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At least 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Conversion of dietary trans-vaccenic acid to trans11,cis13-conjugated linoleic acid in the rat lactating mammary gland by Fatty Acid Desaturase 3-catalyzed methyl-end Δ13-desaturation

Highlights: • FADS3 was shown in vitro to catalyze the Δ13-desaturation of trans-vaccenic acid. • The product is the trans11,cis13-18:2 conjugated linoleic acid isomer. • The proof of this concept is so far lacking in vivo. • Lactating female rats fed with trans-vaccenic acid produced the trans11,cis13-18:2. • This study demonstrates this new pathway in the lactating mammary gland. In vitro, the rat Fatty Acid Desaturase 3 (FADS3) gene was shown to code for an enzyme able to catalyze the unexpected Δ13-desaturation of trans-vaccenic acid, producing the trans11,cis13-conjugated linoleic acid (CLA) isomer. FADS3 may therefore be the first methyl-end trans-vaccenate Δ13-desaturase functionally characterized in mammals, but the proof of this concept is so far lacking in vivo. The present study therefore aimed at investigating further the putative in vivo synthesis of trans11,cis13-CLA from dietary trans-vaccenic acid in rodents. During one week of pregnancy and two weeks post-partum, Sprague-Dawley female rats were fed two diets either high (10.0% of fatty acids and 3.8% of energy intake) or low (0.4% of fatty acids and 0.2% of energy intake) in trans-vaccenic acid. The trans11,cis13-CLA was specifically detected, formally identified and reproducibly quantified (0.06% of total fatty acids) in the mammary gland phospholipids of lactating female rats fed the high trans-vaccenic acid-enriched diet. This result was consistent with FADS3 mRNA expression being significantly higher in the lactating mammary gland than in the liver. Although the apparent metabolic conversion is low, this physiological evidence demonstrates the existence of this new pathway described in the lactating mammary gland and establishes the FADS3 enzyme as a reliable mammalian trans-vaccenate Δ13-desaturase in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Radioprotective Effect of Lidocaine on Function and Ultrastructure of Salivary Glands Receiving Fractionated Radiation

Purpose: Radiation-induced xerostomia still represents a common side effect after radiotherapy for head-and-neck malignancies. The aim of the present study was to examine the radioprotective effect of lidocaine hydrochloride during fractionated radiation in an experimental animal model. Methods and Materials: To evaluate the influence of different radiation doses on salivary gland function and the radioprotective effect of lidocaine, rabbits were irradiated with 15, 25, 30, and 35 Gy (equivalent doses in 2-Gy fractions equivalent to 24, 40, 48, and 56 Gy, respectively). Lidocaine hydrochloride (10 and 12 mg/kg) was administered before every radiation fraction in the treatment groups. Salivary gland function was assessed by flow sialometry and sialoscintigraphy, and the morphologic changes were evaluated using transmission electron microscopy. Results: Functional impairment was first observed after 35 Gy and pretreatment with lidocaine improved radiation tolerance of both parotid and submandibular glands. The use of 12 mg/kg lidocaine was superior and displayed significant radioprotection with regard to flow sialometry and sialoscintigraphy. The ultrastructure was largely preserved after pretreatment with both lidocaine doses. Conclusions: Lidocaine represents an effective radioprotective agent and a promising approach for clinical application to avoid radiation-induced functional impairment of salivary glands.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Automated Segmentation of the Parotid Gland Based on Atlas Registration and Machine Learning: A Longitudinal MRI Study in Head-and-Neck Radiation Therapy

Purpose: To develop an automated magnetic resonance imaging (MRI) parotid segmentation method to monitor radiation-induced parotid gland changes in patients after head and neck radiation therapy (RT). Methods and Materials: The proposed method combines the atlas registration method, which captures the global variation of anatomy, with a machine learning technology, which captures the local statistical features, to automatically segment the parotid glands from the MRIs. The segmentation method consists of 3 major steps. First, an atlas (pre-RT MRI and manually contoured parotid gland mask) is built for each patient. A hybrid deformable image registration is used to map the pre-RT MRI to the post-RT MRI, and the transformation is applied to the pre-RT parotid volume. Second, the kernel support vector machine (SVM) is trained with the subject-specific atlas pair consisting of multiple features (intensity, gradient, and others) from the aligned pre-RT MRI and the transformed parotid volume. Third, the well-trained kernel SVM is used to differentiate the parotid from surrounding tissues in the post-RT MRIs by statistically matching multiple texture features. A longitudinal study of 15 patients undergoing head and neck RT was conducted: baseline MRI was acquired prior to RT, and the post-RT MRIs were acquired at 3-, 6-, and 12-month follow-up examinations. The resulting segmentations were compared with the physicians' manual contours. Results: Successful parotid segmentation was achieved for all 15 patients (42 post-RT MRIs). The average percentage of volume differences between the automated segmentations and those of the physicians' manual contours were 7.98% for the left parotid and 8.12% for the right parotid. The average volume overlap was 91.1% ± 1.6% for the left parotid and 90.5% ± 2.4% for the right parotid. The parotid gland volume reduction at follow-up was 25% at 3 months, 27% at 6 months, and 16% at 12 months. Conclusions: We have validated our automated parotid segmentation algorithm in a longitudinal study. This segmentation method may be useful in future studies to address radiation-induced xerostomia in head and neck radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Profiling of adrenocorticotropic hormone and arginine vasopressin in human pituitary gland and tumor thin tissue sections using droplet-based liquid-microjunction surface-sampling-HPLC–ESI-MS–MS

Described here are the results from the profiling of the proteins arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) from normal human pituitary gland and pituitary adenoma tissue sections using a fully automated droplet-based liquid microjunction surface sampling-HPLC-ESI-MS/MS system for spatially resolved sampling, HPLC separation, and mass spectral detection. Excellent correlation was found between the protein distribution data obtained with this droplet-based liquid microjunction surface sampling-HPLC-ESI-MS/MS system and those data obtained with matrix assisted laser desorption ionization (MALDI) chemical imaging analyses of serial sections of the same tissue. The protein distributions correlated with the visible anatomic pattern of the pituitary gland. AVP was most abundant in the posterior pituitary gland region (neurohypophysis) and ATCH was dominant in the anterior pituitary gland region (adenohypophysis). The relative amounts of AVP and ACTH sampled from a series of ACTH secreting and non-secreting pituitary adenomas correlated with histopathological evaluation. ACTH was readily detected at significantly higher levels in regions of ACTH secreting adenomas and in normal anterior adenohypophysis compared to non-secreting adenoma and neurohypophysis. AVP was mostly detected in normal neurohypophysis as anticipated. This work demonstrates that a fully automated droplet-based liquid microjunction surface sampling system coupled to HPLC-ESI-MS/MS can be readily used for spatially resolved sampling, separation, detection, and semi-quantitation of physiologically-relevant peptide and protein hormones, such as AVP and ACTH, directly from human tissue. In addition, the relative simplicity, rapidity and specificity of the current methodology support the potential of this basic technology with further advancement for assisting surgical decision-making.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Whole-Gland Prostate Cancer Cryoablation with Magnetic Resonance Imaging Guidance: One-Year Follow-Up

PurposePatients who develop prostate cancer after prior abdominal perineal resection are poor surgical candidates, and have limited treatment options. Therefore, our goal is to present results from a single institutional experience of four patients who underwent whole gland MRI-guided cryoablation with a history complicated by prior abdominoperineal resection.Materials and MethodsFour MRI-guided cryoablative treatments (mean age 64, range 59-69 years) for primary and locally recurrent prostate adenocarcinoma were retrospectively reviewed in patients with prior abdominal perineal resection for colorectal cancer (3) and juvenile polyposis (1). Average prostate volume prior to ablation was 23 cc, with an average PSA of 5.6 ng/mL. For each gland, 7-10 cryoprobes were placed approximately 0.5 cm apart in the prostate gland under MRI guidance by a transperineal approach with 3-4 freeze-thaw cycles performed. Each patient had follow up imaging and PSA measurements out to 12 months post ablation.ResultsAll four patient’s PSA dropped below 0.1 ng/mL at 3-6 month post-ablation and remained at these levels at 12 months. Three of the 4 patients had PSA measurements to 33 months post-ablation, with no evidence of recurrence. No patient developed urinary incontinence due to the whole gland cryoablation.ConclusionWith all four patients in our study having undetectable PSAs 12 months post ablation, and with no patient developing urinary incontinence due to the cryoablation, MRI-guided cryoablation appears to be a promising treatment option in patients who are poor surgical candidates due to prior pelvic surgery and/or radiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Potential Benefits of Scanned Intensity-Modulated Proton Therapy Versus Advanced Photon Therapy With Regard to Sparing of the Salivary Glands in Oropharyngeal Cancer

Purpose: To test the hypothesis that scanned intensity-modulated proton therapy (IMPT) results in a significant dose reduction to the parotid and submandibular glands as compared with intensity-modulated radiotherapy with photons (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for oropharyngeal cancer. In addition, we investigated whether the achieved dose reductions would theoretically translate into a reduction of salivary dysfunction and xerostomia. Methods and Materials: Ten patients with N0 oropharyngeal carcinoma were used. The intensity-modulated plans delivered simultaneously 70 Gy to the boost planning target volume (PTV2) and 54 Gy to the elective nodal areas (PTV1). The 3D-CRT technique delivered sequentially 70 Gy and 46 Gy to PTV2 and PTV1, respectively. Normal tissue complication probabilities were calculated for salivary dysfunction and xerostomia. Results: Planning target volume coverage results were similar for IMPT and IMRT. Intensity-modulated proton therapy clearly improved the conformity. The 3D-CRT results were inferior to these results. The mean dose to the parotid glands by 3D-CRT (50.8 Gy), IMRT (25.5 Gy), and IMPT (16.8 Gy) differed significantly. For the submandibular glands no significant differences between IMRT and IMPT were found. The dose reductions obtained with IMPT theoretically translated into a significant reduction in normal tissue complication probability. Conclusion: Compared with IMRT and 3D-CRT, IMPT improved sparing of the organs at risk, while keeping similar target coverage results. The dose reductions obtained with IMPT vs. IMRT and 3D-CRT varied widely per individual patient. Intensity-modulated proton therapy theoretically translated into a clinical benefit for most cases, but this requires clinical validation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Maintenance of sweat glands by stem cells located in the acral epithelium

The skin is responsible for a variety of physiological functions and is critical for wound healing and repair. Therefore, the regenerative capacity of the skin is important. However, stem cells responsible for maintaining the acral epithelium had not previously been identified. In this study, we identified the specific stem cells in the acral epithelium that participate in the long-term maintenance of sweat glands, ducts, and interadnexal epidermis and that facilitate the regeneration of these structures following injury. Lgr6-positive cells and Bmi1-positive cells were found to function as long-term multipotent stem cells that maintained the entire eccrine unit and the interadnexal epidermis. However, while Lgr6-positive cells were rapidly cycled and constantly supplied differentiated cells, Bmi1-positive cells were slow to cycle and occasionally entered the cell cycle under physiological conditions. Upon irradiation-induced injury, Bmi1-positive cells rapidly proliferated and regenerated injured epithelial tissue. Therefore, Bmi1-positive stem cells served as reservoir stem cells. Lgr5-positive cells were rapidly cycled and maintained only sweat glands; therefore, we concluded that these cells functioned as lineage-restricted progenitors. Taken together, our data demonstrated the identification of stem cells that maintained the entire acral epithelium and supported the different roles of three cellular classes. - Highlights: • The acral epithelium have two types of stem cells. • Lgr6-positive cells are rapid-cycling, short-term stem cells. • Bmi1-positive cells are slow-cycling stem cells that act as reserver stem cells. • Lgr5 may be a useful sweat gland marker in mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The normal trachea is cleaned by MUC5B mucin bundles from the submucosal glands coated with the MUC5AC mucin

To understand the mucociliary clearance system, mucins were visualized by light, confocal and electron microscopy, and mucus was stained by Alcian blue and tracked by video microscopy on tracheal explants of newborn piglets. We observed long linear mucus bundles that appeared at the submucosal gland openings and were transported cephalically. The mucus bundles were shown by mass spectrometry and immunostaining to have a core made of MUC5B mucin and were coated with MUC5AC mucin produced by surface goblet cells. The transport speed of the bundles was slower than the airway surface liquid flow. We suggest that the goblet cell MUC5AC mucin anchors the mucus bundles and thus controls their transport. Normal clearance of the respiratory tree of pigs and humans, both rich in submucosal glands, is performed by thick and long mucus bundles. - Highlights: • Submucosal glands in the piglet trachea form bundles of MUC5B mucin. • The mucus bundles are coated with MUC5AC mucin produced by surface goblet cells. • The mucus bundles are transported 10-times slower than the airway surface liquid. • The surface goblet cells are suggested to control the mucus bundle movement.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

COSMIC: A Regimen of Intensity Modulated Radiation Therapy Plus Dose-Escalated, Raster-Scanned Carbon Ion Boost for Malignant Salivary Gland Tumors: Results of the Prospective Phase 2 Trial

Purpose: To investigate the effect of intensity modulated radiation therapy (IMRT) and dose-escalated carbon ion (C12) therapy in adenoid cystic carcinoma (ACC) and other malignant salivary gland tumors (MSGTs) of the head and neck. Patients and Methods: COSMIC (combined treatment of malignant salivary gland tumors with intensity modulated radiation therapy and carbon ions) is a prospective phase 2 trial of 24 Gy(RBE) C12 followed by 50 Gy IMRT in patients with pathologically confirmed MSGT. The primary endpoint is mucositis Common Terminology Criteria grade 3; the secondary endpoints are locoregional control (LC), progression-free survival (PFS), overall survival (OS), and toxicity. Toxicity was scored according to the Common Terminology Criteria for Adverse Events version 3; treatment response was scored according to Response Evaluation Criteria in Solid Tumors 1.1. Results: Between July 2010 and August 2011, 54 patients were accrued, and 53 were available for evaluation. The median follow-up time was 42 months; patients with microscopically incomplete resections (R1, n=20), gross residual disease (R2, n=17), and inoperable disease (n=16) were included. Eighty-nine percent of patients had ACC, and 57% had T4 tumors. The most common primary sites were paranasal sinus (34%), submandibular gland, and palate. At the completion of radiation therapy, 26% of patients experienced grade 3 mucositis, and 20 patients reported adverse events of the ear (38%). The most common observed late effects were grade 1 xerostomia (49%), hearing impairment (25%, 2% ipsilateral hearing loss), and adverse events of the eye (20%), but no visual impairment or loss of vision. Grade 1 central nervous system necrosis occurred in 6%, and 1 grade 4 ICA hemorrhage without neurologic sequelae. The best response was 54% (complete response/partial remission). At 3 years, the LC, PFS, and OS were 81.9%, 57.9%, and 78.4%, respectively. No difference was found regarding resection status. The most common site of failure was distant (55%). Local relapse was predominantly in field (79%). Conclusion: Treatment was tolerated, with moderate acute and late toxicity. The LC at 3 years was promising. No significant difference could be shown regarding resection status; hence, extensive and mutilating surgical procedures should be rediscussed. Further dose escalation may be limited in view of potential vascular adverse events.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling

Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR +/+ and AhR −/− models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05 μM HCB induced cell migration and TGF-β1 signaling, whereas 5 μM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5 μM) enhanced α-smooth muscle actin expression and decreased TGF-β receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR +/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3 mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR +/+ mice. Primary culture of mammary epithelial cells from AhR +/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5 μM). Interestingly, AhR −/− mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-β1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds. - Highlights: • 0.05 μM HCB induces migration and TGF-β1 signaling in mammary epithelial cells NMuMG. • 5 μM HCB reduces migration, and promotes cell cycle arrest and AhR nuclear pathway in NMuMG. • HCB enhances α-SMA and decreases TGF-β receptor II expression in fibroblasts AhR +/+. • Conditioned medium from fibroblasts AhR +/+ exposed to HCB enhances NMuMG migration. • HCB increases hyperplasia and branching morphogenesis in AhR +/+ mice mammary gland.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Transdifferentiation of mouse adipose-derived stromal cells into acinar cells of the submandibular gland using a co-culture system

A loss of salivary gland function often occurs after radiation therapy in head and neck tumors, though secretion of saliva by the salivary glands is essential for the health and maintenance of the oral environment. Transplantation of salivary acinar cells (ACs), in part, may overcome the side effects of therapy. Here we directly differentiated mouse adipose-derived stromal cells (ADSCs) into ACs using a co-culture system. Multipotent ADSCs can be easily collected from stromal vascular fractions of adipose tissues. The isolated ADSCs showed positive expression of markers such as integrin beta-1 (CD29), cell surface glycoprotein (CD44), endoglin (CD105), and Nanog. The cells were able to differentiate into adipocytes, osteoblasts, and neural-like cells after 14 days in culture. ADSCs at passage 2 were co-cultured with mouse ACs in AC culture medium using the double-chamber (co-culture system) to avoid mixing the cell types. The ADSCs in this co-culture system expressed markers of ACs, such as α-amylases and aquaporin5, in both mRNA and protein. ADSCs cultured in AC-conditioned medium also expressed AC markers. Cellular proliferation and senescence analyses demonstrated that cells in the co-culture group showed lower senescence and a higher proliferation rate than the AC-conditioned medium group at Days 14 and 21. The results above imply direct conversion of ADSCs into ACs under the co-culture system; therefore, ADSCs may be a stem cell source for the therapy for salivary gland damage. - Highlights: • ADSCs could transdifferentiate into acinar cells (ACs) using ACs co-culture (CCA). • Transdifferentiated ADSCs expressed ACs markers such as α-amylase and aquaporin5. • High proliferation and low senescence were presented in CCA at Day 14. • Transdifferentiation of ADSCs into ACs using CCA may be an appropriate method for cell-based therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Guanylate binding protein-1-mediated epithelial barrier in human salivary gland duct epithelium

Highlights: • GBP-1 is involved in the epithelial barrier at tight junction during gut inflammation. • IFNγ enhances claudin-7, LSR and the salivary duct epithelial barrier via GBP-1. • Loss of GBP-1 induces endocytosis of tight junctions, and disrupts tight junction. • PKCα inhibitor induces claudin-7, LSR and salivary duct epithelial barrier via GBP-1. • In almost intact salivary ducts with IgG4-RD, GBP-1, claudin-7 and LSR are increased. Guanylate-binding protein-1 (GBP-1) is an interferon-inducible large GTPase involved in the epithelial barrier at tight junctions. To investigate the role of GBP-1 in the epithelial barrier, primary human salivary gland duct epithelial cells were treated with the the proinflammatory cytokines IFNγ, IL-1β, TNFα and the growth factor TGF-β. Treatment with IFNγ, IL-1β, or TNFα markedly enhanced GBP-1 and the epithelial barrier function, and induced not only CLDN-7 but also the tricellular tight junction molecule lipolysis-stimulated lipoprotein receptor (LSR). Knockdown of GBP-1 by its siRNA induced endocytosis of tight junction molecules, and prevented the increases of CLDN-7 and LSR with the upregulation of the epithelial barrier function induced by treatment with IFNγ or TNFα. Treatment with a PKCα inhibitor induced expression of GBP-1, CLDN-7 and LSR and enhanced the epithelial barrier function. In almost intact salivary gland ducts from patients with IgG4-related disease (IgG4-RD) indicated significant infiltration of IgG-positive plasma cells, expression of GBP-1, CLDN-7 and LSR was increased. These findings indicated that GBP-1 might play a crucial role in barrier function of normal human salivary gland duct epithelium and perform a preventive role in the duct epithelium of IgG4-RD disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Sci—Fri PM: Topics — 06: The influence of regional dose sensitivity on salivary loss and recovery in the parotid gland

Purpose: The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC 2010) survey of radiation dose-volume effects on salivary gland function has called for improved understanding of intragland dose sensitivity and the effectiveness of partial sparing in salivary glands. Regional dose susceptibility of sagittally- and coronally-sub-segmented parotid gland has been studied. Specifically, we examine whether individual consideration of sub-segments leads to improved prediction of xerostomia compared with whole parotid mean dose. Methods: Data from 102 patients treated for head-and-neck cancers at the BC Cancer Agency were used in this study. Whole mouth stimulated saliva was collected before (baseline), three months, and one year after cessation of radiotherapy. Organ volumes were contoured using treatment planning CT images and sub-segmented into regional portions. Both non-parametric (local regression) and parametric (mean dose exponential fitting) methods were employed. A bootstrap technique was used for reliability estimation and cross-comparison. Results: Salivary loss is described well using non-parametric and mean dose models. Parametric fits suggest a significant distinction in dose response between medial-lateral and anterior-posterior aspects of the parotid (p<0.01). Least-squares and least-median squares estimates differ significantly (p<0.00001), indicating fits may be skewed by noise or outliers. Salivary recovery exhibits a weakly arched dose response: the highest recovery is seen at intermediate doses. Conclusions: Salivary function loss is strongly dose dependent. In contrast no useful dose dependence was observed for function recovery. Regional dose dependence was observed, but may have resulted from a bias in dose distributions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MO-F-CAMPUS-I-01: EIT Imaging to Monitor Human Salivary Gland Functionality: A Feasibility Study

Purpose: Clinically, there exists a need to develop a non-invasive technique for monitoring salivary activity. In this study, we investigate the feasibility of a using the electrical conductivity information from Electrical Impedance Tomography (EIT) to monitor salivary flow activity. Methods: To acquire EIT data, eight Ag/AgCl ECG electrodes were placed around the mandible of the subject. An EIT scan was obtained by injecting current at 50 KHz, 0.4 mA through each pair of electrodes and recording voltage across other electrode pairs. The functional conductivity image was obtained through reconstruction of the voltage data, using Electrical Impedance Tomography and Diffuse Optical Tomography Reconstruction Software (EIDORS) in Matlab. In using EIDORS, forward solution was obtained using a user-defined finite element model shape and inverse solution was obtained using one-step Gaussian solver. EIT scans of volunteer research team members were acquired for three different physiological states: pre-stimulation, stimulation and post-stimulation. For pre-stimulation phase, data were collected in intervals of 5 minutes for 15 minutes. The salivary glands were then stimulated in the subject using lemon and the data were collected immediately. Post-stimulation data were collected at 4 different timings after stimulation. Results: Variations were observed in the electrical conductivity patterns near parotid regions between the pre- and post-stimulation stages. The three images acquired during the 15 minute pre-stimulation phase showed no major changes in the conductivity. Immediately after stimulation, electrical conductivity increased near parotid regions and 15 minutes later slowly returned to pre-stimulation level. Conclusion: In the present study involving human subjects, the change in electrical conductivity pattern shown in the EIT images, acquired at different times with and without stimulation of salivary glands, appeared to be consistent with the change in salivary gland activity. The conductivity changes imaged through EIT are potentially useful for the purpose of salivary monitoring.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer

Perp is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development. Perp-/- mice exhibit postnatal lethality associated with dramatic blistering of the epidermis and oral mucosa, reflecting a critical role in desmosome-mediated intercellular adhesion in keratinocytes. However, the role of Perp in tissue homeostasis in other p63-dependent stratified epithelial tissues is poorly understood. Given that p63 is essential for proper mammary gland development and that cell adhesion is fundamental for ensuring the proper architecture and function of the mammary epithelium, here we investigate Perp function in the mammary gland. Immunofluorescence and Western blot analysis were performed to characterize Perp expression and localization in the mouse mammary epithelium throughout development. The consequences of Perp deficiency for mammary epithelial development and homeostasis were examined by using in vivo mammary transplant assays. Perp protein levels in a variety of human breast cancer cell lines were compared with those in untransformed cells with Western blot analysis. The role of Perp in mouse mammary tumorigenesis was investigated by aging cohorts of K14-Cre/+;p53 fl/fl mice that were wild-type or deficient for Perp. Mammary tumor latency was analyzed, and tumor-free survival was assessed using Kaplan-Meier analysis. We show that Perp protein is expressed in the mammary epithelium, where it colocalizes with desmosomes. Interestingly, although altering desmosomes through genetic inactivation of Perp does not dramatically impair mammary gland ductal development, Perp loss affects mammary epithelial homeostasis by causing the accumulation of inflammatory cells around mature mammary epithelium. Moreover, we show reduced Perp expression in many human breast cancer cell lines compared with untransformed cells. Importantly, Perp deficiency also promotes the development of mouse mammary cancer. Together, these observations demonstrate an important role for Perp in normal mammary tissue function and in mammary cancer suppression. In addition, our findings highlight the importance of desmosomes in cancer suppression and suggest the merit of evaluating Perp as a potential prognostic indicator or molecular target in breast cancer therapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

TU-C-12A-05: Repeatability Study of Reduced Field-Of-View Diffusion-Weighted MRI On Human Thyroid Gland

Purpose: To investigate the repeatability of reduced field-of-view diffusion-weighted imaging (rFOV DWI) in quantifying apparent diffusion coefficients (ADCs) for human thyroid glands in a clinical setting. Methods: Nine healthy human volunteers were enrolled and underwent 3T MRI exams. For each volunteer, 3 longitudinal exams (2 weeks apart) with 2 repetitive sessions within each exam, including rFOV and conventional full field-of-view (fFOV) DWI scans, were performed. In the acquired DWI images, a fixed-size region of interest (ROI; diameter=8mm) was placed on thyroid glands to calculate ADC. ADC was calculated using a monoexponential function with a noise correction scheme. The repeatability of ADC was assessed by using coefficient variation (CV) across sessions or exams, which was defined to be: r = 1-CV, 0 < r < 1, where CV=STD/m, STD is the standard deviation of ADC, and m is the average of ADC across sessions or exams. An experienced radiologist assessed and scored rFOV and fFOV DW images based on image characteristics (1, nondiagnostic; 2, poor; 3, satisfactory; 4, good; and 5, excellent).Analysis of variance (ANOVA) was performed to compare ADC values, CV of ADC, repeatability of ADC across sessions and exams, and radiologic scores between rFOV and fFOV DWI techniques. Results: There was no significant difference in ADC values across sessions and exams either in rFOV or fFOV DWI. The average CVs of both rFOV and fFOV DWI were less than 13%. The repeatability of ADC measurement between rFOV and fFOV DWI was not significantly different. The overall image quality was significantly higher with rFOV DWI than with fFOV DWI. Conclusion: This study suggested that ADCs from both rFOV and fFOV DWI were repeatable, but rFOV DWI had superior imaging quality for human thyroid glands in a clinical setting.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Transient knockdown of Anopheles stephensi LRIM1 using RNAi increases Plasmodium falciparum sporozoite salivary gland infections

Abstract Background Plasmodium falciparum (Pf) sporozoites (PfSPZ) can be administered as a highly protective vaccine conferring the highest protection seen to date. Sanaria® PfSPZ vaccines are produced using aseptically reared Anopheles stephensi mosquitoes. The bionomics of sporogonic development of P. falciparum in A. stephensi to fully mature salivary gland PfSPZ is thought to be modulated by several components of the mosquito innate immune system. In order to increase salivary gland PfSPZ infections in A. stephensi and thereby increase vaccine production efficiency, a gene knock down approach was used to investigate the activity of the immune deficiency (IMD) signaling pathway downstream effector leucine-rich repeat immune molecule 1 ( LRIM1 ), an antagonist to Plasmodium development. Methods Expression of LRIM1 in A. stephensi was reduced following injection of double stranded (ds) RNA into mosquitoes. By combining the Gal4/UAS bipartite system with in vivo expression of short hairpin (sh) RNA coding for LRIM1 reduced expression of LRIM1 was targeted in the midgut, fat body, and salivary glands. RT-qPCR was used to demonstrate fold-changes in gene expression in three transgenic crosses and the effects on P. falciparum infections determined in mosquitoes showing the greatest reduction in LRIM1 expression. Results LRIM1 expression could be reduced, but not completely silenced, by expression of LRIM1 dsRNA. Infections of P. falciparum oocysts and PfSPZ were consistently and significantly higher in transgenic mosquitoes than wild type controls, with increases in PfSPZ ranging from 2.5- to tenfold. Conclusions Plasmodium falciparum infections in A. stephensi can be increased following reduced expression of LRIM1. These data provide the springboard for more precise knockout of LRIM1 for the eventual incorporation of immune-compromised A. stephensi into manufacturing of Sanaria’s PfSPZ products.

Billingsley, Peter F. (ORCID:0000000311424813)↗
NASA NTRS1975

Effects of a 2X gravity environment on the ultrastructure of the gerbil parathyroid gland

A number of studies concerning the effects of hypergravity on bone have shown increases in bone mass or bone dimensions. Correlative studies, which could provide clues to the mechanism for such a response, have been lacking. The purpose of the present study was to evaluate the ultrastructure of parathyroid glands of Mongolian gerbils exposed to a continuous 2 X gravity force for 60 d. It was found that the experimental animals had parathyroid glands which had a greater percentage of chief cells in the active stage of their secretory cycle when compared with control animals. This result was interpreted to indicate an increase in parathyroid gland secretory activity and, hence, an increase in parathyroid hormone release. It was suggested that increased parathyroid secretory activity was necessary to maintain serum calcium levels of hypergravity animals within normal limits. Cellular forms resembling water clear cells and highly compact, degenerating cells were described in experimental animals but not in controls. Areas suggestive of cellular dissolution and disorganization were also reported in experimental parathyroids.

Sannes, P. L.↗