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Fitting cochlear implant (CI) users can be challenging. Anatomy-based fitting (ABF) maps may have the potential to lead to better objective and subjective outcomes than conventional clinically based fitting (CBF) methods. ABF maps were created via information derived from exact electrode contact positions, which were determined via post-operative high-resolution flat panel volume computer tomography and clinical fitting software. The outcome measures were speech understanding in quiet and noise and self-perceived sound quality with the CBF map and with the ABF map. Participants were 10 experienced bilateral CI users. The ABF map provided better speech understanding in quiet and noisy environments compared to the CBF map. Additionally, two approaches of reducing the frequency-to-place mismatch revealed that participants are more likely to accept the ABF map if their electrode array is inserted deep enough to stimulate the apical region of their cochlea. This suggests an Angular Insertion Depth of the most apical contact of around 720°–620°. Participants had better speech understanding in quiet and noise with the ABF map. The maps’ self-perceived sound quality was similar. ABF mapping may be an effective tool for compensating the frequency-to-place mismatch in experienced bilateral CI users.

The dense desmoplastic and fibrotic stroma is a characteristic feature of pancreatic ductal adenocarcinoma (PDAC), regulating disease progression, metastasis and response to treatment. Reciprocal interactions between the tumour and stroma are mediated by bidirectional integrin-mediated signalling, in particular by Focal Adhesion Kinase (FAK). FAK is often hyperactivated and overexpressed in aggressive cancers, promoting stromal remodelling and inducing tissue stiffness which can accelerate cancer cell proliferation, survival and chemoresistance. Therapeutic targeting of the PDAC stroma is an evolving area of interest for pre-clinical and clinical research, where a subtle reshaping of the stromal architecture prior to chemotherapy may prove promising in the clinical management of disease and overall patient survival. Here, we describe how transient stromal manipulation (or ‘priming’) via short-term FAK inhibition, rather than chronic treatment, can render PDAC cells exquisitely vulnerable to subsequent standard-of-care chemotherapy. We assess how our priming publication fits with the recent literature and describe in this perspective how this could impact future cancer treatment. This highlights the significance of treatment timing and warrants further consideration of anti-fibrotic therapies in the clinical management of PDAC and other fibrotic diseases.

Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in diverse tissues, including in individual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications. ispartof: SCIENCE ADVANCES vol:9 issue:17 ispartof: location:United States status: published

Metallization induced recombination losses are one dominant loss mechanism for current industrial solar cells. A precise determination of these losses is important for contacting technology optimization, as well as precise solar cell modeling. Usually, for state-of-the-art approaches to determine j 0,met, it is assumed that the samples itself exhibit spatially uniform properties (e.g., carrier lifetime or sheet resistance) or that the used reference samples are identical to the metallized samples. Finally, in most cases, only one global j 0,met-value for the entire sample is given, neglecting possible spatial inhomogeneities. In this article, we mostly eliminate the necessity for the assumptions of perfect sample homogeneity by means of an interpolation scheme of the photoluminescence (PL) signal. Thereby, we can predict the PL signal of a virtually nonmetallized test field with a relative standard deviation of about σ a 0.7%. Additionally, we determine j 0,met for specific test fields at different positions on the sample and correlate the results to the local emitter sheet resistance R sh, the local peak firing temperature of the sample during the fast firing process T peak, and the test field finger spacing d . For our samples, a reduction of d from d = 1000 μm to d = 200 μm leads to a reduction of j 0,met by up to 18%. This strong effect is physically unexpected and so far not considered by the state-of-the-art approach, frequently performed in the photovoltaic community. Further, we perform a sensitivity and error analysis which reveals that we are able to determine j 0,met within an estimated accuracy between 15% and 18%.

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Purpose: This proof of concept describes the use of evoked electromyographic (EMG) activation of the facial nerve for intraoperative monitoring of the electrode insertion during cochlear implantation (CI).Methods: Intraoperative EMG measurements from the facial nerve were conducted in nine patients undergoing CI implantation. Electric pulses were emitted from contacts on the CI array during and immediately after electrode insertion. For control, the results of EMG measurements were compared to postoperative flat panel volume computed tomography scans with secondary reconstruction (fpVCTSECO).Results: During insertion, the EMG response evoked by the electrical stimulation from the CI was growing with the stimulating contact approaching the facial nerve and declined with increasing distance. After full insertion, contacts on the apical half of the CI array stimulated higher EMG responses compared with those on the basal half. Comparison with postoperative imaging demonstrated that electrode contacts stimulating high EMG responses had the shortest distances to the facial nerve. Conclusion: It could be demonstrated that electrically evoked EMG activation of the facial nerve can be used to monitor the progress during CI electrode insertion and to control the intracochlear electrode position after full insertion.

Background The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC. Methods Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated. Results High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort. Conclusion ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq.

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, with a five-year survival rate of only ~10%. Pancreatic tissue becomes increasingly fibrotic (known as desmoplasia) during cancer development and progression. This extensive, heterogeneous reaction is largely mediated through the actions of stromal cells such as cancer-associated fibroblasts (CAFs). In this review, we will discuss how heterotypical reciprocal tumor-stromal and tumor-immune cell interactions in the pancreatic tumor microenvironment (TME) can both promote and restrain PDAC development and progression, with particular focus on the role of extracellular matrix (ECM) in potentiating tumor cell proliferation, survival, metastasis, and treatment resistance. We also give a snapshot of the current and emerging stromal co-therapies used in combination with chemotherapy or immunotherapy to treat this highly deadly disease. Abstract Many cancer studies now recognize that disease initiation, progression, and response to treatment are strongly influenced by the microenvironmental niche. Widespread desmoplasia, or fibrosis, is fundamental to pancreatic cancer development, growth, metastasis, and treatment resistance. This fibrotic landscape is largely regulated by cancer-associated fibroblasts (CAFs), which deposit and remodel extracellular matrix (ECM) in the tumor microenvironment (TME). This review will explore the prognostic and functional value of the stromal compartment in predicting outcomes and clinical prognosis in pancreatic ductal adenocarcinoma (PDAC). We will also discuss the major dynamic stromal alterations that occur in the pancreatic TME during tumor development and progression, and how the stromal ECM can influence cancer cell phenotype, metabolism, and immune response from a biochemical and biomechanical viewpoint. Lastly, we will provide an outlook on the latest clinical advances in the field of anti-fibrotic co-targeting in combination with chemotherapy or immunotherapy in PDAC, providing insight into the current challenges in treating this highly aggressive, fibrotic malignancy.

One major loss mechanism for currently relevant solar cells [e.g., passivated emitter and rear cells (PERC)] is locally enhanced recombination at the interface between semiconductor and metalization. For investigating these losses in detail, a reliable detection technique is crucial. The photovoltaics community frequently applies an area-weighted model to extract the local dark saturation current density in the metalized area of the emitter j 0,met—e.g., from photoluminescence imaging (PLI) data. However, this model does not account for the nonuniformity of the excess carrier density Δ n within the sample during the measurement. Therefore, we compare numerical PLI simulations using Quokka3 to PLI measurements, to quantitatively reveal the impact of the nonuniformity of Δ n . Test structures with locally laser-ablated passivation on one side—serving as ideal test structures—are used for the experimental verification. Additionally, we show results on metalized samples. We find that the results ( j 0,met*) using the simulative approach for the laser-ablated samples exceed the results using the conventional area-weighted approach by more than 20%. For the metalized samples, we see a similar trend where the area-weighted approach again underestimates the results ( j 0,met), in this case by up to 20%. Based on our investigations, we show that the deviation between the results arises due to the assumption of uniform Δ n applied by the area-weighted approach.

The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published

Intravital imaging is a powerful technology used to quantify and track dynamic changes in live cells and tissues within an intact environment. The ability to watch cell biology in real-time 'as it happens' has provided novel insight into tissue homeostasis, as well as disease initiation, progression and response to treatment. In this minireview, we highlight recent advances in the field of intravital microscopy, touching upon advances in awake versus anaesthesia-based approaches, as well as the integration of biosensors into intravital imaging. We also discuss current challenges that, in our opinion, need to be overcome to further advance the field of intravital imaging at the single-cell, subcellular and molecular resolution to reveal nuances of cell behaviour that can be targeted in complex disease settings.

Assessing drug response within live native tissue provides increased fidelity with regards to optimizing efficacy while minimizing off-target effects. Here, using longitudinal intravital imaging of a Rac1-Forster resonance energy transfer (FRET) biosensor mouse coupled with in vivo photoswitching to track intratumoral movement, we help guide treatment scheduling in a live breast cancer setting to impair metastatic progression. We uncover altered Rac1 activity at the center versus invasive border of tumors and demonstrate enhanced Rac1 activity of cells in close proximity to live tumor vasculature using optical window imaging. We further reveal that Rac1 inhibition can enhance tumor cell vulnerability to fluid-flow-induced shear stress and therefore improves overall anti-metastatic response to therapy during transit to secondary sites such as the lung. Collectively, this study demonstrates the utility of single-cell intravital imaging in vivo to demonstrate that Rac1 inhibition can reduce tumor progression and metastases in an autochthonous setting to improve overall survival.

We investigate the effective surface recombination velocity Seff of alkaline textured, Phosphorus-diffused and thermal SiO2/SiNx passivated surfaces with an emphasis on the impact of the thermal oxidation temperature. The application of a recent calibration procedure for the carrier lifetime measurements enables a precise determination of the dark saturation current density. The experimental results include 25 diffusion/oxidation process combinations that cover a wide range of final surface concentration levels Ns between 3⋅1020 cm−3 and 1⋅1019 cm−3, using oxidation temperatures Tox from 650 °C to 900 °C. This yields a data set that enables a revision of the commonly applied parameterization of the effective surface recombination velocity of this passivation scheme using numerical simulation. In addition, the impact of fixed surface charges is modeled for separating field effect and chemical passivation properties. Also, the role of the oxidation temperature on the passivation quality is investigated.

The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. Here, we isolate EVs from both raw and commercial bovine milk and characterize them by electron microscopy, nanoparticle tracking analysis, western blotting, quantitative proteomics and small RNA sequencing analysis. Orally administered bovine milk-derived EVs survive the harsh degrading conditions of the gut, in mice, and is subsequently detected in multiple organs. Milk-derived EVs orally administered to mice implanted with colorectal and breast cancer cells reduce the primary tumor burden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVs accelerate metastasis in breast and pancreatic cancer mouse models. Proteomic and biochemical analysis reveal the induction of senescence and epithelial-to-mesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timing of EV administration is critical as oral administration after resection of the primary tumor reverses the pro-metastatic effects of milk-derived EVs in breast cancer models. Taken together, our study provides context-based and opposing roles of milk-derived EVs as metastasis inducers and suppressors., Dietary extracellular vesicles (EVs) could potentially be absorbed by the intestinal tract of the host and exert multiple phenotypic changes. Here, the authors isolate and characterize EVs from raw and commercial bovine milk and show orally administered EVs to have a context specific role in promoting or suppressing primary tumor growth and metastasis in multiple mouse tumor models.

Description, Intravital imaging guides a personalized medicine approach to target mechanoreciprocity in pancreatic cancer., Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy.

Today, there are 310 million surgical procedures performed worldwide every year, and an additional 143 million procedures are required to fill the current need. Complications from surgical procedures and subsequent deaths are highly dependent on the location and experience of the surgeon. Digital surgery aims to bring a new level of scientific rigor and transparency to the field of surgery by providing tools that augment the surgeon and staff with better perception and judgment, so as to improve the efficiency and outcomes for patients. By delivering care more efficiently, digital surgery will make surgical care accessible to a larger number of patients worldwide. By harnessing data, optimizing best practices, and mentoring surgeons on how to deliver quality care consistently, it will reduce the variability of outcomes and identify the key factors to improve them.

The extraction of the implied open-circuit voltage ( iV OC ) and saturation current density under the metal fingers ( j 0met ) using a single photoluminescence (PL) image is demonstrated in this article. The method employed to derive these parameters is based on an analytical modeling of the local p-n-junction voltage between the metallization fingers and on the analysis of the p-n-junction voltage variations obtained using a calibrated PL image. The image is analyzed in the Fourier space; taking advantage of the periodicity of the metal grid, the relevant information is extracted from the first two Fourier peaks. The ( iV OC ) and ( j 0met ) are calculated from the peaks intensities. This method is compared with one that uses two PL images. Both methods agree within their uncertainty ( ± 200 fA/cm² for j 0met ). The main advantage of the method developed in this article is that only one image is required.

Most facial bones, including frontal bones, are derived from neural crest cells through intramembranous ossification. Fibroblast growth factor receptor 1 (Fgfr1) plays a pivotal role in craniofacial bone development, and loss of Fgfr1 leads to cleft palate and facial cleft defects in newborn mice. However, the potential role of the Fgfr1 gene in neural crest cell-mediated craniofacial development remains unclear. To investigate the role of Fgfr1 in neural crest cells, we analyzed Wnt1-Cre;Fgfr1flox/flox mice. Our results show that specific knockout of Fgfr1 in neural crest cells induced heterotopic chondrogenesis and osteogenesis at the interface of the anterior portions of frontal bones. We observed that heterotopic bone formation continued through postnatal day 28, whereas heterotopic chondrogenesis lasted only through the embryonic period. In summary, our results indicate that loss of Fgfr1 in neural crest cells leads to heterotopic chondrogenesis and osteogenesis.

Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1Cre;Robo2F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2low;ROBO1high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents., SLIT-ROBO alterations arise in pancreatic ductal adenocarcinoma (PDAC), but their role in the pancreas is unclear. Here, the authors use mouse models to show that loss of epithelial Robo2 activates the neighbouring stroma via TGF-β signalling; findings are relevant to PDAC patients, where ROBO expression correlates with survival outcomes.