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Abstract Background Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed. Methods To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC. Results We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines. Conclusion The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.

This study evaluated the in vivo therapeutic efficacy of oncolytic serotype 5 adenovirus TAV255 in CAR-deficient tumors. In vitro experiments were performed with cell lines that expressed different levels of CAR (HEK293, A549, CT26, 4T1, and MCF-7). Low CAR cells, such as CT26, were poorly transduced by Ad in vitro unless the adenovirus was encapsulated in liposomes. However, the CT26 tumor in an immune-competent mouse model responded to the unencapsulated TAV255; 33% of the tumors were induced into complete remission, and mice with complete remission rejected the rechallenge with cancer cell injection. Encapsulation of TAV255 improves its therapeutic efficacy by transducing more CT26 cells, as expected from in vitro results. In a bilateral tumor model, nonencapsulated TAV255 reduced the growth rate of the locally treated tumors but had no effect on the growth rate of the distant tumor site. Conversely, encapsulated TAV255-infected CT26 induced a delayed growth rate of both the primary injected tumor and the distant tumor, consistent with a robust immune response. In vivo, intratumorally injected unencapsulated adenoviruses infect CAR-negative cells with only limited efficiency. However, unencapsulated adenoviruses robustly inhibit the growth of CAR-deficient tumors, an effect that constitutes an 'in situ vaccination' by stimulating cytotoxic T cells.

Compact millimeter-wave arrays demand novel packaging solutions that feature low-cost dielectric materials with significant thermal conductivity ($\sim$100 W/m ⋅ K). To characterize the permittivity and loss tangent of the dielectric materials above 100 GHz, free-space characterization is proposed to avoid de-embedding conductor losses. We review current approaches for characterization to investigate the properties of ultradense diamond composite materials at D-band. We compare free-space calibration multiple methods to extract the permittivity and loss tangent. Time-domain gating is employed to reduce the uncertainty in the free space characterization. Material characterizations of the dielectric constant and loss tangent include pure polymer TMPTA, PDMS, TMPTA-based, PDMS-based diamond composites as well as quartz and sapphire wafers for calibration from 120–160 GHz. To the author's knowledge, this is the first characterization of diamond composites for thermally conductive dielectric packaging requirements at D-band.

Adenovirus (Ad) is a widely studied viral vector for cancer therapy as it can be engineered to cause selective lysis of cancer cells. However, Ad delivery is limited in treating cancers that do not have coxsackievirus and adenovirus receptors (CAR). To overcome this challenge, Ad-encapsulated liposomes were developed that enhance the delivery of Ads and increase therapeutic efficacy. Cationic empty liposomes were manufactured first, to which an anionic Ad were added, which resulted in encapsulated Ad liposomes through charge interaction. Optimization of the liposome formula was carried out with series of formulation variables experiments using an extrusion process, which is ideal for laboratory-scale small batches. Later, the optimized formulation was manufactured with a homogenization technique-A high shear rotor-stator blending, that is ideal for large-scale manufacturing and is in compliance with Good Manufacturing Practices (GMP). Comparative in vitro transduction, physicochemical characterization, long-term storage stability at different temperature conditions, and in vivo animal studies were performed. Ad encapsulated liposomes transduced CAR deficient cells 100-fold more efficiently than the unencapsulated Ad (p ≤ 0.0001) in vitro, and 4-fold higher in tumors injected in nude mice in vivo. Both extrusion and homogenization performed similarly-with equivalent in vitro and in vivo transduction efficiencies, physicochemical characterization, and long-term storage stability. Thus, two Ad encapsulated liposomes preparation methods used herein, i.e., extrusion vs. homogenization were equivalent in terms of enhanced Ad performance and long-term storage stability; this will, hopefully, facilitate translation to the clinic.

[This corrects the article DOI: 10.1039/D1NA00230A.].

Density functional theory (DFT) is employed to investigate ferroelectric (FE) hafnium-zirconium oxide stack models for both metal-insulator-metal (MIM) and metal-insulator-semiconductor (MIS) structures. The role of dielectric (DE) interlayers at the ferroelectric interfaces with metals and semiconductors and the effects of thickness scaling of FE and DE layers were investigated using atomic stack models. A high internal field is induced in the FE and DE layers by the FE polarization field which can promote defect generation leading to limited endurance. It is also shown that device operation will be adversely affected by too thick DE interlayers due to high operating voltage. These DFT models elucidate the underlying mechanisms of the lower endurance in experimental MIS devices compared to MIM devices and provide insights into the fundamental mechanisms at the interfaces.

Mono- or dual-checkpoint inhibitors for immunotherapy have changed the paradigm of cancer care; however, only a minority of patients responds to such treatment. Combining small molecule immuno-stimulators can improve treatment efficacy, but they are restricted by poor pharmacokinetics. In this study, TLR7 agonists conjugated onto silica nanoparticles showed extended drug localization after intratumoral injection. The nanoparticle-based TLR7 agonist increased immune stimulation by activating the TLR7 signaling pathway. When treating CT26 colon cancer, nanoparticle conjugated TLR7 agonists increased T cell infiltration into the tumors by > 4× and upregulated expression of the interferon γ gene compared to its unconjugated counterpart by ~2×. Toxicity assays established that the conjugated TLR7 agonist is a safe agent at the effective dose. When combined with checkpoint inhibitors that target programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a 10-100× increase in immune cell migration was observed; furthermore, 100 mm3 tumors were treated and a 60% remission rate was observed including remission at contralateral non-injected tumors. The data show that nanoparticle based TLR7 agonists are safe and can potentiate the effectiveness of checkpoint inhibitors in immunotherapy resistant tumor models and promote a long-term specific memory immune function.

Silicon germanium (SiGe) is a multifunctional material considered for quantum computing, neuromorphic devices, and CMOS transistors. However, implementation of SiGe in nanoscale electronic devices necessitates suppression of surface states dominating the electronic properties. The absence of a stable and passive surface oxide for SiGe results in the formation of charge traps at the SiGe-oxide interface induced by GeOx. In an ideal ALD process in which oxide is grown layer by layer, the GeOx formation should be prevented with selective surface oxidation (i.e., formation of an SiOx interface) by controlling the oxidant dose in the first few ALD cycles of the oxide deposition on SiGe. However, in a real ALD process, the interface evolves during the entire ALD oxide deposition due to diffusion of reactant species through the gate oxide. In this work, this diffusion process in nonideal ALD is investigated and exploited: the diffusion through the oxide during ALD is utilized to passivate the interfacial defects by employing ozone as a secondary oxidant. Periodic ozone exposure during gate oxide ALD on SiGe is shown to reduce the integrated trap density (Dit) across the band gap by nearly 1 order of magnitude in Al2O3 (

Silica particles are convenient ultrasound imaging contrast agents because of their long imaging time and ease of modification; however, they require a relatively high insonation power for imaging and have low biodegradability. In this study, 2 μm ultrathin asymmetric hollow silica particles doped with iron (III) (Fe(III)-SiO2) are synthesized to produce biodegradable hard shelled particles with a low acoustic power threshold comparable with commercial soft microbubble contrast agents (Definity) yet with much longer in vivo ultrasound imaging time. Furthermore, high intensity focused ultrasound ablation enhancement with these particles shows a 2.5-fold higher temperature elevation than with Definity at the same applied power. The low power visualization improves utilization of the silica shells as an adjuvant in localized immunotherapy. The data are consistent with asymmetric engineering of hard particle properties that improve functionality of hard versus soft particles.

Suppression of electronic defects induced by GeO x at the high- k gate oxide/SiGe interface is critical for implementation of high-mobility SiGe channels in complementary metal-oxide-semiconductor (CMOS) technology. Theoretical and experimental studies have shown that a low defect density interface can be formed with an SiO x-rich interlayer on SiGe. Experimental studies in the literature indicate a better interface formation with Al2O3 in contrast to HfO2 on SiGe; however, the mechanism behind this is not well understood. In this study, the mechanism of forming a low defect density interface between Al2O3/SiGe is investigated using atomic layer deposited (ALD) Al2O3 insertion into or on top of ALD HfO2 gate oxides. To elucidate the mechanism, correlations are made between the defect density determined by impedance measurements and the chemical and physical structures of the interface determined by high-resolution scanning transmission electron microscopy and electron energy loss spectroscopy. The compositional analysis reveals an SiO x rich interlayer for both Al2O3/SiGe and HfO2/SiGe interfaces with the insertion of Al2O3 into or on top of the HfO2 oxide. The data is consistent with the Al2O3 insertion inducing decomposition of the GeO x from the interface to form an electrically passive, SiO x rich interface on SiGe. This mechanism shows that nanolaminate gate oxide chemistry cannot be interpreted as resulting from a simple layer-by-layer ideal ALD process, because the precursor or its reaction products can diffuse through the oxide during growth and react at the semiconductor interface. This result shows that in scaled CMOS, remote oxide ALD (oxide ALD on top of the gate oxide) can be used to suppress electronic defects at gate oxide semiconductor interfaces by oxygen scavenging.

PurposeIn this study, the efficacy of transurethral prostate ablation in the presence of silica-shell ultrasound-triggered phase-shift emulsions (sUPEs) doped with MR contrast was evaluated. The influence of sUPEs on MR imaging assessment of the ablation zone was also investigated.MethodssUPEs were doped with a magnetic resonance (MR) contrast agent, Gd2 O3 , to assess ultrasound transition. Injections of saline (sham), saline and sUPEs alone, and saline and sUPEs with Optison microbubbles were performed under guidance of a prototype interventional MRI navigation platform in a healthy canine prostate. Treatment arms were evaluated for differences in lesion size, T1  contrast, and temperature. In addition, non-perfused areas (NPAs) on dynamic contrast-enhanced (DCE) MRI, 55°C isotherms, and areas of 240 cumulative equivalent minutes at 43°C (CEM43 ) dose or greater computed from MR thermometry were measured and correlated with ablated areas indicated by histology.ResultsFor treatment arms including sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55°C isotherm, and 240 CEM43 area ranged from 0.96-0.99, 0.98-0.99, and 0.91-0.99, respectively. In the absence of sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55°C isotherm, and 240 CEM43 area were 0.69, 0.54, and 0.50, respectively. Across all treatment arms, the areas of thermal tissue damage and NPAs were not significantly different (P = 0.47). Areas denoted by 55°C isotherms and 240 CEM43 dose boundaries were significantly larger than the areas of thermal damage, again for all treatment arms (P = 0.009 and 0.003, respectively). No significant differences in lesion size, T1 contrast, or temperature were observed between any of the treatment arms (P > 0.0167). Lesions exhibiting thermal fixation on histological analysis were present in six of nine insonations involving sUPE injections and one of five insonations involving saline sham injections. Significantly larger areas (P = 0.002), higher temperatures (P = 0.004), and more frequent ring patterns of restricted diffusion on ex vivo diffusion-weighted imaging (P = 0.005) were apparent in lesions with thermal fixation.ConclusionsT1 contrast suggesting sUPE transition was not evident in sUPE treatment arms. The use of MR imaging metrics to predict prostate ablation was not diminished by the presence of sUPEs. Lesions generated in the presence of sUPEs exhibited more frequent thermal fixation, though there were no significant changes in the ablation areas when comparing arms with and without sUPEs. Thermal fixation corresponded to some qualitative imaging features.

Treeline advance is a well-established response of treeline ecotones to climate change. However, the degree to which tree growth and establishment drives treeline movement is widely debated. We used geographic information system (GIS) analysis of aerial photographs and dendrochronological analysis of tree growth and age structure to examine treeline dynamics on Pikes Peak (Colorado). The rate of treeline advance at the site (1938-2017) was 0.235 m [year.sup.-1], and it accelerated through time. Several sites have transformed from abrupt to diffuse topology. Regional temperatures significantly increased after the 1890s, particularly in the last half-century. Tree growth was inhibited by late spring snow in the 1935-1985 window and enhanced by growing season temperature in the 1965-2009 window. Tree establishment above treeline appears to have transformed treeline topology and set up the potential for further treeline advance. We conclude that if current climatic trends and system relationships continue, treeline should continue to advance because (i) there are large numbers of seedlings and saplings above the treeline due to continuous significant seedling recruitment and (ii) growth of trees in the treeline ecotone is positively related to growing season temperatures, which are increasing. Other limits to the system, such as drought or topographic barriers, may arise in the future. Key words: treeline advance, tree establishment, tree growth, GIS. L'avancee de la limite des arbres est une reaction au changement climatique bien connue des ecotones de la limite des arbres. Cependant, la mesure dans laquelle l'etablissement et la croissance des arbres determinent le mouvement de la limite des arbres fait l'objet d'un vaste debat. Nous avons utilise l'analyse de photographies aeriennes a l'aide d'un systeme d'information geographique (SIG) et l'analyse dendrochronologique de la croissance et de la structure d'age des arbres pour etudier la dynamique de la limite des arbres au Pic Pikes, dans l'Etat du Colorado. Le taux de deplacement de la limite des arbres au site d'etude (1938-2017) etait de 0,235 m [an.sup.-1] et a augmente avec le temps. Plusieurs sites se sont transformes, passant d'une topologie abrupte a diffuse. Les temperatures regionales ont significativement augmente apres les annees 1890, particulierement au cours du dernier demi-siecle. La croissance des arbres a ete inhibee par la neige tardive au printemps durant la periode de 1935 a 1985 et favorisee par la temperature durant la saison de croissance durant la periode de 1965 a 2009. L'etablissement des arbres au-dela de la limite des arbres semble avoir transforme la topologie de la limite des arbres et enclenche la possibilite d'une avancee ulterieure de la limite des arbres. En conclusion, si les tendances courantes du climat et des relations du systeme persistent, la limite des arbres devrait continuer a avancer parce que : (i) il y a un grand nombre de semis et de gaules au-dela de la limite des arbres a cause du recrutement important et continu de semis et (ii) la croissance des arbres dans l'ecotone de la limite des arbres est positivement reliee a la temperature qui va en augmentant durant la saison de croissance. D'autres limites du systeme, telles que la secheresse ou des barrieres topographiques, pourraient survenir dans le futur. [Traduit par la Redaction] Mots-cles: avancee de la limite des arbres, etablissement des arbres, croissance des arbres, SIG., Introduction As average global temperature continues to increase (IPCC 2018), ecosystems that have climatically constrained boundaries are beginning to undergo significant geographical shifts (Walther et al. 2002). The alpine treeline [...]

Purpose To assess the performance of computer-aided diagnosis (CAD) systems and to determine the dominant ultrasonographic (US) features when classifying benign versus malignant focal liver lesions (FLLs) by using contrast material-enhanced US cine clips. Materials and Methods One hundred six US data sets in all subjects enrolled by three centers from a multicenter trial that included 54 malignant, 51 benign, and one indeterminate FLL were retrospectively analyzed. The 105 benign or malignant lesions were confirmed at histologic examination, contrast-enhanced computed tomography (CT), dynamic contrast-enhanced magnetic resonance (MR) imaging, and/or 6 or more months of clinical follow-up. Data sets included 3-minute cine clips that were automatically corrected for in-plane motion and automatically filtered out frames acquired off plane. B-mode and contrast-specific features were automatically extracted on a pixel-by-pixel basis and analyzed by using an artificial neural network (ANN) and a support vector machine (SVM). Areas under the receiver operating characteristic curve (AUCs) for CAD were compared with those for one experienced and one inexperienced blinded reader. A third observer graded cine quality to assess its effects on CAD performance. Results CAD, the inexperienced observer, and the experienced observer were able to analyze 95, 100, and 102 cine clips, respectively. The AUCs for the SVM, ANN, and experienced and inexperienced observers were 0.883 (95% confidence interval [CI]: 0.793, 0.940), 0.829 (95% CI: 0.724, 0.901), 0.843 (95% CI: 0.756, 0.903), and 0.702 (95% CI: 0.586, 0.782), respectively; only the difference between SVM and the inexperienced observer was statistically significant. Accuracy improved from 71.3% (67 of 94; 95% CI: 60.6%, 79.8%) to 87.7% (57 of 65; 95% CI: 78.5%, 93.8%) and from 80.9% (76 of 94; 95% CI: 72.3%, 88.3%) to 90.3% (65 of 72; 95% CI: 80.6%, 95.8%) when CAD was in agreement with the inexperienced reader and when it was in agreement with the experienced reader, respectively. B-mode heterogeneity and contrast material washout were the most discriminating features selected by CAD for all iterations. CAD selected time-based time-intensity curve (TIC) features 99.0% (207 of 209) of the time to classify FLLs, versus 1.0% (two of 209) of the time for intensity-based features. None of the 15 video-quality criteria had a statistically significant effect on CAD accuracy-all P values were greater than the Holm-Sidak α-level correction for multiple comparisons. Conclusion CAD systems classified benign and malignant FLLs with an accuracy similar to that of an expert reader. CAD improved the accuracy of both readers. Time-based features of TIC were more discriminating than intensity-based features. © RSNA, 2017 Online supplemental material is available for this article.

An on-demand long-lived ultrasound contrast agent that can be activated with single pulse stimulated imaging (SPSI) has been developed using hard shell liquid perfluoropentane filled silica 500-nm nanoparticles for tumor ultrasound imaging. SPSI was tested on LnCAP prostate tumor models in mice; tumor localization was observed after intravenous (IV) injection of the contrast agent. Consistent with enhanced permeability and retention, the silica nanoparticles displayed an extended imaging lifetime of 3.3±1 days (mean±standard deviation). With added tumor specific folate functionalization, the useful lifetime was extended to 12 ± 2 days; in contrast to ligand-based tumor targeting, the effect of the ligands in this application is enhanced nanoparticle retention by the tumor. This paper demonstrates for the first time that IV injected functionalized silica contrast agents can be imaged with an in vivo lifetime ~500 times longer than current microbubble-based contrast agents. Such functionalized long-lived contrast agents may lead to new applications in tumor monitoring and therapy.

This study evaluated the in vivo therapeutic efficacy of oncolytic serotype 5 adenovirus TAV255 in CAR-deficient tumors. In vitro experiments were performed with cell lines that expressed different levels of CAR (HEK293, A549, CT26, 4T1, and MCF-7). Low CAR cells, such as CT26, were poorly transduced by Ad in vitro unless the adenovirus was encapsulated in liposomes. However, the CT26 tumor in an immune-competent mouse model responded to the unencapsulated TAV255; 33% of the tumors were induced into complete remission, and mice with complete remission rejected the rechallenge with cancer cell injection. Encapsulation of TAV255 improves its therapeutic efficacy by transducing more CT26 cells, as expected from in vitro results. In a bilateral tumor model, nonencapsulated TAV255 reduced the growth rate of the locally treated tumors but had no effect on the growth rate of the distant tumor site. Conversely, encapsulated TAV255-infected CT26 induced a delayed growth rate of both the primary injected tumor and the distant tumor, consistent with a robust immune response. In vivo, intratumorally injected unencapsulated adenoviruses infect CAR-negative cells with only limited efficiency. However, unencapsulated adenoviruses robustly inhibit the growth of CAR-deficient tumors, an effect that constitutes an ‘in situ vaccination’ by stimulating cytotoxic T cells.

Integration of transition metal dichalcogenides (TMDs) into next-generation semiconductor platforms has been limited due to a lack of effective passivation techniques for defects in TMDs. The formation of an organic-inorganic van der Waals interface between a monolayer (ML) of titanyl phthalocyanine (TiOPc) and a ML of MoS2 is investigated as a defect passivation method. A strong negative charge transfer from MoS2 to TiOPc molecules is observed in scanning tunneling microscopy. As a result of the formation of a van der Waals interface, the ION/IOFF in back-gated MoS2 transistors increases by more than two orders of magnitude, whereas the degradation in the photoluminescence signal is suppressed. Density functional theory modeling reveals a van der Waals interaction that allows sufficient charge transfer to remove defect states in MoS2. The present organic-TMD interface is a model system to control the surface/interface states in TMDs by using charge transfer to a van der Waals bonded complex.

The combination of near-infrared (NIR) and visible wavelengths in light microscopy for biological studies is increasingly common. For example, many fields of biology are developing the use of NIR for optogenetics, in which an NIR laser induces a change in gene expression and/or protein function. One major technical barrier in working with both NIR and visible light on an optical microscope is obtaining their precise coalignment at the imaging plane position. Photon upconverting particles (UCPs) can bridge this gap as they are excited by NIR light but emit in the visible range via an anti-Stokes luminescence mechanism. Here, two different UCPs have been identified, high-efficiency micro540-UCPs and lower efficiency nano545-UCPs, that respond to NIR light and emit visible light with high photostability even at very high NIR power densities (>25 000 Suns). Both of these UCPs can be rapidly and reversibly excited by visible and NIR light and emit light at visible wavelengths detectable with standard emission settings used for Green Fluorescent Protein (GFP), a commonly used genetically encoded fluorophore. However, the high efficiency micro540-UCPs were suboptimal for NIR and visible light coalignment, due to their larger size and spatial broadening from particle-to-particle energy transfer consistent with a long-lived excited state and saturated power dependence. In contrast, the lower efficiency nano-UCPs were superior for precise coalignment of the NIR beam with the visible light path (∼2 μm versus ∼8 μm beam broadening, respectively) consistent with limited particle-to-particle energy transfer, superlinear power dependence for emission, and much smaller particle size. Furthermore, the nano-UCPs were superior to a traditional two-camera method for NIR and visible light path alignment in an in vivo Infrared-Laser-Evoked Gene Operator (IR-LEGO) optogenetics assay in the budding yeast Saccharomyces cerevisiae. In summary, nano-UCPs are powerful new tools for coaligning NIR and visible light paths on a light microscope.