Faculty Bibliography

Due to their large size, charged surfaces, and environmental sensitivity, proteins do not naturally cross cell-membranes in intact form and, therefore, are difficult to deliver for both diagnostic and therapeutic purposes. Based upon the observation that clustered oligonucleotides can naturally engage scavenger receptors that facilitate cellular transfection, nucleic acid-metal organic framework nanoparticle (MOF NP) conjugates have been designed and synthesized from NU-1000 and PCN-222/MOF-545, respectively, and phosphate-terminated oligonucleotides. They have been characterized structurally and with respect to their ability to enter mammalian cells. The MOFs act as protein hosts, and their densely functionalized, oligonucleotide-rich surfaces make them colloidally stable and ensure facile cellular entry. With insulin as a model protein, high loading and a 10-fold enhancement of cellular uptake (as compared to that of the native protein) were achieved. Importantly, this approach can be generalized to facilitate the delivery of a variety of proteins as biological probes or potential therapeutics.

Ubiquitously-expressed, prefoldin-like chaperone (UXT) also called Androgen Receptor Trapped clone-27 (ART-27) is widely expressed in human tissues. Our previous studies showed that UXT regulates transcription repression including androgen receptor (AR) signaling in prostate cancer. Here we analyzed a tissue microarray consisting of normal prostate, benign prostatic hyperplasia, high grade prostatic intraepithelial neoplasia (HGPIN) and primary prostate cancer cases for UXT protein expression. We found that HGPIN and malignant tumors have significantly decreased UXT expression compared to the normal prostate. Loss of UXT expression in primary prostate cancer is positively associated with high Gleason grade and poor relapse-free survival. We engineered prostate-specific Uxt

CONTEXT/BACKGROUND:- In Gleason score GS (7) prostate cancers, the quantity of Gleason pattern 4 (GP 4) is an important prognostic factor and influences treatment decisions. Magnetic resonance imaging (MRI)-targeted biopsy has been increasingly used in clinical practice. OBJECTIVE:- To investigate whether MRI-targeted biopsy may detect GS 7 prostate cancer with greater GP 4 quantity, and whether it improves biopsy/radical prostatectomy GS concordance. DESIGN/METHODS:- A total of 243 paired standard and MRI-targeted biopsies with cancer in either standard or targeted or both were studied, 65 of which had subsequent radical prostatectomy. The biopsy findings, including GS and tumor volume, were correlated with the radical prostatectomy findings. RESULTS:- More prostate cancers detected by MRI-targeted biopsy were GS 7 or higher. Mean GP 4 percentage in GS 7 cancers was 31.0% ± 29.3% by MRI-targeted biopsy versus 25.1% ± 29.5% by standard biopsy. A total of 122 of 218 (56.0%) and 96 of 217 (44.2%) prostate cancers diagnosed on targeted biopsy and standard biopsy, respectively, had a GP 4 of 10% or greater ( P = .01). Gleason upgrading was seen in 12 of 59 cases (20.3%) from MRI-targeted biopsy and in 24 of 57 cases (42.1%) from standard biopsy ( P = .01). Gleason upgrading correlated with the biopsy cancer volume inversely and GP 4 of 30% or less in standard biopsy. Such correlation was not found in MRI-targeted biopsy. CONCLUSIONS:- Magnetic resonance imaging-targeted biopsy may detect more aggressive prostate cancers and reduce the risk of Gleason upgrading in radical prostatectomy. This study supports a potential role for MRI-targeted biopsy in the workup of prostate cancer and inclusion of percentage of GP 4 in the prostate biopsy reports.

Importance/UNASSIGNED:There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases. Objective/UNASSIGNED:To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria. Design, Setting, and Participants/UNASSIGNED:Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS). Main Outcomes and Measures/UNASSIGNED:Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity). Results/UNASSIGNED:In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model. Conclusions and Relevance/UNASSIGNED:This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening.

Nanoscale UiO-66 Zr₆(OH)₄O₄(C₈O₄H₄)₆ has been synthesized with a series of carboxylic acid modulators, R-COOH (where R = H, CH₃, CF₃, and CHCl₂). The phase purity and size of each MOF was confirmed by powder X-ray diffraction, BET surface area analysis, and scanning transmission electron microscopy (STEM). Size control of UiO-66 crystals from 20 nm to over 1 μm was achieved, and confirmed by STEM. The colloidal stability of each MOF was evaluated by dynamic light scattering and was found to be highly dependent on the modulator conditions utilized in the synthesis, with both lower pKa and higher acid concentration resulting in more stable structures. Furthermore, STEM was carried out on both colloidally stable samples and those that exhibited a large degree of aggregation, which allowed for visualization of the different degrees of dispersion of the samples. The use of modulators at higher concentrations and with lower pK_as leads to the formation of more defects, as a consequence of terephthalic acid ligands being replaced by modulator molecules, thereby enhancing the colloidal stability of the UiO-66 nanoparticles. These findings could have a significant impact on nanoscale MOF material syntheses and applications, especially in the areas of catalysis and drug delivery.

Distinguishing between indolent and aggressive prostate adenocarcinoma (PCa) remains a priority to accurately identify patients who need therapeutic intervention. SIN3B has been implicated in the initiation of senescence in vitro Here we show that in a mouse model of prostate cancer, SIN3B provides a barrier to malignant progression. SIN3B was required for PTEN-induced cellular senescence and prevented progression to invasive PCa. Furthermore, SIN3B was downregulated in human PCa correlating with upregulation of its target genes. Our results suggest a tumor suppressor function for SIN3B that limits PCa progression, with potential implications for the use of SIN3B and its target genes as candidate diagnostic markers to distinguish indolent from aggressive disease.

BACKGROUND:CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone. METHODS:Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided. RESULTS:Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set). CONCLUSION:The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.