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DOE OSTI2014

SU-E-J-192: Verification of 4D-MRI Internal Target Volume Using Cine MRI

Purpose: To investigate the accuracy of 4D-MRI in determining the Internal Target Volume (ITV) used in radiation oncology treatment planning of liver cancers. Cine MRI is used as the standard baseline in establishing the feasibility and accuracy of 4D-MRI tumor motion within the liver. Methods: IRB approval was obtained for this retrospective study. Analysis was performed on MR images from four patients receiving external beam radiation therapy for liver cancer at our institution. Eligible patients received both Cine and 4D-MRI scans before treatment. Cine images were acquired sagittally in real time at a slice bisecting the tumor, while 4D images were acquired volumetrically. Cine MR DICOM headers were manipulated such that each respiratory frame was assigned a unique slice location. This approach permitted the treatment planning system (Eclipse, Varian Medical Systems) to recognize a complete respiratory cycle as a “volume”, where the gross tumor was contoured temporally. Software was developed to calculate the union of all frame contours in the structure set, resulting in the corresponding plane of the ITV projecting through the middle of the tumor, defined as the Internal Target Area (ITA). This was repeated for 4D-MRI, at the corresponding slice location, allowing a direct comparison of ITAs obtained from each modality. Results: Four patients have been analyzed. ITAs contoured from 4D-MRI correlate with contours from Cine MRI. The mean error of 4D values relative to Cine values is 7.67 +/− 2.55 %. No single ITA contoured from 4D-MRI demonstrated more than 10.5 % error compared to its Cine MRI counterpart. Conclusion: Motion management is a significant aspect of treatment planning within dynamic environments such as the liver, where diaphragmatic and cardiac activity influence plan accuracy. This small pilot study suggests that 4D-MRI based ITA measurements agree with Cine MRI based measurements, an important step towards clinical implementation. NIH 1R21CA165384-01A1.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

PET optimization for improved assessment and accurate quantification of {sup 90}Y-microsphere biodistribution after radioembolization

Purpose: {sup 90}Y-microspheres are widely used for the radioembolization of metastatic liver cancer or hepatocellular carcinoma and there is a growing interest for imaging {sup 90}Y-microspheres with PET. The aim of this study is to evaluate the performance of a current generation PET/CT scanner for {sup 90}Y imaging and to optimize the PET protocol to improve the assessment and the quantification of {sup 90}Y-microsphere biodistribution after radioembolization. Methods: Data were acquired on a Biograph mCT-TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. Spatial resolution was measured with a{sup 90}Y point source. Sensitivity was evaluated using the NEMA 70 cm line source filled with {sup 90}Y. To evaluate the count rate performance, {sup 90}Y vials with activity ranging from 3.64 to 0.035 GBq were measured in the center of the field of view (CFOV). The energy spectrum was evaluated. Image quality with different reconstructions was studied using the Jaszczak phantom containing six hollow spheres (diameters: 31.3, 28.1, 21.8, 16.1, 13.3, and 10.5 mm), filled with a 207 kBq/ml {sup 90}Y concentration and a 5:1 sphere-to-background ratio. Acquisition time was adjusted to simulate the quality of a realistic clinical PET acquisition of a patient treated with SIR-Spheres{sup ®}. The developed methodology was applied to ten patients after SIR-Spheres{sup ®} treatment acquiring a 10 min per bed PET. Results: The energy spectrum showed the{sup 90}Y bremsstrahlung radiation. The {sup 90}Y transverse resolution, with filtered backprojection reconstruction, was 4.5 mm in the CFOV and degraded to 5.0 mm at 10 cm off-axis. {sup 90}Y absolute sensitivity was 0.40 kcps/MBq in the center of the field of view. Tendency of true and random rates as a function of the {sup 90}Y activity could be accurately described using linear and quadratic models, respectively. Phantom studies demonstrated that, due to low count statistics in {sup 90}Y PET acquisition, the optimal parameters for the standard OSEM+PSF reconstruction were only one iteration and a postreconstruction filter of 6 mm FWHM, for both TOF and non-TOF reconstructions. Moreover, when TOF is included, the signal to noise ratio increased and visibility achieved 100% by the experienced observers and 93.3% according to the Rose model of statistical detection. In 50% of patients, TOF allowed the visualization of {sup 90}Y radioembolized lesions not seen without TOF, confirming phantom results. Liver activity was accurately quantified, with no significant differences between reconstructed and actual delivered activity to the whole-liver [mean relative difference (10.2 ± 14.7)%]. Conclusions: Qualitative and quantitative{sup 90}Y PET imaging improved with the introduction of TOF in a PET/CT scanner, thereby allowing the visualization of microsphere deposition in lesions not visible in non-TOF images. This technique accurately quantifies the total activity delivered to the liver during radioembolization with {sup 90}Y-microspheres and allows dose estimation.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

SU-E-P-52: Dose-Volume Toxicity Analysis of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

Purpose: To investigate the relationship between physical and biological effective dose (BED) to liver toxicity for SBRT fractionations. Methods: A total of 16 patients (13–10×3Gy, 2–5×10Gy and 1–3×15Gy were selected. Physical dose distributions were converted to voxel based BED values using the linear-quadratic (LQ) and linear-quadratic linear (LQ-L) models for doses per fraction larger than 6Gy. Patients were graded for effective toxicity (post-treatment minus pre-treatment grades) using the RTOG Late Radiation Morbidity Scoring Schema associated with Radiation Induced Liver Disease (RILD). Evaluated physical dose-volume levels consisted of V10Gy, V15Gy, V20Gy, V25Gy and V30Gy which were then converted to BED values corresponding to V16.7Gy3, V30Gy3, V46.7Gy3, V66.7Gy3 and V90Gy3, respectively. All levels were normalized to their respective patient normal liver volumes (NLV) and evaluated for correlation to RILD. Results were measured quantitatively using R-squared regression analysis. Results: Mean Dose Tolerable to Normal Liver (MDTNL) against RILD grade resulted in an R-squared value of 0.0104. NLV-normalized physical dose linear regression fit of V10Gy, V15Gy, V20Gy, V25Gy and V30Gy against RILD yielded R-squared values of 0.1041, 0.0895, 0.0698, 0.0398 and 0.0009 while BED levels of V16.7Gy3, V30Gy3, V46.7Gy3, V66.7Gy3 and V90Gy3 resulted in values of 0.0002, 0.0153, 0.0533, 0.0427 and 0.0072, respectively. The average NLV-normalized V10Gy, V15Gy, V20Gy, V25Gy and V30Gy per grade plotted against RILD grade yielded R-squared correlations of 0.8092, 0.6362, 0.5899, 0.5846 and 0.0224 while the BED levels of V16.7Gy3, V30Gy3, V46.7Gy3, V66.7Gy3 and V90Gy3 resulted in R-squared correlations of 0.0003, 0.3831, 0.8476, 0.678 and 0.076, respectively. Conclusion: Regression analysis between physical dose, BED and RILD showed strong correlation for the V30Gy and V46.7Gy3 dose-levels. Average BED and physical dose per grade both exhibit strong correlations to RILD however, a lack of statistical significance exists due to small patient sample size.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

TU-G-210-00: Treatment Planning Strategies, Modeling, Control

Modeling can play a vital role in predicting, optimizing and analyzing the results of therapeutic ultrasound treatments. Simulating the propagating acoustic beam in various targeted regions of the body allows for the prediction of the resulting power deposition and temperature profiles. In this session we will apply various modeling approaches to breast, abdominal organ and brain treatments. Of particular interest is the effectiveness of procedures for correcting for phase aberrations caused by intervening irregular tissues, such as the skull in transcranial applications or inhomogeneous breast tissues. Also described are methods to compensate for motion in targeted abdominal organs such as the liver or kidney. Douglas Christensen – Modeling for Breast and Brain HIFU Treatment Planning Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Learning Objectives: Understand the role of acoustic beam modeling for predicting the effectiveness of therapeutic ultrasound treatments. Apply acoustic modeling to specific breast, liver, kidney and transcranial anatomies. Determine how to obtain appropriate acoustic modeling parameters from clinical images. Understand the separate role of absorption and scattering in energy delivery to tissues. See how organ motion can be compensated for in ultrasound therapies. Compare simulated data with clinical temperature measurements in transcranial applications. Supported by NIH R01 HL172787 and R01 EB013433 (DC); EU Seventh Framework Programme (FP7/2007-2013) under 270186 (FUSIMO) and 611889 (TRANS-FUSIMO)(TP); and P01 CA159992, GE, FUSF and InSightec (UV)

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

TU-G-210-01: Modeling for Breast and Brain HIFU Treatment Planning

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-F-I-47: Optimizing Protocols for Image Quality and Dose in Abdominal CT of Large Patients

Purpose: Newer CT scanners are able to use scout views to adjust mA throughout the scan in order to achieve a given noise level. However, given constraints of radiologist preferences for kVp and rotation time, it may not be possible to achieve an acceptable noise level for large patients. A study was initiated to determine for which patients kVp and/or rotation time should be changed in order to achieve acceptable image quality. Methods: Patient scans were reviewed on two new Emergency Department scanners (Philips iCT) to identify patients over a large range of sizes. These iCTs were set with a limit of 500 mA to safeguard against a failure that might cause a CT scan to be (incorrectly) obtained at too-high mA. Scout views of these scans were assessed for both AP and LAT patient width and AP and LAT standard deviation in an ROI over the liver. Effective diameter and product of the scout standard deviations over the liver were both studied as possible metrics for identifying patients who would need kVp and/or rotation time changed. The mA used for the liver in the CT was compared to these metrics for those patients whose CT scans showed acceptable image quality. Results: Both effective diameter and product of the scout standard deviations over the liver result in similar predictions for which patients will require the kVp and/or rotation time to be changed to achieve an optimal combination of image quality and dose. Conclusion: Two mechanisms for CT technologists to determine based on scout characteristics what kVp, mA limit, and rotation time to use when DoseRight with our physicians’ preferred kVp and rotation time will not yield adequate image quality are described.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-F-J-85: Evaluation of the Velocity Deformable Image Registration Algorithm

Purpose: To perform validation and commissioning of a commercial deformable image registration (DIR) algorithm (Velocity, Varian Medical Systems) for numerous clinical sites using single and multi-modality images. Methods: In this retrospective study, the DIR algorithm was evaluated for 10 patients in each of the following body sites: head and neck (HN), prostate, liver, and gynecological (GYN). HN DIRs were evaluated from planning (p)CT to re-pCT and pCTs to daily CBCTs using dice similarity coefficients (DSC) of corresponding anatomical structures. Prostate DIRs were evaluated from pCT to CBCTs using DSC and target registration error (TRE) of implanted RF beacons within the prostate. Liver DIRs were evaluated from pMR to pCT using DSC and TRE of vessel bifurcations. GYN DIRs were evaluated between fractionated brachytherapy MRIs using DSC of corresponding anatomical structures. Results: Analysis to date has given average DSCs for HN pCT-to-(re)pCT DIR for the brainstem, cochleas, constrictors, spinal canal, cord, esophagus, larynx, parotids, and submandibular glands as 0.88, 0.65, 0.67, 0.91, 0.77, 0.69, 0.77, 0.87, and 0.71, respectively. Average DSCs for HN pCT-to-CBCT DIR for the constrictors, spinal canal, esophagus, larynx, parotids, and submandibular glands were 0.64, 0.90, 0.62, 0.82, 0.75, and 0.69, respectively. For prostate pCT-to-CBCT DIR the DSC for the bladder, femoral heads, prostate, and rectum were 0.71, 0.82, 0.69, and 0.61, respectively. Average TRE using implanted beacons was 3.35 mm. For liver pCT-to-pMR, the average liver DSC was 0.94 and TRE was 5.26 mm. For GYN MR-to-MR DIR the DSC for the bladder, sigmoid colon, GTV, and rectum were 0.79, 0.58, 0.67, and 0.76, respectively. Conclusion: The Velocity DIR algorithm has been evaluated over a number of anatomical sites. This work functions to document the uncertainties in the DIR in the commissioning process so that these can be accounted for in the development of downstream clinical processes. This work was supported in part by a co-development agreement with Varian Medical Systems.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-G-JeP2-07: Fusion Optimization of Multi-Contrast MRI Scans for MR-Based Treatment Planning

Purpose: To develop an image fusion method using multiple contrast MRI scans for MR-based treatment planning. Methods: T1 weighted (T1-w), T2 weighted (T2-w) and diffusion weighted images (DWI) were acquired from liver cancer patient with breath-holding. Image fade correction and deformable image registration were performed using VelocityAI (Varian Medical Systems, CA). Registered images were normalized to mean voxel intensity for each image dataset. Contrast to noise ratio (CNR) between tumor and liver was quantified. Tumor area was defined as the GTV contoured by physicians. Normal liver area with equivalent dimension was used as background. Noise was defined by the standard deviation of voxel intensities in the same liver area. Linear weightings were applied to T1-w, T2-w and DWI images to generate composite image and CNR was calculated for each composite image. Optimization process were performed to achieve different clinical goals. Results: With a goal of maximizing tumor contrast, the composite image achieved a 7–12 fold increase in tumor CNR (142.8 vs. −2.3, 11.4 and 20.6 for T1-w, T2-w and DWI only, respectively), while anatomical details were largely invisible. With a weighting combination of 100%, −10% and −10%, respectively, tumor contrast was enhanced from −2.3 to −5.4, while the anatomical details were clear. With a weighting combination of 25%, 20% and 55%, balanced tumor contrast and anatomy was achieved. Conclusion: We have investigated the feasibility of performing image fusion optimization on multiple contrast MRI images. This mechanism could help utilize multiple contrast MRI scans to potentially facilitate future MR-based treatment planning.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

Robotic Left Hepatectomy and Roux-en-Y Hepaticojejunostomy After Bile Duct Injury

Background: Bile duct injuries after cholecystectomy remain a major concern because their incidence has not changed through the years despite technical advances. This video presents a robotic left hepatectomy and Roux-en-Y hepaticojejunostomy as a treatment for a complex bile duct injury after laparoscopic cholecystectomy. Methods: A 52-year-old man underwent laparoscopic cholecystectomy at another institution 8 years previously, which resulted in a bile duct injury. His postoperative period was complicated by jaundice and cholangitis. He was treated with endoscopic retrograde cholangiopancreatography and multiple endoprostheses for 3 years, after which the endoprostheses were removed, and he was sent to the authors’ institution. Computed tomography showed that the left liver had signs of disturbed perfusion and dilation of the left intrahepatic bile duct. The patient was asymptomatic and refused any further attempt at surgical correction of the lesion. He was accompanied for 5 years. Magnetic resonance imaging showed progressive atrophy of the left liver. Finally, 3 months before this writing, he presented with intermittent episodes of cholangitis. A multidisciplinary team decided to perform left hepatectomy with Roux-en-Y hepatojejunostomy via a robotic approach. The left liver was atrophied, and left hepatectomy was performed. Fluorescence imaging was used to identify the right bile duct. At opening of the right bile duct, small stones were found and removed. Antecolic Roux-en-Y hepaticojejunostomy then was performed. Results: The operative time was 335 min. Recovery was uneventful, and the patient was discharged on postoperative day 4. Conclusions: Robotic repair of bile duct injuries is feasible and safe, even when liver resection is necessary. This video may help oncologic surgeons to perform this complex procedure.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2021

Use of X-Ray Fluorescence Microscopy for Studies on Research Models of Hepatocellular Carcinoma

Introduction: TheraSphere ® microspheres containing yttrium 90 Y are among many radioembolization agents used clinically to reduce liver tumor burden, and their effects on cancer volume reduction are well-established. At the same time, concerns about off target tissue injury often limit their use. Deeper investigation into tissue distribution and long-term impact of these microspheres could inform us about additional ways to use them in practice. Methods: Healthy rat liver and rabbit liver tumor samples from animals treated with TheraSpheres were sectioned and their elemental maps were generated by X-ray fluorescence microscopy (XFM) at the Advanced Photon Source (APS) synchrotron at Argonne National Laboratory (ANL). Results: Elemental imaging allowed us to identify the presence and distribution of TheraSpheres in animal tissues without the need for additional sample manipulation or staining. Ionizing radiation produced by 90 Y radioactive contaminants present in these microspheres makes processing TheraSphere treated samples complex. Accumulation of microspheres in macrophages was observed. Conclusions: This is the first study that used XFM to evaluate the location of microspheres and radionuclides in animal liver and tumor samples introduced through radioembolization. XFM has shown promise in expanding our understanding of radioembolization and could be used for investigation of human patient samples in the future.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Systems pharmacology modeling of drug‐induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters

Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model‐predicted drug exposure and enzyme/transporter inhibition constants determined in vitro , our model correctly predicted indinavir‐mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug‐induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.

Yang, K.↗

DOE OSTI2019

No difference in 4‐nitroquinoline induced tumorigenesis between germ‐free and colonized mice

Variations in oral bacterial communities have been linked to oral cancer suggesting that the oral microbiome is an etiological factor that can influence oral cancer development. The 4‐nitroquinoline 1‐oxide (4‐NQO)‐induced murine oral and esophageal cancer model is frequently used to assess the effects of preventive and/or therapeutic agents. We used this model to assess the impact of the microbiome on tumorigenesis using axenic (germ‐free) and conventionally housed mice. Increased toxicity was observed in germ‐free mice, however, no difference in tumor incidence, multiplicity, and size was observed. Transcriptional profiling of liver tissue from germ‐free and conventionally housed mice identified 254 differentially expressed genes including ten cytochrome p450 enzymes, the largest family of phase‐1 drug metabolizing enzymes in the liver. Gene ontology revealed that differentially expressed genes were enriched for liver steatosis, inflammation, and oxidative stress in livers of germ‐free mice. Our observations emphasize the importance of the microbiome in mediating chemical toxicity at least in part by altering host gene expression. Studies on the role of the microbiome in chemical‐induced cancer using germ‐free animal models should consider the potential difference in dose due to the microbiome‐mediated changes in host metabolizing capacity, which might influence the ability to draw conclusions especially for tumor induction models that are dose dependent.

Zhou, Yan‐Xia↗

DOE OSTI2018

PET imaging of glucose and fatty acid metabolism for NAFLD patients

The study presented in this issue of the Journal by Tang and colleagues illuminate the deficiency in our knowledge of the reciprocal metabolic relationship between liver and heart in health and disease. The results presented in this paper used a large number of previously acquired 18 F-FDG PET studies to investigate the association between non-alcoholic fatty liver disease (NAFLD) (Figure 1A) and myocardial glucose uptake. Previous work published by Lee and colleagues in Metabolism, had found a significant correlation between NAFLD and vascular inflammation using 18 F-FDG PET to measure maximum target-to-background uptake in the carotid arteries; however, the present study is the first to elicit through imaging the correlation between NAFLD and potential cardiac metabolic abnormalities. Patients with NAFLD have a high risk of related cardiovascular disease (CVD). It has been pointed out that the leading cause of death in NAFLD patients is CVD rather than liver-associated complications, of which only 5% of NAFLD patients die from liver-related diseases. 18 F-FGD PET is an important indicator of cardiac glucose metabolism and its alteration in the presence of disease; however, to systematically understand the relation between NAFLD and the risk of cardiovascular disease, other probes, in addition to 18 FDG, should be used to study the complex and dynamic pathways of energy substrate metabolism in the heart in health and disease and their relationship to the metabolic pathways of other body organs.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis

Alcohol-associated hepatitis (AH) is a form of liver failure with high short-term mortality. Recent results have shown that HNF4a defective function and systemic inflammation are major disease drivers of AH. Plasma biomarkers of hepatocyte function could be useful for diagnostic and prognostic purposes. Herein an integrative analysis of hepatic RNAseq and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to identify plasma protein signatures for mild and severe AH patients. Alcohol-related liver disease cirrhosis (ALD)(AC), non-alcoholic fatty liver disease (NALFD), and healthy subjects (HC) were used as comparator groups. Identified proteins primarily involved in hepatocellular function were decreased in AH patients which included hepatokines, clotting factors, complement cascade components, and hepatocyte growth activators. A protein signature of AH disease severity was identified including thrombin (THRB), hepatocyte growth factor alpha (HGFA), clusterin (CLUS), human serum factor H-related protein (FHR1) and kallistatin (KAIN), which exhibited large abundance shifts between severe and non-severe AH. The combination of THRB and HGFA discriminated between severe and non-severe AH with high sensitivity and specificity. These findings were correlated with the liver expression of genes encoding secreted proteins in a similar cohort, finding a highly consistent plasma protein signature reflecting HNF4A and HNF1A functions. This unbiased proteomic-transcriptome analysis identified plasma protein signatures and pathways associated with disease severity, reflecting HNF4A/1A activity useful for diagnostic assessment in AH.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Supplemental microalgal astaxanthin produced coordinated changes in intrinsic antioxidant systems of layer hens exposed to heat stress

Not provided.

Biotechnology & Applied Microbiology↗

DOE OSTI2017

Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid N -oxides

There are 660 pyrrolizidine alkaloids (PAs) and PA N-oxides present in the plants, with approximately half being possible carcinogens. We previously reported that a set of four PA-derived DNA adducts is formed in the liver of rats administered a series of hepatocarcinogenic PAs and a PA N-oxide. Based on our findings, we hypothesized that this set of DNA adducts is a common biological biomarker of PA-induced liver tumor formation. In this study, we determined that rat liver microsomal metabolism of five hepatocarcinogenic PAs (lasiocarpine, retrorsine, riddelliine, monocrotaline, and heliotrine) and their corresponding PA N-oxides produced the same set of DNA adducts. Among these compounds, lasiocarpine N-oxide, retrorsine N-oxide, monocrotaline N-oxide, and heliotrine N-oxide are for first time shown to be able to produce these DNA adducts. These results further support the role of these DNA adducts as potential common biomarkers of PA-induced liver tumor initiation.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

Tumour exosome integrins determine organotropic metastasis

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. In this paper, we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α 6 β 4 and α 6 β 1 were associated with lung metastasis, while exosomal integrin α v β 5 was linked to liver metastasis. Targeting the integrins α 6 β 4 and α v β 5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2017

Ly6Chi inflammatory monocytes promote susceptibility to Leishmania donovani infection

Ly6C hi inflammatory monocytes (iMO) are critical for host defense against toxoplasmosis and malaria but their role in leishmaniasis is unclear. In this study, we report a detrimental role of Ly6C hi iMOs in visceral leishmaniasis (VL) caused by Leishmania donovani . We demonstrate that Ly6C hi iMOs are continuously recruited into the spleen and liver during L. donovani infection and they are preferential targets for the parasite. Using microarray-based gene expression profiling, we show that Ly6C hi iMOs isolated from the infected liver and spleen have distinct phenotypic and activation profiles. Furthermore, we demonstrate that blocking the recruitment of Ly6C hi iMOs into the liver and spleen during L. donovani infection using a CCR2 antagonist reduces the frequency of the pathogenic IFN-γ/IL10 dual producer CD4+ T cells in the spleen and leads to a significant reduction in parasite loads in the liver and spleen. Using STAT1-/- mice we show that STAT1 is critical for mediating the recruitment of Ly6C hi iMOs into organs during L. donovani infection, and adaptive transfer of wild type Ly6C hi iMOs into STAT1-/- recipients renders them susceptible to disease. Our findings reveal an unexpected pathogenic role for Ly6C hi iMOs in promoting parasite survival in VL and open the possibility of targeting this population for host-directed therapy during VL.

Science & Technology - Other Topics↗