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Abstract Background Despite dramatic improvements in the management of burns, infection still remains a serious risk for the burn patient. The aim of this study was to shed light on the impact of acute burn injury with or without infection on cytokine profiles. Methods Sprague-Dawley rats (n = 21) were randomized into three groups: 1) burn only 2) burn and infection or 3) sham burn. Weight was monitored and blood was collected for cytokine ELISA, LPS quantification, and peripheral blood analysis. Animals were sacrificed either after 6 or 12 days. Results Infected animals showed substantial weight loss until day 6 post-burn as compared to burn alone. Endotoxin and TNF-α levels were elevated early in the infected burn group within 48 hours post-burn. In contrast, significant up-regulation of the anti-inflammatory cytokine IL-10 occurred later in the clinical course and was associated with the recovery from weight loss. Conclusion Our results suggest that in the presence of infection, you get a SIRS response possibly due to transient endotoxemia that is only seen in the infection group. In contrast, both burn and infection get a late IL-10 (CARS) response, which is then associated with a return to normal weight in the infection group.

Background: Remodelling and spacing factor 1 (RSF1) is involved in the regulation of chromatin remodelling and represents a potential therapeutic target. High RSF1 expression has been linked to adverse tumour features in many cancer types, but its role in prostate cancer is uncertain. Methods: In this study, RSF1 expression was analysed by immunohistochemistry on a tissue microarray with 17,747 prostate cancers. Results: Nuclear RSF1 staining of 16,456 interpetable cancers was considered strong, moderate, weak and negative in 25.2%, 48.7%, 5.3% and 20.8% of cancers respectively. Positive RSF1 expression was associated with advanced tumour stage, high Gleason grade, lymph node metastasis (p <.0001 each), early biochemical recurrence (p <.0003) and more frequent in the ERG positive than in the ERG negative subset (88% versus 71%; p <.0001). Subset analysis revealed, that associations between RSF1 expression and unfavourable tumour phenotype and PSA recurrence were present in both subgroups but stronger in the ERG negative than in the ERG positive subset. The univariate Cox proportional hazard ratio for PSA recurrence-free survival for strong versus negative RSF1 expression was a weak 1.60 compared with 5.91 for the biopsy Gleason grade ≥4 + 4 versus ≤3 + 3. The positive association of RSF1 protein detection with deletion of 3p13, 10q23 (PTEN), 12p13, 16q23, and 17p13 (p <.0001 each) suggest a role of high RSF1 expression in the development of genomic instability. Conclusion: In summary, the results of our study identify RSF1 as an independent prognostic marker in prostate cancer with a particularly strong role in ERG negative cases. [ABSTRACT FROM AUTHOR]

Cadherin-17 (CDH17) is a membranous cell adhesion protein predominantly expressed in intestinal epithelial cells. CDH17 is therefore considered a possible diagnostic and therapeutic target. This study was to comprehensively determine the expression of CDH17 in cancer and to further assess the diagnostic utility of CDH17 immunohistochemistry (IHC). A tissue microarray containing 14,948 interpretable samples from 150 different tumor types and subtypes as well as 76 different normal tissue types was analyzed by IHC. In normal tissues, a membranous CDH17 staining was predominantly seen in the epithelium of the intestine and pancreatic excretory ducts. In tumors, 53 of 150 analyzed categories showed CDH17 positivity including 26 categories with at least one strongly positive case. CDH17 positivity was most common in epithelial and neuroendocrine colorectal neoplasms (50.0%−100%), other gastrointestinal adenocarcinomas (42.7%−61.6%), mucinous ovarian cancer (61.1%), pancreatic acinar cell carcinoma (28.6%), cervical adenocarcinoma (52.6%), bilio-pancreatic adenocarcinomas (40.5–69.8%), and other neuroendocrine neoplasms (5.6%−100%). OnIy 9.9% of 182 pulmonary adenocarcinomas were CDH17 positive. In colorectal adenocarcinomas, reduced CDH17 staining was linked to high pT (p = 0.0147), nodal metastasis (p = 0.0041), V1 (p = 0.0025), L1 (p = 0.0054), location in the right colon (p = 0.0033), and microsatellite instability (p < 0.0001). The CDH17 expression level was unrelated to tumor phenotype in gastric and pancreatic cancer. In summary, our comprehensive overview on CDH17 expression in human tumors identified various tumor entities that might often benefit from anti-CDH17 therapies and suggest utility of CDH17 IHC for the distinction of metastatic gastrointestinal or bilio-pancreatic adenocarcinomas (often positive) from primary pulmonary adenocarcinomas (mostly negative). [ABSTRACT FROM AUTHOR]

Background. Transfection efficacy after nonviral gene transfer in primary epithelial cells is limited. The aim of this study was to compare transfection efficacy of the recently available method of nucleofection [...]

Introduction: Sporadic inclusion body myositis (sIBM) is characterized by myopathological features including rimmed vacuoles (RVs) and proteins associated with protein aggregation, autophagy, and inflammation. Previous proteomic studies of RV areas revealed an overrepresentation of several chaperones and subunits of the T-complex protein 1 (TCP-1), which is involved in prevention of protein aggregation.Methods: To validate our proteomic findings, immunofluorescence analyses of selected chaperones and quantitative Western blot analysis of TCP-1 proteins were performed in five sIBM patients and five healthy controls.Results: Immunofluorescence studies confirmed increased immunoreactivity for VCP, UNC45B, GRP-75, αB-crystallin, LAMP-2, Rab-7a, and TCP-1α and TCP-θ in RVs. Quantitative Western blot analysis revealed a significantly higher level of TCP-1 in sIBM muscle tissue when compared with healthy controls.Discussion: Our study findings validate new insights in protein quality control and degradation processes that seem to be relevant in sIBM. These data provide an important basis for future functional and therapeutic studies. [ABSTRACT FROM AUTHOR]

The chromatin‐organizing factor CCCTC‐binding factor (CTCF) is involved in transcriptional regulation, DNA‐loop formation, and telomere maintenance. To evaluate the clinical impact of CTCF in prostate cancer, we analyzed CTCF expression by immunohistochemistry on a tissue microarray containing 17 747 prostate cancers. Normal prostate tissue showed negative to low CTCF expression, while in prostate cancers, CTCF expression was seen in 7726 of our 12 555 (61.5%) tumors and was considered low in 44.6% and high in 17% of cancers. Particularly, high CTCF expression was significantly associated with the presence of the transmembrane protease, serine 2:ETS‐related gene fusion: Only 10% of ERG‐negative cancers, but 30% of ERG‐positive cancers had high‐level CTCF expression (P < 0.0001). CTCF expression was significantly associated with advanced pathological tumor stage, high Gleason grade (P < 0.0001 each), nodal metastasis (P = 0.0122), and early biochemical recurrence (P < 0.0001). Multivariable modeling revealed that the prognostic impact of CTCF was independent from established presurgical parameters such as clinical stage and Gleason grade of the biopsy. Comparison with key molecular alterations showed strong associations with the expression of the Ki‐67 proliferation marker and presence of phosphatase and tensin homolog deletions (P < 0.0001 each). The results of our study identify CTCF expression as a candidate biomarker for prognosis assessment in prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: Prostate secretory protein of 94 amino acids (PSP94) is a target gene of the EZH2 transcriptional repressor and is often downregulated in prostate cancer; however, its prognostic value is disputed. Methods: Immunohistochemical analysis of a tissue microarray of 12, 432 prostate cancer specimens was performed to evaluate PSP94 expression. Correlation of PSP94 expression with tumor phenotype, patient prognosis, TMPRSS2:ERG fusion status, EZH2 expression and PTEN deletion was studied. Results: PSP94 expression was increased in benign prostatic hyperplasia; however, it was downregulated in 48% and negative in 42% of the 9, 881 interpretable prostate cancer specimens. The loss of PSP94 expression was inversely correlated to EZH2 expression (P < 0.0001) and largely unrelated to the ERG status, but strongly correlated with high Gleason grade, advanced tumor stage, and nodal metastasis (P <0.0001 each). The fraction of PSP94-negative cancer specimens increased from 40% in pT2 to 52% in pT3b-pT4 (P < 0.0001) and from 40% in Gleason 3+3 = 6 to 46% in Gleason 4+3 = 7 and 60% in Gleason =4+4 = 8 (P < 0.0001). Loss of PSP94 was linked to early prostate-specific antigen recurrence, but with little absolute effect (P < 0.0001). However, it provided additional prognostic impact in cancer specimens with PTEN deletion. Loss of PSP94 deteriorated prognosis of cancer patients with PTEN deletion by more than 10% (P < 0.0001). The combination of PTEN deletion and PSP94 loss provided independent prognostic information that was observed in several subgroups defined by classical and quantitative Gleason grade. Conclusions: The results of our study suggest that combined PSP94/PTEN analysis can be potentially used in the clinical prognosis of prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: Autologous transplantation of adipose tissue into the breast is commonly performed in clinical practice, but its oncological safety has not been established.Methods: We conducted an in vitro study to assess the influence of factors released by adipose-derived stem cells (ASCs), from multiple source tissues and harvested using different techniques, on proliferation and invasiveness of two breast cancer cell lines.Results: Fat specimens of 66 donors (57 female, 9 male) were collected and 44 ASC cultures were established. ASC conditioning of the medium (CM) increased the proliferation of MCF-7 cells (178.4 ± 62.8%; P < 0.001), whereas MDA-MB321 proliferation was decreased (87.3 ± 15.3%; P = 0.032). We observed increased cell migration (174.0 ± 62.8%; P = 0.002), but not cell invasion (1.28 ± 0.51; P = 0.14) in MDA-MB231. Migration and invasion of MCF-7 cells were not affected by exposure to ASC-CM. For MCF-7 cell migration, lower BMI (< 25 kg/m2) was associated with increased migration, both in univariate (P = 0.015) and multivariate (P = 0.039) analyses. Regarding the cytokine secretome, proliferation of MCF-7 was positively correlated with levels of eotaxin 1 and insulin-like growth factor-binding protein 3 in the CM, and inversely correlated with levels of interleukin 1β and transforming growth factor β-3. In case of MDA-MB231, granulocyte colony-stimulating factor, angiogenin, eotaxin 1 and 3, neutrophil activating peptide 2, and neurotrophin-3 were positively correlated with proliferation.Conclusions: We conclude that fat tissue transplantation increases proliferation and migration, but not invasion, of breast cancer cells. These findings are consistent with clinical data regarding the safety of autologous fat transplantation in breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: RBM3 expression has been suggested as prognostic marker in several cancer types. The purpose of this study was to assess the prevalence and clinical significance of altered RBM3 expression in esophageal cancer.Methods: RBM3 protein expression was measured by immunohistochemistry using tissue microarrays containing samples from 359 esophageal adenocarcinoma (EAC) and 254 esophageal squamous cell cancer (ESCC) patients with oncological follow-up data.Results: While nuclear RBM3 expression was always high in benign esophageal epithelium, high RBM3 expression was only detectable in 66.4% of interpretable EACs and 59.3% of ESCCs. Decreased RBM3 expression was linked to a subset of EACs with advanced UICC stage and presence of distant metastasis (P = 0.0031 and P = 0.0024). In ESCC, decreased RBM3 expression was associated with advanced UICC stage, high tumor stage, and positive lymph node status (P = 0.0213, P = 0.0061, and P = 0.0192). However, RBM3 expression was largely unrelated to survival of patients with esophageal cancer (EAC: P = 0.212 and ESCC: P = 0.5992).Conclusions: In summary, the present study shows that decreased RBM3 expression is associated with unfavourable esophageal cancer phenotype, but not significantly linked to patient prognosis. [ABSTRACT FROM AUTHOR]

background. In contrast, none of the cancers showed a pattern that would be consistent with 3p13 deletion preceding ERG fusion. Conclusion: Our study identifies 3p13 deletion as a highly heterogeneous alteration in prostate cancer preferentially developing at rather late stages of progression in TMPRSS2:ERG fusion-positive tumors. [ABSTRACT FROM AUTHOR]

Objectives: To develop a routinely applicable severity index for the management of acute appendicitis in adults using combined clinical and radiological parameters and retroperitoneal space planes (RSP).Methods: Two hundred consecutive patients with histologically proven acute appendicitis and available presurgical CT scans were analysed retrospectively. Two radiologists assessed all CT scans for morphologic sings of appendicitis and six RSP. Clinical parameters were age, body temperature, C-reactive protein (CRP), white blood cell count, and duration of symptoms. Radiological parameters were appendix diameter and wall thickness, periappendiceal fat stranding and fluid, intraluminal and extraluminal air, thinning of appendiceal wall, caecal wall thickening, appendicolith and abscess formation.Results: One hundred and three patients (51%) had histologically proven complicated appendicitis. Based on three clinical (age ≥52 years, body temperature ≥37.5°C, duration of symptoms ≥48 h) and four computed tomography (CT) findings (appendix diameter ≥14 mm, presence of periappendiceal fluid, extraluminal air, perityphlitic abscess), the APSI was developed using regression coefficients of multivariate logistic regression analyses with a maximum of 10 points. A score of ≥4 points predicted complicated appendicitis with a positive predictive value of 92% and a negative predictive value of 83%. Substantial to excellent interobserver agreement was found for the four radiological parameters of the APSI [intraclass correlation coefficient (ICC), 0.78-0.83]. The RSP evaluation presented no added value for the diagnosis of complicated appendicitis.Conclusions: Using APSI, an accurate and simple prediction of complicated appendicitis in adults was possible. The RSP count was not useful for the diagnosis of complicated appendicitis.Key Points: • Appendicitis severity score provides an accurate and simple prediction of complicated appendicitis • Appendicitis severity score ≥4 accurately predicted complicated appendicitis (PPV 92%;NPV 83%) • Evaluation of retroperitoneal space planes was not useful in diagnosing complicated appendicitis. [ABSTRACT FROM AUTHOR]

Background: IDH1 mutations are oncogenic through induction of DNA damage and genome instability. They are of therapeutic interest because they confer increased sensitivity to radiation and cytotoxic therapy and hold potential for vaccination therapy.Methods: In this study, we analyzed more than 17,000 primary prostate cancer tissues with a mutation-specific antibody for the IDH1R132H mutation.Results: IDH1 mutation-specific staining was found in 42 of 15,531 (0.3%) interpretable cancers. IDH1 mutation was associated with higher preoperative PSA and Gleason grade (p < 0.05, each) but was unrelated to PSA recurrence. A comparison with other molecular tumor features available from earlier studies revealed that TMPRSS2-ERG fusion as well as deletion of PTEN, 5q21, 6q15, and 3p13 was less frequent in IDH1-mutated than in non-mutated cancer. Increased lethality of genetically instable, “aberration-rich” cancer cells in the presence of IDH1 mutations could possibly explain this observation. Heterogeneity analysis revealed a homogeneous mutation in only 1 of 16 IDH1-mutated cancers. This high degree of heterogeneity may profoundly limit therapeutic targeting of IDH1 mutations in prostate cancer.Conclusions: The data show that 0.3% of prostate cancers have an IDH1R132H mutation and that these are mostly heterogeneous. Once specific anti-IDH1 therapy becomes reality, only a very small group of prostate cancer patients may benefit from such a treatment. [ABSTRACT FROM AUTHOR]

Summary Background Adipose-derived stem cells represent an interesting option for soft tissue replacement as they are easy to procure and can generate their own blood supply through the production of angiogenic factors. We seeded adipose-derived stem cells on a bioresorbable, biocompatible polymer alginate scaffold to generate autologous soft tissue constructs for repair. Materials and methods We built and optimized an alginate scaffold and tested its biocompatibility using the MTT assay and its hydration capacity. We then isolated, characterized, and differentiated murine, porcine, and human adipose-derived stem cells. We characterized their angiogenic potential in vitro by VEGF ELISA and HUVEC tube formation assay in traditional cell culture substrate and in the actual three-dimensional scaffold. We assessed the angiogenic potential of adipose-derived stem cell-colonized scaffolds in ovo by chorion allantois membrane angiogenesis assay. Results Adipose-derived stem cells differentiated into adipocytes within the alginate scaffolds and demonstrated angiogenic activity. VEGF secretion by adipose-derived stem cells decreased significantly over the 21-day course of adipocyte differentiation in traditional cell culture substrate, but not in scaffolds. Adipose-derived stem cells differentiated for 21 days in scaffolds led to the longest HUVEC tube formation. Scaffolds colonized with adipose-derived stem cells resulted in significantly improved vascularization in ovo . Conclusions We demonstrate the feasibility of implant production based on adipose-derived stem cell-colonized alginate scaffolds. The implants demonstrate biocompatibility and promote angiogenesis in vitro and in ovo . Therefore, they provide a combination of essential properties for an implant intended for soft tissue replacement. [ABSTRACT FROM AUTHOR]