Patient-derived tumor models are the new standard for pre-clinical drug testing and biomarker discovery. However, the emerging technology of primary pancreatic cancer organoids has not yet been ...broadly implemented in research, and complex organotypic models using organoids in co-culture with stromal and immune cellular components of the tumor have yet to be established. In this study, our objective was to develop and characterize pancreatic cancer organoids and multi-cell type organotypic co-culture models to demonstrate their applicability to the study of pancreatic cancer.
We employed organoid culture methods and flow cytometric, cytologic, immunofluorescent and immunohistochemical methods to develop and characterize patient-derived pancreatic cancer organoids and multi-cell type organotypic co-culture models of the tumor microenvironment.
We describe the culture and characterization of human pancreatic cancer organoids from resection, ascites and rapid autopsy sources and the derivation of adherent tumor cell monocultures and tumor-associated fibroblasts from these sources. Primary human organoids displayed tumor-like cellular morphology, tissue architecture and polarity in contrast to cell line spheroids, which formed homogenous, non-lumen forming spheres. Importantly, we demonstrate the construction of complex organotypic models of tumor, stromal and immune components of the tumor microenvironment. Activation of myofibroblast-like cancer associated fibroblasts and tumor-dependent lymphocyte infiltration were observed in these models.
These studies provide the first report of novel and disease-relevant 3D in-vitro models representing pancreatic tumor, stromal and immune components using primary organoid co-cultures representative of the tumor-microenvironment. These models promise to facilitate the study of tumor-stroma and tumor-immune interaction and may be valuable for the assessment of immunotherapeutics such as checkpoint inhibitors in the context of T-cell infiltration.
Single-nanowire solar cells were created by forming rectifying junctions in electrically contacted vapor-liquid-solid-grown Si nanowires. The nanowires had diameters in the range of 200 nm to 1.5 ...microm. Dark and light current-voltage measurements were made under simulated Air Mass 1.5 global illumination. Photovoltaic spectral response measurements were also performed. Scanning photocurrent microscopy indicated that the Si nanowire devices had minority carrier diffusion lengths of approximately 2 microm. Assuming bulk-dominated recombination, this value corresponds to a minimum carrier lifetime of approximately 15 ns, or assuming surface-dominated recombination, to a maximum surface recombination velocity of approximately 1350 cm s(-1). The methods described herein comprise a valuable platform for measuring the properties of semiconductor nanowires, and are expected to be instrumental when designing an efficient macroscopic solar cell based on arrays of such nanostructures.
Abstract Background Percutaneous needle core biopsy has become established in the management of small renal masses ≤4 cm (SRMs). Recent series have reported success rates of ≥80%. Nondiagnostic ...results continue to be problematic. Objective To determine the results of SRM biopsy and the outcomes of nondiagnostic biopsy and repeat biopsy. Design, setting, and participants Patients undergoing renal tumor biopsy (RTB) for suspected renal cell carcinoma (RCC) were included in a prospectively maintained database. Measurements The database was analyzed retrospectively to determine the pathology and outcomes of SRM biopsy. Outcomes of patients with nondiagnostic biopsy were determined. Patients undergoing repeat biopsy were identified and their outcomes analyzed. Results and limitations Three hundred forty-five biopsies were performed (mean diameter: 2.5 cm). Biopsy was diagnostic in 278 cases (80.6%) and nondiagnostic in 67 cases (19.4%). Among diagnostic biopsies, 221 (79.4%) were malignant, 94.1% of which were RCC. Histologic subtyping and grading of RCC was possible in 88.0% and 63.5% of cases, respectively. Repeat biopsy was performed in 12 of the 67 nondiagnostic cases, and a diagnosis was possible in 10 (83.3%). Eight lesions were malignant and two were oncocytic neoplasms. Pathology was available for 15 masses after initial nondiagnostic biopsy; 11 (73%) were malignant. Larger tumor size and a solid nature on imaging predicted a successful biopsy on multivariate analysis. Grade 1 complications were experienced in 10.1% of cases, with no major bleeding and no seeding of the biopsy tract. There was one grade 3a complication (0.3%). This is a retrospective study and some data are unavailable on factors that may affect biopsy success rates. Repeat biopsy was not standard practice prior to this analysis. Conclusions RTB can be performed safely and accurately in the investigation of renal masses ≤4 cm. A nondiagnostic biopsy should not be considered a surrogate for the absence of malignancy. Repeat biopsy can be performed with similar accuracy, providing a diagnosis for most patients.
Carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are a growing threat. The objective of this study was to describe CRAB and CRPA epidemiology ...and identify factors associated with mortality and length of stay (LOS) post-culture.
This was a national retrospective cohort study of Veterans with CRAB or CRPA positive cultures from 2013 to 2018, conducted at Hines Veterans Affairs Hospital. Carbapenem resistance was defined as non-susceptibility to imipenem, meropenem and/or doripenem. Multivariable cluster adjusted regression models were fit to assess the association of post-culture LOS among inpatient and long-term care (LTC) and to identify factors associated with 90-day and 365-day mortality after positive CRAB and CRPA cultures.
CRAB and CRPA were identified in 1,048 and 8,204 unique patients respectively, with 90-day mortality rates of 30.3% and 24.5% and inpatient post-LOS of 26 and 27 days. Positive blood cultures were associated with an increased odds of 90-day mortality compared to urine cultures in patients with CRAB (OR 6.98, 95% CI 3.55-13.73) and CRPA (OR 2.82, 95% CI 2.04-3.90). In patients with CRAB and CRPA blood cultures, higher Charlson score was associated with increased odds of 90-day mortality. In CRAB and CRPA, among patients from inpatient care settings, blood cultures were associated with a decreased LOS compared to urine cultures.
Positive blood cultures and more comorbidities were associated with higher odds for mortality in patients with CRAB and CRPA. Recognizing these factors would encourage clinicians to treat these patients in a timely manner to improve outcomes of patients infected with these organisms.
•We compare isogeometric collocation (IGA-C) with isogeometric Galerkin and FEA.•Of particular interest are quadrature cost and accuracy vs. computing time.•IGA-C has the potential to offer a more ...efficient alternative to existing technology.•Motivated by the two-scale relation of B-splines we introduce the concept of weighted collocation.•Its combination with hierarchical refinement of NURBS leads to efficient and robust adaptive IGA-C.
We compare isogeometric collocation with isogeometric Galerkin and standard C0 finite element methods with respect to the cost of forming the matrix and residual vector, the cost of direct and iterative solvers, the accuracy versus degrees of freedom and the accuracy versus computing time. On this basis, we show that isogeometric collocation has the potential to increase the computational efficiency of isogeometric analysis and to outperform both isogeometric Galerkin and standard C0 finite element methods, when a specified level of accuracy is to be achieved with minimum computational cost. We then explore an adaptive isogeometric collocation method that is based on local hierarchical refinement of NURBS basis functions and collocation points derived from the corresponding multi-level Greville abscissae. We introduce the concept of weighted collocation that can be consistently developed from the weighted residual form and the two-scale relation of B-splines. Using weighted collocation in the transition regions between hierarchical levels, we are able to reliably handle coincident collocation points that naturally occur for multi-level Greville abscissae. The resulting method combines the favorable properties of isogeometric collocation and hierarchical refinement in terms of computational efficiency, local adaptivity, robustness and straightforward implementation, which we illustrate by numerical examples in one, two and three dimensions.
► Hierarchical refinement of NURBS offers full analysis suitability, straightforward implementation and simple generalization to 3D. ► We first explore local hierarchical refinement for adaptive ...NURBS-based IGA. ► We then combine the B-spline version of the FCM and hierarchical refinement for a seamless design-through-analysis integration of 3D T-spline surface based models.
We explore hierarchical refinement of NURBS as a basis for adaptive isogeometric and immersed boundary analysis. We use the principle of B-spline subdivision to derive a local refinement procedure, which combines full analysis suitability of the basis with straightforward implementation in tree data structures and simple generalization to higher dimensions. We test hierarchical refinement of NURBS for some elementary fluid and structural analysis problems in two and three dimensions and attain good results in all cases. Using the B-spline version of the finite cell method, we illustrate the potential of immersed boundary methods as a seamless isogeometric design-through-analysis procedure for complex engineering parts defined by T-spline CAD surfaces, specifically a ship propeller and an automobile wheel. We show that hierarchical refinement considerably increases the flexibility of this approach by adaptively resolving local features.
Adoptive cell transfers have emerged as a disruptive approach to treat disease in a manner that is more specific than using small-molecule drugs; however, unlike traditional drugs, cells are living ...entities that can alter their function in response to environmental cues. In the present study, we report an engineered particle referred to as a "backpack" that can robustly adhere to macrophage surfaces and regulate cellular phenotypes in vivo. Backpacks evade phagocytosis for several days and release cytokines to continuously guide the polarization of macrophages toward antitumor phenotypes. We demonstrate that these antitumor phenotypes are durable, even in the strongly immunosuppressive environment of a murine breast cancer model. Conserved phenotypes led to reduced metastatic burdens and slowed tumor growths compared with those of mice treated with an equal dose of macrophages with free cytokine. Overall, these studies highlight a new pathway to control and maintain phenotypes of adoptive cellular immunotherapies.
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