An artificial anion receptor is presented, in which two cyclohexapeptide subunits containing l-proline and 6-aminopicolinic acid subunits in an alternating sequence are connected via an adipinic acid ...spacer. This compound was devised to stabilize the 2:1 sandwich-type anion complexes that are observed when the two cyclopeptide moieties are not covalently connected and to obtain a 1:1 stoichiometry for these aggregates. Electrospray ionization mass spectrometry and NMR spectroscopic investigations showed that the bridged bis(cyclopeptide) does indeed form defined 1:1 complexes with halides, sulfate, and nitrate. ROESY NMR spectroscopy and molecular modeling allowed a structural assignment of the sulfate complex in solution. The stabilities of various anion complexes were determined by means of NMR titrations and isothermal titration microcalorimetry in 50% water/methanol. Both methods gave essentially the same quantitative results, namely stability constants that varied in the range 105−102 M-1 and decreased in the order SO4 2- > I- > Br- > Cl- > NO3 -. This order was rationalized in terms of the size of the anions with the larger anions forming the more stable complexes because they better fit into the cavity of the host. The ability of sulfate to form stronger hydrogen bonds to the NH groups of the receptor, in addition to its slightly larger ionic radius with respect to iodide, causes the higher stability of the sulfate complex. No significant effect of the countercation on complex stability was observed. Furthermore, complex stability is enthalpically as well as entropically favored. A comparison of the iodide and sulfate complex stabilities of the ditopic receptor with those of a cyclopeptide that forms 1:1 anion complexes in solution showed that the presence of a second binding site increases complex stability by a factor of 100−350.
Follow-up care after kidney transplantation is performed in transplant centers as well as in local nephrologist's practices in Germany. However, organized integrated care of these different sectors ...of the German health care system is missing. This organizational deficit as well as non-adherence of kidney recipients and longterm cardiovascular complications are major reasons for an impaired patient and graft survival.
The KTx360° study is supported by a grant from the Federal Joint Committee of the Federal Republic of Germany. The study will include 448 (39 children) incident patients of all ages with KTx after study start in May 2017 and 963 (83 children) prevalent patients with KTx between 2010 and 2016. The collaboration between transplant centers and nephrologists in private local practices will be supported by internet-based case-files and scheduled virtual visits (patient consultation via video conferencing). At specified points of the care process patients will receive cardiovascular and adherence assessments and respective interventions. Care will be coordinated by an additional case management. The goals of the study will be evaluated by an independent institute using claims data from the statutory health insurances and data collected from patients and their caregivers during study participation. To model longitudinal changes after transplantation and differences in changes and levels of immunosuppresive therapy after transplantation between study participants and historical data as well as data from control patients who do not participate in KTx360°, adjusted regression analyses, such as mixed models with repeated measures, will be used. Relevant confounders will be controlled in all analyses.
The study aims to prolong patient and graft survival, to reduce avoidable hospitalizations, co-morbidities and health care costs, and to enhance quality of life of patients after kidney transplantation.
ISRCTN29416382 (retrospectively registered on 05.05.2017).
To evaluate noninvasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and ...molecular imaging of apoptosis, glucose metabolism, and cellular proliferation was evaluated longitudinally in responding and nonresponding tumor-bearing cohorts.
Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic female mice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin V accumulation), glucose metabolism 2-deoxy-2-18Ffluoro-d-glucose positron emission tomography (18FFDG-PET), and proliferation 3'-18Ffluoro-3'-deoxythymidine-PET (18FFLT-PET) were evaluated throughout a biweekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical analysis of cleaved caspase-3, phosphorylated AKT, and Ki67.
NIR700-Annexin V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed but not in nonresponding or vehicle-treated tumors. Uptake of 18FFDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. 18FFLT-PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of 18FFLT. Close agreement was observed between imaging metrics and immunohistochemical analysis.
Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2+ tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not seem to alter glucose metabolism substantially enough to afford 18FFDG-PET significant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of 18FFLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer.
Azulene has been recognized for its application in medicinal therapy against inflammation. Recently, azulene analogs have been used in optical technology. Nevertheless, synthesis of this family of ...compounds is always associated with multiple challenges. In this protocol, we describe a time-efficient and cost-effective procedure for the preparation of azulene derivatives from 2-hydroxycyclohepta-2,4,6-trienone (tropolone), a readily available starting material. The technique illustrated here involves a cycloaddition reaction of a lactone with the in situ-generated vinyl ether from 2,2-dimethoxypropane during the thermolysis reaction. The three-step synthesis should take <4 d, resulting in an overall yield of 74% with a final step yield of 91%.
On 14 September 2015, a gravitational wave signal from a coalescing black hole binary system was observed by the Advanced LIGO detectors. This paper describes the transient noise backgrounds used to ...determine the significance of the event (designated GW150914) and presents the results of investigations into potential correlated or uncorrelated sources of transient noise in the detectors around the time of the event. The detectors were operating nominally at the time of GW150914. We have ruled out environmental influences and non-Gaussian instrument noise at either LIGO detector as the cause of the observed gravitational wave signal.
The first observing run of Advanced LIGO spanned 4 months, from 12 September 2015 to 19 January 2016, during which gravitational waves were directly detected from two binary black hole systems, ...namely GW150914 and GW151226. Confident detection of gravitational waves requires an understanding of instrumental transients and artifacts that can reduce the sensitivity of a search. Studies of the quality of the detector data yield insights into the cause of instrumental artifacts and data quality vetoes specific to a search are produced to mitigate the effects of problematic data. In this paper, the systematic removal of noisy data from analysis time is shown to improve the sensitivity of searches for compact binary coalescences. The output of the PyCBC pipeline, which is a python-based code package used to search for gravitational wave signals from compact binary coalescences, is used as a metric for improvement. GW150914 was a loud enough signal that removing noisy data did not improve its significance. However, the removal of data with excess noise decreased the false alarm rate of GW151226 by more than two orders of magnitude, from 1 in 770 yr to less than 1 in 186 000 yr.
Structured
Authors – Kjær I, Nolting D
Objectives – The purpose was to examine human osteoblasts immunohistochemically in order to clarify the significance of the innervation for alveolar bone ...growth.
Setting and Sample Population – Unstained sections available from 21 normal human mandibles (foetal gestational ages: 14–22 weeks).
Material and Methods – Before sectioning in 1980–1990, the mandibular tissue had been fixed in 4% neutral‐buffered formaldehyde for 5 days. Tissue blocks were then decalcified in equal parts of 2% citric acid and 20% sodium citrate for 7–15 days, dehydrated, embedded in paraffin, and sagittally cut into 4‐μm‐thick serial sections and mounted on Superfrost® Plus microscope slides. Sections were dried overnight at 40°C. In the present study, paraffin sections were deparaffinized and treated with Tris‐EDTA (Merck, Germany), pH 9.0, and immunohistochemically tested with polyclonal rabbit anti‐PGP 9.5, and the EnVision™+/HRP dual link (K4065; DAKO Denmark A/S, Denmark) method.
Results – A pronounced protein gene product (PGP) 9.5 activity was registered in osteoblasts from alveolar bone in all specimens. In all cases, the activity was intense at the top of and labially to the alveolar bone, while less or no activity was observed on the inner lingual aspects of the alveolar processes. Osteoclasts and osteocytes reacted vaguely or negatively.
Conclusion – As the present study has demonstrated that human osteoblast activity in the alveolar bone seemingly responds to innervation, it is suggested that the peripheral nervous system via the trigeminal ganglion regulates compensatory and dysplastic alveolar bone formation.
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