Inflammatory pathways confer resistance to chemoradiotherapy in anal squamous cell carcinoma.

Anal squamous cell carcinoma (ASCC) is associated with immunosuppression and infection with human papillomavirus (HPV). Response to standard chemoradiotherapy (CRT) varies considerably. A comprehensive molecular characterization of CRT resistance is lacking, and little is known about the interplay between tumor immune contexture, host immunity, and immunosuppressive and/or immune activating effects of CRT. Patients with localized ASCC, treated with CRT at three different sites of the German Cancer Consortium (DKTK) were included. Patient cohorts for molecular analysis included baseline formalin fixed paraffin embedded biopsies for immunohistochemistry (n = 130), baseline RNA sequencing (n = 98), peripheral blood immune profiling (n = 47), and serum cytokine measurement (n = 35). Gene set enrichment analysis showed that pathways for IFNγ, IFNα, inflammatory response, TNFα signaling via NF-κB, and EMT were significantly enriched in poor responders (all p < 0.001). Expression of interferon-induced transmembrane protein 1 (IFITM1), both on mRNA and protein levels, was associated with reduced Freedom from locoregional failure (FFLF, p = 0.037) and freedom from distant metastasis (FFDM, p = 0.014). An increase of PD-L1 expression on CD4+ T-cells (p < 0.001) and an increase in HLA-DR expression on T-cells (p < 0.001) was observed in the peripheral blood after CRT. Elevated levels of regulatory T-cells and CXCL2 were associated with reduced FFLF (p = 0.0044 and p = 0.004, respectively). Inflammatory pathways in tissue in line with elevated levels of regulatory T-cells and CXCL2 in peripheral blood are associated with resistance to CRT. To counteract this resistance mechanism, the RADIANCE randomized phase-2 trial currently tests the addition of the immune checkpoint inhibitor durvalumab to standard CRT in locally advanced ASCC.

A novel method for the accurate quantification of two isomeric mercapturic acids of 1,3-dichlorobenzene in human urine using isotope dilution online-SPE-LC-MS/MS.

1,3-dichlorobenzene (1,3-DCB) is an aromatic solvent that might be formed during thermal decomposition of bis(2,4-dichlorobenzoyl)peroxide used as initiator in silicone rubber production with many workers exposed worldwide. During metabolism of 1,3-DCB, two isomeric mercapturic acids can be formed from ring oxidation of 1,3-DCB in the liver, namely 2,4-dichlorophenylmercapturic acid (24CPhMA) and 3,5-dichlorophenylmercapturic acid (35CPhMA). These urinary mercapturic acids might serve as biomarkers of the toxicologically relevant absorbed dose of 1,3-DCB and have not been determined so far. Thus, we were aimed to develop an analytical method for quantification of these biomarkers. Authentic standards of both mercapturic acids as well as deuterium-labelled analogues were self-synthesized. A method for the quantification of both CPhMAs in human urine using online-SPE LC/MS/MS was developed and validated with an LOQ of 0.1 ng mL-1 for both CPhMAs. The analytes were extracted from urine by online-SPE on a restricted access material phase, transferred to the analytical column and quantified by tandem mass spectrometry. Interday (n = 6) and Intraday (n = 10) precision for both CPhMAs ranged from 1.7 to 4.3 % with accuracies between 99.4 and 109.9 % at concentrations of 0.6 and 3 ng mL-1. We applied the method on post-shift urine samples of 16 workers of the silicone rubber industry with occupational exposure to 1,3-DCB. Both CPhMAs were above LOQ in 15 of 16 urine samples with median levels (range) for 24CPhMA and 35CPhMA of 1.64 ng mL-1 (<0.1 - 8.2 ng mL-1) and 3.98 ng mL-1 (0.36 - 24.1 ng mL-1), respectively. This is the first report on specific urinary mercapturic acids of 1,3-DCB in humans. Our results show that ring oxidation of 1,3-DCB is considered to be a toxicologically relevant metabolic pathway in humans. This might improve risk assessment of 1,3-DCB-emissions in silicone rubber industry.

Excretion kinetics of 1,3-dichlorobenzene and its urinary metabolites after controlled airborne exposure in human volunteers.

The solvent 1,3-dichlorobenzene (1,3-DCB) is formed during thermal decomposition of the initiator 2,4-dichlorobenzoylperoxide in the production of silicone rubber with potential exposure of production workers as shown in previous works. Despite a threshold limit value (MAK value) of 2 ppm in air, there are currently no data about the corresponding internal exposure that would allow for the derivation of a biological limit value. In the present study, we have investigated the absorption of 1,3-DCB and urinary kinetics of its metabolites in 10 human volunteers after controlled inhalative exposure. Due to the strong odour of 1,3-DCB, a subjective evaluation of odour nuisance was also performed. Ten male human volunteers (23-36 yrs.) were exposed 6 h/day to a concentration of 0.7 ppm and 1.5 ppm in the Aachen workplace simulation laboratory (AWSL) with one week between each experiment. In order to investigate potential dermal absorption, the volunteers were exposed to 1.5 ppm wearing a suitable filter mask that prevented inhalative exposure in a third exposure. 1,3-DCB in blood was measured after 3 and 6 h exposure and the urinary metabolites 3,5-dichlorocatechol (3,5-DCC), 2,4-dichlorophenol (2,4-DCP) and 3,5-dichlorophenol (3,5-DCP) were measured over 24 h after exposure via LC/MS/MS. There were clear dose-response relations for all investigated parameters. The maximum excretion of the metabolites was reached at the end of exposure and corresponded to 5.2 ± 0.7 mg/g crea, 1.5 ± 0.35 mg/g crea and 0.07 ± 0.011 mg/g crea at 0.7 ppm and to 12.0 ± 3 mg/g crea, 3.5 ± 1.1 mg/g crea and 0.17 ± 0.05 mg/g crea at 1.5 ppm for 3,5-DCC, 2,4-DCP and 3,5-DCP, respectively. The use of filter masks decreased the internal exposure for about 85-90%, indicating substantial dermal absorption. Odour perception did not show a dose-response, probably due to fast olfactory adaption. The human study presented here provides an excellent basis for deriving a biological limit value for 1,3-DCB.

Evaluation of prognostic factors after primary chemoradiotherapy of anal cancer: A multicenter study of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG).

BACKGROUND AND PURPOSE: Prognosis after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) shows marked differences among patients according to TNM subgroups, however individualized risk assessment tools to better stratify patients for treatment (de-) escalation or intensified follow-up are lacking in ASCC. MATERIALS AND METHODS: Patients' data from eight sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG), comprising a total of 605 patients with ASCC, treated with standard definitive CRT with 5-FU/Mitomycin C or Capecitabine/Mitomycin C between 2004-2018, were used to evaluate prognostic factors based on Cox regression models for disease-free survival (DFS). Evaluated variables included age, gender, Karnofsky performance score (KPS), HIV-status, T-category, lymph node status and laboratory parameters. Multivariate cox models were separately constructed for the whole cohort and the subset of patients with early-stage (cT1-2 N0M0) tumors. RESULTS: After a median follow-up of 46 months, 3-year DFS for patients with early-stage ASCC was 84.9%, and 67.1% for patients with locally-advanced disease (HR 2.4, p < 0.001). T-category (HR vs. T1: T2 2.02; T3 2.11; T4 3.03), N-category (HR versus N0: 1.8 for N1-3), age (HR 1.02 per year), and KPS (HR 0.8 per step) were significant predictors for DFS in multivariate analysis in the entire cohort. The model performed with a C-index of 0.68. In cT1-2N0 patients, T-category (HR 2.14), HIV status (HR 2.57), age (1.026 per year), KPS (HR 0.7 per step) and elevated platelets (HR 1.3 per 100/nl) were associated with worse DFS (C-index of 0.7). CONCLUSION: Classical clinicopathologic parameters like T-category, N-category, age and KPS remain to be significant prognostic factors for DFS in patients treated with contemporary CRT for ASCC. HIV and platelets were significantly associated with worse DFS in patients with early stage ASCC.

Combining ACL Reconstruction and Refixation: the Single Anteromedial Bundle Biological Augmentation and Refixation (SAMBBAR) Technique.

PURPOSE OF THE STUDY Anterior cruciate ligament (ACL) preservation surgical techniques have been rising lately. In the acute setting, proximal ACL tears and femoral avulsions of the ACL are good indications for primary repair of the ACL. However, literature shows a wide range of failure rates. An intact synovial membrane seems to be a predicational factor for the outcome of primary ACL repair. Disruption of the synovial membrane is associated with higher failure rates. We describe a surgical technique repairing the ACL in combination with a semitendinosus augmentation for proximal ACL tears with or without disruption of the synovial membrane. MATERIAL AND METHODS The procedure preserves as much of the original anatomy as possible by repairing the synovial membrane and ACL remnant to the femoral origin. To accomplish this, we have built on the so-called "Single Anteromedial Bundle Biological Augmentation (SAMBBA) technique" and developed it further to the "Single Anteromedial Bundle Biological Augmentation and Refixation (SAMBBAR) technique", which we firstly describe here. RESULTS All three patients treated with the SAMBBAR technique showed very good short-term clinical outcomes comparable with successful standard ACL reconstruction. There were no complications. Twelve months postoperatively, patients had no pain. They had normal range of motion in the affected knee without any signs of instability. DISCUSSION The SAMBBAR technique seems to be an adequate procedure to preserve as much proprioceptive native tissue as possible, while at the same time ensuring high tissue strength in order to reduce failure rates. Prospective randomized controlled trials are needed to compare the new SAMBBAR technique with standard ACL reconstruction, with the original SAMBBA technique, and with techniques of ACL refixation. CONCLUSIONS With the presented surgical procedure, it is possible to perform a standard ACL reconstruction using an autologous semitendinosus graft and at the same time preserving the tissue remnant of the ACL in all proximal tear patterns. This might contribute to improved proprioception and rehabilitation without sacrificing stability. Key words: anterior cruciate ligament, Lachman test, Ligamys, knee instability, semitendinosus tendon.

Acromioclavicular joint separation treated with clavicular hook plate: a study of radiological and functional outcomes.

INTRODUCTION: ACJ separation is a common shoulder injury. A variety of surgical techniques for high-grade ACJ separations have been described. A commonly used technique represents open reduction and fixation by a hook plate. Goal of the present study was to evaluate radiographic and functional outcome in patients with high-grade ACJ separations following surgical treatment with a hook plate before and after surgery as well as after hook plate removal. MATERIALS AND METHODS: Patients undergoing surgery with a hook plate due to traumatic ACJ separation between 2012 and 2014 were included and examined during a follow-up control. Demographic and clinical data as well as radiographs pre- and postoperatively were evaluated. Additionally, range of motion, DASH Score and Constant-Murley Score (CMS) were analysed in a follow-up examination. Wilcoxon signed-rank test and Spearman's rank correlation were used for statistical analysis. RESULTS: 99 patients (88 m/11 w, 44 y) were included in the present study. 69 (64 m/5 w, 49 y) could be examined during long-term follow-up (38 month). After hook plate removal, the CCD increased significantly (13.7 ± 0.9 mm) compared to the hook plate in situ (9.9 ± 0.8 mm, p = 0.000001). 68% of all patients achieved a full range of motion post-operatively. Main limitations of range of motion affected external rotation as well as ante-/retroversion. Mean DASH Score was 5.6 ± 1 points and CMS 90.0 ± 1.4 points. CONCLUSION: In contrast to a significant higher CCD after hook plate removal, nearly all patients achieved good to excellent functional results for DASH and CMS. This indicates that loss of reduction does not necessarily lead to poor functional outcome after ACJ separation surgery.

Metabolic activation and toxicological evaluation of polychlorinated biphenyls in Drosophila melanogaster.

Degradation of polychlorinated biphenyls (PCBs) is initiated by cytochrome P450 (CYP) enzymes and includes PCB oxidation to OH-metabolites, which often display a higher toxicity than their parental compounds. In search of an animal model reflecting PCB metabolism and toxicity, we tested Drosophila melanogaster, a well-known model system for genetics and human disease. Feeding Drosophila with lower chlorinated (LC) PCB congeners 28, 52 or 101 resulted in the detection of a human-like pattern of respective OH-metabolites in fly lysates. Feeding flies high PCB 28 concentrations caused lethality. Thus we silenced selected CYPs via RNA interference and analyzed the effect on PCB 28-derived metabolite formation by assaying 3-OH-2',4,4'-trichlorobiphenyl (3-OHCB 28) and 3'-OH-4',4,6'-trichlorobiphenyl (3'-OHCB 28) in fly lysates. We identified several drosophila CYPs (dCYPs) whose knockdown reduced PCB 28-derived OH-metabolites and suppressed PCB 28 induced lethality including dCYP1A2. Following in vitro analysis using a liver-like CYP-cocktail, containing human orthologues of dCYP1A2, we confirm human CYP1A2 as a PCB 28 metabolizing enzyme. PCB 28-induced mortality in flies was accompanied by locomotor impairment, a common phenotype of neurodegenerative disorders. Along this line, we show PCB 28-initiated caspase activation in differentiated fly neurons. This suggested the loss of neurons through apoptosis. Our findings in flies are congruent with observation in human exposed to high PCB levels. In plasma samples of PCB exposed humans, levels of the neurofilament light chain increase after LC-PCB exposure, indicating neuronal damage. In summary our findings demonstrate parallels between Drosophila and the human systems with respect to CYP mediated metabolism and PCB mediated neurotoxicity.

Trends in fracture development of the upper extremity in Germany-a population-based description of the past 15 years.

BACKGROUND: Recent studies investigating fracture development in Germany are not available especially with regard to demographic change. The primary aim of this study was to report trends in fracture development of the upper extremity in Germany between 2002 and 2017 and to evaluate changes over time. METHODS: Evaluating inpatient data from the German National Hospital Discharge Registry (International Classification of Diseases, ICD-10) between 2002 and 2017. Total count, incidences and percentage changes of the following fracture localizations were analysed: proximal humerus, distal humerus, proximal ulna, proximal radius, ulna diaphysis (including Monteggia lesion) and distal radius. Ten age groups for men and women were formed: 35-44, 45-54, 55-64, 65-74; 75-84; 85-90, and > 90 (years). RESULTS: The total count of proximal humeral fractures increased from 40,839 (2002, men/women 9967/30,872) to 59,545 (2017, men/women 14,484/45,061). Distal humeral fractures increased from 5912 (2002, men/women 1559/4353) to 6493 (2017, men/women1840/4653). The total count of forearm fractures increased from 68,636 (2002, men/women 17,186/51,450) to 89,040 (2017, men/women 20,185/68,855). Women were affected in 70-75% of all cases with rising incidences among nearly every age group in female patients. CONCLUSION: Total count of nearly every evaluated fracture increased. Also, incidences increased especially in the older female age groups. Fracture development already seems to reflect demographic changes in Germany.

Sporting activity is reduced following medial reefing performed for patellar dislocation : A retrospective case series of 144 patients with a minimum follow-up of 24 months.

BACKGROUND: Patellar dislocation is common in young and active patients. The purpose of this study was to determine sporting activity following the medial reefing of patellar dislocation. METHODS: One hundred forty-four patients with objective patellar dislocation were treated between 2004 and 2013. Three groups were analyzed retrospectively with a minimum follow-up of 24 months: (1) primary dislocation that was treated with medial reefing without a recurrent dislocation until the day of follow-up (n = 74), (2) primary dislocation that was initially treated with medial reefing but with a recurrent dislocation until the day of follow-up (n = 44), and (3) medial reefing after failed conservative treatment (n = 26). Sporting activity was assessed using a widely-used sporting activity questionnaire and the Tegner score prior to the injury and at the follow-up (58.7 ± 22.6 months after the injury). Clinical outcomes were assessed using IKDC and Kujala score. RESULTS: The Kujala score was 94.7 ± 9.3 for Group 1, 84.1 ± 16.6 for Group 2 and 93.4 ± 9.7 for Group 3. IKDC at the time of follow-up was 97.2 ± 9.3 for Group 1, 86.1 ± 14.6 for Group 2 and 95.1 ± 11.1 for Group 3. 91.9% of Group 1 and 92.3% of Group 3 were active in sports prior to their injuries and at the time of the follow-up. In Group 2, sporting activity reduced from 81.8 to 75.0%. In all groups, a shift from high performance to recreational sports was found. CONCLUSIONS: Despite good clinical results, sporting activity was reduced following patellar dislocation treated with medial reefing. Also, a shift from engagement in high- to low-impact sports among the participants was noted.

Spatio-temporal dynamics in maturation and spawning of Patagonian toothfish Dissostichus eleginoides on the sub-Antarctic Kerguelen Plateau.

This study investigated maturation and spawning of Patagonian toothfish Dissostichus eleginoides in the Heard Island and McDonald Islands (HIMI) fishery on the Kerguelen Plateau in the Indian Sector of the Southern Ocean based on gonads and otoliths collected between 2004 and 2015 and using histological analyses and calibration of macroscopic staging criteria. Dissostichus eleginoides at HIMI spawn throughout the austral late autumn and winter months of May-August and spawning activity is concentrated on slopes along the west and south of the plateau around HIMI at depths of 1500-1900 m. Comparison between histological analyses and macroscopic gonad staging indicated that many fish that had spawned, as indicated by the presence of post-ovulatory follicles, returned to a resting stage which was macroscopically indistinguishable from maturing fish. Furthermore, the occurrence of females of all size classes with low gonado-somatic index and low macroscopic gonad stage during the spawning season suggested that a proportion of mature females did not spawn every year. Age-at-maturity estimates, based on the assumption that fish of macroscopic stages ≥2 were mature, decreased between the 2004-2009 and 2010-2015 periods for both sexes. The magnitude of this temporal variation in age at maturity, however, varied between gear types and fishing depths and variable sampling regimes probably influenced these variations. This study highlights the importance of correct interpretation of macroscopic gonad stages and understanding the influence of fishery operations on estimations of life-history parameters.

[Malnutrition in Elderly Trauma Patients - Comparison of Two Assessment Tools]. / Die Erfassung des Ernährungsstatus alterstraumatologischer Patienten ­ ein Vergleich zweier etablierter Screeningmethoden.

Background: The prevalence of malnutrition in hospitalised patients is reported to be between 16 and 55 % across disciplines. Within hospital care, screening for malnutrition is required. However, in orthopaedics and trauma surgery, there is still no generally accepted recommendation for the methods for such a data survey. In the present study, the following aspects are to be investigated with the help of two established scores: (1) the prevalence of malnutrition in the patient population of geriatric trauma care, and (2) the correlation between methods of data survey. Material and Methods: Between June 2014 and June 2015, a consecutive series of hospitalised trauma patients were studied prospectively with two validated screening instruments to record nutritional status. The study was carried out at a municipal trauma surgery hospital, which is a first level interregional trauma centre as well as a university hospital. The Nutritional Risk Screening (NRS) and the Mini Nutritional Assessment (MNA Short and Long Form) were used. All patients were divided into three age groups: < 65 years, 65-80 years, and > 80 years. The prevalence of malnutrition in geriatric trauma patients and the correlation between the screening instruments were determined. For a better comparison, prescreening and main assessment were applied to all patients. For statistical evaluation, both quantitative and semi-quantitative parameters were used. Furthermore, the Kolmogorov-Smirnov test, Spearman's correlation analysis and the chi-square test were applied. These tests were two-sided and had a level of significance of 5 %. The present study was partially funded by the Oskar-Helene-Heim Foundation. Results: 521 patients (43.8 % women, 56.2 % men), with a mean age of 53.96 ± 18.13 years, were statistically evaluated within the present study. Depending on the method of the data survey, malnutrition (NRS≥3) in geriatric trauma patients varied from 31.3 % (65-80 years) to 60 % (> 80 years). With MNA, 28.8 and 54.3 % of patients were at risk of malnutrition (MNA 17-23.5), while the fractions of patients already suffering from malnutrition (MNA < 17) were 5.4 and 8.6 %, respectively. The correlation between the NRS and MNA total scores increases with the age of the patients. The correlation coefficient for patients under 65 years is r = - 0.380, while among patients aged between 65 and 80, it is r = - 0.481, and for patients over 80 years, there is a medium to strong correlation of r = - 0.638 (each with a Spearman correlation of p < 0.001). For the total population as well as the different age groups, statistically significant correlations were recorded between the categorised scores (chi-square test for linear trend, p < 0.001). Summary: The present study demonstrates high prevalence of malnutrition among the geriatric trauma patients. Because of its easy and rapid application, the NRS has an advantage in clinical use. It was shown that the two methods of data survey were highly correlated.

[Retrospective Analysis of Diabetics with Regard to Treatment Duration and Costs]. / Retrospektive Analyse von Diabetikern im Hinblick auf Behandlungsdauer und Behandlungskosten in einem überregionalen Traumazentrum.

Background: The increasing incidence of diabetes mellitus is also reflected in the patient population of a trauma and orthopaedic centre. Diabetics also exhibit more comorbidities than non-diabetics. In addition to surgical problems in these patients, hospitalisation is often accompanied by complications, which can prolong treatment and increase costs. The aim of this retrospective study is to analyse hospitalisation of diabetics compared to non-diabetics, as well as differences in treatment costs, depending on associated age and comorbidities. Patients/Material and Methods: 17,185 patients were treated at a transregional trauma and orthopaedic centre and were included in this retrospective analysis between 2012 and 2015. Comorbidities and hospitalisation of diabetics and non-diabetics were recorded. All costs charged by DRG were evaluated to calculate the cost per day and per patient, on the basis of the specific case rate. In this calculation, patient-related case rates were divided by the average residence time and the means of the calculated daily rates were calculated. Inclusion criteria were treatment within the various departments and a minimum hospitalisation of one day. Statistical analysis was performed with the SPSS program (version 22.0, SPSS Inc., Chicago, USA). Results: In comparison to non-diabetics (ND), diabetics (D) exhibited significantly more comorbidities, including: obesity, arterial hypertension, coronary heart disease, myocardial infarction (in the history), peripheral arterial disease, chronic kidney disease and hyperlipidaemia. Pneumonia in hospital was considerably commoner in diabetics (2.45 % [D] vs. 1.02 % [ND], p < 0.001). Time in hospital was significantly longer in diabetics (endoprosthetics 13.52 days [D] vs. 12.54 days [ND], p < 0.001; septic surgery 18.62 days [D] vs. 16.31 days [ND], p = 0.007; traumatology 9.82 days [D] vs. 7.07 days [ND], p < 0.001). For patients aged under 60 years, time in hospital was significantly longer for diabetics than for non-diabetics (9.98 days [D] vs. 6.43 days [ND] p < 0.001). Because of the longer time in hospital, treatment costs were higher by € 1,932,929.42 during the investigated time period. Conclusion: Because of their comorbidities, diabetics need to be categorised at an early stage as high-risk patients in traumatological and orthopaedic departments. Hospitalisation and the associated increased treatment costs, as well as postoperative complications, could be minimised in patients with diabetes by implementing an interdisciplinary treatment concept.

Relative in vitro growth rates of duckweeds (Lemnaceae) - the most rapidly growing higher plants.

Relative growth rates (RGR), doubling times (DT) and relative weekly yields (RY) of 39 clones (ecotypes) from 13 species representing all five genera of duckweeds were determined under standardised cultivation conditions. RGR ranged overall from 0.153 to 0.519 day(-1) , DT from 1.34 to 4.54 days and RY from 2.9 to 37.8 week(-1) . The RGR and RY data can be compared directly to other published findings to only a limited extent on account of missing clonal designations for and limited accessibility to previously investigated clones, as well as the use of different data denominators. However, they are consistent with the published results of other comparative duckweed studies of similar scope in showing that RGR does not vary primarily at the level of the genus or species, but rather reflects the adaptation of individual clones to specific local conditions. The RGR data support the widely held assumption that duckweeds can grow faster than other higher plants and that they can thus surpass land-based agricultural crops in productivity. Duckweeds are highly promising for the production of biomass for nutrition and energy, but extensive clonal comparison will be required to identify the most suitable isolates for this purpose.

Src family kinases mediate cytoplasmic retention of activated STAT5 in BCR-ABL-positive cells.

Persistent activation of the Abl tyrosine kinase in the BCR-ABL fusion protein is the major cause of chronic myeloid leukemia (CML). Among many other substrates BCR-ABL phosphorylates STAT5 and Src family kinases (SFK). Activated pSTAT5 is essential for initial transformation and maintenance of the disease. Cytokine-induced phosphorylation on tyrosine 694 typically leads to nuclear accumulation of pSTAT5 and target gene expression. We verified that in BCR-ABL-positive progenitor cells from a CML patient and in K562 cells pSTAT5 is cytoplasmic. However, upon ectopic expression of BCR-ABL p210 in non-myeloid cells, co-transfected STAT5A is phosphorylated on Y694 and localized in the nucleus arguing for an additional factor mediating cytoplasmic retention in CML cells. Expression of the SFK v-Src, Hck or Lyn together with STAT5A results in phosphorylation on Y694 and cytoplasmic retention. Upon coexpression of BCR-ABL and individual SFK the cytoplasmic retention of activated STAT5A mediated by v-Src and Hck but not Lyn is dominant over nuclear translocation induced by BCR-ABL. Cytoplasmic retention depends on the kinase activity of SFK and is mediated through the interaction of the SH2 domain of STAT5A with the SFK. Interestingly, nuclear accumulation of STAT5A as a result of activation by FLT3-ITD, an oncogene found in acute myeloid leukemia, cannot be prevented by coexpression of SFK. Importantly, inhibition of SFK in K562 cells restored nuclear accumulation of pSTAT5A, enhanced STAT5 target gene expression and increased colony formation. Thus, SFK mediate cytoplasmic retention of pSTAT5A in BCR-ABL-positive cells. Cytoplasmic pSTAT5A in CML cells might balance the controversial functions of STAT5 in cellular senescence and differentiation versus G1/S progression and survival.

Low-molecular weight carbohydrates modulate dormancy and are required for post-germination growth in turions of Spirodela polyrhiza.

The aquatic duckweed Spirodela polyrhiza propagates itself vegetatively by forming turions - bud-like perennation organs - in the autumn, which spend the winter on the bottom of ponds and then germinate in the following spring and proliferate on the water surface. Newly formed turions usually require a period of cold after-ripening and light to germinate effectively, but an ample supply of exogenous sugar can lead to germination even in the dark and independent of after-ripening. The results of the present study indicate that the availability of readily metabolised carbohydrates is a determining factor for turion germination. Freshly harvested turions do not contain soluble, low-molecular weight carbohydrates at a level sufficient to allow germination to take place, but after-ripened turions do. Augmentation of the soluble carbohydrate content during after-ripening derives from gradual breakdown of reserve starch of the turions. The long time required for any germination to be observed in turions incubated in darkness and the limited frequency of germination in the dark (about 50% of turion population), even with an ample external sugar, supply emphasise that both after-ripening and light are essential for ensuring rapid germination and subsequent frond proliferation at an ecologically appropriate time. The carbohydrate supply required for rapid proliferation of the fronds produced at germination is provided by the rapid light-induced breakdown of turion reserve starch.

[Transforming growth factor ß in prostate cancer: cellular effects and basic molecular mechanisms]. / "Transforming growth factor ß" im Prostatakarzinom : Zelluläre Wirkungen und molekulare Grundlagen.

The multifunctional cytokine transforming growth factor ß (TGFß) plays a dual role in prostate cancer (PCa), cell growth and tumorigenesis, reflected by its opposing properties of anti-oncogenic (e.g. growth inhibition and apoptosis) and pro-oncogenic effects (e.g. proliferation, cell motility and remodelling of the microenvironment). In the later stages of PCa, TGFß loses anti-proliferative and thereby tumor-suppressive functions and shifts to a tumorigenic phenotype, mainly initiated by cross-talk between TGFß signalling and other proliferation signal transduction pathways, such as mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signalling. Although TGFß plays an important role in tumor progression little is known about the underlying effects of TGFß in the molecular pathology of PCa.

Smartphone-assisted guide for the placement of ventricular catheters.

OBJECTIVE: Freehand placement of ventricular catheters (VC) is reported to be inaccurate in 10-40 %. Endoscopy, ultrasound, or neuronavigation are used in selected cases with significant technical and time-consuming efforts. We suggest a smartphone-assisted guiding tool for the placement of VC. METHODS: Measurements of relevant parameters in 3D-MRI datasets in a patient cohort with narrow ventricles for a frontal precoronal VC placement were performed. In this context, a guiding tool was developed to apply the respective measures for VC placement. The guiding tool was tested in a phantom followed by CT imaging to quantify placement precision. A smartphone application was designed to assist the relevant measurements. The guide was applied in 35 patients for VC placement. RESULTS: MRI measurements revealed the rectangular approach in the sagittal plane and the individual angle towards the tangent in the coronal section as relevant parameter for a frontal approach. The latter angle ranged from medial (91.96° ± 2.75°) to lateral margins (99.56° ± 4.14°) of the ventricle, which was similar in laterally shifted (±5 mm) entry points. The subsequently developed guiding tool revealed precision measurements in an agarose model with 1.1° ± 0.7° angle deviation. Using the smartphone-assisted guide in patients with narrow ventricles (frontal occipital horn ratio, 0.38 ± 0.05), a primary puncture of the ventricles was possible in all cases. No VC failure was observed during follow-up (9.1 ± 5.3 months). CONCLUSIONS: VC placement in narrow ventricles requires accurate placement with simple means in an every-case routine. The suggested smartphone-assisted guide meets these criteria. Further data are planned to be collected in a prospective randomized study.