Dose-response Curves Research Articles

In Rats, the Chemotherapeutic Drug Vincristine-Induced Neuropathic Nociception is Suppressed When Cannabinoid CB1 and CB2 Receptors are Activated

Rats were used to test the potential of cannabis to reduce mechanical hypersensitivity, or mechanical allodynia, which was brought on by vincristine chemotherapy. After that, action sites were located. Method of experimentation: After ten daily injections of vincristine, mechanical hypersensitivity developed in comparison to those that received saline at the same periods. The effects on chemotherapy-induced neuropathy were assessed for the CB1/CB2 receptor agonist WIN55, 212-2, the receptor-inactive enantiomer WIN55, 212-3, the CB2-selective agonist (R,S)-AM1241, the opiate agonist morphine, and vehicle. To determine the locations of action, WIN55, 212-2 was injected either locally in the hind paw or intrathecally (i.t.). By employing competitive antagonists for either CB1 (SR141716) or CB2 receptors (SR144528), pharmacological selectivity was demonstrated. Vincristine-evoked mechanical allodynia was decreased when WIN55, 212-2, but not WIN55, 212-3, were administered systemically. A change in the dose-response curve to the left was noticed after WIN55, 212-2 in comparison to morphine therapy. Antibodies of CB1 (SR141716) and CB2 (SR144528) inhibited WIN55, 212-2’s anti-allodynic actions. Via a CB2 mechanism, (R,S)-AM1241 reduced c-induced mechanical hypersensitivity. Without causing catalepsy, both cannabinoid agonists reduced the mechanical hypersensitivity brought on by vincristine. Cannabis-induced neuropathy may be modulated by cannabinoids at spinal sites of action. When delivered intraperitoneally, WIN55, 212-2 but not WIN55,212-3 inhibited vincristine-evoked mechanical hypersensitivity at dosages that were inert after local hindpaw injection. Spinal co-administration of CB1 and CB2 antagonists inhibited WIN55,212-2’s anti-allodynic effects.By activating CB1 and CB2 receptors, cannabinoids inhibit the maintenance of vincristine-induced mechanical allodynia. The spinal cord is involved in the mediation of these anti-allodynic actions, at least partially.

Chromium activated Ca9Al (PO4)7 nanophosphors: synthesis, morphology and dosimetry characteristics

In this article, a sol–gel route was employed to prepare nanophosphor materials including Ca9−x CrxAl (PO4)7 series (where 0.05 ≤ x ≤ 0.5 (mol%)). All subseries were irradiated to a γ- test dose of 5 Gy and the thermoluminescence (TL) response of Cr-activated (0.1 mol%) Ca9Al (PO4)7 sample has the best TL response and was chosen for investigations. The phase, particle size, surface morphology, and elemental mapping of the chosen sample Cr0.1 in comparison with other ones (Cr0.05 and Cr0.5) were scrutinized using x-ray diffraction (XRD), transmission electron microscope (TEM), SEM-EDX mapping, and XPS techniques. XRD profiles showed that all diffraction peaks assigned to the trigonal R 3 c space group and the average of particle sizes obtained by the modified Scherer method and TEM data are closely related. The presence of Cr3+ ions in the Ca9Al (PO4)7 lattice was assured by XPS spectra. Cr0.1 chosen sample was studied after irradiation to different γ-doses and displayed a prominent glow curve at 205 °C ± 3.97 °C. It showed a linear dose–response curve from 200 mGy up to 10 Gy with fading of 24% upon 24 h and almost no significant signal loss for further interval times. The average Zeff value was ∼11 at both 662 and 1250 keV energies making this sample a bone-equivalent material (11.3–11.8). Values of activation energies (eV) calculated by different methods were comparable. Results the dosimetric properties of that the Cr0.1 sample can be surely considered as an additional recommended detector as other available ones in marketing.

Photoluminescence, scintillation, and TSL properties of Dy-doped BaCaBO3F

We fabricated BaCaBO3F (BCBF) with various Dy concentrations (0.1 %, 1 %, and 5 %), and evaluated the luminescence properties for radiation dosimetry. Sharp scintillation peaks originating from the 4f → 4f transition of Dy3+ were observed. Furthermore, thermally stimulated luminescence (TSL) glow curves were recorded, and a TSL glow peak at approximately 120 °C was observed. The 0.1 % Dy-doped BCBF exhibited the highest TSL intensity, and dose response curves of the 0.1–1 % Dy-doped BCBF were obtained in the 0.1–10000 mGy range. Moreover, at least seven activation energy levels related to TSL were confirmed by the TSL isothermal decay analysis.

Mechanism of action of <i>Pterorhachis</i> <i>zenkeri</i> (Meliaceae), a sexual enhancer: effect on vas deferens contractility

Background: Pterorhachis. zenkeri commonly known as “Ayilalou” or “Démareur” is an aphrodisiac plant used by Cameroonian traditional healers to enhance libido and sperm production. This study was undertaken to investigate the aphrodisiac mechanism of P. zenkeri on the contractile activity of vas deferens with regard to its function on ejaculation. Materials and Methods: The proximal parts of rat vas deferens were mounted in a 20 mL organ bath containing Krebs solution at 37°C. Cumulative dose-response curves were recorded with KCl (35-280 mM), adrenaline (7-70 µM) and aqueous extract of P. zenkeri (3,55-21,3 mg/mL). Prazosin (type 1 alpha-adrenergic receptor antagonist, 10 µM), Nifedipine (a specific L-type calcium channel antagonist, 5 µM), 2-AminoethoxydiPhenyl Borate (2-APB, IP3 receptor antagonist, 200 μM) and calcium-free medium were further used to study the mechanism of action. Results: KCl, adrenaline and aqueous extract of P. zenkeri showed a concentration-dependent effect on vas deferens contractibility. Nifedipine and Pazosin partially inhibited the effects of P. zenkeri. In calcium-free medium containing Ethylene Glycol-bis (2-aminoethylether)-N,N,N’N’-tetraacetic acid (EGTA, 1µM), P. zenkeri triggered vas deferens contraction which was completely abolished in the presence of 2-APB. These results suggest that the aqueous extract of P. zenkeri possesses bioactive compounds capable of inducing vas deferens contractions through type 1 alpha adrenergic receptors and mobilization of extra and intracellular calcium. Conclusion: These results confirm the aphrodisiac properties of P. zenkeri through the activation of the emissive phase of ejaculation.

Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation

Objective. FLASH radiotherapy (FLASH-RT) with ultra-high dose rate (UHDR) irradiation (i.e. > 40 Gy s−1) spares the function of normal tissues while preserving antitumor efficacy, known as the FLASH effect. The biological effects after conventional dose rate-radiotherapy (CONV-RT) with ≤0.1 Gy s−1 have been well modeled by considering microdosimetry and DNA repair processes, meanwhile modeling of radiosensitivities under UHDR irradiation is insufficient. Here, we developed an integrated microdosimetric-kinetic (IMK) model for UHDR-irradiation enabling the prediction of surviving fraction after UHDR irradiation. Approach. The IMK model for UHDR-irradiation considers the initial DNA damage yields by the modification of indirect effects under UHDR compared to CONV dose rate. The developed model is based on the linear-quadratic (LQ) nature with the dose and dose square coefficients, considering the reduction of DNA damage yields as a function of dose rate. Main results. The estimate by the developed model could successfully reproduce the in vitro experimental dose–response curve for various cell line types and dose rates. Significance. The developed model would be useful for predicting the biological effects under the UHDR irradiation.

Calibration-free electrochemical sensor to monitor factor-Xa inhibitors at the point-of-care anticoagulation therapy

This article presents a novel proof of concept for the blood plasma quantification of clinically relevant concentrations of direct oral anticoagulants, DOACs, including rivaroxaban and edoxaban, as well as low-molecular-weight heparins, LMWHs, such as enoxaparin and dalteparin, utilising a calibration-free disposable electrochemical sensor with co-facing electrodes. A dose-response curve was generated for rivaroxaban and edoxaban to demonstrate the sensor's ability to detect ≥9.00 ng mL−1 rivaroxaban and quantify it in the 11.0–140 ng mL−1 range. Similarly, the lower detection limit for edoxaban was 12.9 ng mL−1, with a quantification range of 16.8–140 ng mL−1. The significance of this sensor lies in its ability to quantify rivaroxaban and edoxaban below 30 ng mL−1, which is crucial in emergency care centres when patients undergoing DOAC therapy require emergency surgery or reversal of DOACs due to bleeding or ischemic stroke. Furthermore, the sensor can detect ≥0.016 IU mL−1 enoxaparin and ≥0.013 IU mL−1 dalteparin and quantify them in the 0.025–0.75 and 0.019–0.75 IU mL−1 range, respectively. Additionally, a dose-response curve was presented to demonstrate the potential ability of this sensor to quantify factor-Xa inhibitors independently of which DOACs or LMWHs are used. With the assay completed in less than 30 s using a minimal volume of 7 μL sample, the possibility to work at physiological pH and under calibration-free format makes this assay an excellent candidate for point-of-care testing.

Nanoemulsion Improves the Anti-Inflammatory Effect of Intraperitoneal and Oral Administration of Carvacryl Acetate.

Carvacryl acetate (CA) is a monoterpene obtained from carvacrol, which exhibits anti-inflammatory activity. However, its low solubility in aqueous media limits its application and bioavailability. Herein, we aimed to develop a carvacryl acetate nanoemulsion (CANE) and assess its anti-inflammatory potential in preclinical trials. The optimized nanoemulsion was produced by ultrasound, and stability parameters were characterized for 90 days using dynamic light scattering after hydrophilic-lipophilic balance (HLB) assessment. To evaluate anti-inflammatory activity, a complete Freund's adjuvant-induced inflammation model was established. Paw edema was measured, and local interleukin (IL)-1β levels were quantified using ELISA. Toxicity was assessed based on behavioral changes and biochemical assays. The optimized nanoemulsion contained 3% CA, 9% surfactants (HLB 9), and 88% water and exhibited good stability over 90 days, with no signs of toxicity. The release study revealed that CANE followed zero-order kinetics. Dose-response curves for CA were generated for intraperitoneal and oral administration, demonstrating anti-inflammatory effects by both routes; however, efficacy was lower when administered orally. Furthermore, CANE showed improved anti-inflammatory activity when compared with free oil, particularly when administered orally. Moreover, daily treatment with CANE did not induce behavioral or biochemical alterations. Overall, these findings indicate that nanoemulsification can enhance the anti-inflammatory properties of CA by oral administration.

Screening Allergenic Potencies of Skin-Contact Products Using the Human-Derived THP-1 Cell Activation Test.

With the prevalence of allergic contact dermatitis (ACD) from the usage of skin-contact products, like wearable, skin care, and hair care products, screening their skin sensitizing potential is necessary, for the sake of alleviating the consequent public health impact. In the present study, a total of 77 skin-contact products classified by four categories, watch bands (WBs), skin care products (SCPs), hair care products (HCPs), and rubber gloves (RGs), were investigated, using an optimized in vitro assay of human cell line activation test (h-CLAT). Extracting the products using neutral artificial sweat simulated well the practical usage scenarios, and testing the extracts showed that 26 of them were allergy test positive, including nine WBs, six SCPs, two HCPs, and nine RGs. The allergenic response was mainly characterized by the induction of CD54 expression, and diverse paradigms of CD54 and CD86 levels were observed by analyzing dose-response curves, which could also be influenced by the compromised viability of the THP-1 cells. The data implicated the intricate regulation by different contributors to suspicious ingredients in the test samples. Altogether, a promising methodology for testing skin allergy potential was well established for commonly used commodities by neutral artificial sweat extraction coupled with h-CLAT screening. The findings would be of great help in tracing the potential allergens in practical products and improving their qualities.

Microbiome Depletion Increases Fentanyl Self-Administration and Alters the Striatal Proteome Through Short-Chain Fatty Acids.

Opioid use disorder (OUD) is a public health crisis currently being exacerbated by increased rates of use and overdose of synthetic opioids, primarily fentanyl. Therefore, the identification of novel biomarkers and treatment strategies to reduce problematic fentanyl use and relapse to fentanyl taking is critical. In recent years, there has been a growing body of work demonstrating that the gut microbiome can serve as a potent modulator of the behavioral and transcriptional responses to both stimulants and opioids. Here, we advance this work to define how manipulations of the microbiome drive fentanyl intake and fentanyl-seeking in a translationally relevant drug self-administration model. Depletion of the microbiome of male rats with broad spectrum antibiotics leads to increased drug administration on increased fixed ratio, progressive ratio, and drug seeking after abstinence. Utilizing 16S sequencing of microbiome contents from these animals, specific populations of bacteria from the gut microbiome correlate closely with levels of drug taking. Additionally, global proteomic analysis of the nucleus accumbens following microbiome manipulation and fentanyl administration to define how microbiome status alters the functional proteomic landscape in this key limbic substructure. These data demonstrate that an altered microbiome leads to marked changes in the synaptic proteome in response to repeated fentanyl treatment. Finally, behavioral effects of microbiome depletion are reversible by upplementation of the microbiome derived short-chain fatty acid metabolites. Taken together, these findings establish clear relevance for gut-brain signaling in models of OUD and lay foundations for further translational work in this space.

Association between cardiometabolic index and erectile dysfunction among US adults: a cross-sectional analysis of the National Health and Nutrition Examination Survey 2001-2004.

The aim of this study was to assess the association between a new metabolic index, the cardiometabolic index (CMI) and erectile dysfunction (ED). The data for this study relied on the National Health and Nutrition Examination Survey (NHANES), a cross-sectional database, between 2001 and 2004. The CMI was calculated as the following formula: Triglyceride (TG) (mmol/L)/ High density lipid-cholesterol (HDL-C) (mmol/L) ×waist-height ratio (WHtR). The multivariate logistic regression analyses were conducted to assess the association between CMI and ED, supplemented by subgroup analysis and dose-response curves. Finally, a total of 1367 adult male participants were identified, and the mean CMI was 0.83 ± 0.02. Multivariate logistic regression analysis showed that in model 2 controlling for all potential confounders, CMI was significantly associated with ED (OR = 1.49, 95% CI: 1.09, 2.04) (p = 0.017). Subsequently, we convert the CMI from a continuous variable to a categorical variable (Tertiles). The results showed that male participants in CMI Tertile 3 group had a higher risk of ED than those in Tertile 1 group in model 2 (OR = 2.07, 95% CI: 1.12, 3.83, P = 0.024). The subgroup analysis of model 2 demonstrated that CMI was significantly associate with ED in participants aged ≥50 y (OR = 2.31, 95% CI: 1.35, 3.95, P = 0.005), body mass index (BMI) > 30 kg/m2 (OR = 1.78, 95% CI: 1.10, 2.90, P = 0.023), with hypertension (OR = 1.89, 95% CI: 1.63, 3.45, P = 0.020), with diabetes mellitus (OR = 1.67, 95% CI: 1.13, 2.47, P = 0.015), with cardiovascular disease (CVD) (OR = 1.54, 95% CI: 1.12, 2.10, P = 0.011) and smoking (OR = 2.07, 95% CI: 1.26, 3.39, P = 0.007). This study demonstrates a strong association between CMI and ED and an increased risk of ED with higher CMI levels. More prospective studies with large samples and good designs are needed to validate our results in the future.

The Roles of IL-18 in a Realistic Partial Body Irradiation with 5% Bone Marrow Sparing (PBI/BM5) Model.

IL-18 has been shown to play important roles in response to total body irradiation. However, homogenous total body irradiation is not a realistic model to reflect the radiation exposure in a real nuclear event. To further study the roles of IL-18 in a real nuclear scenario, we developed a mouse partial body irradiation with 5% bone marrow sparing (PBI/BM5) model to mimic the inhomogeneous radiation exposure. We established the dose response curves of PBI/BM5 using different radiation doses ranging from 12 to 16 Gy. Using the PBI/BM5 model, we showed that IL-18 knockout mice were significantly more radiation resistant than the wild-type mice at 14.73 Gy. We further studied the hematopoietic changes using a complete blood count, bone marrow colony-forming assays, and serum cytokine assays on the mice exposed to PBI/BM5 with IL-18BP treatment and wild-type/IL-18 knockout mice. In conclusion, our data suggest that IL-18 plays important roles in mouse survival in a realistic nuclear exposure model, potentially through the IL-18/IFNγ pathway.

The synergistic health impacts of exposure to multiple stressors in Tulare County, California

Tulare County is located in the Central Valley region of California (CA). Its population is exposed to stressors that include high levels of air, water, and soil pollution, socioeconomic strain, and poor access to walkable areas and healthy foods. As a result, this population suffers from a high disease burden compared to other CA counties. We hypothesize that environmental and socioeconomic stressors interact in complex ways to raise the burden of disease in the Tulare population beyond additive impacts. We used CalEnviroScreen to select Tulare County as the subject of the study and characterized the geographical interaction of stressors. The CalEnviroScreen indicators provided the basis for population-weighted average calculations to determine the most critical environmental and socioeconomic stressors in Tulare County. We also analyzed and interpreted walkability and dietary access through open-source data. In addition, we compared disease-based mortality in Tulare County to CA state averages. Our evaluation reveals that the population living within the census tracts of Tulare County is exposed to environmental stressors at significantly higher levels relative to many other Californian census tracts, specifically for fine particulate matter, ozone, and drinking water quality. Relatively high exposures to socioeconomic stressors can compound resulting health impacts. We use dose–response curves and stressor mapping to characterize how multiple stressors may augment a population’s vulnerability and effective doses from exposure to multiple stressors. According to the Centers for Disease Control and Prevention Data, the differences in mortality rates between Tulare and CA were not significant. However, notable differences in mortality between CA and Tulare occur for Alzheimer’s disease, diseases of the circulatory system, influenza, and pneumonia, which were all statistically higher in Tulare County, and for diabetes, endocrine, nutritional and metabolic diseases, and neoplasms, which were statistically lower Tulare. Previous health-impact studies have linked individual environmental stressors to their respective measures of disease. However, many communities continue to be exposed daily to numerous stressors that individually are within regulatory limits but could significantly magnify risk due to the synergistic effects. Dose–response curves tailored to population vulnerability provide a basis for quantifying the synergistic risks of multiple stressors on specific measures of disease.

Quantitative receptor model for responses that are left- or right-shifted versus occupancy (are more or less concentration sensitive): the SABRE approach.

Simple one-to three-parameter models routinely used to fit typical dose-response curves and calculate EC50 values using the Hill or Clark equation cannot provide the full picture connecting measured response to receptor occupancy, which can be quite complex due to the interplay between partial agonism and (pathway-dependent) signal amplification. The recently introduced SABRE quantitative receptor model is the first one that explicitly includes a parameter for signal amplification (γ) in addition to those for binding affinity (K d), receptor-activation efficacy (ε), constitutive activity (ε R0), and steepness of response (Hill slope, n). It can provide a unified framework to fit complex cases, where fractional response and occupancy do not match, as well as simple ones, where parameters constrained to specific values can be used (e.g., ε R0 = 0, γ = 1, or n = 1). Here, it is shown for the first time that SABRE can fit not only typical cases where response curves are left-shifted compared to occupancy (κ = K d/EC50 > 1) due to signal amplification (γ > 1), but also less common ones where they are right-shifted (i.e., less concentration-sensitive; κ = K d/EC50 < 1) by modeling them as apparent signal attenuation/loss (γ < 1). Illustrations are provided with μ-opioid receptor (MOPr) data from three different experiments with one left- and one right-shifted response (G protein activation and β-arrestin2 recruitment, respectively; EC50,Gprt < K d < EC50,βArr). For such cases of diverging pathways with differently shifted responses, partial agonists can cause very weak responses in the less concentration-sensitive pathway without having to be biased ligands due to the combination of low ligand efficacy and signal attenuation/loss-an illustration with SABRE-fitted oliceridine data is included.

Biodosimetry Based on Gamma-H2AX Quantification in Human Peripheral Blood Lymphocytes after Partial-body Irradiation.

Quantification of gamma-H2AX foci can estimate exposure to ionizing radiation. Most nuclear and radiation accidents are partial-body irradiation, and the doses estimated using the total-body irradiation dose estimation formula are often lower than the actual dose. To evaluate the dose-response relation of gamma-H2AX foci in human peripheral blood lymphocytes after partial-body irradiation and establish a simple and high throughput model to estimate partial-body irradiation dose, we collected human peripheral blood and irradiated with 0-, 0.5-, 1-, 2-, 3-, 4-, 5-, 6-, and 8-Gy gamma rays to simulate total-body irradiation in vitro. Gamma-H2AX foci were quantitated by flow cytometry at 1 h after irradiation, and a dose-response curve was established for total-body irradiation dose estimation. Then, a partial-body irradiation dose-response calibration curve was established by adding calibration coefficients based on the Dolphin method. To reflect the data distribution of all doses more realistically, the partial-body irradiation dose-response calibration curve was divided into two sections. In addition, partial-body irradiation was simulated in vitro, and the PBI data were substituted into curves to verify the accuracy of the two partial-body irradiation calibration curves. Results showed that the dose estimation variations were all less than 30% except the 25% partial-body irradiation group at 1 Gy, and the partial-body irradiation calibration dose-response curves were YF 1 = - 3.444 x 2 + 18.532 x + 3.109, R 2 = 0.92 (YF ≤ 27.95); YF 2 = - 2.704 x 2 + 37.97 x - 56.45, R 2 = 0.86 (YF > 27.95). Results also suggested that the partial-body irradiation dose-response calibration curve based on the gamma-H2AX foci quantification in human peripheral blood lymphocytes is a simple and high throughput model to assess partial-body irradiation dose.

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes.

Iron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM. We enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of <10 points as individuals with SPPB scores of <10 points are most likely to be classified as frail and are at high risk for disability and future adverse events, including death. ID was defined as serum ferritin<100 or 100-299ng/mL when transferrin saturation (TSAT) was <20% according to the HF guidelines. Among the 562 HF patients (72±14years old; 56% male), 329 patients (58%) and 191 patients (34%) had ID and low physical function, respectively. Multivariate logistic regression analysis showed that TSAT as a continuous variable, but not ID, was a predictor of low physical function (odds ratio: 0.980, P=0.024). Subgroup analysis showed that a significant association between low TSAT and low physical function was lost in HF patients with DM (P for interaction<0.001). A spline dose-response curve for the relationship between TSAT and risk of low physical function with adjustments for covariates associated with low physical function in non-DM patients was almost linear with an increase in the risk of low physical function as the TSAT increased, but such a relationship was not found in the analyses of DM patients. A lack of close TSAT-SPPB relationship in HF patients with DM was confirmed also in a propensity-score-matched cohort. TSAT as a continuous variable, but not ID, was independently associated with physical function in HF patients, and a significant association was lost in patients with HF and DM, suggesting a limited impact of iron supplementation therapy in HF patients with DM.

Dose-response association between animal protein sources and risk of gestational diabetes mellitus: a systematic review and meta-analysis.

There are contradictory findings about the relationship between various animal protein sources and the risk of gestational diabetes mellitus (GDM). The purpose of our study was to understand better the associations between total protein, animal protein, and animal protein sources and the risk of developing GDM. A systematic literature search was conducted in PubMed, Scopus, and Web of Science encompassing the literature up until August 2022. A random-effects model was used to combine the data. For estimating the dose-response curves, a one-stage linear mixed-effects meta-analysis was conducted. Data related to the association between animal protein consumption and the risk of GDM in the general population was extracted from prospective cohort studies. It was determined that 17 prospective cohort studies with a total of 49 120 participants met the eligibility criteria. It was concluded with high certainty of evidence that there was a significant association between dietary animal protein intake and GDM risk (1.94, 95% CI 1.42 to 2.65, n = 6). Moreover, a higher intake of total protein, total meat, and red meat was positively and significantly associated with an increased risk of GDM. The pooled relative risks of GDM were 1.50 (95% CI: 1.16, 1.94; n = 3) for a 30 g/d increment in processed meat, 1.68 (95% CI: 1.25, 2.24; n = 2) and 1.94 (95% CI: 1.41, 2.67; n = 4) for a 100 g/d increment in total and red meat, and 1.21 (95% CI: 1.10, 1.33; n = 4) and 1.32 (95% CI: 1.15, 1.52; n = 3) for a 5% increment in total protein and animal protein, respectively. GDM had a positive linear association with total protein, animal protein, total meat consumption, and red meat consumption, based on non-linear dose-response analysis. Overall, consuming more animal protein-rich foods can increase the risk of GDM. The results from the current study need to be validated by other, well-designed prospective studies. PROSPERO registration no. CRD42022352303.

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose-response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration-response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1-/- tumor cells, using immortalized non-tumor NF1+/- cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

Leisure time physical activity: a protective factor against metabolic syndrome development

PurposePhysical activity (PA) is a modifiable factor in preventing/treating cardiometabolic disease. However, no studies have yet compared specific moderate-to-vigorous PA (MVPA) domains with the risk of metabolic syndrome (MetS) in detail. Here, the present study was conducted to examine the impact of different MVPA domains (leisure-time PA (LTPA) vs. occupational PA (OPA) vs. total MVPA) on the risk of MetS in Korean adults. Materials and methods: Data from the 2014 to 2021 Korea National Health and Nutrition Examination Survey were analyzed (N = 31,558). MetS was defined according to the criteria by revised NCEP/ATP-III. The domain-specific MVPA was assessed using the K-GPAQ. The LTPA and OPA status were classified into four categories: (1) 0 min/week, (2) 1 to 149 min/week, (3) 150 to 299 min/week, and 4) ≥ 300 min/week. In addition, the present study calculated total MVPA as a sum of OPA and LTPA and further classified it into six groups; (1) 0 min/week, (2) 1 to 149 min/week, (3) 150 to 299 min/week, (4) 300 to 449 min/week, (5) 450 to 599 min/week, 6) ≥ 600 min/week. Results: The ≥ 300 min/week and the 150 to 299 min/week of LTPA showed better outcomes in cardiometabolic disease risk factors and surrogate markers of insulin resistance compared with the 0 min/week of LTPA regardless of adiposity status. Risk of MetS in ≥ 300 min/week of LTPA was lower than in 0 min/week, 1 to 149 min/week, and 150 to 299. In addition, LTPA was significantly associated with a risk of the MetS in a curvilinear dose-response curve, however, no significant effects of a non-linear relationship between OPA and risk of the MetS. Conclusions: Our findings showed that LTPA was associated with a risk of MetS with a dose-response curve, whereas no significant non-linear effects were found between OPA and the risk of MetS. Therefore, the MVPA domain is an independent factor of the risk of MetS.

Differentiation between chemo- and radiotoxicity of 137Cs and 60Co on Lemna minor

The uptake and effects of stable Cs and Co on L.minor were extensively studied, together with the effects of gamma radiation using a 137Cs or 60Co source. Innovative is that we combined external irradiation (from 137Cs or 60Co sources) with the direct uptake of certain amounts of stable Cs or Co to simulate the impact of the same mass of a radioisotope compared with that of the stable element. Such approach allows to differentiate between chemo- and radiotoxicity of 137Cs or 60Co, permitting to study the 137Cs and 60Co uptake by L. minor without using high concentrations of these elements in solution. Our results indicate that radiotoxicity of both 137Cs and 60Co has a greater importance compared to their chemotoxicity. This was also supported by the independent action and concentration addition concepts. Both concepts resulted in a good prediction of the dose-response curve of the combination exposure. The maximal removal of 137Cs or 60Co per gram dry matter of L. minor was lower compared with the removal of the corresponding stable isotope. The toxicity of 60Co was higher compared to 137Cs based on EC50 values and uptake data. With respect to the effects on photosynthetic pigments, starch and soluble sugars contents, only starch increased in a concentration- and dose-dependent manner.

How do biomarkers dance? Specific moves of defense and damage biomarkers for biological interpretation of dose-response model trends

Omics studies are currently increasingly used in ecotoxicology to highlight the induction of known or novel biomarkers when organisms are exposed to contaminants. Although it is virtually impossible to identify all biomarkers from all organisms, biomarkers can be grouped as defense or damage biomarkers, exhibiting a limited number of response trends. Our working hypothesis is that defense and damage biomarkers follow different dose-response patterns. A meta-analysis of 156 articles and 2595 observations of dose-response curves of defense and damage biomarkers was carried out in order to characterize the response trends of these biological parameters in a large panel of living organisms (18 phyla) exposed to inorganic or organic contaminants (176 in total). Using multinomial logistic regression models, defense biomarkers were found to describe biphasic responses (bell- and U-shaped) to a greater extent (2.5 times) than damage biomarkers. In contrast, damage biomarkers varied mainly monotonically (decreasing or increasing), representing 85% of the observations. Neither the nature of the contaminant nor the type of organisms belonging to 4 kingdoms, influence these specific responses. This result suggests that cellular defense and damage mechanisms are not specific to stressors and are conserved throughout life. Trend analysis of dose-response models as a biological interpretation of biomarkers could thus be a valuable way to exploit large omics datasets.