Notes

End of contract regarding Ca2+ puffs throughout IP3-evoked global Ca2+ signs.
Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.
Single-subject repeated measures study.

Neuromuscular electrical stimulation (NMES) can enhance walking for people with partial paralysis from incomplete spinal cord injury (iSCI). This single-subject study documents an individual's experience who both received an experimental implanted NMES system and underwent clinical bilateral hinged total knee arthroplasty (TKA). She walked in the community with knee pain prior to either intervention. Walking performance improved with an implanted NMES system. Knee pain and instability continued to worsen over time and eventually required TKA. This study evaluates the effects of these interventions.

Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland OH, USA.

The differential and combined effects of NMES and hinged knee replacement were assessed in terms of walking speed, toe clearance, knee angle, and participant perceptions with and without stimulation assistance both before and after TKA.

The combined approach both reduced pain and restored walking ability to levels achieved prior to developing significant knee pain that prevented walking without NMES. There was an interaction effect between NMES and TKA on walking speed. Toe clearance consistently improved with stimulation assistance and TKA prevented significant knee hyperextension. The greatest impact was on endurance. Knee replacement re-enabled long distance walking with the addition of stimulation again more than doubling her maximum walking distance from 214 to 513 m.

These data support further research of combined implantable interventions that may benefit people with iSCI. Furthermore, joint laxity and pain may not necessarily be contraindications to NMES if addressed with conventional clinical treatments.
These data support further research of combined implantable interventions that may benefit people with iSCI. Furthermore, joint laxity and pain may not necessarily be contraindications to NMES if addressed with conventional clinical treatments.Palbociclib, a CDK4/6 inhibitor, has been granted accelerated approval by US FDA for hormone receptor-positive HER2-negative metastatic breast cancer. To determine potential biomarkers of palbociclib sensitivity to assist in patient selection and clinical development, we investigated the effects of palbociclib in a panel of molecularly characterized breast cancer cell lines. We quantified palbociclib sensitivity and c-myc expression in 11 breast cancer cell lines, 124 breast cancer samples, and The Cancer Genome Atlas database. We found non-TNBC subtypes were more sensitive to palbociclib than TNBC. Activation of c-myc led to differential palbociclib sensitivities, and further inhibition of c-myc enhanced palbociclib sensitivity. Moreover, we identified for the first time a c-myc/miR-29b-3p/CDK6 axis in breast cancer that could be responsible for c-myc-induced palbociclib insensitivity, in which c-myc activation resulted in downregulation of miR-29b-3p, further activated CDK6 and inhibited cell-cycle arrest at G1 phase. Moreover, downregulated (inactived) c-myc-induced oncogenic addiction could increase palbociclib efficacy, using both Xenograft model and patient-derived tumor xenograft (PDTX) model. Our finding extends the concept of combined blockade of the CDK4/6 and c-myc signaling pathways to increase palbociclib sensitivity, making c-myc a promising biomarker for palbociclib sensitivity in breast cancer.The knowledge of the spatial and temporal distribution of human population is vital for the study of cities, disaster risk management or planning of infrastructure. However, information on the distribution of population is often based on place-of-residence statistics from official sources, thus ignoring the changing population densities resulting from human mobility. TAK-228 Existing assessments of spatio-temporal population are limited in their detail and geographical coverage, and the promising mobile-phone records are hindered by issues concerning availability and consistency. Here, we present a multi-layered dasymetric approach that combines official statistics with geospatial data from emerging sources to produce and validate a European Union-wide dataset of population grids taking into account intraday and monthly population variations at 1 km2 resolution. The results reproduce and systematically quantify known insights concerning the spatio-temporal population density structure of large European cities, whose daytime population we estimate to be, on average, 1.9 times higher than night time in city centers.Trough mouth fans comprise the largest sediment deposits along glaciated margins, and record Pleistocene climate changes on a multi-decadal time scale. Here we present a model for the formation of the North Sea Fan derived from detailed horizon and attribute interpretations of high-resolution processed 3D seismic reflection data. The interpretation shows that stacked channel-levee systems form up to 400 m thick sedimentary sequences. The channels are elongated and can be traced from the shelf edge towards the deep basin for distances of >150 km, and document long-distance sediment transport in completely disintegrated water-rich turbidite flows. Downslope sediment transport was a continuous process during shelf-edge glaciations, reaching accumulation rates of 100 m/kyr. Our data highlight that exceptionally large volumes of meltwater may discharge to the slopes of trough mouth fans and trigger erosive turbidite flows. We conclude that freshwater supply is likely an underestimated factor for sedimentary processes during glacial cycles.
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