Dose-effect Relationship Research Articles

Does the Choice of Anaesthesia Affect Cancer? A Molecular Crosstalk between Theory and Practice

In recent years, there has been an increasing scientific interest in the interaction between anaesthesia and cancer development. Retrospective studies show that the choice of anaesthetics may influence cancer outcome and cancer recurrence; however, these studies show contradictory results. Recently, some large randomized clinical trials have been completed, yet they show no significant effect of anaesthetics on cancer outcomes. In this scoping review, we compiled a body of in vivo and in vitro studies with the goal of evaluating the biological effects of anaesthetics on cancer cells in comparison to clinical effects as described in recent studies. It was found that sevoflurane, propofol, opioids and lidocaine are likely to display direct biological effects on cancer cells; however, significant effects are only found in studies with exposure to high concentrations of anaesthetics and/or during longer exposure times. When compared to clinical data, these differences in exposure and dose-effect relation, as well as tissue selectivity, population selection and unclear anaesthetic dosing protocols might explain the lack of outcome.

Отрицательная $\lambda$-биномиальная регрессия в зависимости доза-эффект

Эта статья посвящена проблеме оценки функции распределения и ее квантилей в зависимости доза-эффект с непараметрической отрицательной $\lambda$-биномиальной регрессией. Здесь предложены ядерные оценки функции распределения, ядро которых взвешивается отрицательной $\lambda$-биномиальной случайной величиной при каждой ковариате. Наши оценки состоятельны, т.е. сходятся к своим оптимальным значениям когда число наблюдений $n$ возрастает до бесконечности. Показано, что эти оценки имеют меньшую асимптотическую дисперсию по сравнению, в частности, с оценками типа Надарая-Ватсона и других оценок. Представлены непараметрические оценки квантилей, полученные путем инвертирования ядерной оценки функции распределения. Асимптотическая нормальность этих оценок с поправкой на смещение сохраняется при некоторых условиях регулярности. В первой части анализируются соотношения между моментами отрицательного $\lambda$-биномиального распределения. Получена новая характеризация распределения Пуассона. This paper is concern to the problem of estimating the distribution function and its quantiles in the dose-effect relationships with nonparametric negative $\lambda$-binomial regression. Here, a kernel-based estimators of the distribution function are proposed, of which kernel is weighted by the negative $\lambda$-binomial random variable at each covariate. Our estimates are consistent, that is, they converge to their optimal values in probability as $n$, the number of observations, grow to infinity. It is shown that these estimates have a smaller asymptotic variance in comparison, in particular, with estimates of the Nadaray-Watson type and other estimates. Nonparametric quantiles estimators obtained by inverting a kernel estimator of the distribution function are offered. It is shown that the asymptotic normality of this bias-adjusted estimator holds under some regularity conditions. In the first part, the relations between the moments of the negative $\lambda$-binomial distribution are analyzed. A new characterization of the Poisson distribution is obtened.

Dose–effect relationship of stereotactic body radiotherapy in non-small cell lung cancer patients

ObjectiveTo establish the dose effect relationship between the dose parameters of stereotactic body radiation therapy (SBRT) for early non-small cell lung cancer (NSCLC) and the local tumor control rate.Materials and methodsA comprehensive literature search was conducted using PubMed, the Web of Science and the Cochrane databases to determine the articles treated with SBRT in early-stage NSCLC. Original studies with complete prescription dose information, tumor local control rate and other important parameters were screened and reported. Probit model in XLSTAT 2016 was used for regression analysis, and P < 0.05 was set as a statistically significant level.ResultsAfter literature screening, 22 eligible studies were included in probit model regression analysis, involving 1861 patients. There is no significant dose effect relationship between nominal BED10 and peripheral BED10 versus 3 years local control probability. There were significant dose effect relationships between the center BED10 and the average BED10 versus the 3 years local control probability, with P values are 0.001 and < 0.0001, respectively. According to the results of this model, the 3 years local control rate of 90.5% (87.5–92.1%) and 89.5% (86.7–91.0%) can be expected at the center BED10 of 180 Gy or the average BED10 of 140 Gy, prospectively.ConclusionsFor NSCLC treated with SBRT, more attention should be paid to the central dose and average dose of PTV. A set of clear definition in the dose prescription should be established to ensure the effectiveness and comparability of treatment.

Paiteling induces apoptosis of cervical cancer cells by down-regulation of the E6/E7-Pi3k/Akt pathway: A network pharmacology

Ethnopharmacological relevanceHuman papillomavirus (HPV) infection is considered to be the main pathogen causing intraepithelial neoplasia. Paiteling (PTL) has been used to treat intraepithelial neoplasia caused by human papillomavirus (HPV) infection for more than 20 years in China, but its specific mechanism of action is not very clear, and further research is still needed. ObjectiveThis study designed a comprehensive strategy to study the pharmacological mechanism of paiteling in regulating cervical cancer cell apoptosis by integrating LC-MS/MS, network pharmacology and pharmacological experiments. MethodsWe used liquid chromatography–tandem mass spectrometry to detect the active substances in PTL and performed protein–protein interaction analysis on the intersection of the targets of these key compounds and the targets of intraepithelial neoplasia. Additionally, by using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG), the potential pathway of PTL against HPV-induced intraepithelial neoplasia was predicted. Finally, we used HeLa and Ect1/E6E7 cells for experimental verification. ResultsThe protein–protein interaction network predicted that AKT1, TP53, MYC, STAT3, MTOR, and MAPK were pivotal targets for PTL to inhibit epithelial neoplasia. KEGG enrichment analysis showed that the Pi3k/Akt pathway and HPV infection had scientific significance. Compared to the control group, after PTL diluent stimulated HeLa and Ect1/E6E7 cells for 24 h, cell viability, migration, and invasion capabilities were significantly reduced, and cell apoptosis was significantly increased, conforming to a dose-effect relationship and time-effect relationship. PCR, cellular immunohistochemistry, and western blot experiments showed that PTL reduced the expression of E6, Pi3k, E7, Akt, Bcl-xl, while increasing the expression of Bad in HeLa and Ect1/E6E7 cells. ConclusionPTL can induce cervical cancer cell apoptosis by inhibiting the E6/E7-Pi3k/Akt signaling pathway. It may provide an effective alternative strategy of traditional Chinese medicine for the treatment of epithelial neoplasia caused by HPV infection.

Pharmacological effects of Bufei Jianpi granule on chronic obstructive pulmonary disease and its metabolism in rats.

This work was performed to determine the pharmacological effects of Bufei Jianpi granules on chronic obstructive pulmonary disease and its metabolism in rats. Chronic obstructive pulmonary disease (COPD), ranked as the third leading cause of death worldwide, is seriously endangering human health. At present, the pathogenesis of COPD is complex and unclear, and the drug treatment mainly aims to alleviate and improve symptoms; however, they cannot achieve the purpose of eradicating the disease. Bufei Jianpi granule (BJG) is a Chinese medicine developed by the First Affiliated Hospital of Henan University of Traditional Chinese Medicine for treating COPD. This study focuses on the pharmacological effects of BJG on COPD and its metabolism in rats, aiming to provide a scientific basis for developing BJG against COPD. A total of 72 Sprague-Dawley (SD) rats were divided into the blank group, model group, positive control group, and BJG groups (2.36, 1.18, and 0.59g/kg). Except for the blank group, rats in other groups were administered lipopolysaccharide (LPS) combined with smoking for 6 weeks to establish the COPD model. After another 6 weeks of treatment, the therapeutic effect of BJG on COPD rats was evaluated. In the BJG (2.36g/kg) group, the cough condition of rats was significantly relieved and the body weight was close to that of the blank group. Compared with the mortality of 16.7% in the model group, no deaths occurred in the BJG (2.36g/kg) and (1.18g/kg) groups. The lung tissue damage in the BJG groups was less than that in the COPD group. Compared with the model group, MV, PIF, PEF, and EF50 in the BJG groups were observably increased in a dose-dependent manner, while sRaw, Raw, and FRC were obviously decreased. Also, the contents of IL-6, IL-8, TNF-α, PGE2, MMP-9, and NO in the serum and BALF were lowered dramatically in all BJG groups. All indicators present an obvious dose-effect relationship. On this basis, the UPLC-QTOF-MS/MS technology was used to analyze characteristic metabolites in rats under physiological and pathological conditions. A total of 17 prototype and 7 metabolite components were detected, and the concentration of most components was increased in the COPD pathologic state. It is suggested that BJG has a pharmacological effect in the treatment of COPD and the absorption and metabolism of chemical components of BJG in rats exhibited significant differences under physiological and pathological conditions.

Ecotoxicological Effects of the Anionic Surfactant Sodium Dodecyl Sulfate (SDS) in Two Marine Primary Producers: Phaeodactylum tricornutum and Ulva lactuca.

Sodium Dodecyl Sulfate (SDS) is an anionic surfactant, extensively used in detergents, household and personal care products, as well as in industrial processes. The present study aimed to disclose the potential toxicological effects of SDS exposure under environmentally relevant concentrations (0, 0.1, 1, 3, and 10 mg L-1) on the physiology and biochemistry (photosynthesis, pigment, and lipid composition, antioxidative systems, and energy balance) of two marine autotrophs: the diatom Phaeodactylum tricornutum and the macroalgae Ulva lactuca. A growth rate (GR) reduction in P. tricornutum was observed with a classic dose-response effect towards the highest applied concentration, while a GR increase occurred in U. lactuca. Regarding photochemistry, the decrease in the fluorescence of the OJIP curves and laser-induced fluorescence allowed a better separation between SDS treatments in U. lactuca compared with P. tricornutum. Although all pigments significantly decreased in U. lactuca at the highest concentrations (except for antheraxanthin), no significant variations occurred in P. tricornutum. On the other hand, changes in fatty acid content were observed in P. tricornutum but not in U. lactuca. In terms of classical biomarker assessment, a dose-effect relationship of individual biomarkers versus SDS dose applied; U. lactuca displayed a higher number of biomarker candidates, including those in distinct metabolic pathways, increasing its usefulness for ecotoxicological applications. By evaluating the potential application of optical and biochemical traits, it was evident that the fatty acid profiles of the different exposure groups are excellent candidates in P. tricornutum, concomitant with the characteristics of this anionic surfactant. On the other hand, the results presented by laser-induced fluorescence and some parameters of PAM fluorometry in U. lactuca may be an advantage in the field, offering non-invasive, fast, easy-to-use, high-throughput screening techniques as excellent tools for ecotoxicology assessment.

Endoplasmic reticulum stress mediates nickel chloride-induced epithelial‑mesenchymal transition and migration of human lung cancer A549 cells through Smad2/3 and p38 MAPK activation

BackgroundThe endoplasmic reticulum (ER) is a cellular membrane-bound organelle whereby proteins are synthesized, folded and glycosylated. Due to intrinsic (e.g., genetic) and extrinsic (e.g., environmental stressors) perturbations, ER proteostasis can be deregulated within cells which triggers unfolded protein response (UPR) as an adaptive stress response that may impact the migration and invasion properties of cancer cells. However, the mechanisms underlying the nickel compounds on lung cancer cell migration and invasion remain uncertain. ObjectiveWe aimed to study whether Nickel chloride (NiCl2) induces ER stress in lung cancer cells, and whether ER stress is involved in modulating epithelial-mesenchymal transition (EMT) and migration by Smads and MAPKs pathways activation following NiCl2 treatment. MethodsA549 cells were treated with NiCl2 to determine the cell viability using MTT assay. The wound healing assay was used to evaluate cell migration ability. ER ultrastructure was observed by transmission electron microscopy. Western blotting assay was performed to evaluate the protein levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 for ER stress and UPR, E-cadherin and Vimentin for EMT, p-Smad2/3, p-ERK, p-JNK, and p-P38 for activation of Smads and MAPKs signaling pathways. ResultsThe expression levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 were significantly increased following treatment with NiCl2 in time- and dose-effect relationship. The ER stress inhibitor 4-PBA downregulated the expression levels of the above five proteins, and reversed the decrease in E-cadherin protein level and the increase in vimentin protein expression and cell migration abilities caused by NiCl2. Furthermore, 4-PBA significantly reduced nickel chloride-induced Smad2/3 and p38 MAPK pathway activation, while not affected ERK and JNK MAPK pathways. ConclusionNiCl2 triggers ER stress and UPR in A549 cells. Moreover, 4-PBA alleviates NiCl2-induced EMT and migration ability of A549 cells possibly through the Smad2/3 and p38 MAPK pathways activation, rather than ERK and JNK MAPK pathways.

Torsional strabismus and vertical rectus muscle surgery in thyroid eye disease

To assess the torsional component in patients with vertical strabismus due to thyroid eye disease (TED) and its course after vertical rectus muscle surgery. Retrospective chart review of patients undergoing vertical strabismus surgery for TED between 1998 and 2017, having undergone pre- and postoperative Harms tangent screen examination. Forty patients (27 women) were identified. A torsional component was present in all patients. Thirty-three patients had a mean excyclotorsion of 4.5° in primary position, increasing to 8.2° in upgaze, associated with restricted elevation. Inferior rectus muscle recession (n=29) reduced the excyclotorsion in all cases. A 4.4° mean incyclotorsion was present in primary position in 7 cases, increasing to 7.1° in downgaze. Superior rectus muscle recession reduced the incyclotorsion in 5/6 cases. The torsional surgical dose-effect relationship was correlated with the amount of preoperative torsion. The field of binocular single vision improved from 6.5% preoperatively to 71.1% after surgery. Ocular torsion is common in vertical strabismus secondary to TED and is significantly improved by vertical rectus muscle surgery alone. Surgery should be planned according to vertical deviation and motility limitation, and vertical rectus muscles surgery should be considered the first line of treatment, with selective oblique muscle surgery as a second-line option, which was unnecessary in our series.

Inhibition of the cholesterol transporter ABCA1 by probucol decreases capacitation and tyrosine phosphorylation of dog spermatozoa, and is dose dependent

The ATP binding cassette (ABC) transporter molecule ABCA1 participates in the cholesterol transport within and through cell membranes. We recently demonstrated that in dog spermatozoa, capacitation could be decreased with probucol (PRO), an ABCA1 specific antagonist. In this study, a dose-effect relationship of PRO on dog sperm capacitation, tyrosine phosphorylation and cholesterol efflux from the sperm plasma membrane was investigated. A total of 16 ejaculates from dogs of different breeds, aged 2–4 years were used. Sperm motility and membrane integrity in the main fraction was determined by CASA. Samples were stained with a boron dipyrromethene difluoride (BODIPY) fluorophore (P9672, Sigma- Aldrich, A) diluted in DMSO at a final concentration of 0.4 μM. All samples were divided into 5 aliquots, with 0, 100, 250, 500 and 1000 μM of PRO. After incubation at 37 °C for 2 h, PI was added and flow cytometry performed. All aliquots were examined for capacitation and acrosome reaction by using the CTC assay and tyrosine phosphorylation (TP). Membrane integrity was measured in all aliquots to investigate the effect of PRO on cell membranes. Membrane integrity did not differ between controls (0 μM), and 100, 250 and 500 μM PRO, but decreased with 1000 μM PRO (p < 0.05). Increasing PRO concentration decreased the percentage alive cells with cholesterol efflux per PRO group (0 μM: 77.8 ± 10.6%, 100 μM: 63.7 ± 11.7%, 250 μM: 52.1 ± 12.9%, 500 μM: 37.7 ± 11.6%, 1000 μM: 33.1 ± 14.4%; p < 0.05), decreased head and entire tail phosphorylated cells (0 μM: 34.6%, 1000 μM: 5.1% p < 0.05); and decreased the percentage capacitated cells (maximum with PRO 500 μM: capacitated vs. control: 54.2 ± 17% vs 25 ± 7.7%, p < 0.05). Conclusion: PRO decreased the cholesterol efflux, and decreased tyrosine phosphorylation and capacitation in a dose-dependent manner. This suggests a strong involvement of the ABCA1 transporter in different functional aspects of sperm capacitation in dogs.

How to conduct an acupuncture dose–effect relationship study? A discussion based on study methodology

Acupuncture therapy is widely used in the clinic, and its therapeutic effects have been proven by numerous studies. The dose–effect relationship of acupuncture is a fundamental aspect of the acupuncture research system. Recent studies found that different acupuncture dosages altered study results directly, indicating the importance of screening the optimal stimulation dosage. However, the system for studying the acupuncture dose–effect relationship is still in its infancy, and the methodology of the system needs to be improved. This review aimed to define the factors impacting acupuncture “dosage” and “effect,” and to improve the methodological system for research on the dose–effect relationship of acupuncture. By summarizing the current findings of acupuncture dose–effect studies, we discussed the vital acupuncture parameters and methodological problems that influence the relationship between acupuncture dosage and its effects. These factors consist of specific influencing factors (acupoint selection, acupuncture manipulation parameters, de qi response) and nonspecific influencing factors (comparison selection, blinding procedure, patient expectancy). Our perspectives offer suggestions for the design of acupuncture dosage–effect trials. Further studies need to be conducted to establish the methodological system and provide systematic evidence of the acupuncture dose–effect relationship. Graphical abstract: http://links.lww.com/AHM/A37

Association of maternal TSH and neonatal metabolism: A large prospective cohort study in China.

Neonatal metabolites are very important in neonatal disease screening, and maternal thyroid hormones play an important role in fetal and neonatal health. Our study aimed to explore the association of maternal thyroid hormones with neonatal metabolites and identify an important time windows. Pregnant women were recruited in Jinan Maternity and Child Care Hospital and followed up until delivery. Multivariate generalized linear regression models (GLMs) and restricted cubic spline (RCS) regression analysis models were used to investigate the associations of maternal TSH and FT4 with neonatal metabolites. In total, 6,653 pairs of mothers and newborns were enrolled in our study. We identified 5 neonatal metabolites, including arginine/ornithine (Arg/Orn), C14:1/C2, C18:1, C3DC+C4OH and C8:1, that were significantly associated with maternal serum TSH during the whole pregnancy (P < 0.05), especially in the first trimester. Moreover, 10 neonatal metabolites were significantly associated with maternal serum FT4 (P < 0.05), most of which had positive correlations with maternal FT4 in the first trimester (P < 0.05). Some neonatal metabolites also had linear or nonlinear dose-effect relationships with maternal serum TSH and FT4 during the whole pregnancy, particularly in the first trimester. Our study, for the first time, provides epidemiological evidence that maternal serum TSH and FT4, especially during the first trimester, are associated with linear or nonlinear variations in neonatal metabolites. Efforts to identify newborn metabolism levels should carefully consider the effects of maternal thyroid function.

Screening strategy for predominant phenolic components of digestive enzyme inhibitors in passion fruit peel extracts on simulated gastrointestinal digestion.

The targeted biological activity of a natural product is often the result of the combined action of multiple functional components. Screening for predominant contributing components of targeting activity is crucial for quality evaluation. Thirteen and nine phenolic compounds inhibiting α-glucosidase and α-amylase, respectively, were identified in the ethanol extracts of passion fruit peel through liquid chromatography-tandem mass spectrometry and multivariate analysis. Considering the different concentrations of components and their interactions, the role of the semi-inhibitory concentration (IC50 ) in the dose-effect relationship is limited. We proposed the active contribution rate (ACR), which is the ratio of a single component concentration to its IC50 in the whole, to assess the relative activity of each compound. Luteolin, quercetin, and vitexin exhibited a minimum IC50 . Before the simulation of gastrointestinal digestion, quercetin, salicylic acid, and luteolin were identified as the dominant contributors to α-glucosidase inhibition according to ACR, while salicylic acid, 2,3-dihydroxybenzoic acid, and quercetin were identified as dominant contributors to α-amylase inhibition. After simulated digestion, the contents of all polyphenolic compounds decreased by various degrees. Salicylic acid, gentisic acid, and vitexin became the dominant inhibitors of α-glucosidase based on ACR (cumulative 57.96%), while salicylic acid and 2,3-dihydroxybenzoic acid became the dominant inhibitors of α-amylase (cumulative 84.50%). Therefore, the ACR evaluation strategy can provide a quantitative reference for screening the predominant contributor components of a specific activity in complex systems. © 2022 Society of Chemical Industry.

Toxic Effects and Mechanism of Pefloxacin on the Early Life Stage of Zebrafish (Danio rerio)

Pefloxacin (PFLX) is a type of fluoroquinolone (FQ) that has been widely used in aquaculture and animal husbandry. It is also a new kind of pseudo-persistent pollutant, which has some toxic effects. In this study, zebrafish (Danio rerio) embryos were used as exposure models to analyze the toxicity of PFLX. The results showed that PFLX was absorbed on the outer membrane surface at the beginning, and then a few PFLX slowly entered the cytoplasm. The adsorption complied with the Langmuir isotherm adsorption model. The surface morphology of the embryonic membrane was changed. PFLX exposure had no effect on fetal autonomous movement, but it significantly inhibited the embryo hatching rate. After PFLX exposure, the embryo and larval survival rates showed a clear dose–effect relationship. Though PFLX exposure did not cause teratogenic toxicity, it still affected cardiovascular function. The potential toxicity mechanism and developmental toxicity of PFLX to zebrafish were revealed. These results could be important for studies concerning FQ toxicology.

Cell viability and drug evaluation biosensing system based on disposable AuNPs/MWCNT nanocomposite modified screen-printed electrode for exocytosis dopamine detection

Cell viability, as an important index to evaluate drug effects, usually was measured by tetrazolium colorimetric assay, playing a key role in drug development and drug screening. Tedious operating procedures, unsatisfactory sensitivity and abominable environments perplex researchers to acquire more detailed in vivo-relevant biological information. Herein, a simple and low-cost cell viability and drug evaluation biosensing system-based on multiwalled carbon nanotubes, gold nanoparticles and Nafion modified screen-printed electrode (SPE) biosensor was constructed for detection of dopamine (DA) released from living cells to evaluate cytotoxicity of antineoplastic drugs such as cisplatin and resveratrol. The biosensing system was demonstrated to display exceptional selectivity, excellent flexibility and good stability toward DA measurement in complex bio-samples. Additionally, the satisfactory recoveries of DA in real samples revealed the reliability and accuracy of the biosensing system in practical application. The IC50 curves respectively obtained by the biosensing system and tetrazolium colorimetric assay provided similar IC50 value but distinctly different dose-effect relationship, which confirmed the enormous potential of the biosensor in cell viability and described drug efficacy profiles in cell function. In short, the cell viability and drug evaluation system using SPE biosensor paves a new way in drug screening and pharmaceutical application to measure bioactive molecule such as DA.

Bromophenol Induced Multiple Stress Responses in Rice Plants: Impact of Doses and Congener Structures.

Bromophenols (BPs) have both natural and artificial sources in the environment and are frequently detected in plants. Herein, the ubiquitous 2,4,6-TriBP was hydroponically exposed to rice seedlings at two concentrations (0.2 and 2.0 mg/L) to characterize the dose-dependent abiotic stress responses of rice plants to BPs. The 2,4,6-TriBP induced oxidative damage to rice roots and subsequently inhibited plant transpiration and growth at the end of exposure in both concentrations. Moreover, the gene expression of OsUGT72B1 and the activity of glycosyltransferases of exposed rice roots were 2.36-to-4.41-fold and 1.23-to-1.72-fold higher than that of the blank controls after 24 h, following the formation of glycoconjugates in response to 2,4,6-TriBP exposure. It was notable that the glycosylation rates also showed a dose-effect relationship in rice roots. One and six glycoconjugates of 2,4,6-TriBP were detected in 0.2 and 2.0 mg/L exposure groups, respectively. Considering the detected species of glycoconjugates for four other types of BPs, the numbers of bromine atoms were found to dramatically affect their glycosylation process in rice plants. These results improve our fundamental understanding of the impact of congener structures and exposure concentrations of organic contaminants on the glycosylation process in response to phytotoxicity.

Human health risk assessment of cinnamate UV absorbers: In vitro and in silico investigations

Organic UV absorbers (UVAs) are contaminants of emerging concern. Environmental persistence and potential toxicological enrichment studies of UVAs have attracted international concern. It is important to study the toxicity mechanism of UVAs. This study is the first to report the toxicological mechanism of two cinnamate UV absorbers (CUVAs), 2-ethyl 4-methoxycinnamate (OMC) and isoamyl 4-methoxycinnamate (IMC) based on cellular models and molecular models. Cellular models demonstrated that the CUVAs-induced apoptosis might be associated with cellular mitochondrial damage pathways. The results of molecular models showed that OMC and IMC could affect the binding between major proteins and enzymes in the mitochondrial damage pathway and contaminants, ultimately leading to apoptosis. The cellular-molecular models showed that IMC and OMC have dose–effect relationships on cytotoxicity. The composite model is more informative than a single model. This study further indicate that UVAs causes toxicology effects that have implications for the environment and human health.

Patterns of Hearing Loss in Irradiated Survivors of Head and Neck Rhabdomyosarcoma.

The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster ≥ 2b, CTCAE ≥ 2, and SIOP ≥ 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (≥Muenster 2b) (p = 0.047). In our series, HL (≥Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.

Associations of Minor Histocompatibility Antigens with Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation

Introduction Donor T-cell recognition of tumor-presented minor histocompatibility antigens (mHAs) is thought to be a central mediator of the therapeutic graft versus leukemia (GvL) effect following allogeneic hematopoietic cell transplantation (alloHCT). In contrast, graft versus host disease (GvHD) develops when donor T-cells react to mHAs presented by normal recipient cells. While the role of mHAs in outcomes following alloHCT is recognized, it has not been well-characterized. It remains unclear whether GvL and GvHD are mediated by the cumulative effect of total mHAs in a donor-recipient pair (DRP) or individual immunodominant mHAs. We hypothesized that an increased mHA count and individual mHAs would be associated with lower relapse and disease-related mortality (DRM) and/or increased GvHD mortality. To this end, we predicted genome-wide mHA peptides in a large patient population and analyzed the associations between clinical outcomes and 1) the total number of predicted class I and class II mHAs, and (2) individual and groups of mHAs. Methods The study population consisted of 2249 European American DRPs in the DISCOVeRY-BMT dataset treated for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with alloHCT. To predict mHAs in a DRP, we translated nonsynonymous SNP alleles present in alloHCT recipients, but absent in their donor, into all possible peptides of varying lengths that would encompass the altered amino acid. To identify mHAs most likely to be immunogenic, peptides were filtered based on (1) source protein gene expression data in GvL and GvHD target tissues, including AML, liver, skin, and colon, from UCSC's Xena Dataset repository and (2) recipient HLA binding affinity from netMHCpan. To test the association of mHA count and individual mHAs with all-cause mortality (OS) and leukemia-free survival (LFS) we used cox proportional hazard models and competing risk models for DRM, treatment-related mortality (TRM), and GvHD mortality. Individual mHA analyses were stratified by HLA type to recognize that T-cell responses depend on HLA-mHA complexes. Models were adjusted for clinical covariates. Bonferroni correction for multiple testing was based on the number of independent SNPs. Results Patients with a class I mHA count greater than the population median had a 39% (HR=1.39, 95%CI 1.005,1.772, P=0.046) increase in hazard of GvHD mortality compared to those with a count less than the median. Patients with a class II mHA count greater than the population median had a decreased overall survival compared to those with a count less than the median (Fig. 1, P=0.029). In recipients with HLA-B*08:01, the class I mHA DLRCKYISL was associated with increased risk of GVHD mortality (HR=2.84, 95%CI 1.52,5.31, P=0.01). Within HLA-B*40:01, WEHGPTSLL was associated with decreased LFS (HR=1.94, 95%CI 1.27,2.95, P=0.044). Within HLA-C*03:04, STSPTTNVL was associated with increased risk of DRM (HR=2.32, 95%CI 1.5,3.6, P=0.008). In recipients with HLA-DRB1*15:01, the class II mHA YQEIAAIPSAGRERQ was associated with increased risk of TRM (HR=3.05, 95%CI 1.75,5.31, P=0.02). Two mHAs, WEHGPTSLL and STSPTTNVL, were found within the HLA haplotype B*40:01-C*03:04. Recipients with both mHAs (versus neither) had a greater hazard of 1-year all-cause mortality (HR=3.58, P=7.9×10-5) and DRM (HR=3.65, P=0.003) (Fig. 2). Patients with either mHA (versus neither) had greater 1-year all-cause mortality (HR=1.69, P=0.008) and increased DRM (HR=2.05, P=0.008) Conclusions The number of class I mHAs in a DRP was associated with increased GvHD mortality, which is consistent with our hypothesis. We also found two mHAs correlated with GvHD mortality and DRM which may represent increased GvH effects driven by these peptides. However, contrary to our hypothesis, an increased number of class II mHAs was correlated with greater risk of all-cause mortality that may be due to decreased LFS. Similarly, we found two mHAs correlated with increased DRM and decreased LFS. These two mHAs are found in an HLA haplotype where they exhibit a dose effect relationship with the risk of DRM and decreased OS. These findings may reflect an unexpectedly attenuated GvL effect that requires further investigation. Our study reports the first large scale investigation of the role of predicted mHA peptides in clinical outcomes following alloHCT. If validated, these results may be used to help guide clinical decision making. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Токсикологічний профіль пропізохлору у дворічному експерименті на щурах-самцях Wistar Hannover

Abstract. The herbicide propisochlor is widely used in agriculture of Ukraine. Its intensive usage is potentially dangerous due to residues in agricultural products, ecosystems, as well as effects on animals’ and humans’ organisms. This fact necessitates the study of its toxicological properties. Aim. To study the propisochlor carcinogenicity in a long-term experiment on male rats. Materials and Methods. The experiment was performed on Wistar Han male rats. There was investigated a sample of 95 % technicalgrade propisochlor, administered to animals intragastrically at doses of 20 and 200 mg/kg of body weight for two years. At the 52ndweek-term, a group of animals was selected to study the propisochlor toxicity. Carcinogenicity was assessed at the 104th week. Results. The toxic effect of propisochlor on the rats’ bodies was revealed in weight loss affected by a 200 mg/kg dose, starting from the 29th week of testing. According to the analysis results of the clinical biochemistry, it was found that propisochlor at a dose of 200 mg/kg at the 52nd week of exposure tended to decrease the activity of ALT and AST. Histologically at the terminal stage at a dose of 200 mg/kg in rats the hepatocellular necrosis with associated focal hemorrhages were detected, which confirmed hepatotoxicity; and in the thyroid gland it was found the increase of nodular follicular-cell hyperplasia cases. Propisochlor did not affect the survival and life expectancy of rats, did not increase the number of animals with tumors, did not affect the multiplicity of newgrowth, did not change the ratio of benign and malignant tumors, and also did not reduce their latency, the dose-effect relationship was not observed. Conclusions. Propisochlor, 95 % technical-grade generic, did not show the carcinogenic effects in a two-year experiment in male rats. NOAEL was identified according to general toxicological criteria and it was 20 mg/kg. Key Words: propisochlor, carcinogenesis, toxicology, Wistar Han male rats, long-term experiment.

Less is more: Vital roles of bioactive equivalency in assessing food quality

Less is more: Vital roles of bioactive equivalency in assessing food quality