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ObjectiveVaccines against antigens expressed on adenomas could prevent new adenoma formation. We assessed whether a MUC1 peptide vaccine produces an immune response and prevents subsequent colonic adenoma formation.DesignMulticenter, double blind, placebo-controlled randomized trial in individuals age 40-70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.Results53 participants received the MUC1 vaccine and 50 placebo. 13/52 (25%) of MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range 2.9-17.3) at week 12 vs. 0/50 placebo recipients (1-sided Fisher’s exact PConclusionAn immune response was observed only in vaccine recipients. Overall adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence was observed in immune responders.ClinicalTrials.gov Identifier: NCT02134925.https://clinicaltrials.gov/ct2/show/NCT02134925Key PointsWhat is already knownAntigens expressed on colonic adenomas are potential targets for immunopreventive vaccines. An effective vaccine could prevent subsequent adenoma formation.What this Study AddsIn this multicenter, double blind, placebo-controlled randomized trial, MUC1 vaccine recipients developed an immune response. Overall adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence was observed in immune responders.How this study might affect research, practice or policyVaccine immunoprevention is a potential new frontier to colorectal cancer prevention.

Purpose:To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation.Patients and Methods:Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.Results:Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9–17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60–1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15–1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events.Conclusions:An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.

Background Information on Advanced Adenoma

supplementary methods: Detailed laboratory methods

Endpoint titers of plasma antibodies at week 12 amongst vaccine responders

Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells.Patients and Methods: In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood.Results: Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (Conclusions: Poly-ICLC was well tolerated in patients with solid cancer and generated local and systemic immune responses, as evident in the patient achieving clinical benefit. These results warrant further investigation and are currently being explored in a multicenter phase II clinical trial (NCT02423863). Clin Cancer Res; 24(20); 4937–48. ©2018 AACR.

Supplemental Figure 3. Selected BTM geneset enrichments (FDR < 0,25) of SD (patient 002) and PD patients (004 and 008) at tumor site. Gene names of enriched genesets are publicly available online in supplemental data for original paper23.

Supplemental Table 1. Quantitative Immunohistochemistry (IHC). In the patient 002 with clinical benefit (stable disease, right two columns), IHC analysis of tumor showed increased CD4 (60x), CD8 (10x), PD1 (20x) and PDL1 (3x). In patients with disease (001, 004, 005, 008), quantitative IHC showed unchanged or decreased levels of CD4, CD8, PD-1, and PDL-1 over treatment periods. Individual antigens were quantified using the CRI Inform software (Perkin Elmer) which applies user-directed antigen thresholds to generate percentages normalized to the total tumor area.

Natural and vaccine-induced SARS-CoV-2 immunity in humans has been described but correlates of protection are not yet defined. T cells support the SARS-CoV-2 antibody response, clear virus-infected cells, and may be required to block transmission. In this study, we identified peptide epitopes associated with SARS-CoV-2 T-cell immunity. Using immunoinformatic methods, T-cell epitopes from spike, membrane, and envelope were selected for maximal HLA-binding potential, coverage of HLA diversity, coverage of circulating virus, and minimal potential cross-reactivity with self. Direct restimulation of PBMCs collected from SARS-CoV-2 convalescents confirmed 66% of predicted epitopes, whereas only 9% were confirmed in naive individuals. However, following a brief period of epitope-specific T-cell expansion, both cohorts demonstrated robust T-cell responses to 97% of epitopes. HLA-DR3 transgenic mouse immunization with peptides co-formulated with poly-ICLC generated a potent Th1-skewed, epitope-specific memory response, alleviating safety concerns of enhanced respiratory disease associated with Th2 induction. Taken together, these epitopes may be used to improve our understanding of natural and vaccine-induced immunity, and to facilitate the development of T-cell-targeted vaccines that harness pre-existing SARS-CoV-2 immunity.

Seismic is often inferred to be synonymous with high cost. In a mineral environment, it is typically assumed to be viable only for mining operations or brownfield exploration. For greenfield exploration, other geophysical and geochemical/lithogeochemical methods are usually preferred, due in part to their affordability. We show results of a low-cost seismic survey over the Escondida porphyry copper deposit. The results show that low-cost 3D acquisition can improve structural understanding of established porphyry deposits and that there is potential for 3D seismic to be applied in brownfield and perhaps even greenfield exploration. The sparse 3D seismic reflection survey acquired at Escondida illuminates the structural setting and images stock genetically related to the Escondida intrusive complex at depth. The seismic results are compared to a magnetization vector inversion calculated from a regional airborne survey. This illustrates the potential for jointly utilizing the two methods to identify and prioritize anomalies for targeted drilling-based follow-up in exploration settings.

We have systematically shown that the Amastigote Surface Protein-2 (ASP-2) and Transialidase (TS) antigens either in the form of recombinant protein or encoded in the plasmids and human adenovirus 5 (hAd5) confer strong protection against different lineages of Trypanosoma cruzi parasites. Herein we generated a chimeric protein containing the most immunogenic regions for T and B cells from ASP-2 and TS (DTT-1) and evaluated its efficacy in comparison with our standard protocol of heterologous prime-boost using plasmids and hAd5. Our results show that mice immunized with DTT-1 protein together with Poly-ICLC (Hiltonol) become highly resistant to challenge with the Y strain of T. cruzi, showing a large decrease in tissue parasitism, parasitemia and no lethality. This protection lasted for at least 3 months after the last boost of immunization and an equivalent level of protection induced by the DNA/hAd5 protocol. DTT-1 induced high levels of T. cruzi-specific antibodies and IFNγ-producing T cells and protection was mediated by B lymphocytes, CD8 T cells and IFNγ. Finally, we evaluated the toxicity, immunogenicity and efficacy of the DTT-1 and DNA/hAd5 formulations in dogs. Mild collateral effects were detected at the site of vaccine inoculation. While the chimeric protein associated to Poly-ICLC induced high levels of antibodies and CD4+ T cell responses, the DNA/hAd5 induced no antibodies, but a strong CD8+ T cell response. Immunization with either vaccine formulations protected dogs against challenge with the Berenice strain of T. cruzi. Despite to the similar efficacy, we conclude that moving ahead with DTT-1 together with Hiltonol is advantageous over the hAd5 vaccine due to the cost-benefit for development and large-scale production.

Islanded nanogrids (NGs) are autonomous systems consisting of small-scale generation units including renewable energy sources and traditional fuel generators and energy storage systems (ESS) that typically serve few buildings or loads. This work aims at developing and validating a new optimal energy management (EM) algorithm for an islanded NG. To minimize the generator's operating cost and maximize battery availability at each operating cycle, dynamic programming (DP) framework is employed to solve the underlying optimization problem. The goal of the proposed approach is to ensure the use of maximum available solar power and to achieve optimal battery state of charge. To meet that goal, the management of the ESS is formulated as a stochastic optimal control problem, where nonlinearities in the battery discharging process are considered. A Markov model is constructed for predicting the probability distribution of the solar production used in the stochastic DP formulation. Simulation results are given to illustrate the efficacy of the proposed DP-based approach compared to a rule-based algorithm. Finally, a hardware-in-the-loop system is used to evaluate the real-time operation of the proposed EM algorithm.

This work introduces some of the most widely usedcompression algorithms, and their relevance to the field oflivestock farming, which has been historically characterizedfor requiring menial and inefficient labor, introducingenvironmental. And also for lacking the scale andautomation that cutting edge technologies can provide. Bydoing this we will explain how this opens the door tolocations untouched by technology, and the generaladvantages, and possibilities that integrating patternrecognition models bring to the table. In addition, we willexplain the ins and outs of these compression algorithms,and our reasoning behind our decision to choose analgorithm to implement in our pattern recognition model.To solve this problem, Seam Carving, Image Scaling andRun-Length encoding were used. With them we compressedthe images an average of 17.5% of their original size in atime complexity of O(L*N*M). This research shows howyou can create an efficient compression algorithm for usagein PLF.

Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (UPR) signaling contribute to the development of type 2 diabetes in obesity. UPR signaling is a complex signaling pathway, which is still being explored in many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.

Celastrol is a leptin-sensitizing agent with profound anti-obesity effects in diet-induced obese (DIO) mice. However, the genes and pathways that mediate celastrol-induced leptin sensitization have not been fully understood. By comparing the hypothalamic transcriptomes of celastrol and vehicle-treated DIO mice, we identified lipocalin-2 (Lcn2) as the gene most strongly upregulated by celastrol. LCN2 was previously suggested as an anorexigenic and anti-obesity agent. Celastrol increased LCN2 protein levels in hypothalamus, liver, fat, muscle, and bone marrow, as well as in the plasma. However, genetic deficiency of LCN2 altered neither the development of diet-induced obesity, nor the ability of celastrol to promote weight loss and improve obesity-associated dyshomeostasis. We conclude that LCN2 is dispensable for both high fat diet-induced obesity and its therapeutic reduction by celastrol.

Nanogrids (NGs) are small scale microgrids typically serving few buildings or loads. An islanded NG is an autonomous system that consists of generation units including renewable energy sources and traditional fuel generators, energy storage systems (ESS) and loads. This paper presents the design and validation of a new optimal energy management (EM) algorithm for an islanded NG. To minimize the generator's operating cost and maximize battery availability at each operating cycle, dynamic programming (DP) framework is employed to solve the underlying optimization problem. The goal of the proposed EM algorithm is to ensure both the use of maximum available solar power and optimal battery state of charge. To meet that goal, the management of the ESS is formulated as a stochastic optimal control problem, where nonlinearities in the battery charging and discharging process are considered. A Markov model is built in order to predict the probability distribution of the solar production used in the stochastic DP formulation. Simulation results are given to illustrate the efficacy of the proposed DP-based approach compared to a rule-based algorithm. Finally, a hardware-in-the-loop system is used to evaluate the real-time operation of the proposed EM algorithms.

The demand for grid-tied residential battery storage systems (BSS), especially lithium-ion, has increased over the past few years. The power electronics elements inside these systems are responsible for regulating the energy flow between batteries and the mains, while maintaining overall system efficiency as high as possible. This paper presents the design and implementation of a nonlinear controller for a synchronous buck-boost converter used in residential BSS applications. The nonlinear control is based on a change of state-space variables on the underlying nonlinear converter model, where the control law is developed using full state feedback linearization. The main control objective is to regulate the output voltage (dc-link voltage), improving the transient performance in the presence of a split-phase grid-tied inverter which is connected as a load. System stability conditions are studied leading to a design constraint in terms of the output capacitance value. Simulations and Hardware-in-the-Loop implementation results are provided at the end.