Impact In Combination Research Articles

Production Possibility of Raw Ingredients of Plant Origin with Increased Bioavailability

The physical exposure methods use combined with amino acids to intensify the biologically active substances synthesis and the directional germination process flow is a promising for processing plant raw materials. The study aim is to obtain new data on the effectiveness of the combined action use of ultrasound and exogenous γ-aminobutyric acid solutions in the grain crop germination process to increase its nutritional value and bioavailability. The following types of grain crops were the research objects: wheat, barley and oats. Before the germination process, a man treated the grain with ultrasonic exposure ((22 ± 1.25) kHz; 245 W/l; 5 min) in the exogenous γ-aminobutyric acid solution. The researchers practiced two-factor planning. The γ-aminobutyric acid concentration (1; 3; 5 %) and the germination duration (12; 24; 36 h) acted as variable factors. The data obtained indicate a significant ultrasound exposure impact in combination with exogenous γ-aminobutyric acid on the synthesis and flavonoid accumulation, its bioavailability, antioxidant and membrane stabilizing effect, as well as the digestibility criterion of sprouted cereals. The average increase in the flavonoid content in the experimental samples during germination was 93% for wheat grain, 58 % for barley grain and 64 % for oat grain, respectively. The researchers proved an increase in the bioavailability index of this biologically active substance by 11–24 %. The experimental samples demonstrated a raise in the Tetrahymena pyriformis protozoa growth by 143–195 %, whereas for control germinated cereal samples – 65, 85 and 102 %, respectively. The long-life cycle duration of the simplest Parametium caudatum culture in the stress model was while using an extract from experimental sprouted grain crop samples. The conducted studies confirm the combination use effectiveness of ultrasonic exposure with exogenous γ-aminobutyric acid solutions of a given concentration in germination technology and enable obtaining plant raw ingredients with the desired properties.

Immunomodulation of NK, NKT and B/T cell subtypes in relapsed/refractory multiple myeloma patients treated with pomalidomide along with velcade and dexamethasone and its association with improved progression-free survival.

Multiple Myeloma (MM) patients exhibit dysregulated immune system, which is further weakened by chemotherapeutic agents. While cereblon-modulating agents, such as pomalidomide and lenalidomide, have been found to improve the immune profile, the efficacy of their impact in combination with other treatments is yet unknown. We conducted an immune-profiling of a longitudinal cohort of 366 peripheral blood samples from the CC4047-MM-007 (OPTIMISMM, NCT01734928) study. This study followed relapsed/refractory Multiple Myeloma (RRMM) patients who were treated with Velcade + dexamethasone (Vd), or Vd with pomalidomide (PVd). 366 blood samples from 186 patients were evaluated using multi-color flow cytometry at 3 timepoints: screening, day 8 of cycle 1, and cycle 3. Among NK and NKT cell populations, adding pomalidomide showed no inhibition in the frequency of NK cells. When expression of double positivity for activation markers like, p46/NKG2D, on NK cells was higher than the median, PVd treated patients showed significantly better (p=0.05) progression-free survival (PFS) (additional 15 months) than patients with lower than the median expression of p46/NKG2D on NK cells. PVd treated patients who expressed CD158a/b below the median at cycle 1 demonstrated a significantly better PFS (more than 18months). Among B cell subtypes, PVd treatment significantly increased the abundance of B1b cells (p<0.05) and decreased Bregs (p<0.05) at day 8 of both cycle 1 and cycle 3 when compared to screening samples. Of all the B cell-markers evaluated among paired samples, a higher expression of MZB cells at day 8 of cycle 1 has resulted in enhanced PFS in PVd treated patients. Within T cells, pomalidomide treatment did not decrease the frequency of CD8 T cells when compared with screening samples. The higher the surface expression of OX-40 on CD8 T cells and the lower the expression of PD-1 and CD25 on CD4 T cells by PVd treatment resulted in improved PFS. The prognostic significance for the number of immune markers is only seen in the PVd arm and none of these immune markers exhibit prognostic values in the Vd arm. This study demonstrates the importance of the immunomodulatory effects and the therapeutic benefit of adding pomalidomide to Vd treatment.

The Impact of Electoral Gender Quotas on Women’s Political Participation in Bosnia and Herzegovina

Abstract Although representing half of the world population, women remain largely excluded from political power and government structures. Various strategies have been introduced to increase women’s political representation, including electoral gender quotas. This paper explores the impact of electoral gender quotas on women’s quantitative participation in politics of Bosnia and Herzegovina, analysing quota impact in combination with other related factors, such as the quota design, implementation and broader political context. A diversity of techniques has been used to collect a combination of quantitative and qualitative data, including academic resources collection and analysis, desk research, statistical data analysis and online questionnaire. The paper argues that electoral gender quotas have generally had a positive impact on getting women elected in BiH, though their efficacy depends on their formulation and other aspects of electoral law. Still, quantitative representation of women is not sufficient to facilitate their agency in politics. Social attitudes also continue to affect the electoral success of women once they secure a spot on the candidate list. Therefore, quotas must be implemented within a broader democratic, accountable and gender-sensitive political context to deliver qualitative representation of women in politics. Finally, the paper offers concrete recommendations to promote women’s political participation in BiH.

Impact of agronomic practices on physical surface crusts and some soil technical attributes of two winter wheat fields in southern Iraq

PurposeAgricultural management as tillage systems and manure application can contribute effectively to controlling physical surface crusts (SCs), improving the soil’s technical characteristics and germination rates. While agronomic practices are generally applied to winter wheat fields in southern Iraq, no previous study has explored their impact in combination with SCs and soil physical attributes on wheat productivity (WP) under different soil textures.Materials and methodsThe impact of different agronomic management practices on the formation of soil physical surface crusts (SCs), soil compaction (measured by soil penetration resistance, SPR), soil volumetric water content (VWC), soil bulk density (ρb), mean weight diameter of aggregates (MWD), and WP was examined in two soil textures (clay loam, clay) during 2020 and 2022.Experimental data were subjected to an identical and randomized complete block design (RCBD) under a nested-factorial experimental design, where nine treatments with three replicates each were selected. This included three tillage practices (conventional tillage system (CT), till-plant (TP), and rotational tillage (NTCT)), alongside a sub-treatment with organic fertilizers (cattle manure (CF), and wheat straw (WR)), or without added fertilizer (WT).Results and discussionResults showed that CT treatment increased SCs during wheat growth stages by significantly increasing aggregate stability. A significant difference in ρb and SPR and a higher distribution of VWC were seen under CT treatment when compared to TP and NTCT treatments. TP treatment showed a significantly increased in SPR and ρb, particularly in clay loam. The MWD under TP and NTCT was significantly different to CT treatment, which may be explained by an increase in soil stability due to their management practices. Additionally, both organic fertilizers (CF and WR) significantly enhanced SCs, SPR, VWC, ρb, MWD, and WP.ConclusionsThese data showed a strong relationship between SCs and ρb and between VWC and SPR, which are directly affected by the soil’s water content.

Facility and Community Results-Based Financing to Improve Maternal and Child Nutrition and Health in The Gambia

ABSTRACT In 2013, the Government of The Gambia implemented a novel results-based financing (RBF) intervention designed to improve maternal and child nutrition and health through a combination of community, facility and individual incentives. In a mixed-methods study, we used a randomized 2 × 2 study design to measure these interventions’ impact on the uptake of priority maternal health services, hygiene and sanitation. Conditional cash transfers to individuals were bundled with facility results-based payments. Community groups received incentive payments conditional on completion of locally-designed health projects. Randomization occurred separately at health facility and community levels. Our model pools baseline, midline and endline exposure data to identify evidence of the interventions’ impact in isolation or combination. Multivariable linear regression models were estimated. A qualitative study was embedded, with data thematically analyzed. We analyzed 5,927 household surveys: 1,939 baseline, 1,951 midline, and 2,037 endline. On average, community group interventions increased skilled deliveries by 11 percentage points, while the facility interventions package increased them by seven percentage points. No impact was found, either in the community group or facility intervention package arms on early ANC. The community group intervention led to 49, 43 and 48 percentage point increases in handwashing stations, soaps at station and water at station, respectively. No impact was found on improved sanitation facilities. The qualitative data help understand factors underlying these changes. No interaction was found between the community and facility interventions. Where demand-side barriers predominate and community governance structures exist, community group RBF interventions may be more effective than facility designs.

Synthesis, characterization and biological activity of bifunctional ionic liquids based on dodine ion.

Development of new plant protection strategies has become an urgent matter in modern agriculture, in view of the evidently proved negative effect of currently used active ingredients of pesticides. In recent years, much effort has been made to eliminate the use of pesticides established to be toxic to pollinators. In this study, we present a group of new bifunctional ionic liquids based on dodine (N-dodecylguanidine) cation whose physical and biological properties have been modified relative to those of the commercially available N-dodecylguanidine acetate. The decreased level of residue of active substances in plant tissues reduces their availability to pollinators, which increases the safety of their use. Moreover, lower environmental impact in combination with high antifungal activity and an additional biological function, that is the systemic acquired resistance induction, are in line with the goals of sustainable agriculture. The presented approach shows the possibility of derivatization of commonly used fungicide into the form of bifunctional salts whose physical and biological properties can be easily modified. The paper reports successful design and synthesis of new sustainable and green chemicals for the modern agriculture, being less toxic to the environment and human health but still effective against pathogens. © 2021 Society of Chemical Industry.

Efficacy and Safety of Regorafenib Combined with Toripalimab in the Third-Line and beyond Treatment of Advanced Colorectal Cancer.

Background The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are completely ineffective in advanced colorectal cancer patients with microsatellite stable (MSS), according to literatures published. Regorafenib is a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood vessels by inhibiting vascular endothelial growth factor receptor and its downstream, thus improving cytotoxic T cell infiltration in tumor microenvironment, which has a synergistic effect with ICIs. Toripalimab is a type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China. Herein, we aimed to explore the efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer. Methods We evaluated the outcomes of MSS patients with advanced colorectal cancer who received regorafenib combined with toripalimab in the Second Affiliated Hospital of Nanchang University from June 2019 to January 2021. These patients had previously received at least second-line treatment; the regimens were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with bevacizumab or cetuximab. Thirty-three patients were treated orally with regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined with intravenous toripalimab until disease progression or intolerant to adverse reactions. We used the Kaplan–Meier method to estimate the rate of progression-free survival (PFS) and log-rank method to do a statistical test of the survival curve. The Cox regression model was used to analyze the influence of multiple factors on PFS. The primary endpoints were objective remission rate (ORR) and disease control rate (DCR). The secondary endpoints were the incidence of adverse reactions and median progression-free survival (mPFS). Results The evaluation of treatment effects was assessed according to RECIST 1.1. Four patients (12.12%) got partial response, twelve patients (36.36%) experienced stable disease, and seventeen patients (51.52%) suffered progressive disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0–272.1). In univariate analysis, patients who had previously received second-line treatment were significantly better than those who had received third-line or more treatment (p=0.005). Lung metastasis was a negative factor in combined therapy (p=0.032). Five patients without previous treatment of bevacizumab were effective. Previous treatment without bevacizumab showed a trend of effective when combination therapy (p=0.034). It was also a positive factor that the Eastern Cooperative Oncology Group performance status (ECOG) score was 0 (p=0.034). Multivariable Cox regression analysis showed the number of previous chemotherapy lines and excision of primary lesions were independent prognostic factors. The most common treatment-related adverse reactions were hand-foot syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever (24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions was 9.09%. Conclusions Regorafenib combined with toripalimab has a promising effect in the third-line and beyond treatment of advanced colorectal cancer. In the early use of combination therapy, excision of primary lesions can have a positive impact in regorafenib and toripalimab combination. This treatment-related adverse reactions are tolerant in combined therapy.

The food industry by-products in bread making: single and combined effect of carob pod flour, sugar beet fibers and molasses on dough rheology, quality and food safety.

Obtaining high-quality value-added bread with extended shelf-life by utilizing food industry by-products that would have minimal negative effect on gluten structure while avoiding the usage of synthetic preservatives, was the challenge of this study. For this purpose the influence of the combination of carob pod flour (C, 0-15%), sugar beet fibers (F, 0-10%) and sugar beet molasses (M, 0-6%) on dough rheology and bread quality was investigated. Selected materials were of good microbiological quality, while carob flour and sugar beet fibers were rich in dietary fibers (43.6% and 67.0%, respectively). The presence of high share of dietary fibers (combination of C and F) increased dough resistance to extension up to 2.5 times, while dough extensibility was reduced by 50%. The addition of molasses had less pronounced single effect on dough properties however its impact in combination with fiber-rich materials outweighed the individual effect (an increase of dough resistance at about 55%). Molasses alone and in combination with other ingredients had positive effect on bread quality. Sample M6F5 attained crumb quality score (6.0 of maximum 7.0) higher than in control sample (5.6). High share of C and F reduced loaf volume and crumb quality of bread up to 56% and 50%, respectively and increased hardness 7.5 times. However, carob flour (7.5%) increased polyphenols content and antioxidant capacity 3 and 4 times, respectively. Moreover, carob flour and molasses and their combination showed inhibitory effect on mold mycelia growth and spores formation. Regarding all of the above, C7.5M3F5 was chosen as optimal sample.

A Quality Improvement Initiative to Reduce Rejected Laboratory Samples and Enhance Specimen Acceptability

Clinical laboratories play a vital role in patient diagnosis and management. However, blood specimens may be rejected for a variety of reasons, which may have substantial clinical consequences for patient safety. The quality team observed significant numbers of rejected samples from the emergency department and inpatient units due to hemolysis. A total of 1.43% of the blood samples were rejected, which was considerably higher than the target of 0.4%. This project aimed to reduce the percentage of rejected blood samples from 1.43% (measured between January 2015 and April 2016) by 50% in the emergency department and the coronary ICU by December 2017. The team identified preanalytical errors as the primary reason for rejections. A multidisciplinary team was formed and tested several changes, including phlebotomy education, competency validation by direct observations, the use of appropriate consumables for sampling, and physician education for proper orders.. All specimens sent for blood chemistry, arterial blood gas analysis, hematology, and coagulation tests were included. Microbiology test specimens and point-of-care testing samples were excluded. The percentage of rejected blood samples dropped from 1.43% (January 2015-April 2016) to 0.47% in 2018, which was a statistically significant reduction (p < 0.001). Using a quality improvement approach for the detailed analyses of specimen rejection rates and related issues helped to formulate efficient plans to target this issue. Weekly rapid cycle improvements from January 2018 helped to achieve the team's goals quickly and had a major impact in combination with other interventions.

Bioprospecting Sulfuric Acid Assisted Hydrothermal Pretreatment of Sugarcane Bagasse and Microbial Community Structure for Methane Production

The complex chemical and structural arrangement of lignocellulosic biomass demand a pretreatment step to dismantle its coherent nature. The current study was designed to study H2SO4 impregnation before hydrothermal pretreatment (HP) of sugarcane bagasse for biogas production using response surface methodology based on defining factors: temperature (160, 180, 200 °C), time (5, 12, 19 min), and H2SO4 concentration (1, 2, 3% w/v). The H2SO4 impregnation had a paramount impact in combination with temperature and treatment time parameters. The lowest solid yield 12.3% was recorded in pretreatment run A-HSO (200 °C, 19 min, 3% H2SO4), up to 100% xylan removal was noted in four pretreatment runs (A-HSO; 200 °C, 19 min, 3% H2SO4, B-HSO; 200 °C, 19 min, 1% H2SO4, C-HSO; 200 °C, 5 min, 3% H2SO4, and O-HSO; 213.6 °C, 12 min, 2% H2SO4), maximum klason lignin increase in insoluble solid fraction (ISF) verified was 358.85% in pretreatment run O-HSO at 213.6 °C, while glucan content reduction (33.18–74.14%) was also observed in pretreatment runs A-HSO, C-HSO, and O-HSO. Results verified maximum methane recovery of 160.16 NmL (g TVS)−1 in pretreatment run I-SHO (180 °C, 12 min, 2% H2SO4). Microbial community analysis observed the predominance of Flavobacterium and Desulfosporosinus genera of Bacterial domain and Methanolinea of Archaea domain. H2SO4 impregnation before HP though not suitable for methane production from ISF could be employed in a biorefinery perspective to obtain valuables (chemicals and fuels) due to the production of organic acids rich liquid stream and lignin-rich solid fraction.

Агроэкологические условия возделывания озимой пшеницы под защитой лесных полос

Abstract. The purpose of the research is to identify the features of functioning of forest-reclaimed agrobiocenoses and assess their impact in combination with various soil treatments on the formation of winter wheat yield. The object of research was field agrobiocenosis in combination with protective stands. Observations and accounting were carried out according to generally accepted methods. Research result. Research has shown that protective forest belts have an impact on agroecological conditions within the inter-band space and on the yield of winter wheat. It is established that the highest content of productive moisture in the inter-lane space is observed at a distance of 5 to 10 Н from the forest strip. The average content of productive moisture in this zone was 49.4 mm, which is 11.3 mm more than in a field without protective plantings. Differentiated changes in soil moisture in the interband space persist throughout the growing season of winter wheat. Zonal distribution of moisture reserves in the soil affects the formation of the total water consumption of winter wheat, the value of the water consumption coefficient. In a protected field, the total water flow is from 1418.8 to 1758.6 m3/ha, in a field without protective plantings – 1329.7 m3/ha. The yield of winter wheat under the protection of stands is higher than in the field without protective stands. On average, over 5 years of research, depending on the applied technology of soil cultivation, the increase in yield was 0.21–0.29 t/ha. Scientific novelty. In result of the conducted researches the features of moisture and the content of major nutrients in crops in light-chestnut soil in terms of agroecology, the dependence of the activity of soil microbiota from remoteness from planting shelterbelts, assessed the effectiveness of the soil treatment methods and their influence on productivity of winter wheat.

Crosstown Traffic: Lymphodepleting Chemotherapy Drives CAR T Cells

CAR-engineered Tcell immunotherapy has proven transformative in selected hematological malignancies. However, solid tumors largely remain impervious to these approaches. In addressing this challenge, Srivastava etal. in this issue demonstrate that oxaliplatin-based lymphodepleting chemotherapy promotes enhanced CAR Tcell recruitment to lung tumors, boosting therapeutic impact in combination with anti-PD-L1.

Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in gastrointestinal cancer patients with massive ascites treated with systemic chemotherapy.

Gastrointestinal cancer is frequently associated with malignant ascites, resulting in poor prognosis. While cell-free and concentrated ascites reinfusion therapy (CART) improves ascites-related symptoms, its clinical impact in combination with systemic chemotherapy is unclear. The purpose of this study was to evaluate the safety and efficacy of CART in gastrointestinal cancer patients with massive ascites treated with chemotherapy. We retrospectively reviewed the medical records of gastrointestinal cancer patients with massive ascites who received CART and chemotherapy at our hospital between July 2015 and September 2017. A total of 30 patients received CART and chemotherapy: gastric cancer (n = 21) and colorectal cancer (n = 9). The initial CART improved performance status in 20% of the patients, and the mean serum albumin and creatinine was significantly improved. Median time to treatment failure and overall survival of chemotherapy following CART were 2.1 and 3.5months in gastric cancer patients and 5.8 and 5.8months in colorectal cancer patients, respectively. The frequency of paracentesis was decreased after introduction of CART followed by chemotherapy in 83% of gastric cancer and in all colorectal cancer patients who had received paracentesis before the initial CART. There were no grade 3/4 adverse events during the CART procedure. Grade 3/4 hematotoxic and non-hematotoxic adverse events of chemotherapy following CART were 30% and less than 10%, respectively. The combination of CART followed by chemotherapy is safe and could be a treatment option for gastrointestinal cancer patients with massive ascites.

The Value and Potential Integration of Pharmacy Technician National Certification into Processes That Help Assure a Competent Workforce.

The purposes of this study were: (1) to determine pharmacists’ perceptions of the impact of certification on competence in specific job skills, its impact in combination with job experience, and its impact in combination with other types of vocational education/training; (2) to identify elements that could potentially enhance the value, or impact of national certification; and (3) to determine how pharmacists view certification in light of various personnel management and organizational behavior phenomena. A self-administered survey was constructed and delivered in spring of 2019 to a random sample of four U.S. states chosen for their geographic diversity and relatively high proportions of both certified and non-certified pharmacy technicians. Following multiple reminders, a response rate of 19.3% was obtained. The 326 responding pharmacists saw certification being less impactful alone than when combined with other types of education/training and previous job experiences. They saw the need for more skills-related and “soft skills” content on the certification examination and agreed that certification is a factor in hiring decisions and that it should be required for designation for advanced practice status. Taken together, respondents saw the need for pharmacy leaders to integrate certification with other aspects of preparation to make for a more competent and professional workforce support team.

Changes in forest bird abundance, community structure and composition following a hurricane in Sweden

The effect that extreme natural events have on biological diversity is relatively poorly known. We used a before–after control‐impact (BACI) design to analyze changes in bird abundances and communities following Hurricane Gudrun, which struck southern Sweden in January 2005, felling 75 million m3 of forest and causing damage to 5% of forested areas (half a million hectares) in a few hours. We used recent measures of impact in combination with classical BACI contrasts to analyze bird count data from a monitoring program in Sweden. We investigated changes in the abundance of 17 species commonly found in forests, along with changes in species composition and functional structure of the bird community. In total, we considered 34 response variables and examined whether responses were immediate or long‐term. There was no evidence of a strong effect of the hurricane on the abundances of six species. Estimates of the effects on five species were too uncertain to draw inferences. We detected positive and negative effects of the hurricane on the abundances of the remaining six species, but the magnitude of effects often was small. Generally, the effects were in the expected direction: negative on birds associated with mature forest and positive on birds associated with open land or young forest. We found evidence of an increase in the proportion of species that nest on the ground and a decrease in the proportion of species that nest in cavities and trees. In contrast, the hurricane had no discernible effect on functional measures of diversity (richness, evenness or divergence), or on communities’ reproductive or morphological characteristics. Our results suggest that the hurricane affected bird populations and communities, but the magnitude of effects was generally small.

Abstract 2205: CBT-102, an oral small molecule multi-kinase inhibitor, demonstrates favorable CSF-1R activity, offering means of controlling tumor associated macrophages

Abstract Background: The role of the tumor microenvironment (TME) in fostering the development of malignancies is prompting the pursuit of anticancer therapies that target its components as to opposed to the tumor itself. As part of their immune surveillance duties, immune cells form part of this microenvironment, and yet, cancer cells have devised means to downplay their tumoricidal capabilities. Colony stimulating factor 1 receptor (CSF-1R) may offer such a means of controlling tumor associated macrophages in the tumor microenvironment. Methods: The IC50 of CBT-102 against CSF1R was evaluated in both cell free system and cell based assays, where enzyme activity was evaluated with radiometric assay format, and cell growth inhibition was evaluated in the Ba/F3 hCSF1R cell line by the CellTiter-Glo (CTG) method. Further evaluation of CBT-102 IC50 was undertaken in M-NFS-60 syngeneic cell lines and human monocytes. In vivo studies of CBT-102 in combination with anti-PD1 antibody were performed in H22 and MC38 syngeneic models. Results: CBT-102 demonstrated a reproducible activity against CSF1R in a radiometric enzyme activity assay. Using engineered BaF3 hCSF1R cell lines, we demonstrated the IC50 value of CBT-102 was 0.588 µM compared to 1.333 µM of sulfatinib, a similar multi-kinase inhibitor, and 0.279 µM of GW2580, a more specific CSF1R kinase inhibitor. Similar studies conducted in M-NFS-60 cell lines and human monocyte also showed sub-micromolar activities of CBT-102. In vivo study combining CBT-102 with anti-PD1 antibody in syngeneic models demonstrated a favorable combination effect compared to each of the single agents. Conclusions: We demonstrated previously that CBT-102 effectively inhibits VEGFR and angiogenesis. The newly revealed mechanism of CBT-102, inhibiting CSF1R and macrophages, offers a promising dual mechanism of action in addition to targeting VEGFR and angiogenesis. Rational combination with check-point inhibitors (CPIs) may improve the efficacy of CBT-102 and broaden the impact of CPIs. Further studies may be needed to delineate the interplay among CBT-102’s different mechanisms and its impact in combination with CPIs. Citation Format: Elaine Liu, Lan Yang, Gavin Choy, Xiaoling Zhang, Tillman Pearce, Mamatha Reddy, Sanjeev Redkar, Qian Shi. CBT-102, an oral small molecule multi-kinase inhibitor, demonstrates favorable CSF-1R activity, offering means of controlling tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2205.

Abstract 3971: MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma.

Abstract Cholangiocarcinoma (CC) is a rare but aggressive cancer of the bile ducts with a five-year survival rate of only 2% in patients with metastatic disease. MAP kinase signaling is important in the pathogenesis of CC and serves as a key regulator of cell proliferation and survival. Our data indicate this pathway is constitutively active in several CC cell lines and accompanied by production of immunomodulatory cytokines including IL-6, MCP-1 and GM-CSF. Cobimetinib is a potent and selective inhibitor of MEK that has been utilized clinically in patients with advanced CC. Although MEK inhibitors (MEKi) have been studied in a variety of solid tumors, the mechanisms by which they act upon CC cells are not completely defined. These agents have modest single agent activity in CC, and their impact in combination with immunotherapy is under active investigation. We hypothesized that MEKi can modulate cytokine and chemokine expression from CC tumors, thereby complementing immunotherapy in this aggressive disease. Using a novel panel of human CC cell lines, we demonstrated a variable impact of cobimetinib on in vitro cell proliferation, with a reduction in viability no greater than 35%. However, MEKi reproducibly limited cytokine (GM-CSF and IL-1β) and chemokine (MIP-1α) production from human CC cell lines in vitro. The ability of cobimetinib to limit MAPK signal transduction in these cells was confirmed via immunoblot. These data complement prior published observations by Ebert et al.in 2016 indicating that single agent MEKi is sufficient to elicit T cell infiltration into tumors. We have completed enrollment of a Phase II clinical trial (NCT03201458) evaluating the efficacy of cobimetinib in combination with the PD-L1 inhibitor, atezolizumab. An extensive series of correlative studies are underway in peripheral blood and tumor biopsies to examine the impact of cobimetinib on modulating cytokine and chemokine signatures in the context of PD-L1 targeted therapy. These data will provide new insight into the impact of MEK inhibitors as a complement to immunotherapy in a disease that is refractory to most conventional therapies. Citation Format: Amanda N. Ruggieri, Matthew R. Farren, Mark Yarchoan, Nilofer S. Azad, Lauren Dennison, Bassel El-Reyes, Gregory B. Lesinski. MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3971.

Physics affecting heavy impurity migration in tokamaks: Benchmarking test-ion code ASCOT against TEXTOR tracer experiment

Abstract Erosion, transport and deposition of wall impurities are major concerns in future magnetic fusion devices, both from the perspective of the fusion plasma and the machine wall. An extensive study on molybdenum transport and deposition performed in the TEXTOR tokamak yielded a detailed deposition map that is ideal for benchmark deposition studies. A qualitative benchmark is attempted in this article with the ASCOT code. We set up a full 3D model of the TEXTOR tokamak and studied the influence of different physical mechanisms and their strengths on molybdenum deposition patterns on the simulated plasma-facing components: atomic processes, Coulomb collisions, scrape-off layer (SOL) profiles, source distribution, marker starting energy, radial electric field strength, SOL flow and toroidal plasma rotation. The outcome comprises 13 simulations, each with 100,000 markers. The findings are: • Toroidal plasma movement, either within the LCFS or as SOL flow, is negligible. • SOL profile and marker starting energy have modest impact on deposition. • Source distribution has a large impact in combination with radial electric field profiles. • The E ⇀ × B ⇀ drift has the highest impact on the deposition profiles.

OC77 THE OCS HEART SYSTEM FOR EX-VIVO PERFUSION OF THE DONOR HEART: THE NIGUARDA EXPERIENCE

Abstract Background: The “Organ Care System (OCS)- Heart”-TransMedics (TM) is the only clinical platform for ex-vivo perfusion of human donor hearts, preserving the graft in a warm beating state. AIM: To analyze results of HTX performed with OCS. Methods: From 2015 to 2018, 7 patients (mean age: 46y) received a donor heart (mean age: 39y) preserved with the OCS-Heart system. Ischemic, cardiopulmonary (CPB) bypass time and day-0/day-1 CK-MB levels (TM-group) were compared with those of 95 patients transplanted with the cold static storage (CSS-group). The OCS was used for expected long ischemic times or for adverse donor (cardiac arrest) or recipient (infected LVAD, ECMO and unusual anatomy) features. Results: Mean out-of-the-body perfusion time was 296 minutes. Overall ischemic time was 124 (TM-group) vs. 187 minutes in the CSS-group (P = 0.01). The OCS allowed to spare 159 minutes of estimated ischemia. D0/D1 CK-MB was 115 and 36 vs. 125 and 47 ng/ml in the CSS-group (P = NS). ICU stay was 20 days. Two patients died for hemorragic shock (LVAD recipient) and for multiorgan failure. One patient developed a severe right failure, treated by mechanical assistance, weaned after 8 days. Five recipients are alive at a mean FU of 18 months. Conclusions: Ex-vivo perfusion of donor hearts is technically safe and permits a significant reduction of the ischemic time. A trend toward reduction of myocardial damage was observed when compared to CSS. The real impact in unfavourable donor-recipient combination needs further investigations. A potential expansion of donors’pool is predictable with this innovative system.

Abstract 1732: Gp96-Ig/costimulator combination platform improves T cell priming and enhances immunity, memory, and tumor elimination

Abstract In this study, we report that addition of checkpoint inhibition and T cell costimulators into the Heat Biologics gp96-Ig-based vaccine platform elicits stronger antigen-specific CD8+ T cell activation and expansion, stimulates memory precursor cell activation, and enhances rejection of murine tumors. Despite the dramatic successes of checkpoint inhibitors in limited populations of cancer patients, 60-90% of patients are still failing to respond to these therapies. It is widely believed that approaches such as ours that target multiple facets of the immune system, including combinations with checkpoint inhibition and costimulator agonism, will be required to improve patient outcomes. Heat Biologics' first-generation ImPACT vaccine is a cell-based therapy that utilizes representative tumor cell lines expressing the antigen chaperone, gp96-Ig, to efficiently prime antigen-specific CD8+ T cells. Heat recently developed a next generation vaccine called ComPACT (COMbination Pan-Antigen Cytotoxic Therapy) that incorporates expression of a T cell costimulator (OX40L-Ig) and gp96-Ig within a single vaccine cell line. In multiple murine tumor and tumor-naive models, ComPACT elicits more potent activation of antigen-specific T cells as well as expansion of CD127+KLRG1- memory precursor cells, leading to a detectable memory response. Furthermore, ComPACT lacks the toxic systemic inflammatory cytokine production and proliferation of non-specific CD4+ T cells and Tregs observed with systemic administration of OX40 agonist antibodies. ComPACT also leads to high frequencies of IFNγ+, TNFα+, granzyme B+ and IL-2+ antigen-specific CD8+ T cells in mice at both priming and boosting, which increases rejection of established murine melanoma (B16.F10) and colon cancer (CT26) tumors and increased overall survival. Here, we have further assessed ImPACT and ComPACT-OX40L in combination with the anti-PD1 checkpoint inhibitor and with expression of an additional cell-secreted T cell costimulator, TL1A-Ig. In various murine models we show that these treatments synergize effectively to amplify antigen-specific T cells, program a functional memory response, and eliminate tumors. The combination of ComPACT-OX40L/TL1A with αPD1 or αPD-L1 may therefore translate into an efficacious approach to treat human cancers. Citation Format: Louise Giffin, Louis Gonzalez, Jason Rose, Jeff Hutchins. Gp96-Ig/costimulator combination platform improves T cell priming and enhances immunity, memory, and tumor elimination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1732.