Klinische Bedeutung des Karzinoembryonalen antigen Zelladhäsionsmoleküls (CEACAM)-1 bei operablen Bronchialkarzinomen

Das Karzinoembryonale Antigen Zelladhäsionsmolekül CEACAM-1 ist an interzellulären Adhäsionen beteiligt und begünstigt die Tumorangiogenese. In dieser Studie wurde die Expression von CEACAM-1 bei operablen nicht-kleinzelligen Bronchialkarzinomen und ihr prognostischer Einfluss untersucht. Primärtumoren von 145 Patienten mit operablen nicht-kleinzelligen Bronchialkarzinomen wurden mittels eines monoklonalen anti-CEACAM-1 Antikörpers immunhistochemisch untersucht. Die CEACAM-1 Expression wurde in 3 Kategorien eingeteilt: niedrig: £33% gefärbte Tumorzellen, intermediär: >33% und <66% gefärbte Tumorzellen, erhöht: ≥66% gefärbte Tumorzellen. Die Krankheitsverläufe wurden über den Zeitraum von 10 Jahren im Rahmen der Tumornachsorge beobachtet und anhand von Kaplan-Meier-Überlebenskurven durch log-rank Analyse verglichen. Normales respiratorisches Epithel und Stromazellen zeigten keine CEACAM-1 Expression. Primärtumoren von 31 Patienten (21,4%) wurden als niedrig CEACAM-1 exprimierend eingestuft und Präparate von 42 Patienten (29%) zeigten eine intermediäre CEACAM-1 Expression. Eine erhöhte CEACAM-1 Expression wurde bei Tumoren von 72 Patienten (49,6%) beobachtet und korrelierte nicht mit dem pT-Status, pN-Status, Differenzierungsgrad oder UICC-Stadium. Bei Adenokarzinomen trat eine erhöhte CEACAM-1 Expression mit 61,9% signifikant häufiger auf als bei Plattenepithelkarzinomen mit 35,7% (p= 0.017, X2 Test). In der univariaten Überlebensanalyse war eine hohe CEACAM-1 Expression mit signifikant ungünstigen Verläufen bei pN1-pN2 Patienten (n=60; p=0.024; Log Rank Test), pT3-pT4 Patienten (n=22; p=0.009; Log Rank Test), und Stadium IIa-IIIa Patienten (n=69; p=0.012; Log Rank test) assoziiert. Die multivariate Cox Regressionsanalyse zeigte, dass die erhöhte CEACAM-1 Expression ein unabhängiger prognostischer Parameter ist (p=0.018; Relatives Risiko 1.8; 95%Confidence Intervall 1.1-2.8). Eine erhöhte Expression von CEACAM-1 ist mit einer ungünstigen Prognose von Patienten mit fortgeschrittenen operablen nicht-kleinzelligen Bronchialkarzinomen assoziiert. Diese Beobachtung spricht gegen eine bisher postulierte tumorhemmende Wirkung von CEACAM-1 und zeigt, dass gegenteilig, CEACAM-1 sogar in die Tumorprogression von operablen Bronchialkarzinomen involviert ist

Initial experience with a synthetic sealant PleuraSeal™ after pulmonary resections: a prospective study with retrospective case matched controls

The objective of this study was to evaluate postoperative outcome and efficacy of a hydrogel tissue sealant for prevention of alveolar leakage after open lung resections

The histone demethylase LSD1/KDM1A promotes the DNA damage response

Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to γ-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway

The role of a pseudocapsula in thymic epithelial tumors: outcome and correlation with established prognostic parameters. Results of a 20-year single centre retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Treatment of thymoma is often based on observation of only a few patients. Surgical resection is considered to be the most important step. Role of a pseudocapsula for surgery, its clinical significance and outcome compared with established prognostic parameters is discussed which has not been reported so far.</p> <p>Methods</p> <p>84 patients with thymoma underwent resection and analysis was carried out for clinical features, prognostic factors and long-term survival.</p> <p>Results</p> <p>Fifteen patients were classified in WHO subgroup A, 21 in AB, 29 in B and 19 patients in C. Forty two patients were classified in Masaoka stage I, 19 stage II, 9 stage III and 14 stage IV. Encapsulated thymoma was seen in 40, incomplete or missing capsula in 44 patients. In 71 complete resections, local recurrence was 5%. 5-year survival was 88.1%. Thymomas with pseudocapsula showed a significant better survival (94.9% vs. 61.1%, respectively) (p = 0.001) and was correlated with the absence of nodal or distant metastasis (p = 0.04 and 0.001, respectively). Presence of pseudocapsula as well as the Masaoka and WHO classification, and R-status were of prognostic significance. R-status and Masaoka stage appeared to be of independent prognostic significance in multivariate analysis.</p> <p>Conclusion</p> <p>Intraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate prognosis. Although the presence of a capsula is of strong significance in the univariate analysis, it failed in the multivariate analysis due to its correlation with clinical Masaoka stage. Masaoka stage has a stronger relevance than WHO classification to determinate long-term outcome.</p

The oxidative demethylase ALKBH3 marks hyperactive gene promoters in human cancer cells

Background: The oxidative DNA demethylase ALKBH3 targets single-stranded DNA (ssDNA) in order to perform DNA alkylation damage repair. ALKBH3 becomes upregulated during tumorigenesis and is necessary for proliferation. However, the underlying molecular mechanism remains to be understood. Methods: To further elucidate the function of ALKBH3 in cancer, we performed ChIP-seq to investigate the genomic binding pattern of endogenous ALKBH3 in PC3 prostate cancer cells coupled with microarray experiments to examine the expression effects of ALKBH3 depletion. Results: We demonstrate that ALKBH3 binds to transcription associated locations, such as places of promoter-proximal paused RNA polymerase II and enhancers. Strikingly, ALKBH3 strongly binds to the transcription initiation sites of a small number of highly active gene promoters. These promoters are characterized by high levels of transcriptional regulators, including transcription factors, the Mediator complex, cohesin, histone modifiers, and active histone marks. Gene expression analysis showed that ALKBH3 does not directly influence the transcription of its target genes, but its depletion induces an upregulation of ALKBH3 non-bound inflammatory genes. Conclusions: The genomic binding pattern of ALKBH3 revealed a putative novel hyperactive promoter type. Further, we propose that ALKBH3 is an intrinsic DNA repair protein that suppresses transcription associated DNA damage at highly expressed genes and thereby plays a role to maintain genomic integrity in ALKBH3-overexpressing cancer cells. These results raise the possibility that ALKBH3 may be a potential target for inhibiting cancer progression. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0180-0) contains supplementary material, which is available to authorized users