CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing

BACKGROUND: Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects. METHODS: CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3+) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs. RESULTS: All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing. CONCLUSION: Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing

Experimental validation of image contrast correlation between ultra-small-angle X-ray scattering and grating-based dark-field imaging using a laser-driven compact X-ray source: Experimentelle Verifizierung des Zusammenhangs zwischen Röntgen-Kleinwinkelstreuung und gitter-basierter Röntgen-Dunkelfeldbildgebung unter Verwendung eines laser-getriebenen Kompaktsynchrotrons

X-ray phase and dark-field contrast have recently been the source of much attention in the field of X-ray imaging, as they both contribute new imaging signals based on physical principles that differ from conventional X-ray imaging. With a so-called Talbot grating interferometer, both phase-contrast and dark-field images are obtained simultaneously with the conventional attenuation-based X-ray image, providing three complementary image modalities that are intrinsically registered. Whereas the physical contrast mechanisms behind attenuation and phase contrast are well understood, a formalism to describe the dark-field signal is still in progress. In this article, we report on correlative experimental results obtained with a grating interferometer and with small-angle X-ray scattering. Furthermore, we use a proposed model to quantitatively describe the results, which could be of great importance for future clinical and biomedical applications of grating-based X-ray imagin

THETA-rhythm makes the world go round:dissociative effects of TMS theta versus alpha entrainment of right pTPJ on embodied perspective transformations

Being able to imagine another person's experience and perspective of the world is a crucial human ability and recent reports suggest that humans "embody" another's viewpoint by mentally rotating their own body representation into the other's orientation. Our recent Magnetoencephalography (MEG) data further confirmed this notion of embodied perspective transformations and pinpointed the right posterior temporo-parietal junction (pTPJ) as the crucial hub in a distributed network oscillating at theta frequency (3-7 Hz). In a subsequent transcranial magnetic stimulation (TMS) experiment we interfered with right pTPJ processing and observed a modulation of the embodied aspects of perspective transformations. While these results corroborated the role of right pTPJ, the notion of theta oscillations being the crucial neural code remained a correlational observation based on our MEG data. In the current study we therefore set out to confirm the importance of theta oscillations directly by means of TMS entrainment. We compared entrainment of right pTPJ at 6 Hz vs. 10 Hz and confirmed that only 6 Hz entrainment facilitated embodied perspective transformations (at 160° angular disparity) while 10 Hz slowed it down. The reverse was true at low angular disparity (60° between egocentric and target perspective) where a perspective transformation was not strictly necessary. Our results further corroborate right pTPJ involvement in embodied perspective transformations and highlight theta oscillations as a crucial neural code

Isometric muscle training of the spine musculature in patients with spinal bony metastases under radiation therapy

<p/> <p>Background</p> <p>Osseous metastatic involvement of the spinal column affects many patients with a primary tumour disease of all entities. The consequences are pain both at rest and under exertion, impairments in going about day-to-day activities, diminished performance, the risk of pathological fractures, and neurological deficits. Palliative percutaneous radiotherapy is one of the therapeutical options available in this connection. The aim of this explorative study is to investigate the feasibility of muscle-training exercises and to evaluate the progression- and fracture-free survival time and the improvement of bone density, as well as to assess other clinical parameters such as pain, quality of life, and fatigue as secondary endpoints.</p> <p>Methods/Design</p> <p>This study is a prospective, randomized, monocentre, controlled explorative intervention study in the parallel-group design to determine the multidimensional effects of a course of exercises at first under physiotherapeutic instruction and subsequently performed by the patients independently for strengthening the paravertebral muscles of patients with metastases of the vertebral column parallel to their percutaneous radiotherapy. On the days of radiation treatment the patients in the control group shall be given physical treatment in the form of respiratory therapy and the so-called "hot roll". The patients will be randomized into one of the two groups: differentiated muscle training or physiotherapy with thirty patients in each group.</p> <p>Discussion</p> <p>The aim of the study is to evaluate the feasibility of the training programme described here. Progression-free and fracture-free survival, improved response to radiotherapy by means of bone density, and clinical parameters such as pain, quality of life, and fatigue constitute secondary study objectives.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01409720">NCT01409720</a></p

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM

Effective suckling in relation to naked maternal-infant body contact in the first hour of life: an observation study

Background Best practice guidelines to promote breastfeeding suggest that (i) mothers hold their babies in naked body contact immediately after birth, (ii) babies remain undisturbed for at least one hour and (iii) breastfeeding assistance be offered during this period. Few studies have closely observed the implementation of these guidelines in practice. We sought to evaluate these practices on suckling achievement within the first hour after birth. Methods Observations of seventy-eight mother-baby dyads recorded newborn feeding behaviours, the help received by mothers and birthing room practices each minute, for sixty minutes. Results Duration of naked body contact between mothers and their newborn babies varied widely from 1 to 60 minutes, as did commencement of suckling (range = 10 to 60 minutes). Naked maternal-infant body contact immediately after birth, uninterrupted for at least thirty minutes did not predict effective suckling within the first hour of birth. Newborns were four times more likely to sustain deep rhythmical suckling when their chin made contact with their mother’s breast as they approached the nipple (OR 3.8; CI 1.03 - 14) and if their mothers had given birth previously (OR 6.7; CI 1.35 - 33). Infants who had any naso-oropharyngeal suctioning administered at birth were six times less likely to suckle effectively (OR .176; CI .04 - .9). Conclusion Effective suckling within the first hour of life was associated with a collection of practices including infants positioned so their chin can instinctively nudge the underside of their mother’s breast as they approach to grasp the nipple and attach to suckle. The best type of assistance provided in the birthing room that enables newborns to sustain an effective latch was paying attention to newborn feeding behaviours and not administering naso-oropharyngeal suction routinely

1993 Progress Reports

The 1993 Progress Reports which contain Blueberry Tax Supported Weed Management and Pruning Project Reports, and CSRS Supported Weed Management and Pruning Project Reports, pertain to and report on research conducted in 1992. They were prepared for the Maine Wild Blueberry Commission and the University of Maine Wild Blueberry Advisory Committee by researchers at the University of Maine, Orono. Projects in this report include: Progress Reports 1. Effects of Irrigation on Low bush Blueberry Yield and Quality 2. Economics of Investing in Irrigation for Lowbush Blueberries 3. Diammonium Phosphate Study 4. Phosphorus Dose/Response Curve 5. Winter Injury Protection by Potassium 6. Multiple Cropping of Wild Stands 7. Effect of Boron on Lowbush Blueberry Fruit Set and Yield 8.Determination of Pesticide Residue Levels in Freshly Harvested and Processed Lowbush Blueberries 9. Effects of Calcium Salts and Citric Acids on the Quality of Canned Lowbush Blueberries- missing 10. Investigation of PreProcess Changes- missing 11. The Effect of Fertilization and Irrigation on Blueberry Fruit Control - missing 12. Pollination Ecology of Lowbush Blueberry in Maine 13. Control of Secondary Blueberry Pests 14. Control of Blueberry Maggot 15. Biology and Action Thresholds of Secondary Blueberry Pests 16. Cold-Hardiness of Native Lowbush Blueberries 17. Design, Fabrication, and Testing of an Experimental Sterilizer for Blueberry Fields 18. Canned Product Quality - Heat Resistant Molds 19. Sanitation for Disease Control Blueberry Tax Supported Weed Management and Pruning Project Reports 20. Evaluation of Postemergence Applications of Tribenuron Methyl for Bunchberry Control 21. Comparison of Poast and Select for Suppression of Bunchgrass 22. Effect of Time of Fall Pruning on Growth and Productivity of Blueberries. and Evaluation of Infrared Burner to Prune Blueberries 23. Evaluation of Velpar impregnated DAP for weed control 24. Thresholds of Dogbane and Bracken Fern for Mechanical and Chemical Control in Lowbush Blueberry Fields 25. Effect of Time and Rate of Application of Clopyralid for Control of Vetch in Lowbush Blueberries 26. Hexazinone Ground Water Survey 27. Composting Blueberry Processing Waste 28. Hexazinone Movement in a Blueberry Soil in Maine CSRS Supported Weed Management and Pruning Project Reports 29. Evaluation of the Suitability of Remote Sensing to Evaluate Plant Cover in Lowbush Blueberry Fields 30. Obstruction Removal in Lowbush Blueberry Fields 31. Evaluation of Pressurized Rope Wick Wick Master Wiper for Treating Weeds Growing Above Lowbush Blueberries 32. Evaluation of Infrared Burner for Weed Control 33. Blueberry Extension Education Program Base Miscellaneous 34. Comparison of N, NP, and NPK Fertilizers to Correct Nitrogen and Phosphorus Deficienc