The 10 most recently published documents
Highlights
• In survival analyses, 3-year BCR-free survival rates were 95% in pT2 ISUP4/5 vs. 88% in pT3/4 ISUP2 vs. 65% in pT3/4 ISUP3 patients.
• Compared to prostate cancer patients with pT2 ISUP4/5 pathology, the combination of pT3/4 ISUP3 pathology is associated with higher BCR rate after RP.
• Conversely, BCR rates in patients with pT3/4 ISUP2 and pT2 ISUP4/5 pathology were comparable.
• Therefore, patients with pT3/4 ISUP3 should be considered for a closer follow-up.
Abstract
Background: To test for differences in organ-confined pathological tumor stage (pT) and intermediate International Society of Urological Pathologists (ISUP) grade vs. nonorgan confined pT stage and high ISUP grade and biochemical recurrence (BCR) after radical prostatectomy (RP).
Methods: Relying on a tertiary-care database, prostate cancer patients undergoing RP between January 2014 and December 2021 were stratified according to their combination of pT stage and ISUP grade in RP specimens (pT2 ISUP4/5 vs. pT3/4 ISUP2 vs. pT3/4 ISUP3). As Active Surveillance is recommended in ISUP1, these patients were excluded. Moreover, patients with pT2 ISUP2/3 are known for their good prognosis and pT3/4 ISUP4/5 patients for their poor prognosis. Therefore, these patients were also excluded from analyses. Kaplan-Meier survival analyses and multivariable Cox regression models addressed BCR after RP.
Results: Of 215 RP patients, 29 (13%) exhibited pT2 ISUP4/5 vs. 122 (57%) pT3/4 ISUP2 vs. 64 (30%) pT3/4 ISUP3 pathology. In survival analyses, 3-year BCR-free survival rates were 95% in pT2 ISUP4/5 vs. 88% in pT3/4 ISUP2 vs. 65% in pT3/4 ISUP3 patients (P < 0.001). In multivariable Cox regression models addressing BCR, pT3/4 ISUP3 pathology was associated with higher BCR rate relative to pT2 ISUP4/5 pathology (hazard ratio 3.42, 95% confidence interval 1.07-10.94; P = 0.039), but not pT3/4 ISUP2 pathology (P = 0.6).
Conclusion: Compared to prostate cancer patients with pT2 ISUP4/5 pathology, the combination of pT3/4 ISUP3 pathology is associated with higher risk of BCR after RP. In consequence, patients with pT3/4 ISUP3 pathology should be considered for a closer postoperative follow-up.
With the STAR experiment at the BNL Relativisic Heavy Ion Collider, we characterize sNN−−−√ = 200 GeV p+Au collisions by event activity (EA) measured within the pseudorapidity range eta in [-5, -3.4] in the Au-going direction and report correlations between this EA and hard- and soft- scale particle production at midrapidity (η ∈ [-1, 1]). At the soft scale, charged particle production in low-EA p+Au collisions is comparable to that in p+p collisions and increases monotonically with increasing EA. At the hard scale, we report measurements of high transverse momentum (pT) jets in events of different EAs. In contrast with the soft particle production, high-pT particle production and EA are found to be inversely related. To investigate whether this is a signal of jet quenching in high-EA events, we also report ratios of pT imbalance and azimuthal separation of dijets in high- and low-EA events. Within our measurement precision, no significant differences are observed, disfavoring the presence of jet quenching in the highest 30% EA p+Au collisions at sNN−−−√ = 200 GeV.
For the search of the chiral magnetic effect (CME), STAR previously presented the results from isobar collisions (9644Ru+9644Ru, 9640Zr+9640Zr) obtained through a blind analysis. The ratio of results in Ru+Ru to Zr+Zr collisions for the CME-sensitive charge-dependent azimuthal correlator (Δγ), normalized by elliptic anisotropy (v2), was observed to be close to but systematically larger than the inverse multiplicity ratio. The background baseline for the isobar ratio, Y=(Δγ/v2)Ru(Δγ/v2)Zr, is naively expected to be (1/N)Ru(1/N)Zr; however, genuine two- and three-particle correlations are expected to alter it. We estimate the contributions to Y from those correlations, utilizing both the isobar data and HIJING simulations. After including those contributions, we arrive at a final background baseline for Y, which is consistent with the isobar data. We extract an upper limit for the CME fraction in the Δγ measurement of approximately 10% at a 95% confidence level on in isobar collisions at sNN−−−√=200 GeV, with an expected 15% difference in their squared magnetic fields.
We report on the charged-particle multiplicity dependence of net-proton cumulant ratios up to sixth order from s√=200 GeV p+p collisions at the Relativistic Heavy Ion Collider (RHIC). The measured ratios C4/C2, C5/C1, and C6/C2 decrease with increased charged-particle multiplicity and rapidity acceptance. Neither the Skellam baselines nor PYTHIA8 calculations account for the observed multiplicity dependence. In addition, the ratios C5/C1 and C6/C2 approach negative values in the highest-multiplicity events, which implies that thermalized QCD matter may be formed in p+p collisions.
The publication-based dissertation elaborates on the theoretical modelling of ultrafast processes of charge separation and migration as well as investigations of vibronic coupling and temperature effects on these processes in typical representatives of organic semiconductor materials. The systems considered were an aggregate of poly(3-hexylthiophene-2,5-diyl) (P3HT) molecules stacked along the molecular normal direction, a donor-acceptor interface of a mixture of P3HT and phenyl-C61-butyric acid methyl ester (PCBM), and a highly ordered aggregate of perylenediimide molecules linked to fluorene-thiophene donor molecules by benzothiadiazole units. The parametrisation is mainly based on electronic structure calculations (density functional theory and time-dependent density functional theory) while for quantum dynamical simulations the multiconfigurational time-dependent Hartree method (within the MCTDH program package) has been applied. The thesis is divided into four parts: In part I, fundamental theoretical concepts for the interpretation of the photophysical properties and processes relevant for charge separation in organic semiconductor materials on the one hand, and for the modelling, simulation and analysis of these processes on the other hand, are examined. In particular, methods used or further developed in the underlying publications are summarised and analysed. Part II of the thesis summarises the main results and contains detailed information on the parameterisation of the models, the simulation setup, the results and their interpretation. The publications itself are included in part III. Finally, the appendix in part IV contains detailed explanations of the theoretical background of the methods used and the references.
We report on the charged-particle multiplicity dependence of net-proton cumulant ratios up to sixth order from s√=200 GeV p+p collisions at the Relativistic Heavy Ion Collider (RHIC). The measured ratios C4/C2, C5/C1, and C6/C2 decrease with increased charged-particle multiplicity and rapidity acceptance. Neither the Skellam baselines nor PYTHIA8 calculations account for the observed multiplicity dependence. In addition, the ratios C5/C1 and C6/C2 approach negative values in the highest-multiplicity events, which implies that thermalized QCD matter may be formed in p+p collisions.
Highlights
• Time to mCRPC and OS differences can be observed for De Novo vs. secondary mHSPC patients.
• After stratification according to metastatic disease volume, patients with DNHV mHSPC harbored the worst outcomes, while patients with SecLV mHSPC harbored best prognosis.
• These effects can also be observed after progression to mCRPC.
Abstract
Objective: In recently published phase III trials, overall survival (OS) differences were demonstrated in patients with secondary vs. De Novo and low vs. high volume metastatic hormone-sensitive prostate cancer (mHSPC). We hypothesized that these factors may also be attributable in real-world setting of new intensified combination therapies and in metastatic castration resistant prostate cancer (mCRPC) patients.
Materials and methods
We relied on an institutional tertiary-care database to identify mHSPC and subsequent mCRPC patients. The main outcome consisted of time to mCRPC and OS. Patients were stratified according to De Novo vs. secondary and low vs. high volume mHSPC and mCRPC, respectively.
Results: Of 504 mHSPC patients, 371 (73.6%) were De Novo vs. 133 (26.4%) secondary mHSPC. Patients with De Novo and high volume mHSPC harbored shorter time to mCRPC and OS than secondary and low volume mHSPC patients (both P < 0.01). After stratification regarding disease volume, median time to mCRPC differed significantly between De Novo high volume (DNHV) vs. De Novo low volume (DNLV) vs. secondary high volume (SecHV) vs. secondary low volume mHSPC patients (SecLV, P < 0.001). Similarly in OS analyses, median OS was 44 vs. 53 vs. 88 vs. 120 months for respectively DNHV vs. SecHV vs. SecLV vs. DNLV mHSPC (P < 0.001). After progression to mCRPC, the effect of onset of metastatic disease and metastatic volume was still observed (all P < 0.01).
Conclusion: Patients with DNHV mHSPC harbor worse prognosis in a real world setting and in the light of combination therapies. This effect is also discernible in the context of mCRPC.
Dentale Implantate werden immer häufiger zum Ersatz fehlender Zähne verwendet. Vor zwanzig Jahren betrug die Anzahl der jährlich gesetzten Implantate circa 380.000, mittlerweile werden in Deutschland jährlich circa 1,3 Millionen Implantate inseriert. Das Interesse an einer zuverlässigen Reinigungsmethode für ossäre Implantate wird stetig größer. Wie bei den natürlichen Zähnen, können auf der Implantatoberfläche persistierende Mikroorgansimen gravierende Komplikationen auslösen, die die Langlebigkeit der Implantatversorgung beeinflussen können. Nicht selten kommt es zu einer Biofilm-assoziierten Entzündung des periimplantären Weichgewebes, auch Mukositis genannt. Unbehandelt geht sie in eine Periimplantitis über , bei der es zu einer Schädigung des Implantat-Knochen-Verbundes kommt. Für eine Reosseointegration und einer langfristigen Perspektive der Implantatversorgung ist die vollständige Eliminierung der pathogenen Beläge obligat. Ein neues Reinigungsverfahren soll die Behandlung revolutionieren und die Wiederherstellung gesunder periimplantärer Verhältnisse sichern. Neu bei dieser Methode ist die elektrolytische Reaktion (Elektrolyse), die eine Bildung von Wasserstoff (H2) an der Implantatoberfläche hervorruft. Dabei entstehen Gasblasen, die den an der Implantatoberfläche haftenden Biofilm sanft ablösen. Für die gewünschte Reosseointegration ist eine biologische und strukturelle Unversehrtheit der Implantatoberfläche essentiell. Die Evaluierung der Oberflächengüte nach elektrolytsicher Reinigung ist Ziel dieser in-vitro Studie. Untersucht wurden drei verschiedene Oberflächenmorphologien (Prüfgruppe1= maschiniert Grade 4, Prüfgruppe 2= gestrahlt Grade 4, Prüfgruppe 3= gestrahlt und geätzt Grade 4). Jede Prüfgruppe bestand aus je 10 Prüfkörpern. Alle Prüfkörper waren mit zwei Prüfflächen (PF) versehen. Sie sollten sowohl leicht zugängliche (gPF) als auch schwer zugängliche (sPF) Areale der Implantate imitierten. Die Untersuchung der Prüfkörper bestand aus struktur- und elementaranalytischen Verfahren. Für die visuelle Inspektion wurde das Rasterelektronenmikroskop (REM) gewählt. Die quantitative Elementanalyse erfolgte mittels einer energiedispersiven Röntgenspektroskopie (EDX). Zur Messung der mittleren Rauigkeit wurde die konfokale 3-D Laserscanningmikroskopie verwendet. Alle Prüfgruppen wurden dreimal untersucht: vor der Reinigung (vor R), nach der Reinigung (nach R) und nach Biofilmentfernung (BR), sowie miteinander verglichen, um mögliche Oberflächenveränderungen der jeweiligen Untersuchungsphase zuordnen zu können. Die erhobenen Daten im unbehandelten Zustand dienten in der Untersuchung als Referenz und wurden als Ausgangszustand der Prüfkörper festgelegt. Die Auswertung der REM - Ergebnisse ergab deutlich, dass bei den Prüfgruppen Sb und SbAe zu keinem Zeitpunkt der Untersuchung signifikante Veränderungen an der Implantatoberfläche zu beobachten waren. Bei der Prüfgruppe Sb wurden weder strukturelle Ab/-Auftragungen wie zum Beispiel Risse oder Kratzer, noch signifikante Schwankungen im elementaren Massenanteil dokumentiert. Die Prüfgruppen M und SbAe zeigte bei der EDX Analyse teilweise signifikante Veränderungen. Die Rauigkeitsmessung wurde nicht berücksichtigt. Die Wiederholungsmessungen (Mehrfachmessungen unter identischen Bedingungen) zeigten hohe Schwankungen der Messwerte. Eine aussagekräftige Beurteilung war nicht möglich. Die gängigen Implantate weisen ein makroskopisch und mikroskopisch komplexes Oberflächenprofil auf, was einen positiven Einfluss auf die (Re-) Osseointegration hat aber zeitgleich die mikrobielle Besiedlung und damit das Fortschreiten der Entzündungsprozesse begünstigt152. Vor allem die schwerzugänglichen Mikrostrukturen der Implantatoberflächen stellen eine große Hürde bezüglich der vollständigen Keimbefreiung dar. Trotz der Vielzahl zur Verfügung stehender Reinigungsverfahren ist aktuell keiner bekannten Methode die Wiederherstellung des gesunden periimplantären Hart- und Weichgewebes auch in Kombination mit einer Reosseointegration der zuvor kontaminierten Implantatoberfläche zuverlässig gelungen. Die Auswertung dieser Versuchsreihe zeigt, dass das untersuchte elektrolytische Reinigungsverfahren - im Gegensatz zu den gängigen Reinigingsmethoden - keinerlei visuelle Qualitätseinbüße der Implantatoberfläche mit sich bringt. Es konnte eine vollständig strukturelle und größtenteils elementare Stabilität der verschiedenen Implantatoberflächen bewiesen werden. Mithilfe dieses Verfahrens wäre erstmals auch eine in-vivo Reosseointegration nach einer Periimplantitis denkbar. Für die Implantologie ist dies ein erheblicher Fortschritt und revolutioniert die Behandlung periimplantärer Erkrankungen. Weitere Studien sind für die Bestärkung dieser Erkenntnisse erforderlich.
Lymphoma remains a significant global health challenge, contributing substantially to morbidity and mortality. Among the diverse subtypes of lymphoma, diffuse large B-cell lymphoma (DLBCL), an aggressive form, constitutes 30 to 40% of cases within Non-Hodgkin lymphomas (NHL). The evolving understanding of DLBCL subtypes emphasizes the urgent need for tailored treatment approaches, considering the substantial heterogeneity within this disease. Recognizing this, there is a critical demand for novel strategies and a deeper comprehension of resistance mechanisms against therapy to enhance the overall cure rates for individuals with DLBCL. Furthermore, it was shown that resistance to apoptosis is a common characteristic in cancer, often linked to the overexpression of anti-apoptotic BCL-2 proteins. To counteract this imbalance, the development of BH3-mimetics for inhibiting anti-apoptotic BCL-2 proteins is a promising strategy in cancer treatment. Venetoclax (ABT-199), a selective BCL-2 inhibitor, has demonstrated preclinical effectiveness against tumors and is the first BH3-mimetic approved for clinical use. Unfortunately, also resistance to ABT-199 can occur in patients, resulting in unfavorable treatment outcomes. This underscores the significance of ongoing research and clinical trials focused on elucidating and mitigating resistance mechanisms associated with ABT-199. The ultimate goal is to improve therapeutic strategies and enhance the effectiveness of ABT-199-based treatments. In this thesis our aim was to understand and explain the mechanisms behind the pre-existing resistance and the acquired resistance in DLBCL cell lines.
To investigate mechanisms of pre-existing resistance, we used specific DLBCL cell lines characterized by high BCL-2 to undergo cell death following ABT-199 treatment. These experiments are described under Part 1. To this end, we initially ruled out the possibility that protein expression patterns within the BCL-2 family contribute to resistance, as well as the expression of MDR1, which pumps out the drug from the cell, was not present in the selected cell DLBCL cell lines. Next, we selected two cell lines with high BCL-2 expression that displayed different responses to ABT-199 treatment. Our findings revealed notable variations in the binding patterns of anti-apoptotic and pro-apoptotic proteins upon treatment in the chosen sensitive (RIVA) and resistant (HBL-1) cell line. Upon observing the notable discrepancy in HBL-1 cells, where MCL-1 sequesters free BIM from BCL-2 in response to ABT-199, we hypothesized that MCL-1 was involved in the resistance. This was proven mechanistically by co-treatment with ABT-199 and the MCL-1 inhibitor S63845.
In the second part of the thesis, we investigated the role of the BH3-only protein NOXA in conferring resistance to cell death triggered by ABT-199 in the initially sensitive RIVA cell line. Employing CRISPR/Cas9-mediated knockout, we demonstrated that the absence of NOXA influenced sensitivity to ABT-199, both in vitro and in vivo. The absence of NOXA reinforced the role of MCL-1 as an anti-apoptotic protein, emphasizing its longer half-life and the newly identified interaction partner BIM. This hypothesis was validated through genetic silencing of MCL-1, resulting in the resensitization to ABT-199. Furthermore, in the absence of NOXA, we induced synergistic cell death through the co-treatment of ABT-199/S63845. Notably, we identified variations in the retranslocation of BAX in the presence and absence of NOXA, asserting that NOXA presence is crucial for BAX activation at the MOM, leading to pore formation with BAK.
The final section of the thesis explores the mechanism behind acquired resistance to ABT-199. To this end, RIVA cells were subjected to prolonged exposure to ABT-199. These adapted cells demonstrated the ability to overcome sensitivity to ABT-199 by elevating the expression of alternative anti-apoptotic proteins, specifically BCL-XL. To highlight this reliance, we utilized genetic silencing of BCL-XL, effectively resensitizing the cells to ABT-199. Furthermore, adapted RIVA cells exhibited sensitivity to co-treatment of ABT-199 with the BCL-XL inhibitor A1331852, resulting in synergistic cell death. In essence, our goal was to reveal the resistance mechanisms in order to identify better treatment strategies using BH3-mimetics in DLBCL patients. These findings highlight the importance of adopting a comprehensive strategy to address resistance mechanisms and improve the therapeutic effectiveness of ABT-199 in diverse combinations with other BH3-mimetics in treating DLBCL.
