and weight loss ≥ 5% in the prior 12 months). Repeat echocardiograms were obtained usually within 3–6 months for 85 patients. Results Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9–4.2), 0.8 (0.2–2.2), 0.5 (0.3–1.6) ng/mL, p = 0.029; men, 2.1 (0.8–3.2), 0.6 (0.1–1.7), 0.7 (0.2–1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48–116), 72 (48–95), 49 (35–76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r =  − 0.591, p < 0.001; men, r =  − 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r =  − 0.318, p = 0.003). Conclusion In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associated with a decrease in relative LVmass during follow-up

    Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial

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    Background Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan–temozolomide and dasatinib–rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. Methods The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1–25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan–temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2–4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin–dasatinib and irinotecan–temozolomide for four cycles over 8 weeks, then two courses of rapamycin–dasatinib followed by one course of irinotecan–temozolomide for 12 weeks) with irinotecan–temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. Findings Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7–8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31–88), the median progression-free survival was 11 months (95% CI 7–17) in the RIST group and 5 months (2–8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4–24) in the RIST group versus 2 months (2–5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9–7) in the RIST group versus 8 months (4–15) in the control group (HR 0·84 [95% CI 0·51–1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). Interpretation RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting

    Predictors of outcome in juvenile idiopathic arthritis

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    Die juvenile idiopathische Arthritis (JIA) ist die häufigste chronisch- entzündliche rheumatische Erkrankung im Kindes- und Jugendalter. Ihre Gesamtprävalenz wird heute mit etwa 0,1% angenommen. Der JIA bzw. ihren nach der aktuellen ILAR- Klassifikation definierten sieben Subgruppen werden verschiedene Arthritisformen zugeordnet. Zwischen den Arthritisformen, aber auch innerhalb der einzelnen JIA- Subgruppen bestehen große Unterschiede hinsichtlich des Verlaufes der Erkrankung. Während die JIA bei einem Teil der Patienten innerhalb weniger Monate oder Jahre zum Stillstand kommt, schreitet die Erkrankung bei anderen chronisch voran, bleibt bis ins Erwachsenenalter hinein aktiv und führt zu dauerhaften Behinderungen, Organschäden und einer eingeschränkten Teilhabe. Bisher ist es nicht sicher möglich zu Erkrankungsbeginn die Patienten zu identifizieren, die einen ungünstigen Verlauf entwickeln werden und deshalb frühzeitig von einer intensiven Therapie profitieren würden. Deshalb wurde die vorliegende Arbeit mit dem Ziel durchgeführt, Verlaufsprädiktoren für die JIA ausfindig zu machen. Hierfür wurden bereits vorhandene Daten einer 16- Jahres-Follow-up Studie herangezogen, d.h. retrospektiv anhand der Krankenakten erfasste Parameter vom Krankheitsbeginn und im Rahmen einer Nachuntersuchung und Befragung erhobene Parameter zum Follow-up. Die erfassten klinischen, laborchemischen und genetischen Merkmale wurden dann auf ihren prädiktiven Wert hinsichtlich des Outcomes untersucht. Als Outcome-Parameter dienten die Merkmale Remission bzw. persistierende Krankheitsaktivität und Funktionszustand zum Follow-Up sowie die Entwicklung einer Uveitis als schwerwiegende extraartikuläre Manifestation. Zu den untersuchten klinischen Merkmalen gehörten die Dauer bis zum ersten Rheumatologenkontakt, das Erkrankungsalter, Geschlecht und der initiale Gelenkbefall. Neben allgemeinen Laborparametern (z.B. BSG, CRP, Hk, α-2-Globulin, Leukozyten, Thrombozyten, IgG, ANA) wurden auch genetische Polymorphismen der Patienten bestimmt und auf den prädiktiven Wert hin untersucht. Wir wählten HLA-Allele (B27, DRB1, DPB1, DQA1 und DQB1) und Zytokin-Polymorphismen (TNF-α -308,IL-6 -174, IFN-γ +874, IL-10 -1082 und TGF-β +869 und +915) mit funktioneller Relevanz. Die Merkmale, die zunächst bivariat signifikante Korrelationen mit den Outcomeparametern zeigten, wurden in multivariaten Tests überprüft. In den multivariaten Analysen waren das Fehlen von HLA-DRB1*03 und TGF-β Codon 10 C,C mit dem Erreichen einer Remission assoziiert. Der einzige klinische Parameter, der mit dem Eintreten in die Remission korrelierte, war der ILAR-Subtyp. Klinische Parameter, die mit einem schlechten körperlichen Funktionsstatus korrelierten, waren ein erstmaliger Rheumatologenkontakt nach mehr als 6 Monaten Krankheitsdauer, eine Enthesitis-assoziierte Arthritis und der initiale Hüftgelenkbefall. Weder HLA- noch Zytokin-Polymorphismen waren mit dem Funktionsstatus assoziiert. Innerhalb der OA-Gruppe war DQA1*03 mit der persistierenden Verlaufsform assoziiert, was sich möglicherweise aufgrund des insgesamt seltenen Auftretens dieses Allels in unserer Kohorte in den multivariaten Testungen nicht reproduzieren ließ. Der initiale Sprunggelenkbefall und DR5 (DRB1*11+12)-Positivität korrelierten mit der Entwicklung einer Uveitis. Es fanden sich jedoch keine Assoziationen mit Zytokin- Polymorphismen. Aus unseren Ergebnissen kann geschlussfolgert werden, dass die frühe Überweisung von pädiatrischen Patienten mit Arthritis unklarer Genese an eine kinderrheumatologische Einrichtung ein besseres Outcome für die Patienten bewirkt, möglicherweise, aufgrund einer schnelleren Diagnostik und adäquaten Therapieeinleitung. Bei initialem Hüftgelenkbefall sprechen unsere Untersuchungen für eine engmaschige Verlaufsbeobachtung und eher frühzeitige intensive Behandlung, um bleibende Funktionseinschränkungen der Patienten zu verhindern. Bezüglich der in dieser Studie gefundenen genetischen Prädiktoren können derzeit noch keine Schlussfolgerungen für die klinische Praxis gezogen werden. Hier sind Multicenterstudien erforderlich, um genetische Risikofaktoren sicher bestimmen zu können. Die Ergebnisse dieser Auswertung sollten im Rahmen prospektiver Studien überprüft werden. Die vorliegende Untersuchung hat die Vorarbeit für eine prospektive Kohortenstudie geliefert.Juvenile idiopathic arthritis is the most common rheumatic disease in childhood with a prevalence of 0,1%. The term "JIA" encompasses different forms of arthritis with different disease courses. While a part of the patients attend ongoing remission, others suffer from chronic disease activity even in adulthood with persistent articular and organic disability. Today it is still not possible to exactly identify the patients with an unfavourable outcome at the beginning of the disease. In view of new therapeutic options with still unknown longterm side effects for pediatric patients, predictors of a severe disease course are of clinical interest. The aim of this study was to find laboratory, clinical and genetic predictors of continued disease activity and functional loss after a mean disease duration of 16 years. Therefore the data of 191 patients with JIA from the clinic of pediatric rheumatology in Berlin-Buch and a beginning of the disease in the years 1978-1988 were retrospectively analyzed. Patients at follow-up were at least 14 years old, most of them grown-up (mean=23 years). The following parameters of the patient`s outcome were determined: attended remission at follow-up to measure disease activity, the „Health Assessment Questionnaire“-Score to measure the functional outcome of the patient and the presence of uveitis as a severe extraarticular manifestation of the disease which strongly affects the longterm outcome. Besides the whole group of JIA patients, the subgroup with oligoarticular JIA was analysed separately. Features as sex, age at the beginning of the disease, subtype, duration until first presentation to pediatric rheumatology, affected joints in the beginning of the disease, routine laboratory markers and genetic polymorphisms with functional relevance in JIA (HLA-B27, DRB1, DPB1, DQB1, DQA1, TNF-α -308,IL-6 -174, IFN-γ +874, IL-10 -1082 und TGF-β +869 und +915) were proved with regard to a potential predictive function in bivariate and than multivariate tests. Predictors of remission after a mean disease duration of 16 years were the absence of DRB1*03- and the presence of TGF-β +869 C,C as well as the subtype of Enthesitis-associated Arthritis. Predictors of functional disability after a mean disease duration of 16 years were an arthritis of the hip in the beginning of the disease and a duration of the disease of more than 6 months until the first presentation to pediatric rheumatology as well as the subtype of Enthesitis-associated Arthritis. Predictors of uveitis were an arthritis of the ankle in the beginning of the disease and the DR5-polymorphism. These results should be revised and serve as preliminary work for a prospective inception cohort

    Studium neuer Phase II-Reaktionen von ausgewählten Arzneistoffen mithilfe von Hepatozytenkulturen und UDP-Glucuronyltransferasen

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    Primäre Hepatozytenkulturen stellen ein geeignetes in vitro-Modell für Biotransformationsstudien und zur Aufklärung potenzieller Interaktionen von Xenobiotika dar. Im Gegensatz zu den häufig eingesetzten Leberparenchymzellen der Ratte, die jedoch große Speziesunterschiede zum Metabolismus des Menschen aufweist, gelten Hepatozyten porcinen Ursprungs als mögliche Alternative für das begrenzt verfügbare humane Lebermaterial. In dieser Arbeit wurden deshalb vergleichende Phase I- und Phase II-Studien anhand bestimmter stickstoffhaltiger Modellverbindungen in porcinen und humanen Hepatozytenkulturen sowie Studien zur Cytochrom P450-Induktion mit Schweinehepatozyten durchgeführt. Beide Spezies wiesen bezüglich der untersuchten Reaktionen große Übereinstimmungen auf. Aufgrund des Einsatzes zahlreicher N-hydroxylierter Verbindungen als Prodrugs war neben der N-reduktiven Aktivierung insbesondere die Untersuchung von Phase II-Metaboliten der Modellsubstrate Benzamidoxim (Amidoxim), N-Hydroxydebrisoquin (N-Hydroxyguanidin) und Guanoxabenz (N-Hydroxyamidinohydrazon) von großer Bedeutung. LC/MS-Studien lieferten Hinweise auf die Bildung mehrerer Konjugate sowohl in Hepatozytenkulturen als auch mit UDP-Glucuronyltransferasen. Hierbei ermöglichten synthetische Referenzsubstanzen die eindeutige Identifizierung der O-Glucuronide von N-Hydroxydebrisoquin und Benzamidoxim
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