Prognostic Marker Of Disease Progression Research Articles

Abstract 4960: Molecular characterization of in-vivo isolated EpCAM-positive circulating tumor cells in high-risk prostate cancer patients

Abstract Introduction: CTC have been verified as prognostic markers for disease progression in various cancer types. The main aim of the EU project “CTC-SCAN” is to validate the number of CTC isolated from patient's blood as a prognostic marker for relapse in high-risk prostate cancer patients treated with primary radical prostatectomy or radiotherapy. In this study, we present our results on gene expression profiling of CTCs that were isolated, using the CellCollector, a novel clinical device designed for the in vivo isolation of EpCAM-positive CTCs. Patients and methods: We first developed and validated 3 multiplex and 3 single-plex highly sensitive RT-qPCR assays amplifying:a)Epithelial markers:CK-19,EpCAM,E-CAD & PBGD, b)Stem cell markers:PSCA,ALDH1,CD133& HPRT, c) EMT markers: TWIST, VIM, N-CAD and B2M and d)PSA, e)TMPRSS2-ERG fusion, f)Plastin-3. 62 patients and 36 healthy volunteers participated in the study. After in vivo isolation, total RNA was extracted from captured cells,followed by cDNA synthesis. RT-qPCR was performed for the molecular characterization of captured cells. In all cases, peripheral blood was also collected for CTC analysis by CellSearch and the EPISPOT. Results: The findings of our study are summarized in Table 1. Briefly, in 13/15(87%) samples, in which at least one cell was detected by CellSearch, we detected the expression of at least one gene. In 28/47 samples, negative by CellSearch, we detected the expression of several genes by the developed RT-qPCR assays. In 9/14 samples that were exclusively found to be positive by EPISPOT for PSA immunospots, at least one of the analyzed genes was also expressed. Conclusions: In vivo isolation of CTC in combination with a downstream molecular analysis is minimally invasive, and in combination with high specific and sensitive RT-qPCR assays for CTC detection and molecular characterization seems very promising. Comparison studies with the CellSearch and the EPISPOT have shown a higher sensitivity, but a poor agreement. in vivo(n = 18)in vitro(n = 18)GENEPOSITIVE(%)POSITIVE(%)POSITIVE(%)CK-1920(32%)1(0.5%)0(0%)E-CAD0(0%)0(0%)0(0%)EpCAM16(26%)1(0.5%)0(0%)CD1330(0%)0(0%)0(0%)ALDH111(18%)0(0%)0(0%)PSCA0(0%)0(0%)0(0%)VIMENTIN10(16%)0(0%)0(0%)TWIST15(24%)0(0%)0(0%)N-CAD11(18%)0(0%)0(0%)PLASTIN-36(10%)0(0%)0(0%)PSA6(10%)0(0%)0(0%)TMPRSS:ERG0(0%)0(0%)0(0%)CELLSEARCH(cut-off>1cells/ml)15(24%)0(0%)EPISPOT15(24%)0(0%) Citation Format: Athina N. Markou, Marifili Lazaridou, Panagiotis Paraskevopoulos, Shukun Chen, Thomas Kroneis, Monika Swierczewska, Joanna Budna, Andra Kuske, Tobias M. Gorges, Maciej Zabel, Peter Sedlmayr, Catherine Alix-Panabieres, Klaus Pantel, Evi S. Lianidou. Molecular characterization of in-vivo isolated EpCAM-positive circulating tumor cells in high-risk prostate cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4960.

Arterial spin labeling perfusion predicts longitudinal decline in semantic variant primary progressive aphasia.

The objective of the study was to evaluate the prognostic value of regional cerebral blood flow (CBF) measured by arterial spin labeled (ASL) perfusion MRI in patients with semantic variant primary progressive aphasia (svPPA). We acquired pseudo-continuous ASL (pCASL) MRI and whole-brain T1-weighted structural MRI in svPPA patients (N=13) with cerebrospinal fluid biomarkers consistent with frontotemporal lobar degeneration pathology. Follow-up T1-weighted MRI was available in a subset of patients (N=8). We performed whole-brain comparisons of partial volume-corrected CBF and cortical thickness between svPPA and controls, and compared baseline and follow-up cortical thickness in regions of significant hypoperfusion and hyperperfusion. Patients with svPPA showed partial volume-corrected hypoperfusion relative to controls in left temporal lobe and insula. svPPA patients also had typical cortical thinning in anterior temporal, insula, and inferior frontal regions at baseline. Volume-corrected hypoperfusion was seen in areas of significant cortical thinning such as the left temporal lobe and insula. Additional regions of hypoperfusion corresponded to areas without cortical thinning. We also observed regions of hyperperfusion, some associated with cortical thinning and others without cortical thinning, including right superior temporal, inferior parietal, and orbitofrontal cortices. Regions of hypoperfusion and hyperperfusion near cortical thinning at baseline had significant longitudinal thinning between baseline and follow-up scans, but perfusion changes in distant areas did not show progressive thinning. Our findings suggest ASL MRI may be sensitive to functional changes not readily apparent in structural MRI, and specific changes in perfusion may be prognostic markers of disease progression in a manner consistent with cell-to-cell spreading pathology.

NF-κB/p65 expression before and after treatment in rectal cancer patients undergoing neoadjuvant (chemo)radiotherapy and surgery: prognostic marker for disease progression and survival

Nuclear factor-kappaB (NF-κB), especially p65 subunit, has been associated with origin and progression of cancer as well as with the resistance to radiotherapy and chemotherapy in experimental models. The aim of the present study was to determine expression of NF-κB/p65 in tumor specimens before and after treatment of rectal cancer patients and to evaluate possible relationship between expression of NF-κB/p65 before and after (chemo)radiotherapy, other tumor characteristics and the clinical outcome. Furthermore, NF-κB/p65 was studied in relationship to pathologic response to preoperative (chemo)radiotherapy. Fifty patients with rectal cancer undergoing neoadjuvant (chemo)radiotherapy and surgery were included in the study. Pre-treatment rectal cancer specimens were obtained from diagnostic colonoscopy. Post-treatment rectal cancer specimens were obtained from surgically removed part of the rectum with the tumor. NF-κB/p65 expression was determined by immunohistochemistry and analysis was performed both in biopsies and in post-treatment tumor samples. Cytoplasmic positivity in tumor cells and nuclear positivity in lymphocytes were detected. High NF-κB/p65 positivity in pre-treatment tumor samples was significantly associated with shortened overall survival (OS). Disease-free survival (DFS) tends to be shortened as well. In post-treatment tumor samples, high NF-κB/p65 positivity was neither associated with shortened OS nor with shortened DFS. In post-treatment samples residual tumor cells deeply infiltrating the wall of the rectum with high NF-κB/p65 expression were found. The cells were linked to significantly worse clinical outcome in terms of shortened OS and DFS. NF-κB/p65 positivity did not correlate with pathologic response to preoperative (chemo)radiotherapy. In conclusion, our data suggest that high level of NF-κB/p65 subunit may be associated with more aggressive features of the tumor, higher metastatic potential, and shortened overall survival, but it does not correlate with resistance to (chemo)radiotherapy. Consequently, the level of NF-κB/p65 may help to select those patients who have poor prognosis and are candidates for more intensive anticancer therapy. For these purposes both pre-treatment and post-treatment tumor samples may be used.

Immune monitoring in patients with colorectal cancer stage II

Immunoscore has been shown to be a very powerful prognositc indicator in patients with clinically localized colorectal cancer, with no detectable tumour spread to lymph nodes or distant organs. These patients are usually treated with surgical removal of the tumour only. However, approximately 25% of these patients will have recurrence of their disease. No tumour-associated marker to predict the recurrence of this subgroup of patients and define who could benefit from adjuvant therapy is used in clinical routine[1] In addition to immunoscore, other parameters of the immune response are investigated – mostly cellular immunity and the production of immunosuppressive and neoangiogenic markers. Vascular endothelial growth factor (VEGF) is the factor responsible for neoangiogenesis and it is being considered as a possible prognostic marker of disease progression. Transforming growth factor-beta (TGF-beta) is also neoangiogenic and a highly immunosuppressive factor as it suppresses the body's natural immunity against tumours and is also being considered as another possible prognostic marker of disease progression.

Prognostic Significance of VEGF and bFGF in Egyptian CLL Patients

Though an impressive number of prognostic factors have been identified in chronic lymphocytic leukemia (CLL), which exhibits a high variability in its clinical presentation and course, many of them have not yet been applied in routine clinical practice. Among these factors are the angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), previously reported as prognostic markers for disease progression. The objective of the present study was to assess the impact of serum VEGF and bFGF levels at diagnosis in Egyptian CLL patients and their relationship with disease prognostic parameters and patients' outcome, aiming to apply them in routine clinical practice. For this purpose, 45 newly diagnosed CLL patients and 25 healthy controls were recruited. VEGF and bFGF were found to be significantly higher in the CLL group when compared to the control group (P 320 pg/ml for VEGF and >145 pg/ml for bFGF was able to predict poor prognosis (treatment failure) in CLL patients with prognostic accuracies of 96.7% and 89.10% respectively. In conclusion: VEGF and bFGF represent powerful prognostic markers in B-CLL, partially because of the simplicity of obtaining their samples and their assays procedure, the reliability of their assessment besides being optimal targets for potential novel therapies in conjunction with classical therapies.

CD49d and CD26 are independent prognostic markers for disease progression in patients with chronic lymphocytic leukemia.

CLL is characterized by extremely variable clinical course. Several prognostic factors can predict disease progression and therapeutic outcomes in those patients. The aim was to evaluate the use of CD49d and CD26 as independent prognostic markers in CLL patients. The present study measured surface expression of CD49d and CD26 by three-color flow cytometry in a series of 103 untreated CLL patients. We evaluated the prognostic role of CD49d and CD26 to predict the risk of lymphocyte doubling, disease progression and overall survival. We confirmed that CD49d and CD26 were significant predictors of lymphocyte doubling(P<0.001 for both markers) and disease progression (P<0.001 for both markers) but insignificant for overall survival(P=0.303 and 0.519 respectively. Multivariate analysis between clinical parameters and flow cytometry markers revealed that CD49d and CD26 are independent prognostic markers for lymphocyte doubling (HR=1.487 P=007 and HR=2.248, P=0.014 respectively) and progression to a more advanced stage (HR=3.191, P=0.049 and HR=7.887, P=0.003). Also, concordant expression of both markers was found to improve their predictive power. Many studies reported that CD49d and CD26 combined analysis was found to improve their power to predict the risk of lymphocyte doubling and disease progression. CD49d and CD26 have independent prognostic value and we suggest its use as a part of routine panel for prognostic stratification of CLL.

CD49d and CD26 are Independent Prognostic Markers for Disease Progression in Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a clonal expansion of small mature lymphocytes accumulating in blood, bone marrow, and lymphoid organs. CLL is characterized by extremely variable clinical courses with survivals ranging from one to more than 15 years [1]. Rai and Binet clinical staging systems were established for prognostic stratification of these cases [2,3].

Fundus autofluorescence imaging in dry AMD: 2014 Jules Gonin lecture of the Retina Research Foundation.

Fundus autofluorescence (FAF) imaging allows for topographic mapping of intrisnic fluorophores in the retinal pigment epithelial cell monolayer, as well as mapping of other fluorophores that may occur with disease in the outer retina and the sub-neurosensory space. FAF imaging provides information not obtainable with other imaging modalities. Near-infrared fundus autofluorescence images can also be obtained in vivo, and may be largely melanin-derived. FAF imaging has been shown to be useful in a wide spectrum of macular and retinal diseases. The scope of applications now includes identification of diseased RPE in macular/retinal diseases, elucidating pathophysiological mechanisms, identification of early disease stages, refined phenotyping, identification of prognostic markers for disease progression, monitoring disease progression in the context of both natural history and interventional therapeutic studies, and objective assessment of luteal pigment distribution and density as well as RPE melanin distribution. Here, we review the use of FAF imaging in various phenotypic manifestations of dry AMD.

Optimal treatment of Alzheimer's disease psychosis: challenges and solutions.

Psychotic symptoms emerging in the context of neurodegeneration as a consequence of Alzheimer’s disease was recognized and documented by Alois Alzheimer himself in his description of the first reported case of the disease. Over a quarter of a century ago, in the context of attempting to develop prognostic markers of disease progression, psychosis was identified as an independent predictor of a more-rapid cognitive decline. This finding has been subsequently well replicated, rendering psychotic symptoms an important area of exploration in clinical history taking – above and beyond treatment necessity – as their presence has prognostic significance. Further, there is now a rapidly accreting body of research that suggests that psychosis in Alzheimer’s disease (AD+P) is a heritable disease subtype that enjoys neuropathological specificity and localization. There is now hope that the elucidation of the neurobiology of the syndrome will pave the way to translational research eventuating in new treatments. To date, however, the primary treatments employed in alleviating the suffering caused by AD+P are the atypical antipsychotics. These agents are approved by the US Food and Drug Administration for the treatment of schizophrenia, but they have only marginal efficacy in treating AD+P and are associated with troubling levels of morbidity and mortality. For clinical approaches to AD+P to be optimized, this syndrome must be disentangled from other primary psychotic disorders, and recent scientific advances must be translated into disease-specific therapeutic interventions. Here we provide a review of atypical antipsychotic efficacy in AD+P, followed by an overview of critical neurobiological observations that point towards a frontal, tau-mediated model of disease, and we suggest a new preclinical animal model for future translational research.

ERG protein expression is predictive of disease progression for prostate cancer patients managed on active surveillance

<h3>Background</h3> Active surveillance (AS) is an observational strategy for selected prostate cancer (PCa) patients. This study analysed whether ERG protein expression in diagnostic biopsies could be used as a prognostic marker for disease progression. <h3>Methods</h3> We followed 265 patients on AS with regular prostate-specific antigen (PSA) measurements, clinical examinations, and re-biopsies. ERG immunohistochemical analyses were performed using monoclonal antibodies (EPR3864; Roche/Ventana). ERG-positive patients showed minimum one positive focus. Progression that prompted consideration of curative treatment was defined as either (1) increase of tumour stage to ≥cT2b, (2) increased Gleason score or either >3 positive biopsies or bilaterality on re-biopsy, or (3) PSA doubling-time. <h3>Results</h3> Complete information was available for 217 patients; 96 were ERG-positive and 121 were ERG-negative. ERG-positive patients had significantly higher risk of progression (<i>p</i><0.0001) with 2-year cumulative incidence of 58.6% (95%CI 48.7–68.5%) for ERG-positive patients and 21.7% (95%CI 14.3–29.1%) for ERG-negative patients. In multiple cause-specific Cox models, ERG-positivity independently predicted progression [HR:2.45, (95%CI 1.62–3.72), <i>p<</i>0.0001]. <h3>Conclusion</h3> ERG-positive PCa runs a more aggressive course if left untreated. ERG immunostaining can be applied as a prognostic marker for conservatively managed patients for individualisation of AS programmes.

Usefulness of 64Cu-ATSM in Head and Neck Cancer

Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a hypoxia-avid, positron emitter radiotracer. The primary aim of this study is to assess the efficacy of pretherapy Cu-ATSM PET/CT as a prognostic factor of response to therapy. The secondary aims are to investigate if there is a difference between early and late PET/CT scans and if there is a difference between the biologic tumor volume (BTV) in radiotherapy treatment planning calculated between Cu-ATSM and F-FDG, and to assess if Cu-ATSM is a prognostic marker of disease progression. Eleven patients with head and neck cancer treated with chemoradiotherapy were enrolled prospectively; both Cu-ATSM and F-FDG PET/CT scans before and after treatment were obtained. The Cu-ATSM scans were performed after 1 hour (early) and 16 hours (late). All patients had stage III or IV squamous cell head and neck cancer; 7 of 11 patients had nodal metastasis, and 22 cancer foci were detected with Cu-ATSM. SUVmax was 16.2 ± 7.9, and there was no significant SUVmax difference between early and late imaging. F-FDG SUVmax before therapy was 15.6 ± 9.4, whereas F-FDG SUVmax after therapy was 1.5 ± 1.2. Sensitivity and specificity values of Cu-ATSM calculated with receiver operating characteristic curves were 100% and 50% considering the SUVmax and 100% and 33% considering the volume, respectively. No difference has been found between the BTV contoured with Cu-ATSM and F-FDG. The Cu-ATSM scans showed high sensitivity but low specificity in predicting neoadjuvant chemoradiotherapy response. No difference was noted between early and late scans. F-FDG and Cu-ATSM provided similar results about delineation of BTV.

Estimation of Circulating Immune Complexes in patients with Oral Leukoplakia and Oral Submucous Fibrosis: A Case Control Study.

The present study was conducted to estimate the serum levels of Circulating Immune Complexes in patients with Oral Leukoplakia ,Oral sub mucous fibrosis and normal subjects and correlate these values with the clinical grades of the diseases. The study consisted of 25 Oral Leukoplakia patients, 25 Oral sub mucous fibrosis patients and 25 Normal subjects. The mean serum levels of CIC showed a gradual increase from normal subjects to Oral Leukoplakia patients and showed a high values in Oral sub mucous fibrosis patients. The mean serum levels of CIC also showed a gradual increase from clinical grade I to grade IV of Oral sub mucous fibrosis. Serum levels of CIC may be taken as a prognostic marker for disease progression of patients with Oral Leukoplakia and Oral sub mucous fibrosis.

Immunohistochemical evaluation of myofibroblasts using alpha-smooth muscle actin in oral submucous fibrosis

Introduction: Oral submucous fibrosis (OSMF) is a chronic debilitating disease and a premalignant condition of the oral cavity characterized by generalized submucosal fibrosis with a multifactorial etiology. Myofibroblasts are a unique group of cells phenotypically intermediate between smooth muscle cells and fibroblast exhibiting contractile properties, expressing α-smooth muscle actin (α-SMA) and are considered primary producers of extracellular matrix after injury. Their accumulation has been established as a marker of progressive fibrosis in various organs. The aim of the present study is to evaluate and compare the myofibroblasts in various histological grades of OSMF. Materials and Method: Fifteen cases of OSMF, which were further categorized histologically into early (5 cases), moderately advanced (5 cases) and advanced (5 cases), were subjected to immunohistochemical evaluation using α-SMA antibody for detection of myofibroblasts. Fifteen benign mucosal proliferation specimens were also stained for comparison. Results: The number of myofibroblasts in OSMF was significantly increased when compared to that of benign mucosal proliferations (P < 0.05). Additionally, a statistically significant increase in the myofibroblasts population between early and advanced stages was observed (P < 0.05). Conclusions: The results of the present study showed that expression of myofibroblasts within the OSMF group showed a progressive increase from the early OSMF through moderate OSMF and the advanced OSMF group indicating that myofibroblasts could serve as effective prognostic marker for disease progression in oral submucous fibrosis.

Colorectal cancer patients show decrease in cellular immunity and enhanced plasma level of transforming growth factor – beta and vascular endothelial growth factor (VEGF)

Background Colorectal cancer is the second leading cause of cancer death in the world. The cause of high mortality is that almost half the cancers are detected at an advanced stage of disease. In addition to surgical and chemotherapy treatment in recent years, applied monoclonal antibody therapy may target against growth factors, and particularly against the receptors for growth factors. In clinical practice, an antibody against vascular endotelial growth factor (VEGF) - bevacizumab-is already used. VEGF is the factor responsible for neoangiogenesis and it was considered as a possible prognostic marker of disease progression. The correlation of higher levels of VEGF with the response to applied therapy, disease progress levels and a poor prognosis in patients with solid tumors is recently discussed. Transforming growth factor - beta (Transforming growth factor - beta, TGF-beta) is also neoangiogenetic and highly immunosuppressive factor. TGF-beta suppresses natural immunity against tumors. The TGF is considered as another possible prognostic marker of disease progression. The purpose of the study was to monitor immune responses in patients with colorectal cancer, particularly the examination of cellular as well as humoral immunity. TGF beta, and VEGF production was monitored. Methods

SP0204 The pathogenesis of sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unclear aetiology. It is generally viewed as a Th1 mediated inflammatory disease with a prelidiction for the lung, lymph nodes and skin. There...

Cell-associated HIV RNA: a dynamic biomarker of viral persistence

In most HIV-infected individuals adherent to modern antiretroviral therapy (ART), plasma viremia stays undetectable by clinical assays and therefore, additional virological markers for monitoring and predicting therapy responses and for measuring the degree of HIV persistence in patients on ART should be identified. For the above purposes, quantitation of cell-associated HIV biomarkers could provide a useful alternative to measurements of viral RNA in plasma. This review concentrates on cell-associated (CA) HIV RNA with the emphasis on its use as a virological biomarker. We discuss the significance of CA HIV RNA as a prognostic marker of disease progression in untreated patients and as an indicator of residual virus replication and the size of the dynamic viral reservoir in ART-treated patients. Potential value of this biomarker for monitoring the response to ART and to novel HIV eradication therapies is highlighted.

Side Population Cells as Prototype of Chemoresistant, Tumor-Initiating Cells

Classically, isolation of CSCs from tumors exploits the detection of cell surface markers associated with normal stem cells. Invariable expression of these cell surface markers in almost all proliferating tumor cells that albeit impart specific functionality, the universality, and clinical credibility of CSC phenotype based on markers is still dubious. Side Population (SP) cells, as defined by Hoechst dye exclusion in flow cytometry, have been identified in many solid tumors and cell lines and the SP phenotype can be considered as an enriched source of stem cells as well as an alternative source for the isolation of cancer stem cells especially when molecular markers for stem cells are unknown. SP cells may be responsible for the maintenance and propagation of tumors and the proportion of SP cells may be a predictor of patient outcome. Several of these markers used in cell sorting have emerged as prognostic markers of disease progression though it is seen that the development of new CSC-targeted strategies is often hindered by poor understanding of their regulatory networks and functions. This review intends to appraise the experimental progress towards enhanced isolation and drug screening based on property of acquired chemoresistance of cancer stem cells.

MiQ—A novel microRNA based diagnostic and prognostic tool for prostate cancer

Today, the majority of prostate tumors are detected at early stages with uncertain prognosis. Therefore, we set out to identify early predictive markers of prostate cancer with aggressive progression characteristics. We measured the expression of microRNAs (miRNA) using qRT-PCR in formalin fixed and paraffin embedded prostatic tissue samples from a Swedish cohort of 49 patients with prostate cancer and 25 without cancer and found seven of 13 preselected miRNAs to discriminate between the two groups. Subsequently, four discriminatory miRNAs were combined to a quota, denoted the miRNA index quote (miQ); ((miR-96-5p × miR-183-5p)/(miR-145-5p × miR221-5p)). The advantage of using a quote is increased discrimination, no need for house-keepings, and most important it may be an advantage considering the heterogeneity of the disease. miQ was found to successfully predict diagnosis (p < 0.0001) with high accuracy (area under the curve, AUC = 0.931) that was verified in an independent Dutch cohort and three external cohorts, and significantly outperforming prostate-specific antigen. Importantly, miQ also has prognostic power to predict aggressiveness of tumors (AUC = 0.895), metastatic statues (AUC = 0.827) and overall survival (p = 0.0013, Wilcoxon test HR = 6.5, median survival 2 vs. 5 years), verified in the Dutch cohort. In this preliminary study, we propose that miQ has potential to be used as a clinical tool for prostate cancer diagnosis and as a prognostic marker of disease progression.

Precise Determination of Time to Reach Viral Load Set Point After Acute HIV-1 Infection

The HIV viral load set point has long been used as a prognostic marker of disease progression and more recently as an end-point parameter in HIV vaccine clinical trials. The definition of set point, however, is variable. Moreover, the earliest time at which the set point is reached after the onset of infection has never been clearly defined. In this study, we obtained sequential plasma viral load data from 60 acutely HIV-infected Chinese patients among a cohort of men who have sex with men, mathematically determined viral load set point levels, and estimated time to attain set point after infection. We also compared the results derived from our models and that obtained from an empirical method. With novel uncomplicated mathematic model, we discovered that set points may vary from 21 to 119 days dependent on the patients' initial viral load trajectory. The viral load set points were 4.28 ± 0.86 and 4.25 ± 0.87 log10 copies per milliliter (P = 0.08), respectively, as determined by our model and an empirical method, suggesting an excellent agreement between the old and new methods. We provide a novel method to estimate viral load set point at the very early stage of HIV infection. Application of this model can accurately and reliably determine the set point, thus providing a new tool for physicians to better monitor early intervention strategies in acutely infected patients and scientists to rationally design preventative vaccine studies.

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome

Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.