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Introduction: The majority of Apollo 17 sample 77017 constitutes a feldspathic impactite that was recrystallized at subsolidus temperatures as a result of a basin impact [e.g., 1]. We dated this recrystallisation event at ~4.17 Ga using 147Sm-143Nd systematics [2]. On the basis of a geological investigation of craters that could have excavated sample 77017, in combination with a numerical modelling of impact-induced redistribution of basin melts, we also found that a basin-forming event--either Serenitatis or Crisium--was the most likely cause for the recrystallisation [3]. Here, we present 207Pb/206Pb data that provide a more precise recrystallization age and to further constrain the origin of the protolith. Methods: 535 mg of a fine (<20 µm) bulk fraction of split 77017,199 was used for Pb isotope analyses. Stepwise digestion, chemical separation, and isotopic analyses were adopted from [4, 5]. A Monte Carlo approach (10000 cycles) was used for blank subtraction and error propagation. Results: The sample-to-blank ratios of the Pb isotope analyses of the six digestion steps of the bulk fraction range from 0.3 x106 to 9.8 x106. Thus the effect of procedural blanks on the Pb isotope systematics is negligible. Nevertheless, a substantial terrestrial lead component was present in the first two digstion steps and a minor terrestrial component affected the penultimate step. The remaining digestion steps define a 4143 ±9 Ma (MSWD = 0.99) isochron. Additionally, further analyses of mineral fractions combined with the data originally presented in [2] now yield a 4159 ±16 Ma 147Sm-143Nd isochron (MSWD = 1.3; originally a 4170 ±80 Ma errorchron, MSWD = 8.1) when using 6 of the 9 data points. Discussion: The 40Ar/39Ar dating by [1] has established a minimum age estimate (4034 ±58 Ma; recalculated) for the metamorphic sub-solidus recrystallization of 77017. This minimum age is consistent with our 207Pb/206Pb isochron date (4143 ±9 Ma), which, more importantly, is concordant with our 147Sm-143Nd isochron date (4159 ±16 Ma) obtained on the same sample split [2]. We consider the weighted average of the two dates (4147 ± 8 Ma, MSWD = 3.0) to be the best age estimate for the recrystallisation event. Our isochron intersects within error the initial Pb isotopic composition of the LMO at the time of differentiation determined by [6]. As [6] consider this event to have taken place at 4376 ±18 Ma, this would require that the 207Pb/206Pb of the 77017-protolith did not change significantly over the next ~229 Ma until the recrystallisation event at 4147 ± 8 Ma. This in turn, requires a very low µ-value (=238U/204Pb) in the protolith, which is typical for crustal materials and suggests that little or no KREEP component is present. However, U-Th-Pb systematics of 77017 were previously obtained by [7] and on the basis of the U and Th concentrations, the authors concluded that it is possible that "77017 contains about 5-6% KREEP component" [7]. Using our 207Pb/206Pb data, we attempted to constrain whether this KREEP component could have already been present in the protolith before impact. We solved for a protolith isotopic composition that would yield an initial 207Pb/206Pb on our 77017 Pb-Pb isochron using a 2-stage model (Stage 1: bulk moon from moon formation to protolith formation, Stage 2: protolith from its formation to recrystallisation event; after [6]). Even when choosing from the possible range of parameters (time of moon formation, time of protolith formation, µ during stage 1 and 2; [6, 8]) those that produce the highest µ-value (i.e., closest to KREEP) in the protolith, this value never exceeds that of the bulk silicate moon in the respective scenario. This is indicative of crustal material that preferentially incorporated Pb. Furthermore, even the highest possible µ-value in such a 2-stage model is lower than the µ-value of 77017 (658-870) measured by [7]. We conclude that this measured µ-value of 77017, which is suggestive of the presence of a KREEP component, must result from a process (most likely addition of a KREEP component or Pb loss) that occurred during the recrystallisation of the sample or even a later event. Therefore, it seems likely that the protolith of 77017 was free of any KREEP component. A KREEP-free 77017 protolith supports our interpretation that the basin impact that led to the recrystallisation of 77017 was either Serenitatis or Crisium [3]. A 4.15 Ga age of either basin contradicts terminal lunar cataclysm models that require both basins to be ~3.9 Ga [9, and references therein]. [ABSTRACT FROM AUTHOR]

Radiofrequency (RF) ablation requires a complex set of devices as well as profound electrophysiological experience and substantial knowledge of physical science basics. To establish RF ablation in-vitro teaching-system, six workstations were equipped with computer-controlled RF ablation generators. Universal connection boxes allow ablation-essays with catheters of different make and model. Special wetlabs were developed combining a basin containing isotonic saline solution with a thermostat and a pump to simulate blood flow. This hands-on teaching system can be used to demonstrate differences in lesion-forming dependent on tip-electrodes, sensor technology and ablation techniques, influence of blood flow and electrode-angle to the myocardium. It was also utilized to reproduce industrial in-vitro tests. [ABSTRACT FROM AUTHOR]

After prostatectomy due to prostate carcinoma, patients often develop metastases. Although prostate cancer is susceptible to hormonal manipulation, many patients become castration-resistant. Therefore, new therapies are the focus of investigations. We analyzed the effect of the tyrosine kinase inhibitors (TKIs), sorafenib and sunitinib, in combination with rottlerin, a PKCδ inhibitor, on metastatic mechanisms in prostate carcinoma cells. LNCaP and PC-3 prostate carcinoma cells were treated with sorafenib or sunitinib alone at various concentrations (1-20 µM) or in combination with rottlerin (10 µM) for 24 h. Then, cell toxicity (MTT test) and cell proliferation (BrdU incorporation assay) were quantified. The study demonstrated a dose-dependent inhibitory effect of sorafenib and sunitinib on PC-3 and LNCaP cell activity and proliferation. Both agents showed significantly stronger cytotoxic effects in LNCaP cells. At the highest concentrations, sorafenib and sunitinib inhibited the viability of LNCaP cells up to 2 % and 31 %, respectively, and the viability of PC-3 cell line up to 20 % and 43 %, respectively. The proliferation of both cell lines was significantly stronger inhibited by sorafenib than by sunitinib. In LNCaP cells, sorafenib and sunitinib at the highest concentrations inhibited cell proliferation up to 46 % and 49 %, respectively, and the proliferation of PC-3 line up to 40 % and 47 %, respectively. Rottlerin reduced the viability and proliferation of PC3 cells to 81 % and 42 %, whereas the viability and proliferation of LNCaP cells were reduced to 25 % and 57 %, respectively. Sorafenib and sunitinib at low concentrations partly neutralized the inhibitory effect of rottlerin on cell viability and proliferation. On the other hand, in PC-3 cells, rottlerin reduced the inhibitory effects of sorafenib and sunitinib at the highest concentrations on cell viability from 20 % to 30 % and from 43 % to 61 %, respectively. An additive effect on cell activity was observed after treating LNCaP cells with both sunitinib at high concentrations and rottlerin. This combination increased the cytotoxic effect from 31 % to 13 % at the highest sunitinib concentration. Our results showed that monotherapy with sorafenib was the most efficient in both PCa cell lines. A marginally additive effect of rottlerin was only observed in LNCaP cells treated with sunitinib at a high concentration. Sorafenib and sunitinib reduced cell migration in PC-3 cells to 10 % and 32 % of untreated cells, respectively. Co-treatment with sorafenib/sunitinib and rottlerin did not result in a significantly stronger anti-migratory effect than the treatment with each TKI alone. Given the strong cytotoxic effect of TKIs, especially sorafenib, on LNCaP cells, the results of the migration assay in this line were severely biased and not considered in the analysis. Unlike in other malignancies, combination therapy with TKI and rottlerin seems not beneficial in prostate cancer. More promising seems to be monotherapy with rottlerin, but further studies are needed to confirm this observation., (Copyright © 2021 Cieslikowski et al.)

Introduction: Chronic hip pain in middle-aged and older adults is common and disabling. Patient-centred care of chronic hip pain requires a comprehensive understanding of how people with chronic hip pain view their health problem and its care. This paper outlines a protocol to synthesise qualitative evidence of middle-aged and older adults' views, beliefs, expectations and preferences about their chronic hip pain and its care., Methods and Analysis: We will perform a qualitative evidence synthesis using a framework approach. We will conduct this study in accord with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement and the Enhancing Transparency in Reporting the synthesis of Qualitative research checklist. We will search MEDLINE, CINAHL, The Cochrane Central Register of Controlled Trials, EMBASE and PsycINFO using a comprehensive search strategy. A priori selection criteria include qualitative studies involving samples with a mean age over 45 and where 80% or more have chronic hip pain. Two or more reviewers will independently screen studies for eligibility, assess methodological strengths and limitations using the Critical Appraisal Skills Programme qualitative studies checklist, perform data extraction and synthesis and determine ratings of confidence in each review finding using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research approach. Data extraction and synthesis will be guided by the Common-Sense Model of Self-Regulation. All authors will contribute to interpreting, refining and finalising review findings. This protocol is registered on PROSPERO and reported according to the PRISMA Statement for Protocols (PRISMA-P) checklist., Ethics and Dissemination: Ethics approval is not required for this systematic review as primary data will not be collected. The findings of the review will be disseminated through publication in an academic journal and scientific conferences., Prospero Registration Number: PROSPERO registration number: CRD42021246305., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapy is emerging as one of the most effective methods for treating many cancers. However, immunotherapy can still introduce significant off-target toxicity, and methods are sought to enable targeted immunotherapy at tumor sites. Here, we show that relatively large (>100-nm) anionic nanoparticles administered intraperitoneally (i.p.) selectively accumulate in tumor-associated macrophages (TAMs). In a mouse model of metastatic ovarian cancer, fluorescently labeled silica, poly(lactic- co -glycolic acid), and polystyrene nanoparticles administered i.p. were all found to selectively accumulate in TAMs. Quantifying silica particle uptake indicated that >80% of the injected dose was in TAMs. Particles that were smaller than 100 nm or cationic or administered intravenously (i.v.) showed no TAM targeting. Moreover, this phenomenon is likely to occur in humans because when freshly excised human surgical samples were treated with the fluorescent silica nanoparticles no interaction with healthy tissue was seen but selective uptake by TAMs was seen in 13 different patient samples. Ovarian cancer is a deadly disease that afflicts ∼22,000 women per year in the United States, and the presence of immunosuppressive TAMs at tumors is correlated with decreased survival. The ability to selectively target TAMs opens the door to targeted immunotherapy for ovarian cancer., Competing Interests: The authors declare no competing interest.

Background: Over the last years, substantial effort has been put into enhancing our arsenal in fighting epidemics from both technological and theoretical perspectives with scientists from different fields teaming up for rapid assessment of potentially urgent situations. This paper focusses on the computational aspects of infectious disease models and applies commonly available graphics processing units (GPUs) for the simulation of these models. However, fully utilizing the resources of both CPUs and GPUs requires a carefully balanced heterogeneous approach., Results: The contribution of this paper is twofold. First, an efficient GPU implementation for evaluating a small-scale ODE model; here, the basic S(usceptible)-I(nfected)-R(ecovered) model, is discussed. Second, an asynchronous particle swarm optimization (PSO) implementation is proposed where batches of particles are sent asynchronously from the host (CPU) to the GPU for evaluation. The ultimate goal is to infer model parameters that enable the model to correctly describe observed data. The particles of the PSO algorithm are candidate parameters of the model; finding the right one is a matter of optimizing the likelihood function which quantifies how well the model describes the observed data. By employing a heterogeneous approach, in which both CPU and GPU are kept busy with useful work, speedups of 10 to 12 times can be achieved on a moderate machine with a high-end consumer GPU as compared to a high-end system with 32 CPU cores., Conclusions: Utilizing GPUs for parameter inference can bring considerable increases in performance using average host systems with high-end consumer GPUs. Future studies should evaluate the benefit of using newer CPU and GPU architectures as well as applying this method to more complex epidemiological scenarios.

Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo . The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR -transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR -transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression., Competing Interests: CONFLICTS OF INTEREST No conflict of interest.

Optical scattering has traditionally limited the ability to focus light inside scattering media such as biological tissue. Recently developed wavefront shaping techniques promise to overcome this limit by tailoring an optical wavefront to constructively interfere at a target location deep inside scattering media. To find such a wavefront solution, a "guide-star" mechanism is required to identify the target location. However, developing guidestars of practical usefulness is challenging, especially in biological tissue, which hinders the translation of wavefront shaping techniques. Here, we demonstrate a guidestar mechanism that relies on magnetic modulation of small particles. This guidestar method features an optical modulation efficiency of 29% and enables micrometer-scale focusing inside biological tissue with a peak intensity-to-background ratio (PBR) of 140; both numbers are one order of magnitude higher than those achieved with the ultrasound guidestar, a popular guidestar method. We also demonstrate that light can be focused on cells labeled with magnetic particles, and to different target locations by magnetically controlling the position of a particle. Since magnetic fields have a large penetration depth even through bone structures like the skull, this optical focusing method holds great promise for deep-tissue applications such as optogenetic modulation of neurons, targeted light-based therapy, and imaging.

Carcinomas constitute over 80% of all human cancer types with no effective therapy for metastatic disease. Here, we demonstrate, for the first time, the efficacy of therapeutic-ultrasound (TUS) to deliver a human tumor suppressor gene, hSef-b, to prostate tumors in vivo. Sef is downregulated in various human carcinomas, in a manner correlating with tumor aggressiveness. In vitro, hSef-b inhibited proliferation of TRAMP C2 cells and attenuated activation of ERK/MAPK and the master transcription factor NF-κB in response to FGF and IL-1/TNF, respectively. In vivo, transfection efficiency of a plasmid co-expressing hSef-b/eGFP into TRAMP C2 tumors was 14.7 ± 2.5% following a single TUS application. Repeated TUS treatments with hSef-b plasmid, significantly suppressed prostate tumor growth (60%) through inhibition of cell proliferation (60%), and reduction in blood vessel density (56%). In accordance, repeated TUS-treatments with hSef-b significantly inhibited in vivo expression of FGF2 and MMP-9. FGF2 is a known mitogen, and both FGF2/MMP-9 are proangiogenic factors. Taken together our results strongly suggest that hSef-b acts in a cell autonomous as well as non-cell autonomous manner. Moreover, the study demonstrates the efficacy of non-viral TUS-based hSef-b gene delivery approach for the treatment of prostate cancer tumors, and possibly other carcinomas where Sef is downregulated.

Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co-treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo . 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis. Our findings suggest that a combination therapy of IL-6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Mesenchymal stem cells (MSCs) hold tremendous potential as a targeted cell-based delivery platform for inflammatory and cancer therapy. Genetic manipulation of MSCs, however, is challenging, and therefore, most studies using MSCs as therapeutic cell carriers have utilized viral vectors to transduce the cells. Here, we demonstrate, for the first time, an alternative approach for the efficient transfection of MSCs; therapeutic ultrasound (TUS). Using TUS with low intensities and moderate frequencies, MSCs were transfected with a pDNA encoding for PEX, a protein that inhibits tumor angiogenesis, and studied as a cell vehicle for in vivo tumor therapy. TUS application did not alter the MSCs' stemness or their homing capabilities, and the transfected MSCs transcribed biologically active PEX. Additionally, in a mouse model, 70% inhibition of prostate tumor growth was achieved following a single I.V. administration of MSCs that were TUS-transfected with pPEX. Further, the repeated I.V. administration of TUS-pPEX transfected-MSCs enhanced tumor inhibition up to 84%. Altogether, these results provide a proof of concept that TUS-transfected MSCs can be effectively used as a cell-based delivery approach for the prospective treatment of cancer., Competing Interests: The authors declare no competing financial interests.

Radiofrequency (RF) ablation requires a complex set of devices as well as profound electrophysiological experience and substantial knowledge of physical science basics. To establish RF ablation in-vitro teaching-system, six workstations were equipped with computer-controlled RF ablation generators. Universal connection boxes allow ablation-essays with catheters of different make and model. Special wetlabs were developed combining a basin containing isotonic saline solution with a thermostat and a pump to simulate blood flow. This hands-on teaching system can be used to demonstrate differences in lesion-forming dependent on tip-electrodes, sensor technology and ablation techniques, influence of blood flow and electrode-angle to the myocardium. It was also utilized to reproduce industrial in-vitro tests.

Background: The Ebola outbreak in West Africa has infected at least 27,443 individuals and killed 11,207, based on data until 24 June, 2015, released by the World Health Organization (WHO). This outbreak has been characterised by extensive geographic spread across the affected countries Guinea, Liberia and Sierra Leone, and by localized hotspots within these countries. The rapid recognition and quantitative assessment of localised areas of higher transmission can inform the optimal deployment of public health resources., Methods: A variety of mathematical models have been used to estimate the evolution of this epidemic, and some have pointed out the importance of the spatial heterogeneity apparent from incidence maps. However, little is known about the district-level transmission. Given that many response decisions are taken at sub-national level, the current study aimed to investigate the spatial heterogeneity by using a different modelling framework, built on publicly available data at district level. Furthermore, we assessed whether this model could quantify the effect of intervention measures and provide predictions at a local level to guide public health action. We used a two-stage modelling approach: a) a flexible spatiotemporal growth model across all affected districts and b) a deterministic SEIR compartmental model per district whenever deemed appropriate., Findings: Our estimates show substantial differences in the evolution of the outbreak in the various regions of Guinea, Liberia and Sierra Leone, illustrating the importance of monitoring the outbreak at district level. We also provide an estimate of the time-dependent district-specific effective reproduction number, as a quantitative measure to compare transmission between different districts and give input for informed decisions on control measures and resource allocation. Prediction and assessing the impact of control measures proved to be difficult without more accurate data. In conclusion, this study provides us a useful tool at district level for public health, and illustrates the importance of collecting and sharing data.

Background: The prognosis for renal cell carcinoma (RCC) is related to a high rate of metastasis, including 30% of bone metastasis. Characteristic for bone tissue is a high concentration of calcium ions. In this study, we show a promoting effect of an enhanced extracellular calcium concentration on mechanisms of bone metastasis via the calcium-sensing receptor (CaSR) and its downstream signaling molecules., Methods: Our analyses were performed using 33 (11/category) matched specimens of normal and tumor tissue and 9 (3/category) primary cells derived from RCC patients of the 3 categories: non-metastasized, metastasized into the lung and metastasized into bones during a five-year period after nephrectomy. Expression of CaSR was determined by RT-PCR, Western blot analyses and flow cytometry, respectively. Cells were treated by calcium and the CaSR inhibitor NPS 2143. Cell migration was measured in a Boyden chamber with calcium (10 μM) as chemotaxin and proliferation by BrdU incorporation. The activity of intracellular signaling mediators was quantified by a phospho-kinase array and Western blot., Results: The expression of CaSR was highest in specimens and cells of patients with bone metastases. Calcium treatment induced an increased migration (19-fold) and proliferation (2.3-fold) exclusively in RCC cells from patients with bone metastases. The CaSR inhibitor NPS 2143 elucidated the role of CaSR on the calcium-dependent effects. After treatment with calcium, the activity of AKT, PLCγ-1, p38α and JNK was clearly enhanced and PTEN expression was almost completely abolished in bone metastasizing RCC cells., Conclusions: Our results indicate a promoting effect of extracellular calcium on cell migration and proliferation of bone metastasizing RCC cells via highly expressed CaSR and its downstream signaling pathways. Consequently, CaSR may be regarded as a new prognostic marker predicting RCC bone metastasis.

Nonviral gene delivery methods encounter major barriers in plasmid DNA (pDNA) trafficking toward the nucleus. The present study aims to understand the role and contribution of therapeutic ultrasound (TUS), if any, in pDNA trafficking in primary cells such as fibroblasts and cell lines (e.g., baby hamster kidney [BHK]) during the transfection process. Using compounds that alter the endocytic pathways and the cytoskeletal network, we show that after TUS application, pDNA trafficking in the cytoplasm is not mediated by endocytosis or by the cytoskeletal network. Transfection studies and confocal analyses showed that the actin fibers impeded TUS-mediated transfection in BHK cells, but not in fibroblasts. Flow cytometric analyses indicated that pDNA uptake by cells occurs primarily when the pDNA is added before and not after TUS application. Taken together, these results suggest that TUS by itself operates as a mechanical force driving the pDNA through the cell membrane, traversing the cytoplasmic network and into the nucleus.