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Purpose The aim of this study was to evaluate a new guided drill system (MIPS) for placement of bone-anchored hearing systems (BAHS) with respect to cutting performance, generation of heat, and distortion of the bone during drilling and compare it with a conventional drill system (Ponto). Further, the role of irrigation and drilling procedure with respect to the degree of heat generation was evaluated. Materials and methods Compact artificial bone was subjected to each drill in the two systems (conventional vs guided) while measuring thrust force, torque, and temperature. The temperature changes, induced during different drilling procedures, were measured by thermocouples positioned 0.5 mm from the periphery of the drill tract. The degree of bone damage was evaluated histologically after drilling in bovine, compact, tibial bone. Results The mean thrust energy was significantly lower for the drills of the guided system compared with the corresponding conventional drills. In contrast, the mean torque energy was higher using the guided system but only for the initial guide drilling step. Whereas twist drills in combination with a guided drilling approach (MIPS) generated relatively more heat, especially during a prolonged drilling sequence, it was more forgiving in the case of impaired irrigation. The histologic evaluation showed relatively more even cut surfaces and fewer microcracks in the osteotomy wall using the guided system compared with the conventional system. Conclusion Provided the clinically recommended drilling procedure was adhered to, the absolute temperatures using either a conventional drill system or a guided drill system were below the threshold for thermally induced tissue damage. This study suggests that the guided MIPS system conveys a promising design for an efficient and still-safe osteotomy site preparation for BAHS placement.

Background The number of potential options for rehabilitation of patients with conductive or mixed hearing loss is continually expanding. To be able to inform patients and other stakeholders, there is a need to identify and develop patient-centred outcomes for treatment of hearing loss. Objective of review To identify outcome measures in the physical core area used when reporting the outcome after treatment of conductive and mixed hearing loss in adult patients. Type of review Systematic review. Search strategy Systematic review of the literature related to reported physical outcome measures after treatment of mixed or conductive hearing loss without restrictions regarding type of intervention, treatment or device. Evaluation method Any measure reporting the physical outcome after treatment or intervention of mixed or conductive hearing loss was sought and categorised. The physical outcome measures that had been extracted were then grouped into domains. Results The literature search resulted in the identification of 1434 studies, of which 153 were selected for inclusion in the review. The majority (57%) of papers reported results from middle ear surgery, with the remainder reporting results from either bone conduction hearing devices or middle ear implants. Outcomes related to complications were categorised into 17 domains, whereas outcomes related to treatment success was categorised into 22 domains. Conclusions The importance of these domains to patients and other stakeholders needs to be further explored in order to establish which of these domains are most relevant to interventions for conductive or mixed hearing loss. This will allow us to then assess which outcome measures are most suitable for inclusion in the core set.

Objective To study the effect of implanting the percutaneous bone‐anchored hearing system (BAHS) itself and inflammation of the peri‐abutment skin warrant clarification. In this study, we aimed to acquire further insight into the immune responses related to BAHS surgery and peri‐implant skin inflammation. Materials and Methods During surgery and 12 weeks post‐implantation, skin biopsies were obtained. If applicable, additional biopsies were taken during cases of inflammation. The mRNA expression of IL‐1β, IL‐6, IL‐8, TNFα, IL‐17, IL‐10, TGF‐ß, MIP‐1α, MMP‐9, TIMP‐1, COL1α1, VEGF‐A, FGF‐2 TLR‐2, and TLR‐4 was quantified using qRT‐PCR. Results Thirty‐five patients agreed to the surgery and 12‐week biopsy. Twenty‐two patients had mRNA of sufficient quality for analysis. Ten were fitted with a BAHS using the minimally invasive Ponto surgery technique. Twelve were fitted with a BAHS using the linear incision technique with soft‐tissue preservation. Five biopsies were obtained during episodes of inflammation. The post‐implantation mRNA expression of IL‐1β (P = .002), IL‐8 (P = .003), MMP9 (P = .005), TIMP‐1 (P = .002), and COL1α1 (P < .001) was significantly up‐regulated. IL‐6 (P = .009) and FGF‐2 (P = .004) mRNA expression was significantly down‐regulated after implantation. Within patients, no difference between post‐implantation mRNA expression (at 12 weeks) and when inflammation was observed. Between patients, the expression of IL‐1β (P = .015) and IL‐17 (P = .02) was higher during cases of inflammation compared with patients who had no inflammation at 12‐week follow‐up. Conclusions As part of a randomized, prospective, clinical trial, the present study reports the molecular profile of selected cytokines in the soft tissue around BAHS. Within the limit of this study, the results showed that 12 weeks after BAHS implantation the gene expression of some inflammatory cytokines (IL‐8 and IL‐1β) is still relatively high compared with the baseline, steady‐state, expression. The up‐regulation of anabolic (COL1α1) and tissue‐remodeling (MMP‐9 and TIMP1) genes indicates an ongoing remodeling process after 12 weeks of implantation. The results suggest that IL‐1β, IL‐17, and TNF‐α may be interesting markers associated with inflammation.

Purpose In this prospective clinical pilot study, abutments with different topologies (machined versus polished) were compared with respect to the clinical outcome and the microbiological profile. Furthermore, three different sampling methods (retrieval of abutment, collection of peri-abutment exudate using paper-points, and a small peri-abutment soft-tissue biopsy) were evaluated for the identification and quantification of colonising bacteria. Methods Twelve patients, seven with machined abutment and five with polished abutment, were included in the analysis. Three different sampling procedures were employed for the identification and quantification of colonising bacteria from baseline up to 12 months, using quantitative culturing. Clinical outcome measures (Holgers score, hygiene, pain, numbness and implant stability) were investigated. Results The clinical parameters, and total viable bacteria per abutment or in tissue biopsies did not differ significantly between the polished and machined abutments. The total CFU/mm2 abutment and CFU/peri-abutment fluid space of anaerobes, aerobes and staphylococci were significantly higher for the polished abutment. Anaerobic bacteria were detected in the tissue biopsies before BAHS implantation. Anaerobes and Staphylococcus spp. were detected in all three compartments after BAHS installation. For most patients (10/12), the same staphylococcal species were found in at least two of the three compartments at the same time-point. The common skin coloniser Staphylococcus epidermidis was identified in all patients but one (11/12), whereas the pathogen Staphylococcus aureus was isolated in five of the patients. Several associations between clinical and microbiological parameters were found. Conclusions There was no difference in the clinical outcome with the use of polished versus machined abutment at 3 and 12 months after implantation. The present pilot trial largely confirmed a suitable study design, sampling and analytical methodology to determine the effects of modified BAHS abutment properties. Level of evidence 2. Controlled prospective comparative study. Electronic supplementary material The online version of this article (10.1007/s00405-018-4946-z) contains supplementary material, which is available to authorized users.

We present a newly developed end-station at BESSY II dedicated to in situ Spectroscopic Analysis with Tender X-rays (SpAnTeX). The core of the end-station is a new SPECS PHOIBOS 150 HV NAP electron spectrometer. First, we show that the system has successfully achieved high electron transmission and detection efficiency under gas pressures up to 30 mbar and photon energies ranging between 200 eV and 10 keV. Second, using two features of this spectrometer (a new lateral resolution lens and a 3D delay line detector), we show that the endstation enables collection of the photoelectron spatial distribution under realistic working conditions (p ≥ 20 mbar) with a resolution better than 30 μm and the possibility to perform time resolved studies using a continuous tender X-ray source. We conclude by reporting an example of the possible experiments that can be performed using this new endstation using the Dip-and-Pull technique. Although mainly focused on the characterization of solid/liquid interfaces using AP-HAXPES, the end-station can be used at soft X-ray beamlines for more traditional AP-XPS experiments. The Dip-and-Pull module also demonstrates good electrochemical performance. The wide pressure and photon energy range covered by this end-station also enables investigations of solid/solid, solid/gas, liquid/vapor and liquid/liquid interfaces at pressures up to 30 mbar with tender X-rays.

Aim The study was designed to evaluate the ability of the calcium sulfate based NanoZolid® drug delivery technology to locally release the epidermal growth factor (EGF) protein while maintaining its biological activity. Methods NanoZolid-formulated EGF protein labelled with a near infrared dye (EGF-NIR) depots or EGF-NIR dissolved in PBS were injected subcutaneously into mice bearing EGF receptor (EGFR) positive human A549 lung cancer tumors inoculated subcutaneously. The release and biodistribution of the EGF-NIR were investigated in vivo longitudinally up to 96 h post administration, utilizing whole body fluorescence imaging. In order to confirm the in vivo findings, histological analysis of tumor cryosections was performed to investigate EGF-NIR fluorescent signal and EGFR expression level by immunofluorescence labelling. Results The in vivo fluorescence imaging showed a controlled release profile of the EGF-NIR loaded in the NanoZolid depots compared to free EGF-NIR. Histological analysis of the tumors further demonstrated a prevailing distribution of EGF-NIR in regions with high levels of EGFR expression. Conclusion Calcium sulfate based depots can be used to formulate EGF while maintaining its biological activity, e.g. receptor binding capability. This may have a good clinical potential for local delivery of biomolecules to enhance treatment efficacy and minimize systemic adverse effects.

Renal cell carcinoma (RCC), arising from the proximal tubule in the kidney, accounts for approximately 85% of kidney cancers and causes over 140,000 annual deaths worldwide. In the last decade, several new therapies have been identified for treatment of metastatic RCC. Although these therapies increase survival time compared to standard care, none of them has curative properties. The nephrotoxin orellanine specifically targets proximal tubular epithelial cells, leaving other organs unaffected. We therefore hypothesized that the selective toxicity of orellanine extends to clear cell RCC (ccRCC) cells since they emanate from proximal tubular cells. Orellanine would thus target both primary and metastatic ccRCC in vitro and in vivo. We found that orellanine induces dose-dependent cell death in proximal tubular cells and in all ccRCC cells tested, both primary and cell lines, with no toxicity detected in control cells. The toxic action of orellanine involve decreased protein synthesis, disrupted cell metabolism and induction of apoptosis. In nude rats carrying human ccRCC xenografts, brief orellanine treatment eliminated more than 90% of viable tumor mass compared to control rats. This identifies orellanine as a potential treatment concept for ccRCC patients on dialysis, due to its unique selective toxicity towards ccRCC.

Percutaneous titanium implants for bone conduction devices (BCDs) have offered, since 1977, a solution for patients with hearing loss not treatable by conventional hearing aids, such as patients with chronic ear infections or microtia and/or ear canal atresia. Percutaneous implants imply a continuous breach in the mechanical defensive barrier of the skin. To compensate for this breach, immunological mechanisms in the subcutaneous tissue surrounding the implant become more active. This article is protected by copyright. All rights reserved.

Papillary renal cell carcinoma (pRCC) is the second most common type of renal cell carcinoma. The only curative treatment available for pRCC is radical surgery. If the disease becomes widespread, neither chemo- nor radiotherapy will have therapeutic effect, hence further research on pRCC is of utmost importance. Histologically, pRCC is characterized by a papillary growth pattern with focal aggregation of macrophages of the foam cell phenotype. In other forms of cancer, a clear role for tumor-associated macrophages during cancer growth and progression has been shown. Although the presence of foamy macrophages is a histological hallmark of pRCC tumors, little is known regarding their role in pRCC biology. In order to study the interaction between pRCC tumor and myeloid cells, we established primary cultures from pRCC tissue. We show that human pRCC cells secrete the chemokines IL-8, CXCL16, and chemerin, and that these factors attract primary human monocytes in vitro. RNAseq data from The Cancer Genome Atlas confirmed a high expression of these factors in pRCC tissue. Conditioned medium from pRCC cultures induced a shift in human monocytes toward the M2 macrophage phenotype. In extended cultures, these macrophages became enlarged and loaded with lipids, adopting the foam cell morphology found in pRCC tissue. These results show for the first time that pRCC primary tumor cells secrete factors that attract and differentiate monocytes into anti-inflammatory tumor-associated macrophages with foam cell histology.

Respiratory tract infections are one of the leading causes of mortality worldwide urging better understanding of interactions between pathogens causing these infections and the host. Here we report that an extracellular matrix component proline/arginine-rich end leucine-rich repeat protein (PRELP) is a novel antibacterial component of innate immunity. We detected the presence of PRELP in human bronchoalveolar lavage fluid and showed that PRELP can be found in alveolar fluid, resident macrophages/monocytes, myofibroblasts, and the adventitia of blood vessels in lung tissue. PRELP specifically binds respiratory tract pathogens Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumoniae, but not other bacterial pathogens tested. We focused our study on M. catarrhalis and found that PRELP binds the majority of clinical isolates of M. catarrhalis (n = 49) through interaction with the ubiquitous surface protein A2/A2H. M. catarrhalis usually resists complement-mediated serum killing by recruiting to its surface a complement inhibitor C4b-binding protein, which is also a ligand for PRELP. We found that PRELP competitively inhibits binding of C4b-binding protein to bacteria, which enhances membrane attack complex formation on M. catarrhalis and thus leads to increased serum sensitivity. Furthermore, PRELP enhances phagocytic killing of serum-opsonized M. catarrhalis by human neutrophils in vitro. Moreover, PRELP reduces Moraxella adherence to and invasion of human lung epithelial A549 cells. Taken together, PRELP enhances host innate immunity against M. catarrhalis through increasing complement-mediated attack, improving phagocytic killing activity of neutrophils, and preventing bacterial adherence to lung epithelial cells.

Background: Renal cell carcinoma (RCC) is a highly vascularised tumour, where anti-angiogenic treatment with multi-tyrosine-kinase-inhibitor, is used for first-line treatment of metastatic disease. Variations in vascular characteristics are likely to contribute to variations in intrinsic aggressiveness of the disease. Emerging studies are identifying perivascular status, including perivascular PDGFR-β, as a determinant of prognosis in other tumour types. Methods: This work explored the impact on prognosis of vascular characteristics in RCC through analyses of a population-based collection of tumours from surgery-alone-treated patients. The quantitative data from a panel of vascular metrics were obtained through computerised image analysis of sections double-stained for expression of the endothelial cell marker CD34 together with perivascular markers α-SMA or PDGFR-β. Results: Perivascular expression of PDGFR-β and α-SMA were positively correlated to each other, and negatively correlated to vessel density. High expression of PDGFR-β and α-SMA as well as low vessel density was significantly associated with short survival in uni- and multivariate analyses. Subgroup analyses demonstrated that the prognostic impact of the perivascular markers was particularly prominent in the T4-subgroup. A novel metric, related to PDGFR-β perivascular heterogeneity, was also associated with prognosis in uni-and multi-variate analyses. This novel metric also acted as a prognosis marker in ovarian cancer. Conclusions: The study demonstrates previously unrecognised associations between RCC survival and the absolute levels, and variability, of perivascular PDGFR-β. This marker should be further explored in other RCC cohorts. Findings also suggest mechanistic analyses and studies on the relationship between perivascular status and efficacy of multi-tyrosine-kinase-inhibitors.

High levels of ecto-5'-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti-PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating NK cells upregulate CD73 expression and the frequency of these CD73-positive NK cells correlated with larger tumor size in breast cancer patients. In addition, the expression of multiple alternative immune checkpoint receptors including LAG-3, VISTA, PD-1, and PD-L1 was significantly higher in CD73-positive NK cells than in CD73-negative NK cells. Mechanistically, NK cells transport CD73 in intracellular vesicles to the cell surface and the extracellular space via actin polymerization-dependent exocytosis upon engagement of 4-1BBL on tumor cells. These CD73-positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-γ production. Taken together, our results support the notion that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immunoregulatory properties within the tumor microenvironment.

In this paper, we study the effect of element separation in a base station array (BSA) on the downlink line-of-sight achievable sum-rate of MIMO systems in the presence of mutual coupling at the BSA. The channel matrix H is modeled using the embedded field patterns of the BSA and is used to analyze the outage performance for two single-element user equipments assuming no inter-user coupling.

Background: Osteonecrosis of the lunate, Kienbock's disease, can lead to fragmentation of the lunate, carpal collapse, and severe osteoarthritis. Since the etiology of Kienbock's disease is impaired circulation, a diagnostic method capable of assessing perfusion would be valuable. Recent studies have suggested that dynamic contrast-enhanced (DCE) MR examinations at 3 T can assess perfusion in healthy carpal bones. Purpose: To evaluate the use of DCE-MR for assessing perfusion in the lunate bone in patients with Kienbock's disease. Furthermore, to compare perfusion with histopathology with a focus on bone viability. Study Type: Prospective case–control study. Population: Fourteen patients with Kienbock's disease and a control group of 19 healthy subjects. Field Strength: 3 T with T1-weighted fat-saturated contrast-enhanced gradient echo series. Assessment: Features of the enhancement curves from the DCE-MR examinations, time to peak (TTP), maximum slope (MS), and maximum enhancement (ME) assessed by a radiologist. Six of 14 patients were surgerized with lunate excision, allowing comparison between features of the enhancement curves and histopathology. Statistical Tests: Mann–Whitney U-test. P < 0.05 was considered a statistically significant difference. Results: Patients with Kienbock's disease showed significantly higher and faster perfusion parameters compared with the control group, the mean value of the TTP in patients was 126.73 sec, in controls 189.79 sec (P = 0.024), ME in patients 173.55 AU, in controls 28.46 AU (P < 0.001), and MS in patients 5.04 AU, in controls 1.06 AU (P < 0.001). When compared with histopathology, increased perfusion was seen in areas of bone formation but also in necrosis. Areas of normal bone showed low perfusion. Data Conclusion: DCE-MRI at 3 T can diagnose altered perfusion in patients with Kienbock's disease. Increased perfusion cannot definitely be used as a marker of bone viability. Level of Evidence: 1. Technical Efficacy: Stage 3. J. Magn. Reson. Imaging 2018. (Less)

The polymeric Ig receptor (PIgR) constitutes an important part of the immune system by mediating transcytosis of dimeric IgA into mucosal fluids. Although well studied in organs such as the intestine, the regulation and localization of PIgR in human kidney are incompletely characterized. Herein, using immunohistochemistry, we show that in healthy human kidneys, PIgR is expressed by the progenitor-like tubular scattered cells of the proximal tubules and by parietal epithelial cells of glomeruli. We further show that proximal tubular expression of PIgR becomes widespread during kidney disease, correlating to elevated levels of urinary secretory IgA. Urinary secretory IgA levels also correlated to the degree of tubular fibrosis, plasma creatinine, and urea levels. In addition, primary tubular cells were cultured to study the function and regulation of PIgR in vitro. Cellular PIgR expression was induced by conditioned medium from activated human leukocytes, as well as by inflammatory cytokines, whereas transforming growth factor-β1 caused decreased expression. Furthermore, interferon-γ increased the transcytosis of dimeric IgA in cultured tubular cells. Finally, a correlation study of mRNA data from the Genotype-Tissue Expression portal indicated that PIGR mRNA expression in kidney correlates to the expression of TNFSF13, a cytokine involved in plasma cell class switching to IgA. These results indicate that PIgR induction is an integral part of the injury phenotype of renal tubular cells.

Most prostate cancer patients will progress to a castration-resistant state (CRPC) after androgen ablation therapy and despite the development of new potent anti-androgens, like enzalutamide (ENZ), which prolong survival in CRPC, ENZ-resistance (ENZR) rapidly occurs. Re-activation of the androgen receptor (AR) is a major mechanism of resistance. Interrogating our in vivo derived ENZR model, we discovered that transcription factor STAT3 not only displayed increased nuclear localization but also bound to and facilitated AR activity. We observed increased STAT3 S727 phosphorylation in ENZR cells, which has been previously reported to facilitate AR binding. Strikingly, ENZR cells were more sensitive to inhibition with STAT3 DNA-binding inhibitor galiellalactone (GPA500) compared to CRPC cells. Treatment with GPA500 suppressed AR activity and significantly reduced expression of Cyclin D1, thus reducing cell cycle progression into S phase and hindering cell proliferation. In vivo, GPA500 reduced tumor volume and serum PSA in ENZR xenografts. Lastly, the combination of ENZ and GPA500 was additive in the inhibition of AR activity and proliferation in LNCaP and CRPC cells, providing rationale for combination therapy. Overall, these results suggest that STAT3 inhibition is a rational therapeutic approach for ENZR prostate cancer, and could be valuable in CRPC in combination with ENZ.

A series of amine adducts of the fungal metabolite galiellalactone (1) were prepared by reacting galiellalactone with different secondary amines via a Lewis acid catalyzed Michael addition. The adducts were assayed for in vitro effects toward prostate cancer cell lines and found to possess a similar ability to inhibit cell proliferation as galiellalactone itself. It was found that the Michael addition of amines to 1 is a reversible reaction, releasing 1 at different rates depending on the conditions, and that the adducts are potential prodrugs of galiellalactone. The chemical stability of the amine adducts is especially sensitive to pH, increasing at a lower pH.

The transcription factor STAT3 is a potential target for the treatment of castration-resistant prostate cancer. Galiellalactone (1), a direct inhibitor of STAT3, prevents the transcription of STAT3 regulated genes. In this study we characterized 6 (GPA512, Johansson , M. ; Sterner , O. Patent WO 2015/132396 A1, 2015 ), a prodrug of 1. In vitro studies showed that 6 is rapidly converted to 1 in plasma and is stable in a buffer solution. The pharmacokinetics of 6 following a single oral dose indicated that the prodrug was rapidly absorbed and converted to 1 with a tmax of 15 min. Oral administration of 6 in mice increased the plasma exposure of the active parent compound 20-fold compared to when 1 was dosed orally. 6 treated mice bearing DU145 xenograft tumors had significantly reduced tumor growth compared to untreated mice. The favorable druglike properties and safety profile of 6 warrant further studies of 6 for the treatment of castration-resistant prostate cancer.

SummaryMetabolic reprogramming is a hallmark of clear cell renal cell carcinoma (ccRCC) progression. Here, we used genome-scale metabolic modeling to elucidate metabolic reprogramming in 481 ccRCC samples and discovered strongly coordinated regulation of glycosaminoglycan (GAG) biosynthesis at the transcript and protein levels. Extracellular GAGs are implicated in metastasis, so we speculated that such regulation might translate into a non-invasive biomarker for metastatic ccRCC (mccRCC). We measured 18 GAG properties in 34 mccRCC samples versus 16 healthy plasma and/or urine samples. The GAG profiles were distinctively altered in mccRCC. We derived three GAG scores that distinguished mccRCC patients with 93.1%–100% accuracy. We validated the score accuracies in an independent cohort (up to 18 mccRCC versus nine healthy) and verified that the scores normalized in eight patients with no evidence of disease. In conclusion, coordinated regulation of GAG biosynthesis occurs in ccRCC, and non-invasive GAG profiling is suitable for mccRCC diagnosis.

Clear cell adenocarcinoma of the female urethra is a rare tumour of unknown origin. Here, we report 4 patients with such malignancy and argue for proper identification of the disease entity and radical surgery based on the available literature.

Background: Masked language modelling approaches have enjoyed success in improving benchmark performance across many general and biomedical domain natural language processing tasks, including biomedical relationship extraction (RE). However, the recent surge in both the number of novel architectures and the volume of training data they utilise may lead us to question whether domain specific pretrained models are necessary. Additionally, recent work has proposed novel classification heads for RE tasks, further improving performance. Here, we perform ablations over several pretrained models and classification heads to try to untangle the perceived benefits of each. Methods: We use a range of string preprocessing strategies, combined with Bidirectional Encoder Representations from Transformers (BERT), BioBERT and RoBERTa architectures to perform ablations over three RE datasets pertaining to drug-drug and chemical protein interactions, and general domain relationship extraction. We explore the use of the RBERT classification head, compared to a simple linear classification layer across all architectures and datasets. Results: We observe a moderate performance benefit in using the BioBERT pretrained model over the BERT base cased model, although there appears to be little difference when comparing BioBERT to RoBERTa large. In addition, we observe a substantial benefit of using the RBERT head on the general domain RE dataset, but this is not consistently reflected in the biomedical RE datasets. Finally, we discover that randomising the token order of training data does not result in catastrophic performance degradation in our selected tasks. Conclusions: We find a recent general domain pretrained model performs approximately the same as a biomedical specific one, suggesting that domain specific models may be of limited use given the tendency of recent model pretraining regimes to incorporate ever broader sets of data. In addition, we suggest that care must be taken in RE model training, to prevent fitting to non-syntactic features of datasets.

This manuscript introduces a 5G radio access network architecture concept based on ultra-dense wavelength division multiplexing (UDWDM) and incorporating an optical fronthaul network that uses a novel wireless antenna system for radio frequency transmission and reception. A ring topology is proposed where optical signals travel within the 5G UDWDM passive optical networks and millimeter waves are generated in the optical line terminals by optical heterodyning. The wireless transmission of the millimeter waves is conducted by an innovative phased array fed reflector antenna approach for mobile communications that grants high antenna gain due to highly focused radiation characteristics, as well as multiplexing gain by multiple beam generation. Furthermore, beam steering is provided by a radio frequency analog beamformer network. Finally, implementation options synthesizing the total system are discussed.

Initial technology and design decisions are presented as part of a design flow to realize an active integrated antenna (array) element for 5G applications at Ka-band. The objective is to synthesize an antenna impedance that directly matches the amplifier optimal load impedance in order to maximize the overall efficiency of the integrated antenna-amplifier system while attaining an output power in the range of 15–25 dBm. A strategy to subsequently co-optimize this combined system is also discussed. Direct matching overcomes the insertion losses and bandwidth limitations of impedance-transforming networks, obviates the use of a standard 50-Ohm reference impedance, and potentially results in more cost-effective, more compact, and better performing active antenna designs in general.

A set of propagation models for site-specific path loss and channel predictions are introduced. These include a half-screen model for propagation above buildings and terrain and efficient modeling of propagation around buildings including hybrid above/around paths. Frequency-dependent modeling of foliage loss and outdoor-to-indoor propagation is also included. Predictions using a tool that implements the set of models are compared with high quality multi-site channel measurements at 2.6 GHz. Without any model tuning the path loss accuracy is found to be quite good, with very low mean error and a standard deviation of 7–8 dB compared to the measurements. The major sources of error are identified to be deficiencies in the representation of the environment, diffuse scattering, and impact of foliage. The multipath richness in the predictions is assessed and the benefit of adding some stochastic multipath components is demonstrated.

A two-dimensional Luneburg lens multiport antenna at 28GHz is presented, where an all metal metasurface structure is used to control the effective refractive index. The metasurface lens has glide-s ...

Background Caveolae are membrane invaginations measuring 50–100 nm. These organelles, composed of caveolin and cavin proteins, are important for cellular signaling and survival. Caveolae play incompletely defined roles in human kidneys. Induction of caveolin-1/CAV1 in diseased tubules has been described previously, but the responsible mechanism remains to be defined. Methods Healthy and atrophying human kidneys were stained for caveolar proteins, (caveolin 1–3 and cavin 1–4) and examined by electron microscopy. Induction of caveolar proteins was studied in isolated proximal tubules and primary renal epithelial cells. These cells were challenged with hypoxia or H2O2. Primary tubular cells were also subjected to viral overexpression of megakaryoblastic leukemia 1 (MKL1) and MKL1 inhibition by the MKL1 inhibitor CCG-1423. Putative coregulators of MKL1 activity were investigated by Western blotting for suppressor of cancer cell invasion (SCAI) and filamin A (FLNA). Finally, correlative bioinformatic studies of mRNA expression of caveolar proteins and MKL1 were performed. Results In healthy kidneys, caveolar proteins were expressed by the parietal epithelial cells (PECs) of Bowman’s capsule, endothelial cells and vascular smooth muscle. Electron microscopy confirmed caveolae in the PECs. No expression was seen in proximal tubules. In contrast, caveolar proteins were expressed in proximal tubules undergoing atrophy. Caveolar proteins were also induced in cultures of primary epithelial tubular cells. Expression was not enhanced by hypoxia or free radical stress (H2O2), but proved sensitive to inhibition of MKL1. Viral overexpression of MKL1 induced caveolin-1/CAV1, caveolin-2/CAV2 and SDPR/CAVIN2. In kidney tissue, the mRNA level of MKL1 correlated with the mRNA levels for caveolin-1/CAV1, caveolin-2/CAV2 and the archetypal MKL1 target tenascin C (TNC), as did the MKL1 coactivator FLNA. Costaining for TNC as readout for MKL1 activity demonstrated overlap with caveolin-1/CAV1 expression in PECs as well as in atrophic segments of proximal tubules. Conclusions Our findings support the view that MKL1 contributes to the expression of caveolar proteins in healthy kidneys and orchestrates the induction of tubular caveolar proteins in renal injury. Electronic supplementary material The online version of this article (10.1186/s12882-017-0738-8) contains supplementary material, which is available to authorized users.

A Ka-band 2D flat-profiled Luneburg lens antenna implemented with a glide-symmetric holey structure is presented. The required refractive index for the lens design has been investigated via an analysis of the hole depth and the gap between the two metallic layers constituting the lens. The final unit cell is described and applied to create the complete metasurface Luneburg lens showing that a plane wave is obtained when feeding at an opposite arbitrary point with a discrete source.

In the cell, γ-tubulin establishes a cellular network of threads named the γ-string meshwork. However, the functions of this meshwork remain to be determined. We investigated the traits of the meshwork and show that γ-strings have the ability to connect the cytoplasm and the mitochondrial DNA together. We also show that γ-tubulin has a role in the maintenance of the mitochondrial network and functions as reduced levels of γ-tubulin or impairment of its GTPase domain disrupts the mitochondrial network and alters both their respiratory capacity and the expression of mitochondrial-related genes. By contrast, reduced mitochondrial number or increased protein levels of γ-tubulin DNA-binding domain enhanced the association of γ-tubulin with mitochondria. Our results demonstrate that γ-tubulin is an important mitochondrial structural component that maintains the mitochondrial network, providing mitochondria with a cellular infrastructure. We propose that γ-tubulin provides a cytoskeletal element that gives form to the mitochondrial network.

In this work we evaluate the potential of using access-integrated backhaul in a fixed wireless access (FWA) use case. FWA is considered as a potential use case for early 5G deployment. The system is deployed in the 28 GHz band to provide FWA to residential houses in a suburban scenario where the access points (APs) are deployed on utility poles. It is assumed that only a small fraction of the APs has dedicated backhaul transport (e.g. fiber) and the remainder of the APs are instead backhauled wirelessly by using access-integrated backhaul. The access-integrated backhaul shares the radio resources with the FWA and consumes a substantial part of the available resources especially when multi-hop backhaul is considered. The backhaul aggregation points quickly become the bottle necks since they consume a majority of the radio resources. However, when considering the amount of spectrum that is available at 28 GHz then serving at least 25 Mbps in aggregated constant DL/UL traffic to houses seems feasible. This is accomplished by having less than 20% of the APs connected with dedicated backhaul while the rest of the APs are using access-integrated backhaul.

Comprehensive transcriptome studies of cancers often rely on corresponding normal tissue samples to serve as a transcriptional reference. In this study, we performed in-depth analyses of normal kidney tissue transcriptomes from the TCGA and demonstrate that the histological variability in cellularity, inherent in the kidney architecture, lead to considerable transcriptional differences between samples. This should be considered when comparing expression profiles of normal and cancerous kidney tissues. We exploited these differences to define renal-cell-specific gene signatures and used these as a framework to analyze renal cell carcinoma (RCC) ontogeny. Chromophobe RCCs express FOXI1-driven genes that define collecting duct intercalated cells, whereas HNF-regulated genes, specific for proximal tubule cells, are an integral part of clear cell and papillary RCC transcriptomes. These networks may be used as a framework for understanding the interplay between genomic changes in RCC subtypes and the lineage-defining regulatory machinery of their non-neoplastic counterparts.

Short-term results from seventy-six patients receiving a bone-anchored hearing implant installed with a novel minimally invasive surgery technique

How shall a business adapt its management control systems when learning machines enter the arena? Will the control system continue to focus on humans aspects and continue to consider a learning machine to be an automation tool as any other historically programmed computer? Learning machines introduces productivity capabilities that achieve very high levels of efficiency and quality. A learning machine can sort through large amounts of data and make conclusions difficult by a human mind. However, as learning machines become even more complex systems, they introduce an uncertainty not previously considered by automation tools. The algorithms can make their own associations, and the automation engineer will no longer know exactly how a learning machine produces its outcome. What is the motive for a learning machine’s decision? A learning machine in this context becomes more human-like compared to the older generation of automation computers. This thesis concludes that most contemporary Management Control System principles are relevant when deploying machine learning, but some are not. A Management Control System must in contradiction to a historically programmed computer, consider multiple human-like aspects while controlling a deployed learning machine. These conclusions are based on empirical data from web-articles, TED-talks, literature and questionnaires directed to contemporary companies using machine learning within their organizations.

The transcription factor STAT3 is constitutively active in several malignancies including castration-resistant prostate cancer and has been identified as a promising therapeutic target. The fungal metabolite galiellalactone, a STAT3 signaling inhibitor, inhibits the growth, both in vitro and in vivo, of prostate cancer cells expressing active STAT3 and induces apoptosis of prostate cancer stem cell-like cells expressing phosphorylated STAT3 (pSTAT3). However, the molecular mechanism of this STAT3-inhibiting effect by galiellalactone has not been clarified. A biotinylated analogue of galiellalactone (GL-biot) was synthesized to be used for identification of galiellalactone target proteins. By adding streptavidin-Sepharose beads to GL-biot-treated DU145 cell lysates, STAT3 was isolated and identified as a target protein. Confocal microscopy revealed GL-biot in both the cytoplasm and the nucleus of DU145 cells treated with GL-biot, appearing to co-localize with STAT3 in the nucleus. Galiellalactone inhibited STAT3 binding to DNA in DU145 cell lysates without affecting phosphorylation status of STAT3. Mass spectrometry analysis of recombinant STAT3 protein pretreated with galiellalactone revealed three modified cysteines (Cys-367, Cys-468, and Cys-542). Here we demonstrate with chemical and molecular pharmacological methods that galiellalactone is a cysteine reactive inhibitor that covalently binds to one or more cysteines in STAT3 and that this leads to inhibition of STAT3 binding to DNA and thus blocks STAT3 signaling without affecting phosphorylation. This further validates galiellalactone as a promising direct STAT3 inhibitor for treatment of castration-resistant prostate cancer.

Two biotinylated derivatives of the fungal metabolite galiellalactone (1) were synthesized in order to facilitate the investigation of the molecular mechanism of action of the galiellalactonoids. Galiellalactone is a STAT3-signaling inhibitor that inhibits growth in vitro as well as in vivo of prostate cancer cells expressing activated STAT3. To provide a suitable point of attachment for biotin, the 8-hydroxymethyl derivative (3) and its 7-phenyl analogue 4 were synthesized by a modified tandem Pd-catalysed carbonylation and intramolecular vinyl allene Diels-Alder procedure previously developed. The two primary alcohols obtained, 3 and 4, were coupled to biotin as the 6-aminohexanoic acid amide, activated as the acid chloride, yielding the derivatives 5 and 6.

Nitrogen-containing heterocyclic compounds are an important class of molecules that are commonly used for the synthesis of candidate drugs. Phosphatidylinositol-4-phosphate 5-kinase-α (PIP5Kα) is a lipid kinase, similar to PI3K. However, the role of PIP5K1α in oncogenic processes and the development of inhibitors that selectively target PIP5K1α have not been reported. In the present study we report that overexpression of PIP5K1α is associated with poor prognosis in prostate cancer and correlates with an elevated level of the androgen receptor. Overexpression of PIP5K1α in PNT1A nonmalignant cells results in an increased AKT activity and an increased survival, as well as invasive malignant phenotype, whereas siRNA-mediated knockdown of PIP5K1α in aggressive PC-3 cells leads to a reduced AKT activity and an inhibition in tumor growth in xenograft mice. We further report a previously unidentified role for PIP5K1α as a druggable target for our newly developed compound ISA-2011B using a high-throughput KINOMEscan platform. ISA-2011B was discovered during our synthetic studies of C-1 indol-3-yl substituted 1,2,3,4-tetrahydroisoquinolines via a Pictet-Spengler approach. ISA-2011B significantly inhibits growth of tumor cells in xenograft mice, and we show that this is mediated by targeting PIP5K1α-associated PI3K/AKT and the downstream survival, proliferation, and invasion pathways. Further, siRNA-mediated knockdown of PIP5K1α exerts similar effects on PC3 cells as ISA-2011B treatment, significantly inhibiting AKT activity, increasing apoptosis and reducing invasion. Thus, PIP5K1α has high potential as a drug target, and compound ISA-2011B is interesting for further development of targeted cancer therapy.

// Matilda Munksgaard Thoren 1 , Marica Vaapil 1, 5 , Johan Staaf 2 , Maria Planck 2, 3 , Martin E. Johansson 4 , Sofie Mohlin 1 and Sven Pahlman 1 1 Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden 2 Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE Lund, Sweden 3 Department of Oncology, Skane University Hospital, SE Lund, Sweden 4 Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skane University Hospital, Malmo, Sweden 5 Current address: Biosciences Area, Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA Correspondence to: Sven Pahlman, email: Sven.pahlman@med.lu.se Keywords: small cell lung carcinoma (SCLC), hypoxia, hypoxia-inducible factor, MYC, glutamine Received: November 23, 2016 Accepted: March 29, 2017 Published: April 06, 2017 ABSTRACT We previously demonstrated that small cell lung carcinoma (SCLC) cells lack HIF-2α protein expression, whereas HIF-1α in these cells is expressed at both acute and prolonged hypoxia. Here we show that low HIF2A expression correlates with high expression of MYC genes. Knockdown of HIF1A expression had no or limited effect on cell survival and growth in vitro . Unexpectedly, hypoxic ATP levels were not affected by HIF-1α knockdown and SCLC cell viability did not decrease upon glucose deprivation. In line with these in vitro data, xenograft tumor-take and growth were not significantly affected by repressed HIF1A expression. Glutamine withdrawal drastically decreased SCLC cell proliferation and increased cell death at normoxia and hypoxia in a HIF-independent fashion and the dependence on glutaminolysis was linked to amplification of either MYC or MYCL . Downregulation of GLS expression, regulating the first step of the glutaminolysis pathway, in MYC/MYCL overexpressing SCLC cells resulted in both impaired growth and increased cell death. Our results suggest that MYC/MYCL overexpression in SCLC cells overrides the need of HIF-1 activity in response to hypoxia by inducing glutaminolysis and lipogenesis. Targeting the glutaminolysis pathway might hence be a novel approach to selectively kill MYC amplified SCLC cells in vivo .

Background Over the last years, less invasive surgical techniques with soft tissue preservation for bone conduction hearing implants (BCHI) have been introduced such as the linear incision technique combined with a punch. Results using this technique seem favorable in terms of rate of peri-abutment dermatitis (PAD), esthetics, and preservation of skin sensibility. Recently, a new standardized surgical technique for BCHI placement, the Minimally Invasive Ponto Surgery (MIPS) technique has been developed by Oticon Medical AB (Askim, Sweden). This technique aims to standardize surgery by using a novel surgical instrumentation kit and minimize soft tissue trauma. Methods A multicenter randomized controlled trial is designed to compare the MIPS technique to the linear incision technique with soft tissue preservation. The primary investigation center is Maastricht University Medical Center. Sixty-two participants will be included with a 2-year follow-up period. Parameters are introduced to quantify factors such as loss of skin sensibility, dehiscence of the skin next to the abutment, skin overgrowth, and cosmetic results. A new type of sampling method is incorporated to aid in the estimation of complications. To gain further understanding of PAD, swabs and skin biopsies are collected during follow-up visits for evaluation of the bacterial profile and inflammatory cytokine expression. The primary objective of the study is to compare the incidence of PAD during the first 3 months after BCHI placement. Secondary objectives include the assessment of parameters related to surgery, wound healing, pain, loss of sensibility of the skin around the implant, implant extrusion rate, implant stability measurements, dehiscence of the skin next to the abutment, and esthetic appeal. Tertiary objectives include assessment of other factors related to PAD and a health economic evaluation. Discussion This is the first trial to compare the recently developed MIPS technique to the linear incision technique with soft tissue preservation for BCHI surgery. Newly introduced parameters and sampling method will aid in the prediction of results and complications after BCHI placement. Trial registration Registered at the CCMO register in the Netherlands on 24 November 2014: NL50072.068.14. Retrospectively registered on 21 April 2015 at ClinicalTrials.gov: NCT02438618. This trial is sponsored by Oticon Medical AB. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1662-0) contains supplementary material, which is available to authorized users.

Background The complement system has been implicated in pathogenesis of systemic sclerosis (SSc). The goal of the present study was to evaluate improved complement biomarkers in SSc. Methods The presence of C4d, reflecting activation of the classical/lectin pathways, C3bBbP corresponding to activation of the alternative pathway, and soluble terminal complement complexes (all complement pathways), was measured in plasma samples by enzyme-linked immunosorbent assay and correlated to clinical parameters. The study included 81 patients with limited cutaneous SSc and 41 with diffuse cutaneous SSc, as well as 47 matched healthy controls and 81 patients with rheumatoid arthritis, 22 with psoriatic arthritis and 20 with ankylosing spondylitis. Skin and kidney biopsies of selected patients were stained to detect deposited C3b as a marker of local complement activation. Results Biomarkers of activation of all complement pathways were increased in SSc compared with healthy controls and were similar to those in other rheumatic diseases. When patients with SSc were divided into subgroups, a distinct pattern of complement markers was observed in individuals with scleroderma renal crisis (SRC). By functional assay, we confirmed a significant decrease in complement haemolytic activity in SRC vs. non-SRC patients, indicating complement consumption. Further, we detected glomerular deposits of C3b in some patients with SRC. Conclusions The data indicate that complement activation is an important feature of SRC.

Triple-negative (TN) breast cancers (ER−PR−HER2−) are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance., A reactive tumour stroma is associated with poor prognosis. Here, the authors show that in patients with triple negative breast cancer resident monocytes activate cancer-associated fibroblasts and induce production of CXCL16, which acts as a monocyte chemoattractant, resulting in an amplificatory feedback loop.

Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) have been shown to improve the survival of patients with clear cell renal cell carcinoma (CCRCC). However, a benefit for CCCRC patients was observed with the FDA-approved PD-1 inhibitor Nivolumab irrespective of PD-1 ligand (PD-L1) expression status indicating there are potentially additional CCRCC checkpoint molecules worth exploring for targeted therapy. We therefore analyzed RNAseq data (n=534, CCRCCs; n=72, normal kidney specimens) from the TCGA project, and found that PD-L1 was not upregulated in CCRCC when compared to normal tissue whereas other checkpoint members i.e. CD300A and LAIR1 were among the most significantly upregulated genes in CCRCCs. In terms of overall survival, high expression of PD-L1 was associated with better outcome in CCRCCs while high expression of CD300A and LAIR1 were significantly associated with worse outcomes. We confirmed these findings in two independent cohorts of CCRCC patients. Furthermore, we performed cell type enrichment analysis, which showed that CD300A and LAIR1 are most likely expressed by tumor-associated macrophages in the CCRCC tumor microenvironment. Our results suggest that PD1/PDL1 might be suboptimal targets in CCRCC and that there are additional unexplored immune checkpoint molecules that warrant our attention. Note: This abstract was not presented at the meeting. Citation Format: Jonas Sjolund, David Lindgren, Helén Nilsson, Martin E. Johansson, Hakan Axelson, Kristian Pietras. Immune checkpoint inhibitors CD300A and LAIR1 are associated with poor prognosis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1086.

The renal cell carcinomas (RCC) denote a diverse set of neoplasias with unique genetic and histological features. The RCCs emanate from the renal tubule, a highly heterogeneous epithelial structure, and depending on which cell is malignified the resulting cancer displays unique characteristics. Notwithstanding this, the cells of origin for the RCC forms are far from established, and only inferred by the accumulated weight of marker similarities, not always providing an unequivocal picture. The tubular epithelium is normally mitotically quiescent, but demonstrates a considerable regenerative capacity upon renal injury. Recently the hypothesis that regeneration is driven by adult stem cells has been added experimental support, providing further complexity to the issue of renal carcinogenesis. Whether these cells are linked to RCC is an open question. In the present review we therefore present the prevailing theories regarding kidney regeneration, since a better understanding of this process might be of relevance when considering the different malignancies that arise from kidney epithelium. Our own results show that papillary renal cell carcinoma displays considerable similarities to proximal tubular progenitor cells and we suggest that this tumor form may develop in a multi-step fashion via benign renal adenomas. The putative connection between renal stem cells and carcinomas is, however, not clarified, since the current understanding of the renal stem cell system is not complete. It is clear that the efforts to isolate and characterize renal progenitor/stem cells suffer from numerous technical limitations and that it remains likely that the kidney harbors different stem cell pools with a restricted differentiation potential.

Flow in an intermediate turbine duct (ITD) is highly complex, influenced by the upstream turbine stage flow structures, which include tip leakage flow and nonuniformities originating from the upstream high pressure turbine (HPT) vane and rotor. The complexity of the flow structures makes predicting them using numerical methods difficult, hence there exists a need for experimental validation. To evaluate the flow through an intermediate turbine duct including a turning vane, experiments were conducted in the Oxford Turbine Research Facility (OTRF). This is a short duration high speed test facility with a 3/4 engine-sized turbine, operating at the correct nondimensional parameters for aerodynamic and heat transfer measurements. The current configuration consists of a high pressure turbine stage and a downstream duct including a turning vane, for use in a counter-rotating turbine configuration. The facility has the ability to simulate low-NOx combustor swirl at the inlet to the turbine stage. This paper presents experimental aerodynamic results taken with three different turbine stage inlet conditions: a uniform inlet flow and two low-NOx swirl profiles (different clocking positions relative to the high pressure turbine vane). To further explain the flow through the 1.5 stage turbine, results from unsteady computational fluid dynamics (CFD) are included. The effect of varying the high pressure turbine vane inlet condition on the total pressure field through the 1.5 stage turbine, the intermediate turbine duct vane loading, and intermediate turbine duct exit condition are discussed and CFD results are compared with experimental data. The different inlet conditions are found to alter the flow exiting the high pressure turbine rotor. This is seen to have local effects on the intermediate turbine duct vane. With the current stator–stator vane count of 32-24, the effect of relative clocking between the two is found to have a larger effect on the aerodynamics in the intermediate turbine duct than the change in the high pressure turbine stage inlet condition. Given the severity of the low-NOx swirl profiles, this is perhaps surprising.

In this paper, the results from LTE downlink performance evaluations of UE-specific beamforming, aperture-reuse horizontal sectorization, and vertical sectorization are presented for a dual-column 4 TX antenna configuration. System simulations were performed in a dense urban scenario with a deterministic 3D path loss model. The results show that UE-specific beamforming gives the best performance; slightly better than vertical sectorization and significantly better than aperture-reuse horizontal sectorization.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene. Histological examination of the kidneys of the conditional mice demonstrate the existence of nests of dysplastic cells with a clear cytoplasm as a consequence of lipid accumulation, thus displaying a one important hallmark of human ccRCC.

Metastasis is a significant health issue. The standard mode of care is combination of chemotherapy and targeted therapeutics but the 5-year survival rate remains low. New/better drug targets that can improve outcomes of patients with metastatic disease are needed. Metastasis is a complex process, with each step conferred by a set of genetic aberrations. Mapping the molecular changes associated with metastasis improves our understanding of the etiology of this disease and contributes to the pipeline of targeted therapeutics. Here, phosphoproteomics of a xenograft-derived in vitro model comprising 4 isogenic cell lines with increasing metastatic potential implicated Transient Receptor Potential Vanilloid subtype 4 in breast cancer metastasis. TRPV4 mRNA levels in breast, gastric and ovarian cancers correlated with poor clinical outcomes, suggesting a wide role of TRPV4 in human epithelial cancers. TRPV4 was shown to be required for breast cancer cell invasion and transendothelial migration but not growth/proliferation. Knockdown of Trpv4 significantly reduced the number of metastatic nodules in mouse xenografts leaving the size unaffected. Overexpression of TRPV4 promoted breast cancer cell softness, blebbing, and actin reorganization. The findings provide new insights into the role of TRPV4 in cancer extravasation putatively by reducing cell rigidity through controlling the cytoskeleton at the cell cortex.

The performance impact of having a limited scan range capability on street level mounted backhaul antennas is investigated by examining both the statistical angular ray distribution and the consequences on SINR from having a limited scan range. Limitations in both azimuth and elevation scan capabilities are considered. This is done for two different, virtual city scenarios; one typical American city scenario, and one typical European.

Purpose: Renal cell carcinoma (RCC) is derived from a tissue with a remarkable capacity for vectorial transport. We therefore performed an unbiased exploration of transporter proteins in normal kidney and kidney cancer to discover novel clinical targets. Experimental Design: Using The Cancer Genome Atlas (TCGA) database, we investigated differences in membrane transporter expression in clear cell RCC (ccRCC) and normal kidney. We identified the dopamine transporter SLC6A3 as a specific biomarker for ccRCC. To investigate the functionality of SLC6A3, we used a [3H]-dopamine uptake assay on ccRCC cells. We further explored the effect of hypoxia-inducible factor (HIF) proteins on SLC6A3 expression by introducing siRNA in ccRCC cells and by hypoxic treatment of nonmalignant cells. Results: We show that ccRCC expresses very high transcript levels of SLC6A3 in contrast to normal kidney tissue and other tumor types, which do not express appreciable levels of this transporter. Importantly, we demonstrate that the elevated expression of SLC6A3 in ccRCC cells is associated with specific uptake of dopamine. By targeting the expression of HIF-1α and HIF-2α, we could show that SLC6A3 expression is primarily influenced by HIF-2α and that hypoxia can induce SLC6A3 expression in normal renal cells. Conclusions: We conclude that the dopamine transporter SLC6A3 constitutes a novel biomarker that is highly specific for ccRCC. We further postulate that the protein can be exploited for diagnostic or therapeutic purposes for detection or treatment of ccRCC. Clin Cancer Res; 23(8); 2105–15. ©2016 AACR.