Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer.

Sipuleucel-T is the only FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. The mechanism by which this treatment improves survival is not fully understood. We have previously shown that this treatment can induce the recruitment of CD4 and CD8 T cells to the tumor microenvironment. In this study, we examined the functional state of these T cells through gene expression profiling. We found that the magnitude of T cell signatures correlated with the frequency of T cells as measured by immunohistochemistry. Sipuleucel-T treatment was associated with increased expression of Th1-associated genes, but not Th2-, Th17 - or Treg-associated genes. Post-treatment tumor tissues with high CD8+T cell infiltration was associated with high levels of CXCL10 expression. On in situ hybridization, CXCL10+ cells colocalized with CD8+T cells in post-treatment prostatectomy tumor tissue. Neoadjuvant sipuleucel-T was also associated with upregulation of immune inhibitory checkpoints, including CTLA4 and TIGIT, and downregulation of the immune activation marker, dipeptidylpeptidase, DPP4. Treatment-associated declines in serum PSA were correlated with induction of Th1 response. In contrast, rises in serum PSA while on treatment were associated with the induction of multiple immune checkpoints, including CTLA4, CEACAM6 and TIGIT. This could represent adaptive immune resistance mechanisms induced by treatment. Taken together, neoadjuvant sipuleucel-T can induce both a Th1 response and negative immune regulation in the prostate cancer microenvironment

Front-line management of indolent non-Hodgkin lymphoma in Australia. Part 2: mantle cell lymphoma and marginal zone lymphoma

Mantle cell lymphoma (MCL) and the marginal zone lymphoma (MZL) subtypes (nodal MZL, extra-nodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma) and splenic MZL) are uncommon lymphoma subtypes, accounting for less than 5-10% of all non-Hodgkin lymphoma. The evidence base for therapy is therefore limited and enrolment into clinical trials is preferred. Outcomes for patients with MCL have been steadily improving mainly due to the adoption of more intense strategies in younger patients, the use of rituximab maintenance and the recent introduction of bendamustine in older patients. MZL is a more heterogeneous group of cancer with both nodal, extra-nodal and splenic subtypes. Extranodal MZL may be associated with autoimmune or infectious aetiologies, and can respond to eradication of the causative pathogen. Proton pump inhibitor plus dual antibiotics in Helicobacter pylori positive gastric MALT lymphoma is curative in many patients. Watchful waiting is appropriate in most patients with asymptomatic advanced stage disease, which tends to behave in a particularly indolent manner. Other options for symptomatic disease include splenectomy, chemoimmunotherapy with rituximab and, more recently, targeted therapies

Pulmonary Arterial Stiffness: An Early and Pervasive Driver of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a historically neglected and highly morbid vascular disease that leads to right heart failure and, in some cases, death. The molecular origins of this disease have been poorly defined, and as such, current pulmonary vasodilator therapies do not cure or reverse this disease. Although extracellular matrix (ECM) remodeling and pulmonary arterial stiffening have long been associated with end-stage PAH, recent studies have reported that such vascular stiffening can occur early in pathogenesis. Furthermore, there is emerging evidence that ECM stiffening may represent a key first step in pathogenic reprogramming and molecular crosstalk among endothelial, smooth muscle, and fibroblast cells in the remodeled pulmonary vessel. Such processes represent the convergence of activation of a number of specific mechanoactivated signaling pathways, microRNAs, and metabolic pathways in pulmonary vasculature. In this review, we summarize the contemporary understanding of vascular stiffening as a driver of PAH, its mechanisms, potential therapeutic targets and clinical perspectives. Of note, early intervention targeting arterial stiffness may break the vicious cycle of PAH progression, leading to outcome improvement which has not been demonstrated by current vasodilator therapy

An Integrated Content and Metadata based Retrieval System for Art

In this paper we describe aspects of the Artiste project to develop a distributed content and metadata based analysis, retrieval and navigation system for a number of major European Museums. In particular, after a brief overview of the complete system, we describe the design and evaluation of some of the image analysis algorithms developed to meet the specific requirements of the users from the museums. These include a method for retrievals based on sub images, retrievals based on very low quality images and retrieval using craquelure type

Development, Validation, and Limits of Freezing of Gait Detection Using a Single Waist-Worn Device

Objective: Freezing of Gait (FOG) often described as the sensation of “the feet being glued to the ground” is prevalent in people with Parkinson's disease (PD) and severely disturbs mobility. In addition to tracking disease progression, precise detection of the exact boundaries for each FOG episode may enable new technologies capable of “breaking” FOG in real time. This study investigates the limits of sensitivity and performance for automatic device-based FOG detection. Methods: Eight machine-learning classifiers (including Neural Networks, Ensemble & Support Vector Machine) were developed using (i) accelerometer and (ii) accelerometer and gyroscope data from a waist-worn device. While wearing the device, 107 people with PD completed a walking and mobility task designed to elicit FOG. Two clinicians independently annotated the precise FOG episodes using synchronized video according to international guidelines, which were incorporated into a flowchart algorithm developed for this study. Device-detected FOG episodes were compared to the annotated FOG episodes using 10-fold cross-validation to determine accuracy and with Interclass Correlation Coefficients (ICC) to assess level of agreement. Results: Development used 50,962 windows of data representing over 10 hours of data and annotated activities. Very strong agreement between clinicians for precise FOG episodes was observed (90% sensitivity, 92% specificity and ICC 1,1 = 0.97 for total FOG duration). Device-based performance varied by method, complexity and cost matrix. The Neural Network that used only 67 accelerometer features provided a good balance between high sensitivity to FOG (89% sensitivity, 81% specificity and ICC 1,1 = 0.83) and solution stability (validation loss ≤ 5%). Conclusion: The waist-worn device consistently reported accurate detection of precise FOG episodes and compared well to more complex systems. The superior agreement between clinicians indicates there is room to improve future device-based FOG detection by using larger and more varied data sets. Significance: This study has clinical implications with regard to improving PD care by reducing reliance on clinical FOG assessments and time-consuming visual inspection. It shows high sensitivity to automatically detect FOG is possible

Development, Validation, and Limits of Freezing of Gait Detection Using a Single Waist-Worn Device

Objective: Freezing of Gait (FOG) often described as the sensation of “the feet being glued to the ground” is prevalent in people with Parkinson's disease (PD) and severely disturbs mobility. In addition to tracking disease progression, precise detection of the exact boundaries for each FOG episode may enable new technologies capable of “breaking” FOG in real time. This study investigates the limits of sensitivity and performance for automatic device-based FOG detection. Methods: Eight machine-learning classifiers (including Neural Networks, Ensemble & Support Vector Machine) were developed using (i) accelerometer and (ii) accelerometer and gyroscope data from a waist-worn device. While wearing the device, 107 people with PD completed a walking and mobility task designed to elicit FOG. Two clinicians independently annotated the precise FOG episodes using synchronized video according to international guidelines, which were incorporated into a flowchart algorithm developed for this study. Device-detected FOG episodes were compared to the annotated FOG episodes using 10-fold cross-validation to determine accuracy and with Interclass Correlation Coefficients (ICC) to assess level of agreement. Results: Development used 50,962 windows of data representing over 10 hours of data and annotated activities. Very strong agreement between clinicians for precise FOG episodes was observed (90% sensitivity, 92% specificity and ICC 1,1 = 0.97 for total FOG duration). Device-based performance varied by method, complexity and cost matrix. The Neural Network that used only 67 accelerometer features provided a good balance between high sensitivity to FOG (89% sensitivity, 81% specificity and ICC 1,1 = 0.83) and solution stability (validation loss ≤ 5%). Conclusion: The waist-worn device consistently reported accurate detection of precise FOG episodes and compared well to more complex systems. The superior agreement between clinicians indicates there is room to improve future device-based FOG detection by using larger and more varied data sets. Significance: This study has clinical implications with regard to improving PD care by reducing reliance on clinical FOG assessments and time-consuming visual inspection. It shows high sensitivity to automatically detect FOG is possible

Evolutionary optimization of a charge transfer ionic potential model for Ta/Ta-oxide hetero-interfaces

Tantalum, tantalum oxide and their hetero-interfaces are of tremendous technological interest in several applications spanning electronics, thermal management, catalysis and biochemistry. For example, local oxygen stoichiometry variation in TaOx memristors comprising of metallic (Ta) and insulating oxide (Ta2O5) have been shown to result in fast switching on the sub-nanosecond timescale over a billion cycles, relevant to neuromorphic computation. Despite its broad importance, an atomistic scale understanding of oxygen stoichiometry variation across Ta/TaOx hetero-interfaces, such as during early stages of oxidation and oxide growth, is not well understood. This is mainly due to the lack of a variable charge interatomic potential model for tantalum oxides that can accurately describe the ionic interactions in the metallic (Ta) and oxide (TaOx) environment as well as at their interfaces. To address this challenge, we introduce a charge transfer ionic potential (CTIP) model for Ta/Ta-oxide system by training against lattice parameters, cohesive energies, equations of state, and elastic properties of various experimentally observed Ta2O5 polymorphs. The best set of CTIP parameters are determined by employing a single-objective global optimization scheme driven by genetic algorithms followed by local Simplex optimization. Our newly developed CTIP potential accurately predicts structure, thermodynamics, energetic ordering of polymorphs, as well as elastic and surface properties of both Ta and Ta2O5, in excellent agreement with DFT calculations and experiments. We employ our newly parameterized CTIP potential to investigate the early stages of oxidation of Ta at different temperatures and atomic/molecular nature of the oxidizing species