Tissue Concentrations Research Articles

The Role of Tissue Persistent Organic Pollutants and Genetic Polymorphisms in Patients with Benign and Malignant Kidney Tumors

This study aimed to explore whether there is an association between environmental exposure to POPs and kidney tumor induction, and whether blood POP concentrations reflect kidney tissue concentrations. POP derivatives were determined in blood, tumor tissue, tumor surrounding tissue, and perirenal fat tissue samples taken from patients who underwent surgery for renal tumors. A voluntary control group was recruited for blood and urine samples as well. Urinary excretions of o,o'-dityrosine, chlorotyrosine, nitrotyrosine, and 8-OHdG were measured in the same patients. The possible role of genetic polymorphisms in CYP1A1, GST isozymes P, M, and T, and hOGG1 genes on the predisposition to renal cancer was investigated. Some POPs have been found to be associated with kidney cancer, as evidenced by their significantly high ORs. 8-OHdG levels were significantly higher compared to the control group. The GSTT1 null polymorphism can be a risk factor for malignant but not for benign kidney tumors.

The effects of PPARγ agonists on long‑termpotentiation and apoptosis in the hippocampusarea of juvenile hypothyroid rats

The aim of the present study was to evaluate the effect of rosiglitazone (RSG) or pioglitazone (POG) on the synaptic plasticity, neuronal apoptosis, brain-derived neurotrophic factor (BDNF), and nitric oxide (NO) metabolites in the hippocampus of juvenile hypothyroid rats. The animals were divided into four groups: control; propylthiouracil (PTU), 0.05% dose in drinking water for 42 days; PTU–POG; and PTU–RSG. The POG (20 mg/kg) and the RSG (4 mg/kg) were administered by IP injection. We conducted long‑term potentiation (LTP) in the cornu ammonis 1 area of the hippocampus using high‑frequency stimulation of the Schaffer collateral pathway. Then, the hippocampal tissues were collected to determine BDNF and NO levels and the degree of apoptosis. PTU administration decreased the slope (10–90%) and amplitude of the fEPSPs compared to control. Injection of RSG or POG increased the slope, slope (10–90%), and amplitude of the fEPSP in the PTU‑POG or PTU‑RSG groups compared to the PTU group. TUNEL‑positive neurons and NO metabolites in the hippocampus of the PTU group were higher than those of the control group. RSG or POG increased BDNF content in PTU–POG or PTU–RSG groups. Treatment of the rats with POG or RSG decreased apoptotic neurons and NO metabolites in the hippocampus of PTU–POG or PTU–RSG groups, respectively, compared to the PTU group. This study’s results revealed that POG or RSG normalized LTP impairment, neuronal apoptosis, and improved BDNF content in the hippocampal tissue of juvenile hypothyroid rats.

Different ectomycorrhizal fungal species impact poplar growth but not phosphorus utilization under low P supply.

Tree growth is often limited by phosphorus (P) availability. The trade-off between P homeostasis and growth is unknown. Ectomycorrhizal (EM) fungi facilitate P availability but this trait varies among different fungal species and isolates. Here, we tested the hypotheses that (i) colonization with EMF boosts plant growth under P-limited conditions and that (ii) the poplars show P homeostasis because increased P uptake is used for growth and not for P accumulation in the tissues. We used two P treatments (HP: 64 μM Pi, LP: 0.64 μM Pi in the nutrient solution) and four fungal treatments (Paxillus involutus MAJ, Paxillus involutus NAU, Laccaria bicolor dikaryon LBD, Laccaria bicolor monokaryon LBM) in addition to non-inoculated poplar plants (NI) to measure growth, biomass, gas exchange and P contents. HP stimulated growth compared with LP conditions. Poplars colonized with MAJ, NAU and NI showed higher growth and biomass production than those with LBD or LBM. Photosynthesis rates of poplars with lower biomass production were similar to or higher than those of plants with higher growth rates. The tissue concentrations of P were higher under HP than LP conditions and rarely affected by ectomycorrhizal colonization. Under LP, the plants produced 44% greater biomass per unit of P than under HP. At a given P supply, the tissue concentration was stable irrespective of the growth rate indicating P homeostasis. L. bicolor caused growth inhibition, irrespective the P availabilities. These results suggest that in young poplars distinct species-specific ectomycorrhizal traits overshadowed potential growth benefits.

Bridging the buzz: In vivo EPR imaging unlocking the secrets of honey bee health.

Honey bees play a pivotal role in shaping ecosystems and sustaining human health as both pollinators and producers of health-promoting products. However, honey bee colony mortality is on the rise globally, driven by various factors, including parasites, pesticides, habitat loss, poor nutrition, and climate change. This has far-reaching consequences for the environment, economy, and human welfare. While efforts to address these issues are underway, the current progress in electron paramagnetic resonance (EPR) instrumentation affords using the immense potential of this magnetic resonance technique to study small samples such as honey bees. This paper presents the pioneering 2D in vivo EPR imaging experiment on a honey bee, revealing the ongoing redox-status of bees' intestines. This way, by monitoring the spatio-temporal changes of the redox-active spin-probes' EPR signal, it is possible to gain access to valuable information on the course of ongoing bees' pathologies and the prospect of following-up on the efficiency of applied therapies. Employing a selection of diverse spin-probes could further reveal pH levels and oxygen concentrations in bee tissues, allowing a noninvasive assessment of bee physiology. This approach offers promising strategies for safeguarding pollinators and understanding their biology, fostering their well-being and ecological harmony.

Toxicokinetics of selenate in earthworm sub-tissues and potential bio-accessibility assessment of earthworm-derived selenium

Selenium (Se) pollution is mainly caused by anthropogenic activities, and the resulting biosecurity concerns have garnered significant attention in recent years. Using one-compartmental toxicokinetic (TK) modelling, this study explored the kinetic absorption, sub-tissue distribution, and elimination processes of the main Se species (selenate, Se(VI)) in the cultivated aerobic soil of the earthworm Eisenia fetida. The bio-accessibility of earthworm-derived Se was assessed using an in vitro simulated gastrointestinal digestion test to evaluate its potential trophic risk. The results demonstrated that Se accumulated in the pre-clitellum (PC) and total tissues (TT) of earthworms in a time- and dose-dependent manner. The highest Se levels in the PC, post-clitellum (PoC), and TT were 70.54, 57.93, and 64.26 mg/kg during the uptake phase, respectively. The kinetic Se contents in the earthworms PC and TT were consistent with the TK model but not with PoC. The earthworm TT exhibited a faster uptake (Kus = 0.83–1.02 mg/kg/day) and elimination rate of Se (Kee = 0.044–0.049 mg/kg/day), as well as a shorter half-life time (LT1/2 = 15.88–14.22 days) than PC at low soil Se levels (≤5 mg/kg). Conversely, the opposite trend was observed with higher Se concentrations (10 and 20 mg/kg). These results are likely attributable to the tissue specificity and concentration of the toxicant. Earthworms PC and TT exhibited a higher kinetic Se accumulation factor (BAFk) than steady-state BAF (BAFss), with values ranging from 8 to 24 and 3–13, respectively. Furthermore, the bio-accessibility of earthworm-derived Se to poultry ranged from 66.25 % to 84.35 %. As earthworms are at the bottom of the terrestrial food chain, the high bio-accessibility of earthworm-derived Se poses a potential risk to predators. This study offers data support and a theoretical foundation for understanding the biological footprint of soil Se and its toxicological impacts and ecological hazards.

Physiological responses of the nickel hyperaccumulator Bornmuellera emarginata under varying nickel dose levels and pH in hydroponics

Abstract Background and aims The nickel hyperaccumulator Bornmuellera emarginata (Brassicaceae) is a species adapted to thrive on naturally nickel-enriched ultramafic soils in the Balkans and a promising candidate for use in nickel agromining. The main aim of this study was to provide insight into the physiological mechanisms of nickel hyperaccumulation in B. emarginata. Methods Bornmuellera emarginata was cultivated under various nickel exposure concentrations (control, 1, 10, and 100 µM nickel in solution), and different pH levels of the hydroponic solution for four weeks. During this period, the plants underwent assessment for various physiological parameters, including photosynthetic pigments, leaf relative water content, tolerance index, and metal accumulation in plant tissues. Results The results show that the translocation factors and bioconcentration factors were > 1 even at 1 µM nickel in solution. This confirms the ability of B. emarginata to hyperaccumulate nickel (up to 6600 mg kg−1) over a wide range of nickel concentrations in hydroponics. Nickel at 100 µM (a concentration that is an order of magnitude higher than the highest soil solution nickel concentration found in ultramafic soils) induced only mild physiological stress symptoms (e.g. a minor proline response). Alterations in the solution pH did not cause any significant effect on nickel accumulation in the plants. Conclusions Bornmuellera emarginata is a highly adapted nickel-tolerant and nickel hyperaccumulating species that shows very little stress responses even to extreme nickel exposure concentrations in hydroponics. This species shows interesting trade-off responses between nickel and other metals, including non-competitive uptake of zinc. The potential for this species to accumulate zinc should therefore be further explored.

The effect of sucrose consumption on eating behavior and depression during morphine withdrawal period in rats

BACKGROUND: Sugary drink and junk food consumption increases during the withdrawal period, leading to subsequent psychological and metabolic alterations. OBJECTIVES: We aimed to investigate the relationship of sucrose consumption with serum insulin levels, leptin levels, brain Dopamine-2 receptor (D2R) expression, food consumption, and anxiety-depression findings in morphine-withdrawal rats. METHODS: Thirty-six male Wistar albino rats were divided into six groups: Control, sucrose-free, 5% sucrose, 10% sucrose, 20% sucrose, and an addiction test. Saline was intraperitoneally injected to the control group, and morphine was intraperitoneally injected to the other groups for 14 days. After 14 days, naloxone was administered to the addiction test group, and addiction symptoms were observed and this group was sacrificed on the same day. Other groups were fed ad libitum with different concentrations of sucrose solution for one week. Behavioral parameters were evaluated at the end of the experiment. Leptin and insulin concentrations in serum and D2R levels in brain tissues were detected using an enzyme-linked immunosorbent assay. D2R concentrations in brain tissues were evaluated utilizing immunohistochemistry. RESULTS: We observed decreased food consumption and increased fluid consumption in rats that consumed sucrose water during the withdrawal period. The level of depression and binge eating behavior was elevated in groups consuming sucrose, and the 10% sucrose group had the highest carbohydrate consumption and anxiety levels. In addition, the 10% sucrose group had the lowest brain D2R expression. The leptin level was highest in the 20% sucrose group. CONCLUSIONS: These results show the possible effects of sugary drinks consumed during the withdrawal period.

The energy content and demographic composition of Antarctic krill (Euphausia superba) swarms in East Antarctica

Antarctic krill (Euphausia superba) aggregations are important in the Southern Ocean ecosystem; however, the amount of energy that krill swarms contain is unknown. We assessed the population structure of E. superba swarms in East Antarctica for two different sectors corresponding to the study areas of the ENRICH (2019) and TEMPO (2021) voyages. We also estimated swarm energy content based on calorific values for whole animals and key tissues (gonads, digestive gland, and muscle). A relationship between the energy content of muscle and gonads in gravid and adult females was detected: The higher the energy content in muscle tissue, the lower the energy content in the gonad tissue. This relationship was consistent for different female maturity stages, suggesting a trade-off in energy allocation between somatic growth and reproduction. Females will redirect energy to gonad development at the expense of somatic growth. Total swarm energy was calculated using the volumetric density of each swarm estimated from an acoustic survey. Four swarm types (A-D) were determined based on the body length and maturity stage of the individuals. The highest energy contents were found in Type B swarms, composed predominantly of adult males and females, and Type D swarms, comprising mostly gravid females. Trends in swarm demographic composition and energy content were consistent between surveys. We recommend swarm energy be incorporated into ecosystem models to represent energy transfer to top predators.

N-3 polyunsaturated fatty acids in fat-1 transgenic mice prevent obesity by stimulating the IL-27 signaling pathway

Multiple metabolic diseases are caused by obesity. n-3 polyunsaturated fatty acids (n-3 PUFAs) could prevent obesity. However, the mechanism that n-3 PUFAs ameliorates energy metabolism disorder remains to be elucidated. This study attempted to investigate how n-3 PUFAs impact brown adipose tissue (BAT) and obesity-related signaling pathways in high-fat diet (HFD) induced obese mice. We used fat-1 transgenic mice as an animal model with high n-3 PUFAs. The results showed that n-3 PUFAs mitigated negative impacts of the HFD on the contents of glycaemic and lipid, diminished weight, white adipose tissue content and lipid hoarding in liver tissue, prevented BAT from being infiltrated, and increased microbiota diversity. N-3 PUFAs also upregulated serum interleukin-27 (IL-27) level and mRNAs, protein expression of the key BAT thermogenic genes, uncoupling protein-1 (UCP-1), uncoupling protein-2 (UCP-2). These results demonstrated that endogenous n-3 PUFAs increased BAT burning and energy consumption through the IL-27 pathway, inhibiting obesity.

A ratiometric SERS strategy for the prediction of cancer cell proportion and guidance of glioma surgical resection

Rapid and accurate identification of tumor boundaries is critical for the cure of glioma, but it is difficult due to the invasive nature of glioma cells. This paper aimed to explore a rapid diagnostic strategy based on a label-free surface-enhanced Raman scattering (SERS) technique for the quantitative detection of glioma cell proportion intraoperatively. With silver nanoparticles as substrate, an in-depth SERS analysis was performed on simulated clinical samples containing normal brain tissue and different concentrations of patient-derived glioma cells. The results revealed two universal characteristic peaks of 655 and 717 cm−1, which strongly correlated with glioma cell proportion regardless of individual differences. Based on the intensity ratio of the two peaks, a ratiometric SERS strategy for the quantification of glioma cells was established by employing an artificial neuron network model and a polynomial regression model. Such a strategy accurately estimated the proportion of glioma cells in simulated clinical samples (R2 = 0.98) and frozen samples (R2 = 0.85). More importantly, it accurately facilitated the delineation of tumor margins in freshly obtained samples. Taken together, this SERS-based method ensured a rapid and more detailed identification of tumor margins during surgical resection, which could be beneficial for intraoperative decision-making and pathological evaluation.

Determining tissue distribution of the oral antileishmanial agent miltefosine: a physiologically-based pharmacokinetic modeling approach.

Miltefosine (MTS) is the only approved oral drug for treating leishmaniasis caused by intracellular Leishmania parasites that localize in macrophages of the liver, spleen, skin, bone marrow, and lymph nodes. MTS is extensively distributed in tissues and has prolonged elimination half-lives due to its high plasma protein binding, slow metabolic clearance, and minimal urinary excretion. Thus, understanding and predicting the tissue distribution of MTS help assess therapeutic and toxicologic outcomes of MTS, especially in special populations, e.g., pediatrics. In this study, a whole-body physiologically-based pharmacokinetic (PBPK) model of MTS was built on mice and extrapolated to rats and humans. MTS plasma and tissue concentration data obtained by intravenous and oral administration to mice were fitted simultaneously to estimate model parameters. The resulting high tissue-to-plasma partition coefficient values corroborate extensive distribution in all major organs except the bone marrow. Sensitivity analysis suggests that plasma exposure is most susceptible to changes in fraction unbound in plasma. The murine oral-PBPK model was further validated by assessing overlay of simulations with plasma and tissue profiles obtained from an independent study. Subsequently, the murine PBPK model was extrapolated to rats and humans based on species-specific physiological and drug-related parameters, as well as allometrically scaled parameters. Fold errors for pharmacokinetic parameters were within acceptable range in both extrapolated models, except for a slight underprediction in the human plasma exposure. These animal and human PBPK models are expected to provide reliable estimates of MTS tissue distribution and assist dose regimen optimization in special populations.

Seasonal variation of heavy metals in water and Cyprinus carpio L. from Umiam Lake reservoir of Meghalaya, India: Potential health risk assessment for human consumption.

The purpose of this study is to assess the seasonal variation of heavy metal concentration in water and fish tissues of common carp (Cyprinus carpio L.) from the Umiam Lake reservoir located in the Ri bhoi district of Meghalaya, India, and to elucidate the possible human health risk of ingesting fish captured from the contaminated lake. Results show significant (p < 0.05) seasonal differences of heavy metal concentrations in the water and different tissues of fish Cyprinus carpio L.. The total concentration of heavy metals in the water exceeds the WHO and BIS standards and thus poses a significant threat to the aquatic flora and fauna of the reservoir. The heavy metal concentrations in fish tissues were tissue-dependent, where the average concentration of heavy metals in all the tissues of Cyprinus carpio L. was in the order of Cr > Pb > Cu > Cd. In addition, the health risk assessment suggests that the heavy metals in the fish muscle from the Umiam Lake reservoir might have adverse effects on human. Therefore, the overall results of the study provide an understanding on the seasonal distribution of heavy metals in water, provide insight on their bioaccumulation in the fish tissues, and highlights the potential health risk for the local population of long-term fish consumption from Umiam Lake reservoir.

Exact parameter identification in PET pharmacokinetic modeling using the irreversible two tissue compartment model.

In quantitative dynamic positron emission tomography (PET), time series of images, reflecting the tissue response to the arterial tracer supply, are reconstructed. This response is described by kinetic parameters, which are commonly determined on basis of the tracer concentration in tissue and the arterial input function. In clinical routine the latter is estimated by arterial blood sampling and analysis, which is a challenging process and thus, attempted to be derived directly from reconstructed PET images. However, a mathematical analysis about the necessity of measurements of the common arterial whole blood activity concentration, and the concentration of free non-metabolized tracer in the arterial plasma, for a successful kinetic parameter identification does not exist. Here we aim to address this problem mathematically. &#xD;Approach: We consider the identification problem in simultaneous pharmacokinetic modeling of multiple regions of interests of dynamic PET data using the irreversible two-tissue compartment model analytically. In addition to this consideration, the situation of noisy measurements is addressed using Tikhonov regularization. Furthermore, numerical simulations with a regularization approach are carried out to illustrate the analytical results in a synthetic application example.&#xD;Main results: We provide mathematical proofs showing that, under reasonable assumptions, all metabolic tissue parameters can be uniquely identified without requiring additional blood samples to measure the arterial input function. A connection to noisy measurement data is made via a consistency result, showing that exact reconstruction of the ground-truth tissue parameters is stably maintained in the vanishing noise limit. Furthermore, our numerical experiments suggest that an approximate reconstruction of kinetic parameters according to our analytic results is also possible in practice for moderate noise levels.&#xD;Significance: The analytical result, which holds in the idealized, noiseless scenario, suggests that for irreversible tracers, fully quantitative dynamic PET imaging is in principle possible without costly arterial blood sampling and metabolite analysis.

Study of pesticide transformation processes in different wheat varieties and their effects on plant metabolism.

This study aims to obtain systematic understanding of the way by which pesticides are metabolized in plants and the influence of this process on plants' metabolism as this process has a key impact on plant-based food safety and quality. The research was conducted under field conditions, which enabled to capture metabolic processes taking place in plants grown under multihectare cultivation conditions. Research was conducted on three wheat varieties cultivated under field conditions and treated by commercially available preparations (fungicides, herbicides, insecticides, and growth regulator). Plant tissues with distinctions in roots, green parts, and ears were collected periodically during spring-summer vegetation period, harvested grains were also investigated. Sample extracts were examined by chromatographic techniques coupled with tandem mass spectrometry for: dissipation kinetics study, identification of pesticide metabolites, and fingerprint-based assessment of metabolic changes. Tissue type and wheat varieties influenced pesticide dissipation kinetics and resulting metabolites. Metabolic changes of plants were influenced by type of applied pesticide and its concentration in plants tissues. Despite differences in plant metabolic response to pesticide stress during cultivation, grain metabolomes of all investigated wheat varieties were statistically similar. 4-[cyclopropyl(hydroxy)methylidene]-3,5-dioxocyclo-hexanecarboxylic acid and trans-chrysantemic acid - metabolites of crop-applied trinexapac-ethyl and lambda-cyhalothrin, respectively, were identified in cereal grains. These compounds were not considered to be present in cereal grains up to now. The research was conducted under field conditions, enabling the measurement of metabolic processes taking place in plants grown under large-scale management conditions. © 2024 Society of Chemical Industry.

Presence of Heavy Metals in Purple Crab (Platyxanthus orbignyi) Tissues in Southern Peru

Heavy metals (iron, copper, and zinc) were quantified in purple crab (Platyxanthus orbignyi) tissues collected in winter (September 2021), spring (November 2021), and summer (March 2022) at three beaches (Tres Hermanas, Fundición, and El Diablo) in Ilo Harbour (Moquegua), South Peru. The rank order of heavy metal concentrations in purple crab tissues and sediments was similar; iron (Fe) was followed by Copper (Cu), and this last one was followed by Zinc (Zn). The heavy metal concentrations in tissue crabs from the three beaches differed from each other spatially and seasonally. In addition, Fundición Beach was the zone with the highest concentration of those three metals during the summer.

A phase (Ph) 0/Ia study of brigimadlin concentration in brain tissue and a non-randomized, open-label, dose escalation study of brigimadlin in combination with radiotherapy (RT) in patients (pts) with newly diagnosed glioblastoma (GBM).

2017 Background: MDM2 inhibits tumor suppressor p53. Brigimadlin, a potent MDM2–p53 antagonist, restores wild-type (wt) p53 function and has shown early efficacy in pts with solid tumors (LoRusso et al Cancer Disc 2023). GBM is an area of unmet need with 5-year survival &lt;10%. In p53 wt GBM pt-derived xenograft models, brigimadlin promotes tumor cell apoptosis and extends survival in combination with RT. Methods: NCT05376800 is a Ph 0/Ia open-label, single-arm trial that aims to measure brigimadlin concentration in brain tumor tissue in pts with histologically or radiologically newly diagnosed GBM eligible for resection (Ph 0) and determine the maximum tolerated dose of brigimadlin plus RT in pts with TP53wt, IDH wt, MGMT promoter unmethylated GBM (Ph Ia). In Ph 0, pts received one brigimadlin dose (30 mg or 45 mg) ~12–24 h before resection. Ph 0 primary endpoints are the measured total concentration and the calculated unbound concentration of brigimadlin in brain tissue homogenate from non-contrast enhancing (NCE) and contrast enhancing (CE) regions. The predefined threshold for trial continuation is 0.5 nmol/L (corresponding to IC50 in GBM cell lines) unbound brigimadlin in CE samples in ≥50% of pts. Brigimadlin concentration was measured using LC/MS and corrected for amount of brigimadlin in residual blood. Unbound concentration was calculated using an in vitro estimate of unbound fraction (fu): 0.654% (rat brain slice). fu in human plasma was 0.22%. Kp,uu (ratio of unbound concentration in brain vs plasma) was calculated. Biomarker testing was performed. Results: Data are available for 11 pts (brigimadlin 30 mg: n=6; 45 mg: n=5). In the 30 mg group, median total brigimadlin concentration in NCE samples was 267 nmol/L (4 samples, range 86–316 nmol/L) and 332 nmol/L (6 samples, range 272–952 nmol/L) in CE samples. In the 45 mg group, median total brigimadlin concentration in NCE samples was 197 nmol/L (5 samples, range 140–347 nmol/L) and 603 nmol/L (5 samples, range 441–905 nmol/L) in CE samples. Unbound concentration exceeded the 0.5 nmol/L threshold in most cases (Table). Post-brigimadlin, an increase in selected p53 target gene expression was observed in CE vs NCE tissue. Conclusions: Unbound brigimadlin concentrations in CE regions in all pts receiving the low dose of 30 mg brigimadlin exceeded the 0.5 nmol/L threshold. Kp,uu in most patients was close to 1 in CE regions. Biomarker data support target engagement in brain tissue. Our findings support continued investigation of brigimadlin in GBM. Recruitment is ongoing. Updated data will be presented. Clinical trial information: NCT05376800 . [Table: see text]

Mercury Concentrations in Two Populations of the most Endangered Dolphin (Pontoporia blainvillei) from the Southwestern Atlantic Ocean.

Mercury contamination has been aggravated by emerging environmental issues, such as climate change. Top predators present concerning Hg concentrations once this metal bioaccumulates and biomagnifies. This study evaluated total mercury (THg) concentrations in tissues of 43 franciscanas (Pontoporia blainvillei) from two populations: the Franciscana Management Area (FMA) IIb and FMA IIIa. Animals from FMA IIIa showed mean concentration 5-times and 2.5-times higher in the liver and kidney (4.73 ± 6.84 and 0.52 ± 0.51µg.g-1, w.w., respectively) than individuals from FMA IIb (0.89 ± 1.04 and 0.22 ± 0.15µg.g-1, w.w., respectively). This might be due to: (I) individuals sampled from FMA IIIa being larger and older, and/or (II) the area near FMA IIIa presents environmental features leading to higher THg availability. Coastal contamination can affect franciscanas' health and population maintenance at different levels depending on their life history and, therefore, it should be considered to guide specific conservation actions.

A phase 0/1 trigger trial of BDTX-1535 in patients with recurrent high-grade glioma (HGG) with EGFR alterations or fusions.

2069 Background: This Phase 0/1 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of recurrent high-grade glioma (HGG) patients with EGFR alterations and/or fusions to the ATP-competitive, irreversible EGFR inhibitor, BDTX-1535. Methods: Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 (200 mg) prior to planned resection at 2-4 hours following the final dose. In the Phase 0 component of the study, total and unbound drug concentrations were measured in tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug concentration above 5-fold biochemical IC50 in Gadolinium (Gd)-nonenhancing tumor, determined eligibility for Phase 1. PD response was assessed by quantification of percentage of positive pEGFR, pERK and MIB-1 cells in the surgical tumor tissue compared to baseline pre-treatment tissue. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for expansion phase therapeutic dosing of BDTX-1535. Results: A total of 7 patients with recurrent glioblastoma (Arm A) were enrolled in the Phase 0 component of the study. Two patients were excluded from PK analysis due to pseudoprogression. The mean unbound concentrations of BDTX-1535 in Gd-enhancing and nonenhancing tumor regions were 16.0 nM and 10.5 nM respectively. Four of five (80%) evaluable patients exceeded the PK threshold. The suppression of pEGFR and MIB1 was observed in 40% and 60% of patients, respectively. No serious adverse events were observed among patients in the Phase 1 component of the study and a clinical readout is planned in Q2 2024. Conclusions: BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue and is associated with suppression of EGFR signaling. Clinical trial information: NCT06072586 .

Enhancement of growth media for extreme iron limitation in Escherichia coli

Iron is an essential nutrient for microbial growth and bacteria have evolved numerous routes to solubilize and scavenge this biometal, which is often present at very low concentrations in host tissue. We recently used a MOPS-based medium to induce iron limitation in Escherichia coli K-12 during the characterization of novel siderophore-conjugated antibiotics. In this study we confirm that growth media derived from commercially available M9 salts are unsuitable for studies of iron-limited growth, probably through the contamination of the sodium phosphate buffer components with over 100 µM iron. In contrast, MOPS-based media that are treated with metal-binding Chelex resin allow the free iron concentration to be reduced to growth-limiting levels. Despite these measures a small amount of E. coli growth is still observed in these iron-depleted media. By growing E. coli in conditions that theoretically increase the demand for iron-dependent enzymes, namely by replacing the glucose carbon source for acetate and by switching to a microaerobic atmosphere, we can reduce background growth even further. Finally, we demonstrate that by adding an exogeneous siderophore to the growth media which is poorly used by E. coli, we can completely prevent growth, perhaps mimicking the situation in host tissue. In conclusion, this short study provides practical experimental insight into low iron media and how to augment the growth conditions of E. coli for extreme iron-limited growth.

Applying conditioners to address the issues of carbon loss and cadmium pollution in the karst paddy-oil crop system

The fragile ecosystem and unique parent material in the karst region lead to severe carbon loss and cadmium pollution. Additionally, the rice-oilseed rotation system exacerbates the accumulation of cadmium in crops. Therefore, it is necessary to find a sustainable land use approach that ensures crop quality while promoting soil carbon sequestration. This article provides an overview of cutting-edge technologies to enhance soil carbon sequestration capacity, and it discovers that the application of amendments has a significant effect on reducing cadmium content in crops and improving soil organic carbon levels. Through experimental analysis, The results indicate that the conditioner in group T4 (Humic acids) can effectively passivate cadmium elements in the soil, reducing the cadmium content in rice and rapeseed tissues. Overall, our research indicates that humic acid amendments not only enhance soil carbon sequestration capacity but also significantly reduce cadmium content in crops and increase crop yields. These findings highlight the significant value of humic acid amendments in the rice-oilseed rotation system in the karst region, providing scientific evidence and theoretical support for promoting sustainable development in the area.