DNA triple-helix formation at pyrimidine-purine inversion sites

A systematic investigation of a series of triplex forming oligonucleotides (TFOs) containing alpha- and beta-thymidine, alpha- and beta-N7-hypoxanthine, and alpha- and beta- N7 and N9 aminopurine nucleosides, designed to bind to T-A inversion sites in DNA target sequences was performed. Data obtained from gel mobility assays indicate that t-A recognition in the antiparallel triple-helical binding motif is possible if the nucleoside alpha N9-aminopurine is used opposite to the inversion site in the TFO.

Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09

Treatment allocation by epidermal growth factor receptor mutation status is a new standard in patients with metastatic nonesmall-cell lung cancer. Yet, relatively few modern chemotherapy trials were conducted in patients characterized by epidermal growth factor receptor wild type. We describe the results of a multicenter phase II trial, testing in parallel 2 novel combination therapies, predefined molecular markers, and tumor rebiopsy at progression. Objective: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced nonesmall-cell lung cancer are promising for further investigation. Methods: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. Results: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16.

Reconciling Precipitation with Runoff: Observed Hydrological Change in the Midlatitudes

Century-long observed gridded land precipitation datasets are a cornerstone of hydrometeorological research. But recent work has suggested that observed Northern Hemisphere midlatitude (NHML) land mean precipitation does not show evidence of an expected negative response to mid-twentieth-century aerosol forcing. Utilizing observed river discharges, the observed runoff is calculated and compared with observed land precipitation. The results show a near-zero twentieth-century trendinobserved NHML landmean runoff,in contrast to the significant positive trend in observed NHML land mean precipitation. However, precipitation and runoff share common interannual and decadal variability. An obvious split, or breakpoint, is found in the NHML land mean runoff–precipitation relationship in the 1930s. Using runoff simulated by six land surface models (LSMs), which are driven by the observed precipitation dataset, such breakpoints are absent. These findings support previous hypotheses that inhomogeneities exist in the early-twentieth-century NHML land mean precipitation record. Adjusting the observed precipitation record according to the observed runoff record largely accounts for the departure of the observed precipitation response from that predicted given the real-world aerosol forcing estimate, more than halving the discrepancy from about 6 to around 2 W m 22. Consideration of complementary observed runoff adds support to the suggestion that NHML-wide early-twentieth-century precipitation observations are unsuitable for climate change studies. The agreement between precipitation and runoff over Europe, however, is excellent, supporting the use of whole-twentieth-century observed precipitation datasets here.

Polar Nature of Biomimetic Fluorapatite/Gelatin Composites: A Comparison of Bipolar Objects and the Polar State of Natural Tissue

The correspondence of the state of alignment of macromolecules in biomimetic materials and natural tissues is demonstrated by investigating a mechanism of electrical polarity formation: An in vitro grown biomimetic FAp/gelatin composite is investigated for its polar properties by second harmonic (SHGM) and scanning pyroelectric microscopy (SPEM). Hexagonal prismatic seed crystals formed in gelatin gels represent a monodomain polar state, due to aligned mineralized gelatin molecules. Later growth stages, showing dumbbell morphologies, develop into a bipolar state because of surface recognition by gelatin functionality: A reversal of the polar alignment of macromolecules, thus, takes place close to that basal plane of the seed. In natural hard tissues (teeth and bone investigated by SPEM) and the biomimetic FAp/gelatin composite, we find a surprising analogy in view of growth-induced states of polarity: The development of polarity in vivo and in vitro can be explained by a Markov-type mechanism of molecular recognition during the attachment of macromolecules.

Development of an Interleukin-1β Vaccine in Patients with Type 2 Diabetes

Interleukin-1β (IL-1β) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1β activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1β. The vaccine hIL1bQb consisting of full-length, recombinant IL-1β coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1β-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1β-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1β and represents a new treatment option for IL-1β-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).Molecular Therapy (2016); doi:10.1038/mt.2015.227.

Surgery for Stage IIIA Non-Small-cell Lung Cancer: Lack of Predictive and Prognostic Factors Identifying Any Subgroup of Patients Benefiting From It.

Although a trimodality regimen for patients with stage IIIA/pN2 non-small-cell lung cancer (NSCLC) has been variably used owing to limited evidence for its benefits, it remains unknown whether any patient subgroup actually receives benefit from such an approach. To explore this question, the published data were reviewed from 1990 to 2015 to identify the possible predictors and prognosticators in this setting. Overall survival was the endpoint of our study. Of 27 identified studies, none had studied the predictors of improved outcomes with trimodality treatment. Of the potential patient- and tumor-related prognosticators, age, gender, and histologic type were the most frequently formally explored. However, none of the 3 was found to influence overall survival. The most prominent finding of the present review was the substantial lack of data supporting a trimodality treatment approach in any patient subgroup. As demonstrated in completed prospective randomized studies, the use of surgery for stage IIIA NSCLC should be limited to well-defined clinical trials.

Collecting the Painted Netherlands: The Art Collection of Ernest of Austria in Brussels

The (art) collection of Archduke Ernest of Austria (1553-1595) is widely unknown when it comes to early-modern Habsburg collections. Ernest, younger brother of Emperor Rudolf II (b. 1552) and educated at the Madrid court, was appointed Governor-General of the Netherlands by King Philip II of Spain, his uncle, in summer 1593. Ernest relocated his court from Vienna to Brussels in early 1594 and was welcomed there with lavish festivities: the traditional Blijde Inkomst, Joyous Entry, of the new sovereign. Unfortunately, the archduke died in February 1595 after residing in Brussels for a mere thirteen months. This investigation aims to shed new light on the archduke and his short-lived collecting ambitions in the Low Countries, taking into account that he had the mercantile and artistic metropolis Antwerp in his immediate reach. I argue, that his collecting ambitions can be traced back to one specific occasion: Ernest’s Joyous Entry into Antwerp in June 1594. There the archduke received a series of six paintings of Pieter Bruegel the Elder (1525/30-1569) known as The Months (painted in 1565), hanging today in separate locations in Vienna, New York and Prague. These works of art triggered Ernest’s collecting ambitions and prompted him to focus mainly on works of art and artefacts manufactured at or traded within the Netherlands during the last eight months of his lifetime. Additionally, it will be shown that the archduke was inspired by the paintings’ motifs and therefore concentrated on acquiring works of art depicting nature and landscape scenes from the 1560s and 1590s. On the basis of the archduke’s recently published account book (Kassabuch) and of the partially published inventory of his belongings, it becomes clear that Ernest of Austria must be seen in line with the better-known Habsburg collectors and that his specific collection of “the painted Netherlands” can be linked directly to his self-fashioning as a rightful sovereign of the Low Countries.

Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.Leukemia advance online publication, 26 February 2016; doi:10.1038/leu.2016.20.

Grundt und ursach aus der heiligen schrifft, wie und warumb die Eerwirdigen herren/ beyder Pfarkirchen S. Sebalt/ und sant Laurentzen Probst zu Nürmberg/ die mißpreuch bey der heyligen Mess/ Jartag/ geweycht Saltz/ und Wasser/ sampt etlichen andern Ceremonien abgestelt undterlassen und geendert haben

Andreas Osiander [erm. Verf.]

Ms. Praed. 172 - Lateinisch-deutsches Gebetbuch

Vorbesitzer: Philippus Wischius; Dominikanerkloster Frankfurt am Main

Ausst. 209 - UNderweysung der messung mit dem zirckel vn[d] richtscheyt in Linien ebnen vnnd gantzen corporen

Vorbesitzer: Heinrich Anton Cornill-d'Orville (Exlibris auf fol. Iv)

Burden of diabetes in cancer inpatients

Inpatient hyperglycemia has been shown to be associated with higher morbidity and mortality. Treatment of inpatient hyperglycemia reduces morbidity and mortality at least in the intensive care unit. Burden and severity of hyperglycemia in an inpatient population of a cancer center is not known. The study is a secondary analysis of the primary study 'Prevalence of Diabetes in cancer inpatient'. Finger-stick glucose concentration and pharmacy data were collected prospectively for all hospitalizations to a large cancer center. Demographic, clinical and laboratory data were collected in a retrospective fashion. Between May 1 and July 31, 2006; 3,940 patients were admitted 5,489 times. Prior to their first admissions, 920(23.4%) of the 3940 patients had unrecognized or recognized hyperglycemia. Glucose was never tested during 1714 (31.8%) hospitalizations, including 170 (12%) of the 1414 admissions of the 920 patients with previous hyperglycemia, and, 109 (58%) of 188 patients who were not tested for glucose prior to their index admissions. Overall, sustained significant hyperglycemia (>= 200 mg/dL on two separate days) was present in 765 (13.9%). Antidiabetic treatment was dispensed in 1168 (21.3%), though 627 (53.7%) of these received only short/rapid acting insulin, and, 951 (17.3%)diabetes code before and in another 80 (1.5%) during stay in hospital, out of total 5489 admissions. Therefore diabetes mellitus or hyperglycemia affected 1525 (27.8%) out of all admissions and coding alone as a criterion for diagnosis of hyperglycemia would have underreported it by 32%. Hyperglycemia occurred more commonly during hospitalization of patients with older age, males, ethnic minorities, advanced malignancies, and those receiving glucocorticoids, parenteral nutrition, and those who had a past history of coding for diabetes or past hyperglycemia, but not in those with the cancers reported to be associated with diabetes mellitus. Of the recognized diabetics half had sustained significant hyperglycemia and 10% had three quarters glucoses tested above 180 mg/dL. To conclude, diabetes affects at least 27.8% of inpatients at our cancer center. Coding for diabetes significantly underreports the burden of the disease. Significant sustained hyperglycemia of >=200 mg/dL among inpatients at a cancer center is common, under-recognized, and either untreated or inadequately treated with suboptimal glycemic control. The implications of hyperglycemia in cancer inpatient populations need further investigations. Fasting serum or plasma glucose should be checked routinely for every patient admitted to a cancer hospital, to recognize and treat hyperglycemia as clinically appropriate.^

Mean dynamic topography and oceanographic parameters estimated from an inverse model and satellite geodesy, with link to model result in one single NetCDF file (392 MB), including the inverse data error covariance

Geostrophic surface velocities can be derived from the gradients of the mean dynamic topography-the difference between the mean sea surface and the geoid. Therefore, independently observed mean dynamic topography data are valuable input parameters and constraints for ocean circulation models. For a successful fit to observational dynamic topography data, not only the mean dynamic topography on the particular ocean model grid is required, but also information about its inverse covariance matrix. The calculation of the mean dynamic topography from satellite-based gravity field models and altimetric sea surface height measurements, however, is not straightforward. For this purpose, we previously developed an integrated approach to combining these two different observation groups in a consistent way without using the common filter approaches (Becker et al. in J Geodyn 59(60):99-110, 2012, doi:10.1016/j.jog.2011.07.0069; Becker in Konsistente Kombination von Schwerefeld, Altimetrie und hydrographischen Daten zur Modellierung der dynamischen Ozeantopographie, 2012, http://nbn-resolving.de/nbn:de:hbz:5n-29199). Within this combination method, the full spectral range of the observations is considered. Further, it allows the direct determination of the normal equations (i.e., the inverse of the error covariance matrix) of the mean dynamic topography on arbitrary grids, which is one of the requirements for ocean data assimilation. In this paper, we report progress through selection and improved processing of altimetric data sets. We focus on the preprocessing steps of along-track altimetry data from Jason-1 and Envisat to obtain a mean sea surface profile. During this procedure, a rigorous variance propagation is accomplished, so that, for the first time, the full covariance matrix of the mean sea surface is available. The combination of the mean profile and a combined GRACE/GOCE gravity field model yields a mean dynamic topography model for the North Atlantic Ocean that is characterized by a defined set of assumptions. We show that including the geodetically derived mean dynamic topography with the full error structure in a 3D stationary inverse ocean model improves modeled oceanographic features over previous estimates.

Petrography, microprobe analyses and isotope composition of ultramafic rock from the northern Haskard Highlands, Shackleton Range, East Antarctica

In the Shackleton Range of East Antarctica, garnet-bearing ultramafic rocks occur as lenses in supracrustal high-grade gneisses. In the presence of olivine, garnet is an unmistakable indicator of eclogite facies metamorphic conditions. The eclogite facies assemblages are only present in ultramafic rocks, particularly in pyroxenites, whereas other lithologies - including metabasites - lack such assemblages. We conclude that under high-temperature conditions, pyroxenites preserve high-pressure assemblages better than isofacial metabasites, provided the pressure is high enough to stabilize garnet-olivine assemblages (i.e. >=18-20 kbar). The Shackleton Range ultramafic rocks experienced a clockwise P-T path and peak conditions of 800-850 °C and 23-25 kbar. These conditions correspond to ~70 km depth of burial and a metamorphic gradient of 11-12 °C/km that is typical of a convergent plate-margin setting. The age of metamorphism is defined by two garnet-whole-rock Sm-Nd isochrons that give ages of 525 ± 5 and 520 ± 14 Ma corresponding to the time of the Pan-African orogeny. These results are evidence of a Pan-African suture zone within the northern Shackleton Range. This suture marks the site of a palaeo-subduction zone that likely continues to the Herbert Mountains, where ophiolitic rocks of Neoproterozoic age testify to an ocean basin that was closed during Pan-African collision. The garnet-bearing ultramafic rocks in the Shackleton Range are the first known example of eclogite facies metamorphism in Antarctica that is related to the collision of East and West Gondwana and the first example of Pan-African eclogite facies ultramafic rocks worldwide. Eclogites in the Lanterman Range of the Transantarctic Mountains formed during subduction of the palaeo-Pacific beneath the East Antarctic craton.