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Edible insects are often considered a nutritious, protein-rich, environmentally sustainable alternative to traditional livestock with growing popularity among North American consumers. While the nutrient composition of several insects is characterized, all potential health impacts have not been evaluated. In addition to high protein levels, crickets contain chitin and other fibers that may influence gut health. In this study, we evaluated the effects of consuming 25 grams/day whole cricket powder on gut microbiota composition, while assessing safety and tolerability. Twenty healthy adults participated in this six-week, double-blind, crossover dietary intervention. Participants were randomized into two study arms and consumed either cricket-containing or control breakfast foods for 14 days, followed by a washout period and assignment to the opposite treatment. Blood and stool samples were collected at baseline and after each treatment period to assess liver function and microbiota changes. Results demonstrate cricket consumption is tolerable and non-toxic at the studied dose. Cricket powder supported growth of the probiotic bacterium, Bifidobacterium animalis , which increased 5.7-fold. Cricket consumption was also associated with reduced plasma TNF-α. These data suggest that eating crickets may improve gut health and reduce systemic inflammation; however, more research is needed to understand these effects and underlying mechanisms.

Objectives MRI-based R2* mapping may enable reliable and rapid quantification of liver iron concentration (LIC). However, the performance and reproducibility of R2* across acquisition protocols remain unknown. Therefore, the objective of this work was to evaluate the performance and reproducibility of complex confounder-corrected R2* across acquisition protocols, at both 1.5 T and 3.0 T. Methods In this prospective study, 40 patients with suspected iron overload and 10 healthy controls were recruited with IRB approval and informed written consent and imaged at both 1.5 T and 3.0 T. For each subject, acquisitions included four different R2* mapping protocols at each field strength, and an FDA-approved R2-based method performed at 1.5 T as a reference for LIC. R2* maps were reconstructed from the complex data acquisitions including correction for noise effects and fat signal. For each subject, field strength, and R2* acquisition, R2* measurements were performed in each of the nine liver Couinaud segments and the spleen. R2* measurements were compared across protocols and field strength (1.5 T and 3.0 T), and R2* was calibrated to LIC for each acquisition and field strength. Results R2* demonstrated high reproducibility across acquisition protocols ( p  > 0.05 for 96/108 pairwise comparisons across 2 field strengths and 9 liver segments, ICC > 0.91 for each field strength/segment combination) and high predictive ability (AUC > 0.95 for four clinically relevant LIC thresholds). Calibration of R2* to LIC was LIC = − 0.04 + 2.62 × 10 −2 R2* at 1.5 T and LIC = 0.00 + 1.41 × 10 −2 R2* at 3.0 T. Conclusions Complex confounder-corrected R2* mapping enables LIC quantification with high reproducibility across acquisition protocols, at both 1.5 T and 3.0 T. Key Points • Confounder-corrected R2* of the liver provides reproducible R2* across acquisition protocols, including different spatial resolutions, echo times, and slice orientations, at both 1.5 T and 3.0 T. • For all acquisition protocols, high correlation with R2-based liver iron concentration (LIC) quantification was observed. • The calibration between confounder-corrected R2* and LIC, at both 1.5 T and 3.0 T, is determined in this study.

Background The receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) is overexpressed and an important therapeutic target in Head and Neck cancer (HNC). Cetuximab is currently the only EGFR-targeting agent approved by the FDA for treatment of HNC; however, intrinsic and acquired resistance to cetuximab is a major problem in the clinic. Our lab previously reported that AXL leads to cetuximab resistance via activation of HER3. In this study, we investigate the connection between AXL, HER3, and neuregulin1 (NRG1) gene expression with a focus on understanding how their interdependent signaling promotes resistance to cetuximab in HNC. Methods Plasmid or siRNA transfections and cell-based assays were conducted to test cetuximab sensitivity. Quantitative PCR and immunoblot analysis were used to analyze gene and protein expression levels. Seven HNC patient-derived xenografts (PDXs) were evaluated for protein expression levels. Results We found that HER3 expression was necessary but not sufficient for cetuximab resistance without AXL expression. Our results demonstrated that addition of the HER3 ligand NRG1 to cetuximab-sensitive HNC cells leads to cetuximab resistance. Further, AXL-overexpressing cells regulate NRG1 at the level of transcription, thereby promoting cetuximab resistance. Immunoblot analysis revealed that NRG1 expression was relatively high in cetuximab-resistant HNC PDXs compared to cetuximab-sensitive HNC PDXs. Finally, genetic inhibition of NRG1 resensitized AXL-overexpressing cells to cetuximab. Conclusions The results of this study indicate that AXL may signal through HER3 via NRG1 to promote cetuximab resistance and that targeting of NRG1 could have significant clinical implications for HNC therapeutic approaches.

Background Patient-derived xenografts established from human cancers are important tools for investigating novel anti-cancer therapies. Establishing PDXs requires a significant investment and many PDXs may be used infrequently due to their similarity to existing models, their growth rate, or the lack of relevant mutations. We performed this study to determine whether we could efficiently establish PDXs after cryopreservation to allow molecular profiling to be completed prior to implanting the human cancer. Methods Fresh tumor was split with half used to establish a PDX immediately and half cryopreserved for later implantation. Resulting tumors were assessed histologically and tumors established from fresh or cryopreserved tissues compared as to the growth rate, extent of tumor necrosis, mitotic activity, keratinization, and grade. All PDXs were subjected to short tandem repeat testing to confirm identity and assess similarity between methods. Results Tumor growth was seen in 70% of implanted cases. No growth in either condition was seen in 30% of tumors. One developed a SCC from the immediate implant but a lymphoproliferative mass without SCC from the cryopreserved specimen. No difference in growth rate was seen. No difference between histologic parameters was seen between the two approaches. Conclusions Fresh human cancer tissue can be immediately cryopreserved and later thawed and implanted to establish PDXs. This resource saving approach allows for tumor profiling prior to implantation into animals thus maximizing the probability that the tumor will be utilized for future research.

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible.

Background 2D digital subtraction angiography (DSA) is utilized qualitatively to assess blood velocity changes that occur during arterial interventions. Quantitative angiographic metrics, such as blood velocity, could be used to standardize endpoints during angiographic interventions. Purpose To assess the accuracy and precision of a quantitative 2D DSA (qDSA) technique and to determine its feasibility for in vivo measurements of blood velocity. Materials and methods A quantitative DSA technique was developed to calculate intra-procedural blood velocity. In vitro validation was performed by comparing velocities from the qDSA method and an ultrasonic flow probe in a bifurcation phantom. Parameters of interest included baseline flow rate, contrast injection rate, projection angle, and magnification. In vivo qDSA analysis was completed in five different branches of the abdominal aorta in two 50 kg swine and compared to 4D Flow MRI. Linear regression, Bland-Altman, Pearson’s correlation coefficient and chi squared tests were used to assess the accuracy and precision of the technique. Results In vitro validation showed strong correlation between qDSA and flow probe velocities over a range of contrast injection and baseline flow rates (slope = 1.012, 95% CI [0.989,1.035], Pearson’s r = 0.996, p  < .0001). The application of projection angle and magnification corrections decreased variance to less than 5% the average baseline velocity ( p  = 0.999 and p  = 0.956, respectively). In vivo validation showed strong correlation with a small bias between qDSA and 4D Flow MRI velocities for all five abdominopelvic arterial vessels of interest (slope = 1.01, Pearson’s r = 0.880, p = <.01, Bias = 0.117 cm/s). Conclusion The proposed method allows for accurate and precise calculation of blood velocities, in near real-time, from time resolved 2D DSAs.

Background Time-resolved three-dimensional digital subtraction angiography (4D-DSA) can be used to quantify blood velocity. Contrast pulsatility, a major discriminant on 4D-DSA, is yet to be optimized. We investigated the effects of different imaging and injection parameters on sideband ratio (SBR), a measure of contrast pulsatile strength, within the hepatic vasculature of an in vivo porcine model. Methods Fifty-nine hepatic 4D-DSA procedures were performed in three female domestic swine (mean weight 54 kg). Contrast injections were performed in the common hepatic artery with different combinations of imaging duration (6 s or 12 s), injection rates (from 1.0 to 2.5 mL/s), contrast concentration (50% or 100%), and catheter size (4 Fr or 5 Fr). Reflux was recorded. SBR and vessel cross-sectional areas were calculated in 289 arterial segments. Multiple linear mixed-effects models were estimated to determine the effects of parameters on SBR and cross-sectional vessel area. Results Twelve-second acquisitions yielded a SBR higher than 6 s ( p < 0.001). No significant differences in SBR were seen between different catheter sizes ( p = 0.063) or contrast concentration ( p = 0.907). For higher injection rates (2.5 mL/s), SBR was lower ( p = 0.007) and cross-sectional area was higher ( p < 0.001). Reflux of contrast does not significantly affect SBR ( p = 0.087). Conclusions The strength of contrast pulsatility used for flow quantitation with 4D-DSA can be increased by adjusting injection rates and using longer acquisition times. Reduction of contrast concentration to 50% is feasible and reflux of contrast does not significantly hinder contrast pulsatility.

Longitudinal tumor growth studies serve an essential role in preclinical therapeutic evaluation, acting as precursors to human clinical trials. Despite the prevalence of these experiments, there is little consensus on how best to analyze the resulting data, largely due to under-emphasized data challenges such as non-linearity, censoring, and correlated errors. The overarching goal of this dissertation is to introduce prioritized, composite estimators into the preclinical tumor-growth literature, demonstrate their practical utility, and provide several new statistical derivations that address open methodological questions. Chapter 1 considers a two-arm experiment in which each animal has a single tumor under study. Leveraging common design features, a rank-based test statistic is developed from prioritized composite scores, which combine survival outcomes and longitudinal tumor measurements. The resulting non-parametric test is robust to several of the motivating data challenges, yields a simple and interpretable estimand, and can serve as a unified approach for analyzing tumor growth data. In Chapter 2, we consider the case of a two-arm experiment where each animal may have several tumors under study. Here, we extend our testing framework using a time-dependent win ratio kernel and derive a cluster robust variance estimator for the win ratio by finding its influence functions, using the general theory of statistical functionals. Chapter 3 introduces the proportional odds model as a regression framework for assessing synergy in multi-arm experiments under an independent-data design. The chapter explores theoretical connections between the model and well-known rank-based tests, extends transformations that link regression coefficients to interpretable probability indices, and derives a semiparametric estimating equation based on conditional-likelihood principles. Chapter 4 then considers clustered multi-arm experiments. The time-dependent win-ratio kernel from Chapter 2 is embedded in the proportional win-fractions model, and an asymptotically valid cluster-robust variance estimator is derived for use with clustered tumor-growth designs. Throughout the dissertation, interpretation and implementation of the proposed methods are illustrated using several HPV(+) head and neck squamous cell carcinoma xenograft studies. Accompanying software implementations are demonstrated on these same data sets, with an emphasis on generic functions whose use extends well beyond preclinical applications. Extensive simulation studies evaluate operating characteristics such as power, type I error, bias, and compare the proposed methods with existing approaches. Taken together, the methods developed here provide a simple, interpretable, and data-robust framework for statistically assessing therapeutic benefit in tumor growth studies.

Objective To compare the acute and chronic safety and treatment effects of non-invasive hepatic histotripsy vs. percutaneous microwave (MW) ablation in a healthy porcine model. Methods This was a dual-arm study in which each animal ( n = 14) received either a single hepatic microwave ( n = 6) or histotripsy ( n = 6 single treatment; n = 2 double treatment) under ultrasound guidance. The goal was to create 2.5–3.0 cm short-axis treatments in similar locations across modalities. Animals were survived for 1 month with contrast-enhanced CT imaging on days 0, 2, 7, 14, and 28. On day 28, necropsy and histopathology were performed. Results All procedures were well-tolerated. MW ablation zones were longer and more oblong, but equivalent in the short axes to histotripsy zones on immediate post-procedure CT ( p < 0.001 and p = 0.45, respectively). Overall, MW volumes were larger (21.4 cm 3 vs. 13.4 cm 3 ; p = 0.001) and histotripsy treatment zones were more spherical ( p = 0.007). Histotripsy zones were close to the prescribed size ( p < 0.001). Over the study period, histotripsy treatment zones decreased in volume while microwave ablation zones slightly increased (−83% vs. +17%, p = 0.001). There were several imaging-only findings: Branch portal vein thrombus with both histotripsy (7/8) and MW (6/6), hematoma in 2/6 MW only, and a gallbladder injury in 1/6 MW animals. The ablation zones demonstrated complete cellular destruction for both modalities. Conclusion Histotripsy was associated with more spherical treatments, fewer biliary complications, and greater treatment zone involution. Hepatic MW and histotripsy treatment in a normal porcine model appear at least equally effective for creating treatment zones with a similar safety profile. Key Points • Microwave ablation and histotripsy for liver treatment in a healthy porcine model yield equivalent procedural tolerance and cellular destruction. • Histotripsy was associated with more spherical treatments, fewer biliary complications, and greater treatment zone involution over the 28-day follow-up period. • These findings confirm the safety and efficacy of hepatic histotripsy and support the pursuit of clinical trials to further evaluate the translatability of these results.

ObjectiveThere is no standardized and objective method for determining the optimal treatment endpoint (sub-stasis) during transarterial embolization. The objective of this study was to demonstrate the feasibility of using a quantitative digital subtraction angiography (qDSA) technique to characterize intra-procedural changes in hepatic arterial blood flow velocity in response to transarterial embolization in an in vivo porcine model.Materials and MethodsEight domestic swine underwent bland transarterial embolizations to partial- and sub-stasis angiographic endpoints with intraprocedural DSA acquisitions. Embolized lobes were assessed on histopathology for ischemic damage and tissue embolic particle density. Analysis of target vessels used qDSA and a commercially available color-coded DSA (ccDSA) tool to calculate blood flow velocities and time-to-peak, respectively.ResultsBlood flow velocities calculated using qDSA showed a statistically significant difference (p < 0.01) between partial- and sub-stasis endpoints, whereas time-to-peak calculated using ccDSA did not show a significant difference. During the course of embolizations, the average correlation with volume of particles delivered was larger for qDSA (− 0.86) than ccDSA (0.36). There was a statistically smaller mean squared error (p < 0.01) and larger coefficient of determination (p < 0.01) for qDSA compared to ccDSA. On pathology, the degree of embolization as calculated by qDSA had a moderate, positive correlation (p < 0.01) with the tissue embolic particle density of ischemic regions within the embolized lobe.ConclusionsqDSA was able to quantitatively discriminate angiographic embolization endpoints and, compared to a commercially available ccDSA method, improve intra-procedural characterization of blood flow changes. Additionally, the qDSA endpoints correlated with tissue-level changes.