Evidence Of Synergistic Effects Research Articles

Repurposing Osimertinib and Gedatolisib for Glioblastoma Treatment: Evidence of Synergistic Effects in an In Vitro Phenotypic Study

Background/Objectives: Glioblastoma is a malignant tumor with a poor prognosis for the patient due to its high lethality and limited chemotherapy available. Therefore, from the point of view of chemotherapy treatment, glioblastoma can be considered an unmet medical need. This has led to the investigation of new drugs for monotherapy or associations, acting by synergistic pharmacological mechanisms. Methods: Here, we propose the combination of Osimertinib (a potent EGFR inhibitor) and Gedatolisib (a potent PI3K/mTOR dual inhibitor) through an in vitro phenotypic study using five human GB lines and establish the cytotoxic potency, selectivity, and effect on proliferation, apoptosis, and cell cycle by simultaneously inhibiting EGFR, PI3K, and mTOR. Results: Cytotoxic potency of Gedatolisib and Osimertinib in the selected GB cell lines was determined, which highlighted the synergistic response from their combination and its impact on migration reduction, G0/G1 cell cycle arrest, GB cytotoxicity, and apoptosis-inducing effects for different GB cell lines. Conclusions: From the drug combination studies in phenotypic in vitro models, it was possible to suggest a new potential treatment for glioblastoma that justifies further safe in vivo phases of preclinical trials with the combination.

Ivermectin as a promising therapeutic option for onchocerciasis-associated epilepsy.

Onchocerciasis, commonly known as river blindness, is a neglected tropical disease caused by the parasite Onchocerca volvulus. It can lead to blindness and visual impairment. Studies have also demonstrated a link between onchocerciasis and epilepsy, with there being a correlation between onchocerciasis endemicity and epilepsy prevalence. Onchocerciasis-associated epilepsy (OAE) emerges predominantly in individuals aged 3-18, with a notable prevalence in regions where onchocerciasis transmission persists. These areas exhibit elevated rates of epilepsy, underscoring the significant impact of ongoing onchocerciasis on the incidence of epilepsy, particularly within the specified age range. Both epilepsy prevalence and incidence have evolved over the past three decades in a Tanzanian area endemic for onchocerciasis. Researchers have studied the effects of the antiparasitic drug ivermectin on OAE. About one third of Ugandan patients saw reduced seizure frequency or intensity after one 150 μg/kg dose. Clinical research in the Congo among infected epileptics on anti-seizure medications (ASMs) suggested ivermectin may decrease seizure frequency following oral administration of ivermectin tablets (3 mg). Beyond its antiparasitic properties, ivermectin has demonstrated anticonvulsant effects against clonic and tonic-clonic seizures, likely through modulation of GABAA receptor and neuroinflammation. There is evidence of synergistic effects when combined with GABAergic ASMs like diazepam. As neuroinflammation plays a key role in OAE, ivermectin's anti-inflammatory properties by inhibiting cytokines like TNF-α and IL-1β are also relevant. While certain other antiparasitic drugs can interact with ASMs and have side effects like seizures, no such interactions or side effects have been reported for ivermectin. However, there is a need for more randomized controlled trials specifically evaluating ivermectin's impact on seizures in O. volvulus-infected epileptics on ASMs. Given its efficacy against parasites, limited side effects, and potential anticonvulsant mechanisms, ivermectin could be a favorable first-line treatment option, but further research is warranted to confirm benefits for OAE. PLAIN LANGUAGE SUMMARY: This article explores the potential benefits of ivermectin, a drug commonly used to treat parasitic infections, for reducing seizures in people with epilepsy linked to onchocerciasis, also known as river blindness. Research shows that ivermectin not only targets the parasitic cause of the disease but may also help reduce brain inflammation, which plays a key role in epilepsy. While early results are promising, more research is needed to confirm whether ivermectin can be a reliable treatment for epilepsy in people affected by this condition.

Anti-tumor effects of ketogenic diets and their synergism with other treatments in mice: Bayesian evidence synthesis of 1755 individual mouse survival data

BackgroundKetogenic diets (KDs) are high-fat diets with putative anti-tumor effects. The aim of this study was to synthesize the evidence for the anti-tumor effects of KDs in mice, with a focus on their possible synergism with chemotherapy (CT), radiotherapy (RT), or targeted therapies (TT). MethodsRelevant studies were retrieved from a literature search. A total of 43 articles reporting on 65 mouse experiments fulfilled the inclusion criteria, and 1755 individual mouse survival times were collated from the study authors or the publications. The restricted mean survival time ratio (RMSTR) between the KD and control groups served as the effect size. Bayesian evidence synthesis models were used to estimate pooled effect sizes and to assess the impact of putative confounders and synergism between KD and other therapies. ResultsOverall, there was a significant survival-prolonging effect of KD monotherapy (RMSTR = 1.161 ± 0.040), which was confirmed in meta-regression accounting for syngeneic versus xenogeneic models, early versus late KD start and subcutaneous versus other organ growth. Combining the KD with RT or TT, but not CT, was associated with a further 30% (RT) or 21% (TT) prolongation of survival. An analysis accounting for 15 individual tumor entities showed that KDs exerted significant survival-prolonging effects in pancreatic cancer (all treatment combinations), gliomas (KD + RT and KD + TT), head and neck cancer (KD + RT), and stomach cancer (KD+RT and KD + TT). ConclusionsThis analytical study confirmed the overall anti-tumor effects of KDs in a large number of mouse experiments and provides evidence for synergistic effects with RT and TT.

Abstract 3075: Enhanced efficacy of ARV-471, a novel PROTAC® estrogen receptor degrader, in combination with targeted agents in estrogen receptor-positive (ER+) breast cancer models

Abstract ARV-471 is a selective, orally bioavailable PROteolysis-TArgeting Chimera (PROTAC®) small molecule that induces wild-type and mutant estrogen receptor (ER) alpha degradation via the ubiquitin-proteasome system. ARV-471 demonstrates superior ER degradation and antitumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER+ breast cancer patients. Dual pathway inhibition combining ER targeting agents with CDK4/6 or PIK3CA/mTOR pathway inhibitors is now a central strategy for treatment of advanced ER+ breast cancer. However, resistance to aromatase inhibitors resulting from ESR1 gene mutations, suboptimal ER degradation and the intramuscular route of administration of fulvestrant underscore a need for superior orally bioavailable endocrine therapy backbones for these combinations. Here, we assessed the effects of ARV-471 in combination with CDK4/6 or PIK3CA/mTOR pathway inhibitors in preclinical models of ER+ breast cancer. In vitro studies revealed evidence of synergistic interactions between ARV-471 and the CDK4/6 inhibitors abemaciclib and ribociclib, the mTOR inhibitor everolimus, or the PIK3CA inhibitors alpelisib and inavolisib in ER+ breast cancer cells. Evidence of synergistic effects between ARV-471 and everolimus was also observed in ER+ breast cancer cells expressing ER Y537S or D538G mutations. ARV-471 in combination with CDK4/6, PIK3CA or mTOR inhibitors led to tumor regressions in MCF7 xenografts when compared to single agents alone. ARV-471 also displayed greater anti-tumor activity in combination with abemaciclib, ribociclib or inavolisib than that observed with fulvestrant in combination with these agents. Taken together, these data suggest the potential utility of ARV-471 as a combination partner for clinically relevant targeted agents for treatment of early and late-stage ER+ disease. Citation Format: Jessica Teh, Elizabeth Bortolon, Jennifer Pizzano, Melissa Pannone, Sean Landrette, Richard Gedrich, Ian Taylor. Enhanced efficacy of ARV-471, a novel PROTAC® estrogen receptor degrader, in combination with targeted agents in estrogen receptor-positive (ER+) breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3075.

Baicalein as Promising Anticancer Agent: A Comprehensive Analysis on Molecular Mechanisms and Therapeutic Perspectives

Despite significant therapeutic advancements for cancer, an atrocious global burden (for example, health and economic) and radio- and chemo-resistance limit their effectiveness and result in unfavorable health consequences. Natural compounds are generally considered safer than synthetic drugs, and their use in cancer treatment alone, or in combination with conventional therapies, is increasingly becoming accepted. Interesting outcomes from pre-clinical trials using Baicalein in combination with conventional medicines have been reported, and some of them have also undergone clinical trials in later stages. As a result, we investigated the prospects of Baicalein, a naturally occurring substance extracted from the stems of Scutellaria baicalensis Georgi and Oroxylum indicum Kurz, which targets a wide range of molecular changes that are involved in cancer development. In other words, this review is primarily driven by the findings from studies of Baicalein therapy in several cancer cell populations based on promising pre-clinical research. The modifications of numerous signal transduction mechanisms and transcriptional agents have been highlighted as the major players for Baicalein's anti-malignant properties at the micro level. These include AKT serine/threonine protein kinase B (AKT) as well as PI3K/Akt/mTOR, matrix metalloproteinases-2 & 9 (MMP-2 & 9), Wnt/-catenin, Poly(ADP-ribose) polymerase (PARP), Mitogen-activated protein kinase (MAPK), NF-κB, Caspase-3/8/9, Smad4, Notch 1/Hes, Signal transducer and activator of transcription 3 (STAT3), Nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap 1), Adenosine monophosphate-activated protein kinase (AMPK), Src/Id1, ROS signaling, miR 183/ezrin, and Sonic hedgehog (Shh) signaling cascades. The promise of Baicalein as an anti-inflammatory to anti-apoptotic/anti-angiogenic/anti-metastatic medicinal element for treating various malignancies and its capability to inhibit malignant stem cells, evidence of synergistic effects, and design of nanomedicine-based drugs are altogether well supported by the data presented in this review study.

Swimming Behavior of Daphnia magna Is Altered by Pesticides of Concern, as Components of Agricultural Surface Water and in Acute Exposures

Pesticides with novel modes of action including neonicotinoids and anthranilic diamides are increasingly detected in global surface waters. Little is known about how these pesticides of concern interact in mixtures at environmentally relevant concentrations, a common exposure scenario in waterways impacted by pesticide pollution. We examined effects of chlorantraniliprole (CHL) and imidacloprid (IMI) on the sensitive invertebrate, Daphnia magna. Exposures were first performed using surface waters known to be contaminated by agricultural runoff. To evaluate the seasonal variation in chemical concentration and composition of surface waters, we tested surface water samples taken at two time points: during an extended dry period and after a first flush storm event. In surface waters, the concentrations of CHL, IMI, and other pesticides of concern increased after first flush, resulting in hypoactivity and dose-dependent photomotor responses. We then examined mortality and behavior following single and binary chemical mixtures of CHL and IMI. We detected inverse photomotor responses and some evidence of synergistic effects in binary mixture exposures. Taken together, this research demonstrates that CHL, IMI, and contaminated surface waters all cause abnormal swimming behavior in D. magna. Invertebrate swimming behavior is a sensitive endpoint for measuring the biological effects of environmental pesticides of concern.

Promoting growth and production of sunchoke (Helianthus tuberosus) by co-inoculation with phosphate solubilizing bacteria and arbuscular mycorrhizal fungi under drought.

Due to different functions of phosphate solubilizing bacteria (PSB) and arbuscular mycorrhizal fungi (AMF), their potential synergistic effects on enhancing plant growth and yield are worth investigating, especially under adverse conditions. This work focused on the isolation of PSB and characterization for their plant growth promoting properties under drought. The most efficient P solubilizing bacterium was isolated and identified as Burkholderia vietnamiensis strain KKUT8-1. Then, a factorial experiment on the performance of sunchoke (Helianthus tuberosus) was set up with four factors, viz., PSB (presence or absence of KKUT8-1), AMF (presence or absence of Rhizophagus aggregatus), rock phosphate (RP; added or not) and moisture (well-watered (WW) or drought (DS) conditions). Sunchoke performance was enhanced by the presence of AMF, whereas addition of PSB had a positive effect on SPAD values and inulin concentration. Drought reduced plant performance, while addition of RP reduced photosynthetic rate. There was little evidence for synergistic effects between PSB and AMF, except for SPAD values and inulin concentration. Plants that were co-inoculated with AMF and PSB had highest SPAD value, shoot diameter, leaf area, leaf number, chlorophyll concentration, plant biomass, tuber production, root growth and total soluble sugar concentration. Co-inoculated plants also had increased plant water status, reduced electrolyte leakage, and reduced malondialdehyde and proline concentration. Strain KKUT8-1 is the first strain of B. vietnamiensis capable of promoting growth and yield of sunchoke. Enhanced production of sunchoke by a combination of AMF and PSB was much better than the application of RP. Our finding offers an opportunity to develop combinations of biological inoculants for increasing the growth and production of sunchoke under drought in the future.

Conscientiousness and Cognitive Ability as Predictors of Academic Achievement: Evidence of Synergistic Effects From Integrative Data Analysis

Cognitive ability is the most powerful predictor of academic achievement. However, increasing attention is being paid to the role of personality traits in students’ academic achievement. Results indicate incremental effects beyond cognitive ability, especially for conscientiousness. Investigating the interplay of conscientiousness and cognitive ability can increase understanding of students’ academic achievement and learning. This study examined whether there are interaction effects of a synergistic or compensatory nature. We applied the approach of integrative data analysis, using four highly powered data sets with a total of 18,637 upper secondary school students in Germany to investigate this research question across four different achievement measures and three educational domains (i.e., school subjects). We used an integrative approach and pooled the results across the four samples to obtain an average estimate of the hypothesized interaction effects. Findings support a small synergistic interaction, indicating that conscientiousness moderates the association between cognitive ability and achievement. This means conscientiousness can enhance the positive effects of cognitive ability. In conclusion, results highlight the role of the type of academic measure used and the domain investigated in understanding how personality and achievement are related, providing evidence of the interplay between effort-related traits such as conscientiousness and cognitive ability.

More Roads Lead to Rome. HR Configurations and Employee Sustainability Outcomes in Public Sector Organizations

In linking human resource management (HRM) to organizational sustainability, linear variance-based methods are not suited for addressing the complexity of how various HRM practices interact and have an impact on sustainability outcomes for multiple stakeholders. However, so far, empirical evidence for a configurational approach, acknowledging synergy and equifinality between various practices, is scant. Therefore, this study aims to provide empirical evidence for synergistic effects and equifinality in the link between sustainable HRM practices and employee sustainability outcomes. Building on the Ability Motivation Opportunity (AMO) model, this study adopts a configurational approach to unveil how sustainable HRM practices, in various combinations and in different ways, can impact employee sustainability outcomes (commitment and job satisfaction). The study applied a fuzzy set Qualitative Comparative Analysis (fsQCA) on a secondary data set consisting of employee surveys in 30 Dutch public sector organizations. The findings reveal that combinations of various AMO-enhancing practices are especially conducive to commitment and job satisfaction. Moreover, aligning these practices with work context factors (transformational leadership style and low work pressure) can lead to relatively high levels of commitment and job satisfaction. This study indicates that configuration matters and that there is not one best way to achieve employee sustainability outcomes. This leaves ample leeway for human resource managers to design a suitable and integrative HRM system for their own organization.

Does increasing autonomous motivation or perceived competence lead to health behavior change? A meta-analysis.

Despite abundant observational and experimental tests, it is not yet clear whether enhancing autonomous motivation or perceived competence leads to health behavior change. We identified interventions that aimed to change these constructs and quantified the magnitude of changes in behavior observed when interventions generated increases in autonomous motivation, perceived competence, or both. Computerized searches and additional strategies identified 67 articles that yielded 135 effect sizes relevant to our research questions. Random effects meta-analyses were conducted via STATA. Interventions increased autonomous motivation and perceived competence in 31% and 38% of tests, respectively. Increasing autonomous motivation led to a medium change in health behaviors (d+ = .47, 95% CI [.44, .83]) and increasing perceived competence generated a small-to-medium change (d+ = .34, 95% CI [.22, .47]). Interventions that failed to generate significant improvements in autonomous motivation and perceived competence had much smaller effects on behavior change (d+ = .13 and .10, respectively). There was little evidence of synergistic effects. Changing both autonomous motivation and perceived competence (d+ = .42) did not lead to a larger effect on behavior compared with changing autonomous motivation on its own (d+ = .61), but had a larger effect compared with changing perceived competence on its own (d+ = .21). The present review suggests that autonomous motivation and perceived competence are valid targets for interventions to promote health behavior change but also indicates that research is warranted to ensure that interventions more effectively engage these targets. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Single and combined effects of microplastics, pyrethroid and food resources on the life-history traits and microbiome of Chironomus riparius

There is growing evidence of widespread contamination of freshwater ecosystems with microplastics. However, the effects of chronic microplastic ingestion and its interaction with other pollutants and stress factors on the life-history traits and the host-microbiome of aquatic invertebrates are not well understood. This study investigates the effects of exposure to sediment spiked with 1 μm polystyrene-based latex microplastic spheres, an environmentally realistic concentration of a pyrethroid pesticide (esfenvalerate), and a combination of both treatments on the life-history traits of the benthic-dwelling invertebrate, Chironomus riparius and its microbial community. The chironomid larvae were also exposed to two food conditions: abundant or limited food in the sediment, monitored for 28 and 34 days respectively. The microplastics and esfenvalerate had negative effects on adult emergence and survival, and these effects differed between the food level treatments. The microbiome diversity was negatively affected by the exposure to microplastics, while the relative abundances of the four top phyla were significantly affected only in the high food level treatment. Although the combined exposure to microplastics and esfenvalerate showed some negative effects on survival and emergence, there was little evidence for synergistic effects when compared to the single exposure. The food level affected all life-history traits and the microbiota, and lower food levels intensified the negative effects of the exposure to microplastics, esfenvalerate and their combination. We argue that these pollutants can affect crucial life-history traits such as successful metamorphosis and the host-microbiome. Therefore, it should be taken into consideration for toxicological assessment of pollutant acceptability. Our study highlights the importance of investigating possible additive and synergic activities between stressors to understand the effects of pollutants in the life story traits and host-microbiome.

English

BACKGROUND The reported prevalence of diabetic retinopathy in diabetics is around 40 %. Diabetic macular oedema (DME) is defined as macular thickening resulting from diabetic retinopathy, due to leakage from micro aneurysms, or from a diffuse leakage of hyper permeable capillaries. Intravitreal injection of triamcinolone acetonide (IVTA) has gained considerable interest and clinical use because it often has beneficial effect on retinal thickening in DME. The synergistic action of IVTA and laser photocoagulation might increase and prolong the beneficial effects of IVTA in reducing ME. Hence the need for a study to compare efficacies of grid laser, and combination of sequential IVTA and grid laser in treating patients with DME. We wanted to evaluate functional and morphological outcome of grid laser versus combination of sequential intravitreal triamcinolone acetonide and grid laser in treatment of diabetic macular oedema. METHODS The study included 62 eyes with DME. There were 31 eyes which received grid laser photocoagulation (group 1) and 31 eyes which received grid laser photocoagulation following IVTA (group 2) and visual acuity, CMT on OCT was compared at baseline and after day 1, 1st week, 4th week and 12th week. Outcome and comparative efficacies were evaluated. RESULTS Our study shows reduced macular thickness and improved visual acuity in group 2 compared to group 1 in all follow ups. On intragroup analysis, we found a significant reduction in CMT in both groups at 1 week, 4 weeks and 12 weeks as compared to baseline. In our study we also compared CMT between group 1 and group 2 which did not show significant difference at baseline. But, difference in CMT from baseline at each follow up which is at 1 week, 4 weeks and 12 weeks between two groups showed more reduction in CMT in group 2 compared to group 1. CONCLUSIONS There was a significant reduction in CMT in all the follow ups of both groups, but group 2 had more reduction in CMT compared to group 1. The synergistic action of IVTA and laser photocoagulation might increase and prolong the beneficial effect of IVTA in reducing ME. This study found evidence of synergistic effects of IVTA and laser photocoagulation in DME in terms of improving visual acuity and in reducing CMT compared to grid laser alone and should be tried as a modality of treatment in DME. KEYWORDS DME, IVTA, CMT, Macular grid laser, OCT

Reactivity of binary manganese oxide mixtures towards arsenite removal: Evidence of synergistic effects

The effects of manganese (Mn) mineral mixtures on arsenite (As(III)) removal (i.e., the sum of As(III) oxidation to As(V) and As species adsorption) were systematically quantified for the first time using varying ratios of hausmannite and manganite, common Mn(III)-containing oxides that often exist as mixtures in natural environments. Due to smaller particle sizes and a higher surface area, hausmannite alone exhibited a total As(III) removal of 8.86 μM m−2 at pH 5, almost double that of manganite, 4.63 μM m−2, with initially fast but then subsequently slower As(III) oxidation and Mn(II) production rates. Both minerals showed a substantial decrease in As(III) removal as pH increased. High resolution transmission electron microscopy (HRTEM) analysis showed mineral edge sites initially and preferably consumed for As(III) oxidation. Mixtures of hausmannite and manganite resulted in enhanced As(III) removal (9.62–11.2 μM m−2) relative to the single minerals at pH 5, increasing with increasing manganite quantities. The mineral mixtures also displayed two reaction phases, where As(III) oxidation and Mn(II) production were initially fast but then slowed after the first hour. Further, the mineral mixtures produced a Mn(II):As(V) ratio higher than the theoretical two, indicating enhanced mineral dissolution than that of a single Mn oxide. Enhanced reactivity was attributed to the aggregation structure of mixtures, as the presence of manganite effectively limited the aggregation of hausmannite particles, as observed in HRTEM, promoting the exposure of highly active edge sites for the surface-mediated reactions. Thus, mineral mixtures may serve as a better surrogate than a single mineral to examine the extent and magnitude of As(III) removal in natural environments, by more closely reflecting the heterogeneity and complexity in surface interactions and aggregation structures between the minerals.

Effects of Air Pollution on the Risk of Low Birth Weight in a Cold Climate

There is accumulating evidence that prenatal exposure to air pollution disturbs fetal growth and development, but little is known about these effects in cold climates or their season-specific or joint effects. Our objective was to assess independent and joint effects of prenatal exposure to specific air pollutants on the risk of low birth weight (LBW). We utilized the 2568 children of the Espoo Cohort Study, born between 1984 and 1990 and living in the City of Espoo. We conducted stratified analyses for births during warm and cold seasons separately. We analyzed the effect estimates using multi-pollutant Poisson regression models with risk ratio (RR) as the measure of effect. The risk of LBW was related to exposure to CO (adjusted RR 1.44, 95% confidence interval [CI]: 1.04–2.00) and exposure to O3 in the spring–summer season (1.82, 1.11–2.96). There was also evidence of synergistic effects between CO and O3 (relative risk due to interaction (RERI), all year 1.08, 95% CI: 0.27–4.94, spring–summer 3.97, 2.17–25.85) and between PM2.5 and O3 (all year 0.72, −0.07–3.60, spring–summer 2.80, 1.36–19.88). We present new evidence of both independent and joint effects of prenatal exposure to low levels of air pollution in a cold climate on the risk of LBW.

Enhanced Olefin Metathesis Performance of Tungsten and Niobium Incorporated Bimetallic Silicates: Evidence of Synergistic Effects

AbstractTungsten and niobium incorporated KIT‐6 (WNb‐KIT‐6) materials were synthesized by a one‐pot sol‐gel method. During 2‐butene+ethylene metathesis with these materials at 450 °C, the propene yield is maximized (∼70 %) at a certain metal composition (∼20 wt% W and ∼1 wt% Nb), significantly surpassing those reported with an industrial WO3/SiO2 catalyst. The enhanced propene yield is attributed to better dispersion of W species on the catalyst surface and the formation of new active site precursors (O=)2W(O−Si)(O−Nb), as confirmed by XRD, TEM, H2‐TPR, XPS, EXAFS, and ToF‐SIMS techniques. Complementary DFT calculations reveal a positive correlation between the O=W=O bond angle and the propene yield. We therefore speculate that the −O−Nb moiety tunes the electronic environment around the W atom and increases the propene yield.

Differential effect of intermittent hypoxia and sleep fragmentation on PD-1/PD-L1 upregulation.

Immunosurveillance is compromised in patients with obstructive sleep apnea (OSA) as reflected by overexpression of the programmed death cell receptor and its ligand (PD-1/PD-L1) coinhibitory axis. However, the contributions of intermittent hypoxia (IH) and sleep fragmentation (SF) are unclear. We therefore evaluated the expression of PD-1 and PD-L1 on immune cells from mice subjected to IH or SF, and in human cells exposed to IH, oxidative stress, or both conditions. Six-week-old male C57BL/6J mice were exposed to either IH or SF using previously established in vivo models. Moreover, human peripheral blood mononuclear cells (PBMC) were cultured overnight under normoxia, IH, hydrogen peroxide (H2O2), or both. Murine splenocytes and human PBMC were isolated, and labeled using surface-specific antibodies for flow cytometry analysis. Compared to control mice, IH induced higher expression of PD-L1 on F4/80 cells and of PD-1 on CD4+ and CD8+ T-cells, whereas no significant changes emerged after SF. In vitro models of IH and oxidative stress showed similar changes for expression of PD-L1 on human monocytes and PD-1 on CD4+ T-cells. Furthermore, H2O2 increased PD-1 expression on CD8+ T-cells, compromising their cytotoxic capacity assessed by perforin expression, similar to IH. No evidence of synergistic effects was apparent. Therefore, PD-1/PD-L1 upregulation reported in patients with OSA appears to be preferentially mediated by IH rather than SF.

Synergistic Inhibition of Mycotoxigenic Fungi and Mycotoxin Production by Combination of Pomegranate Peel Extract and Azole Fungicide.

Fungal plant pathogens cause considerable losses in yield and quality of field crops worldwide. In addition, under specific environmental conditions, many fungi, including such as some Fusarium and Aspergillus spp., are further able to produce mycotoxins while colonizing their host, which accumulate in human and animal tissues, posing a serious threat to consumer health. Extensive use of azole fungicides in crop protection stimulated the emergence of acquired azole resistance in some plant and human fungal pathogens. Combination treatments, which become popular in clinical practice, offer an alternative strategy for managing potentially resistant toxigenic fungi and reducing the required dosage of specific drugs. In the current study we tested the effect of pomegranate peel extract (PPE) on the growth and toxin production of the mycotoxigenic fungi Aspergillus flavus and Fusarium proliferatum, both alone and in combination with the azole fungicide prochloraz (PRZ). Using time-lapse microscopy and quantitative image analysis we demonstrate significant delay of conidial germination and hyphal elongation rate in both fungi following PPE treatment in combination with PRZ. Moreover, PPE treatment reduced aflatoxin production by A. flavus up to 97%, while a combined treatment with sub-inhibitory doses of PPE and PRZ resulted in complete inhibition of toxin production over a 72 h treatment. These findings were supported by qRT-PCR analysis, showing down-regulation of key genes involved in the aflatoxin biosynthetic pathway under combined PPE/PRZ treatment al low concentrations. Our results provide first evidence for synergistic effects between the commercial drug PRZ and natural compound PPE. Future application of these findings may allow to reduce the required dosage of PRZ, and possibly additional azole drugs, to inhibit mycotoxigenic fungi, ultimately reducing potential concerns over exposure to high doses of these potentially harmful fungicides.

Synergistic Anti-Leukemic Activity of PARP Inhibition Combined with IMGN632, an Anti-CD123 Antibody-Drug Conjugate in Acute Myeloid Leukemia Models

BackgroundCD123 (IL-3 receptor alpha-chain) is a therapeutic target for hematological malignancies based on high expression levels in acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and other cancers. The anti-CD123 antibody-drug conjugate (ADC), IMGN632, comprises a humanized monoclonal antibody covalently linked to a DNA - alkylating cytotoxic payload which is currently in phase 1 evaluation for relapsed/refractory CD123-positive hematological malignancies (NCT03386513). Novel approaches to enhance the efficacy of ADCs are of significant therapeutic interest. Our laboratory has previously demonstrated that the Poly ADP Ribose (PARP) inhibitor, olaparib, synergistically enhances the activity of the CD33-targeted ADC, IMGN779, in preclinical AML models (Portwood S et al, ASH 2016). Based on the hypothesis that PARP inhibition will synergize with DNA damaging mechanism of IMGN632, we investigated the ability of olaparib and other PARP inhibitors (PARPi) in clinical development (talazoparib, niraparib, rucaparib, and veliparib) to enhance the therapeutic efficacy of IMGN632 across diverse human AML cell lines and primary relapsed/refractory AML samples.Materials and MethodsCD123 expression on human AML cell lines (HEL, HL60, MV411, Molm13, EOL-1, THP-1, and Kasumi-1) was quantified by flow cytometry using QuantriBrite beads. AML cells were continuously cultured for 72-96 hours with varying doses of IMGN632 (range 100pM - 100nM) and specific PARP inhibitors (range 100pM -15μM) alone and in combination. Cell viability was measured using a WST-8 colorimetric assay. Primary clinically annotated CD123+ AML cells from patients with relapsed/refractory disease were obtained under IRB-approved protocols from the Roswell Park Hematologic Procurement Shared Resource and cultured short-term in the presence of multiple cytokines plus IMGN632 +/- PARP inhibitors. Apoptosis (Annexin V/PI), cell cycle, and DNA damage (H2AX) were evaluated by flow cytometry. Additive vs. synergistic effects were determined by combination indices using Compusyn software. PARP trapping was evaluated by Western blot analysis in nuclear lysates obtained from IMGN632 +/- PARP inhibitors treated AML cells.ResultsHigh expression levels of CD123 (range 937 - 2231 CD123 molecules/cell) were detected on multiple human AML cell lines (HEL-luc, MV411, Molm13, EOL-1, and THP-1) relative to unstained negative controls. Western blot analysis of nuclear lysates from AML cells demonstrated that all PARP inhibitors had varying degrees of PARP trapping on DNA. Continuous single agent 5-day treatment with all tested PARP inhibitors resulted in dose dependent in vitro inhibition of AML cell line growth with IC50 values ranging from 360 nM (talazoparib, most potent) to 78uM (veliparib, least potent). Combination therapy using PARP inhibitors (doses ranging from 300nM - 15uM) and IMGN632 (10nM) consistently resulted in enhanced anti-leukemic effects over monotherapy (Figure 1 for example). Synergistic anti-proliferative effects were obtained across all tested AML cell lines (n=5) with combination indexes ranging from 0.3-0.7 by Compusyn analysis. Combination therapy correlated with enhanced DNA damage, tumor cell apoptosis, and cell cycle arrest of AML cells. Moreover, IMGN632 and PARPi (olaparib or talazoparib) resulted in single agent activity against clinically annotated primary relapsed/refractory AML patient samples with evidence of synergistic effects when combined in vitro.ConclusionsAddition of PARP inhibitors to IMGN632, a novel anti-CD123 antibody-drug conjugate, further enhances DNA damage effects and consistently results in synergistic in vitro anti-leukemic effects across multiple CD123+ AML cell lines and primary AML patient samples. Further studies investigating this novel combinatorial approach in specific molecular subtypes of AML with variable baseline sensitivities to PARPi are currently ongoing. Our results strongly support future investigation of PARPi as a novel class of agents with the potential to significantly enhance the efficacy of DNA-alkylating ADCs and/or cytotoxic chemotherapy for hematological malignancies. [Display omitted] DisclosuresSloss:ImmunoGen: Employment. Watkins:ImmunoGen Inc.: Employment. Kovtun:ImmunoGen Inc.: Employment. Adams:ImmunoGen Inc.: Employment. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Neonicotinoid pesticides and nutritional stress synergistically reduce survival in honey bees.

The honey bee is a major pollinator whose health is of global concern. Declines in bee health are related to multiple factors, including resource quality and pesticide contamination. Intensive agricultural areas with crop monocultures potentially reduce the quality and quantity of available nutrients and expose bee foragers to pesticides. However, there is, to date, no evidence for synergistic effects between pesticides and nutritional stress in animals. The neonicotinoids clothianidin (CLO) and thiamethoxam (TMX) are common systemic pesticides that are used worldwide and found in nectar and pollen. We therefore tested if nutritional stress (limited access to nectar and access to nectar with low-sugar concentrations) and sublethal, field-realistic acute exposures to two neonicotinoids (CLO and TMX at 1/5 and 1/25 of LD50) could alter bee survival, food consumption and haemolymph sugar levels. Bee survival was synergistically reduced by the combination of poor nutrition and pesticide exposure (-50%). Nutritional and pesticide stressors reduced also food consumption (-48%) and haemolymph levels of glucose (-60%) and trehalose (-27%). Our results provide the first demonstration that field-realistic nutritional stress and pesticide exposure can synergistically interact and cause significant harm to animal survival. These findings have implications for current pesticide risk assessment and pollinator protection.

East Meets West: The Increasing Incidence of Inflammatory Bowel Disease in Asia as a Paradigm for Environmental Effects on the Pathogenesis of Immune-Mediated Disease

East Meets West: The Increasing Incidence of Inflammatory Bowel Disease in Asia as a Paradigm for Environmental Effects on the Pathogenesis of Immune-Mediated Disease