Moderate Toxicity Research Articles

Design, synthesis and insecticidal activity and mechanism research of Chasmanthinine derivatives

Unrestricted reproduction and spread of pest had caused great damage to the quality and yield of crops in recent years. Besides the use of traditional chemical pesticides, natural products also make a huge contribution against pests. Chasmanthinine, a diterpenoid alkaloid isolated from Aconitum franchetii var. villosulum, shown extremely antifeedant activity against Spodoptera exigua. Therefore, a series of novel Chasmanthinine derivatives were synthesized and their biological activity was studied in this work. Compound 33 showed the strongest antifeedant activity (EC50 = 0.10 mg/cm2) among all the test compounds. The mechanism research of 33 revealed that its antifeedant effect was related to the inhibition of carboxylesterase (CES), and proved the thiophene acyl group could form a strong binding effect with CES by molecular docking. Moreover, compound 10 exhibited the strongest cytotoxicity (IC50 = 12.87 μM) against Sf9 cell line and moderate contact toxicity. The mechanism research indicated that compound 10 could induce Sf9 cells apoptosis. In summary, the results lay a foundation for the application of diterpene alkaloids in plant protection.

Cyto-Genotoxicity of Tritiated Stainless Steel and Cement Particles in Human Lung Cell Models.

During the decommissioning of nuclear facilities, the tritiated materials must be removed. These operations generate tritiated steel and cement particles that could be accidentally inhaled by workers. Thus, the consequences of human exposure by inhalation to these particles in terms of radiotoxicology were investigated. Their cyto-genotoxicity was studied using two human lung models: the BEAS-2B cell line and the 3D MucilAirTM model. Exposures of the BEAS-2B cell line to particles (2 and 24 h) did not induce significant cytotoxicity. Nevertheless, DNA damage occurred upon exposure to tritiated and non-tritiated particles, as observed by alkaline comet assay. Tritiated particles only induced cytostasis; however, both induced a significant increase in centromere negative micronuclei. Particles were also assessed for their effects on epithelial integrity and metabolic activity using the MucilAirTM model in a 14-day kinetic mode. No effect was noted. Tritium transfer through the epithelium was observed without intracellular accumulation. Overall, tritiated and non-tritiated stainless steel and cement particles were associated with moderate toxicity. However, these particles induce DNA lesions and chromosome breakage to which tritium seems to contribute. These data should help in a better management of the risk related to the inhalation of these types of particles.

C2-linked alkynyl poly-ethylene glycol(PEG) adenosine conjugates as water-soluble adenosine receptor agonists.

A series of 12 novel polyethylene-glycol(PEG)-alkynyl C2-adenosine(ADN) conjugates were synthesized using a robust Sonogashira coupling protocol and characterized by NMR spectroscopy and mass spectrometry analysis. The ADN-PEG conjugates showed null to moderate toxicity in murine macrophages and 12c was active against Mycobacterium aurum growth (MIC=62.5mg/L). The conjugates were not active against Mycobacterium bovis BCG. Conjugates 10b and 11b exhibited high water solubility with solubility values of 1.22 and 1.18 mg/ml, respectively, in phosphate buffer solutions at pH6.8. Further, 10b and 11b induced a significant increase in cAMP accumulation in RAW264.7 cells comparable with that induced by adenosine. Analogues 10c, 11c and 12c were docked to the A1 , A2A , A2B and A3 adenosine receptors (ARs) using crystal-structures and homology models. ADN-PEG-conjugates bearing chains with up to five ethyleneoxy units could be well accommodated within the binding sites of A1 , A2A and A3 ARs. Docking studies showed that compound 10b and 11b were the best A2A receptor binders of the series, whereas 12c was the best binder for A1 AR. In summary, introduction of hydrophilic PEG substituents at the C2 of adenine ring significantly improved water solubility and did not affect AR binding properties of the ADN-PEG conjugates.

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study

Background Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). Methods Patients with stages T2–4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57–58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41–43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. Results Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3–4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. Conclusion Tetramodal therapy of T2–T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.

Awareness and attitudes of oncology specialists toward dihydropyrimidine dehydrogenase testing in Saudi Arabia.

Fluoropyrimidines (FP) are among the most common class of prescribed anti-neoplastic drugs. This class has severe to moderate toxicity in around 10%-40% of those who take 5-fluorouracil (5-FU) or capecitabine for the treatment of cancer. In practice many patients with severe toxicities from FP use had dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. Several studies have proposed DPD screening before treatment with 5-fluorouracil (5-FU) and capecitabine or other drugs belonging to the FP group. This study aims to assess the level of awareness and attitudes of oncology specialists in Saudi Arabia toward genetic screening for DPD prior to giving FP. This highlights the importance of health guidelines required for implementation in our health care system, as a framework to adopt testing as a regular practice in clinical care. Based on the findings in this study, guidelineshave been suggested for the Middle East North Africa region. A cross-sectional survey study was conducted during 2021 targeting oncologists and clinical pharmacists working in the oncology departments across Saudi Arabia. A total of 130 oncologists and pharmacists completed the questionnaire representing a response rate of 87%. Most of the respondents indicated that they prescribe FP in clinical practice, but 41% of respondents reported that they have never ordered a specific molecular test during their practice. Only 20% of respondents reported that they often screen for DPD deficiency prior to prescribing FP. Significantly higher rates of awareness of potential dihydropyrimidine dehydrogenase gene (DPYD) mutation were observed among respondents in governmental hospitals (81.1% vs. 47.4% in private hospitals), and among those with more years of practice (80.6% if 5 or more years of practice vs. 59.3% if less than 5 years of practice). Also, higher rates of observing the impact of DPD testing were present among respondents with a PharmD (35% vs. 11% for oncologists and 18% for other professions) and among those with 5 or more years of practice (24.6% vs. 7.7% among those with less than 5 years). While in some institutions there is a high level of awareness among oncology specialists in Saudi Arabia regarding the effect of the potentially serious DPD enzyme deficiency as a result of gene mutations, screening for these mutations prior to prescribing FP is not a routine practice in hospitals across the country. The findings of this study should promote personalized medicine with recognition of interpatient variability via DPD testing to manage the risks of FP prescribing more effectively in the Kingdom of Saudi Arabia.

Identification of intrinsic hepatotoxic compounds in Polygonum multiflorum Thunb. using machine-learning methods

Ethnopharmacological relevancePolygonum multiflorum Thunb. (PM) is a herb, extracts of which have been used as Chinese medicine for years. Although it is believed to be beneficial to the liver, heart, and kidneys, it causes idiosyncratic drug-induced liver injury (DILI). Aim of the studyWe propose that the intrinsic DILI caused by natural products in PM (NPPM) is an important complementary mechanism to PM-related herb-induced liver injury, and aim to identify the ingredients with high DILI potential by machine learning methods. Materials and methodsOne hundred and ninety-seven NPPM were collected from the literature to identify the intrinsic hepatotoxic compounds. Additionally, a DILI-labeled dataset consisting of 2384 compounds was collected and randomly split into training and test sets. A diparametric optimization method was developed to tune the parameters of extended-connectivity fingerprints (ECFPs), Rdkit, and atom-pair fingerprints as well as those of machine-learning (ML) algorithms. Subsequently, K means were employed to cluster the NPPM that were predicted to have a high DILI risk. An in vitro cell-viability assay was performed using HepaRG cells to validate the prediction results. ResultsECFPs with the top 35% of features ranked by the F-value with support vector machine (SVM) yielded the best performance. The optimized SVM model achieved an accuracy of 0.761 and recall value of 0.834 on the test dataset. The silico screening for NPPM resulted in 47 ingredients with high DILI potential, which were clustered into six groups based on the elbow method. A representative subgroup that contained 21 ingredients, of which two dianthrones exhibited the lowest IC50 value (0.7–0.9 μM) and anthraquinones showed moderate toxicity (15–25 μM), was constructed. ConclusionUsing ML methods and in vitro screening, two classes of compounds, dianthrones and anthraquinones, were predicted and validated to have a high risk of DILI. The diparametric optimization method used in this study could provide a useful and powerful tool to screen toxicants for large datasets and is available at https://github.com/dreadlesss/Hepatotoxicity_predictor.

New Pyrrole Derivatives as Promising Biological Agents: Design, Synthesis, Characterization, In Silico, and Cytotoxicity Evaluation.

The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new bioactive molecules. The new pyrroles were obtained by reaction of benzimidazolium bromide derivatives with asymmetrical acetylenes in 1,2-epoxybutane under reflux through the Huisgen [3 + 2] cycloaddition of several ylide intermediates to the corresponding dipolarophiles. The intermediates salts were obtained from corresponding benzimidazole with bromoacetonitrile. The structures of the newly synthesized compounds were confirmed by elemental analysis, spectral techniques (i.e., IR, 1H-NMR and 13C-NMR) and single-crystal X-ray analysis. The cytotoxicity of the synthesized compounds was evaluated on plant cells (i.e., Triticum aestivum L.) and animal cells using aquatic crustaceans (i.e., Artemia franciscana Kellogg and Daphnia magna Straus). The potential antitumor activity of several of the pyrrole derivatives was studied by performing in vitro cytotoxicity assays on human adenocarcinoma-derived cell lines (i.e., LoVo (colon), MCF-7 (breast), and SK-OV-3 (ovary)) and normal human umbilical vein endothelial cells (HUVECs). The obtained results of the cytotoxicity assessment indicated that the tested compounds had nontoxic activity on Triticum aestivum L., while on Artemia franciscana Kellogg nauplii, only compounds 2c and 4c had moderate toxicity. On Daphnia magna, 4b and 4c showed high toxicity; 2a, 2b, and 2c moderate to high toxicity; only 4a and 4d were nontoxic. The compound-mediated cytotoxicity assays showed that several pyrrole compounds demonstrated dose- and time-dependent cytotoxic activity against all tested tumor cell lines, the highest antitumor properties being achieved by 4a and its homologue 4d, especially against LoVo colon cells.

The first report of chickpea (Cicer arietinum L.) tolerance to Paraquat in Australia

Chickpea growers in Australia have no post-emergent (POST) herbicides labeled for broadleaf weed control and they rely on pre-emergent herbicides for control of broadleaf weeds. The objective of this study was to evaluate chickpea tolerance to POST application of paraquat (0, 90, 180, 360, and 540 g ai ha-1) in a randomized complete block design. Paraquat (180 g ai ha-1) applied POST (up to 10 days after crop emergence) did not injure chickpeas and reduce plant height, and biomass when compared with nontreated control. When the crop just emerged, even the highest dose of paraquat (540 g ai ha-1) did not cause any injury or reduce chickpea biomass compared with nontreated control. Moderate toxicity to chickpea at paraquat 360 or 540 g ai ha-1 was observed when applied 20 days after crop emergence. This study suggests that paraquat POST has the potential to provide broad-spectrum weed control, including broadleaf weeds at an early stage of chickpea. However, the potential for crop injury to paraquat at higher doses, especially when applied at a late stage of the crop warrants further evaluation under field conditions. The study also suggests that tank mix applications of paraquat with residual herbicides may be useful for season-long weed control in chickpea and result in improved yield. The current study warrants further evaluation of the tank-mix application of paraquat with pre-emergent herbicides for season-long weed control under field conditions.

Paying the highest price: Financial toxicity of gynecologic oncology patients undergoing treatment in the deep south (282)

<b>Objectives:</b> Treatment of gynecologic cancers can lead to significant financial and productivity burdens, causing long-term detriments to patients even after their treatment is complete. This is particularly true in states without Medicaid expansion and with high rates of disease. We use a validated tool to understand financial toxicity in gynecologic oncology patients undergoing treatment in the Deep South, where rurality, poverty, and racial disparities disproportionately affect a much higher percentage of the population. <b>Methods:</b> Patients undergoing active treatment for gynecologic cancers were asked to complete a survey about cancer-related costs. The Comprehensive Score for Financial Toxicity (COST) tool was used with <26 indicating moderate and <14 indicating severe financial toxicity. The COST scores for groups based on demographic and clinical data obtained from the medical record were compared as well as the relationship of COST score was compared to reported opportunity costs. Statistical analyses were done using t-test, Fischer's Exact, and Wilcoxon rank-sign tests. <b>Results:</b> Forty-six patients were approached to complete the survey. Of these, 40 patients filled out the survey completely and had clinical data available. The mean age was 59 years (range: 28-89). Among the participants, 67% were White, and 33% were Black; 52.5% had an annual household income of less than $40,000. Twenty-seven patients (67.5%) had public insurance, and ten (25.0%) had private. Patients were being treated for ovarian (27.5%), uterine (30.0%), cervical (32.5%), or vulvar/vaginal cancers (12.5%). Patients were receiving chemotherapy (90%), radiation (35.0%) and/or immunotherapy (17.5%). Five patients (12.5%) were on a clinical trial. Twenty-eight patients (70%) experienced financial toxicity, with ten (25%) experiencing severe toxicity. Age, race, education level, and insurance status were not significantly different between patients who had financial toxicity versus those who did not, though there was a trend toward higher education level and private insurance with the absence of financial toxicity. Income was associated with moderate and severe financial toxicity (p=0.02). Financial toxicity did not differ for patients based on cancer type, treatment type, or the time spent on travel or in a clinic. The severity of the patients' perceived financial burden directly correlated with the COST score (p<0.01). Lower COST scores were associated with a higher likelihood of unemployment or disability due to treatment (p<0.01). Lower COST scores were also associated with a higher likelihood of having to borrow money (p<0.01), using their savings for medical expenses (p<0.01), and being unable to pay for basic necessities (p<0.01). In addition, family members of patients with lower COST scores were more likely to start working more (p<0.01) (Figure 1). <b>Conclusions:</b> Our patients in the Deep South experience financial toxicity at almost double the rate of previous reports. Financial toxicity has been associated with poor outcomes, bankruptcy, generational poverty, and widening disparities experienced by these patients. More research is needed on financial toxicity to improve cancer care equity, particularly as newer and more expensive agents become the standard of care.

Antibacterial activity of medicinal plants against Streptococcus agalactiae

Streptococcus agalactiae, group B Streptococcus (GBS), infects and causes severe diseases in humans and numerous animal species, including fish, given its ability to cross the host-specific barrier. The emergence of antibiotic resistant GBS strains makes it necessary to look for alternatives to treat and prevent infections that it produces. The aim of the present study was to determine the antibacterial activity of ethanolic and aqueous extracts of medicinal plants from Misiones province, northeast Argentina, against GBS from humans and fish. We used human Streptococcus agalactiae ATCC® BAA-611™ and tilapia Streptococcus agalactiae ATCC® 51487™ strains. Minimum Inhibitory Dose (MID) was determined by the disc diffusion method. Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), MBC/MIC ratio, drug synergism with commercial antibiotics, and resistance assays were determined with extracts that showed antibacterial activity. Medium Lethal Dose 50 (LD50) was determined by the Artemia salina assay. For ethanolic and aqueous Eugenia uniflora L. extracts, we obtained a MID = 0.5 mg.disc-1. For both extracts of Eugenia uniflora L., the MIC and MBC values were 1 mg.mL-1 and 5 mg.mL-1, respectively. The MICI (MBC/MIC ratio) = 5 qualified the action of these extracts as bacteriostatic. The drug synergism assay with ampicillin, erythromycin, and clindamycin combination and extracts showed indifference. The LD50 of the aqueous extract was 0.82 mg.mL-1 indicating moderate toxicity. This work is a first step to identify chemical compounds in native medicinal plants of Misiones, Argentina, that could mean an alternative for the treatment of Streptococcus agalactiae infections.

Experience with olaparib in the treatment of BRCA-associated tumors in real clinical practice. Observational study

Background. PARP inhibitor olaparib shows encouraging results in the treatment of patients with BRCA-associated tumors. The detection of new tumors associated with abnormalities of the BRCA gene, also can lead to the expansion of PARP inhibitors application. The application of PARP inhibitors improved treatment outcomes for ovarian, breast, prostate and pancreatic cancers in comparison with standard drug therapy regimens, demonstrating the moderate toxicity profile. All this makes olaparib the significant option in planning the tactics of treatment of this category of patients.&#x0D; Aim. Assess the efficacy of olaparib in real clinical practice conditions in our region and to demonstrate the clinical experience accumulated in the regional clinical oncology dispensary.&#x0D; Materials and methods. We analyzed the cases of the treatment with olaparib in the Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Bashkortostan. The study included 79 patients.&#x0D; Results. Median progression-free survival reached 12 months and the best response was the stabilization of the disease among patients receiving olaparib. Median progression-free survival was 6 months and the best response was the stabilization of the disease among the patients treated with olaparib during Re-Challenge regimen.&#x0D; Conclusion. Olaparib applying in real clinical practice demonstrated satisfactory results.

Evaluation of Acute and Subacute Toxicity and LC-MS/MS Compositional Alkaloid Determination of the Hydroethanolic Extract of Dysphania ambrosioides (L.) Mosyakin and Clemants Flowers.

Dysphania ambrosioides (L.) Mosyakin and Clemants is a medicinal plant that has traditionally been used to cure a range of diseases. There has been no thorough investigation of the potential toxicity of this plant. The objective of this study is to assess the acute and subacute toxicity of D. ambrosioides hydroethanolic extract (DAHE), as well as it alkaloids composition, utilizing LC-MS/MS analysis. An in silico approach was applied to determine pharmacokinetic parameters and to predict the toxicity of D. ambrosioides identified alkaloids. A 14-day treatment with a single oral dose of 1–7 g/kg was carried out to investigate acute toxicity. DAHE was given orally at dosages of 5, 50, and 500 mg/kg for 15 days in the subacute toxicity investigation, and body weight and biochemical parameters were evaluated. Livers, kidneys, lungs, and heart were examined histologically. Chromatographic investigation revealed the existence of nine alkaloids, with N-formylnorgalanthamine being the most prevalent. The oral LD50 value of DAHE was found to be 5000 mg/kg in an acute toxicity study. No variations were observed with respect to food intake, water consumption, mortality, or body and organ weight in the subacute toxicity study. On the other hand, DAHE (500 mg/kg) significantly enhanced alanineaminotransferase, aspartate aminotransferase, and urea. Liver and kidney histological examinations revealed modest infiltration of hepatocyte trabeculae by inflammatory cells in the liver and slight alteration in the kidney histoarchitecture. According to our findings, DAHE exhibits low to moderate toxicity.

Pemetrexed Plus Lenalidomide for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Prospective Single-Arm Phase II Study.

The prognosis of relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL) is dismal, and there are limited treatment options for these patients. This was a prospective single-arm phase II study of combined pemetrexed and lenalidomide for salvage treatment of R/R PCNSL. Patients with R/R PCNSL (n = 38) who had undergone two or more different therapeutic regimens and experienced disease progression or recurrence were enrolled. The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patients were followed up for a median of 18 (range, 1–36) months. ORR was 68.4%, with median PFS and OS of 6 and 18 months, respectively. Adverse events (AEs) included myelosuppression, fatigue, nausea, fever, infection, cardiac disease, and thrombogenesis. Commonly observed grade ≥ 3 AEs included neutropenia (5.3%), leukopenia (2.6%), thrombocytopenia (7.9%), and infection (2.6%). Elevated lactate dehydrogenase (LDH) levels (χ2 = 13.25; P = 0.0003) and bulky disease (P = 0.032; χ2 = 4.580) were associated with short PFS. Elevated serum LDH level (P = 0.011; χ2 = 6.560), abnormal lymphoma cells in the cerebrospinal fluid (CSF) [P = 0.011; χ2 = 6.445], and multiple lesions (P = 0.036; χ2 = 4.404) were significantly associated with poorer OS. Abnormal lymphoma cells in the CSF were an independent predictor of poor prognosis on multivariate analysis (P = 0.034; hazard ratio (HR) = 2.836; 95% confidence interval, 1.082–7.434). Our results indicate that pemetrexed plus lenalidomide is effective for heavily treated R/R PCNSL, with moderate toxicity. Trial registration: #ChiCTR1900028070.

In Vitro Assessment of Pesticides Toxicity and Data Correlation with Pesticides Physicochemical Properties for Prediction of Toxicity in Gastrointestinal and Skin Contact Exposure.

In this work, three pesticides of different physicochemical properties, namely, glyphosate (herbicide), imidacloprid (insecticide) and imazalil (fungicide), were selected to assess their cytotoxicity against distinct cell models (Caco-2, HepG2, A431, HaCaT, SK-MEL-5 and RAW 264.7 cells) to mimic gastrointestinal and skin exposure with potential systemic effect. Cells were subjected to different concentrations of selected pesticides for 24 h or 48 h. Cell viability was assessed by Alamar Blue assay, morphological changes by bright-field microscopy and the IC50 values were calculated. Cytotoxic profiles were analysed using the physico-chemical parameters of the pesticides, namely: molecular weight, water solubility, the partition coefficient in the n-octanol/water (Log Pow) system, the topological polar surface area (TPSA), and number of hydrogen-bonds (donor/acceptor) and rotatable bonds. Results showed that glyphosate did not reduce cell viability (up to 1 mM), imidacloprid induced moderate toxicity (IC50 > 1 mM for Caco-2 cells while IC50 = 305.9 ± 22.4 μM for RAW 264.7 cells) and imazalil was highly cytotoxic (IC50 > 253.5 ± 3.37 for Caco-2 cells while IC50 = 31.3 ± 2.7 μM for RAW 264.7 cells) after 24 h exposure. Toxicity was time-dependent as IC50 values at 48 h exposure were lower, and decrease in cell viability was accompanied by changes in cell morphology. Pesticides toxicity was found to be directly proportional with their Log Pow, indicating that the affinity to a lipophilic environment such as the cell membranes governs their toxicity. Toxicity is inverse to pesticides TPSA, but lower TPSA favours membrane permeation. The lower toxicity against Caco-2 cells was attributed to the physiology and metabolism of cell barriers equipped with various ABC transporters. In conclusion, physicochemical factors such as Log Pow, TPSA and H-bond are likely to be directly correlated with pesticide-induced toxicity, thus being key factors to potentially predict the toxicity of other compounds.

4-Substituted Thieno[3,2-d]pyrimidines as Dual-Stage Antiplasmodial Derivatives.

Malaria remains one of the major health problems worldwide. The increasing resistance of Plasmodium to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hit, active on the sexual and asexual stages of the parasite and thanked for the introduction of various substituents at position 4 of the thienopyrimidine core by nucleophilic aromatic substitution and pallado-catalyzed coupling reactions, a series of 4-substituted thieno[3,2-d]pyrimidines were identified as displaying in vitro activities against both the erythrocytic stage of P. falciparum and the hepatic stage of P. berghei. Among the 28 compounds evaluated, the chloro analogue of Gamhepathiopine showed good activity against the erythrocytic stage of P. falciparum, moderate toxicity on HepG2, and better activity against hepatic P. berghei parasites, compared to Gamhepathiopine.

Polyethylenimine as a gene delivery tool in triple-negative breast cancer cell line and breast cancer stem cell model

Background and purpose: PEI is a cationic polymer able to neutralise negative DNA charges and to condense large genes which makes it suitable for gene delivery in human cells. Despite its low cost, simplicity of use and moderate toxicity, there is still room for broader usage and experimental adjustments, especially in cell lines that are difficult to transfect. In the presented research, we used PEI for the delivery of plasmid DNA into TNBC cell line SUM159 and breast CSC model HMLE-Twist.Material and methods: Cultured cells were transfected with GFP-expressing plasmid using both PEI and Lipofectamin. Transfection efficiency was determined by flow cytometry measurements of the intensity of the green fluorescence, while viability was determined by measuring intensity of the red fluorescence after propidium iodide staining. Results: In SUM159 and HMLE-Twist cells we obtain transfection efficiency between 30-40% using PEI, while cytotoxicity was generally low to moderate. PEI caused 10% of cell death in SUM159 and 20 % in HMLE-Twist. Transfection efficiency of PEI was comparable and even higher than the efficiency of the Lipofectamine in both SUM159 and HMLE-Twist. In mammary epithelia (control HMLE) we obtained only 20 % transfection efficiency using both carriers.Conclusions: We demonstrated for the first time that PEI represents a suitable nanocarrier for gene delivery into breast CSC model. We successfully transfected both breast CSC model HMLE-Twist and TNBC line SUM159. Since PEI is inexpensive and easy to use, we recommend it for further exploitations of these cell lines in TNBC research.

Synthesis and Evaluation of Bis-Schiff Bases of Carbohydrazide as Antioxidant and Cytotoxic Agents.

Antioxidants are known to prevent oxidative stress-induced damage to the biomolecules and thus, delay the onset of cancers and many age-related diseases. Therefore, the development of novel and potent antioxidants is justified. During this study, we synthesized symmetrical Bis-Schiff bases of carbohydrazide 1-27, and evaluated their in vitro antioxidative activity and cytotoxic activity. Among synthesized compounds, six compounds 20 (IC50 = 12.89 ± 0.02 μM), 16 (IC50 = 14.32 ± 0.43 μM), 17 (IC50 = 18.52 ± 0.83 μM), 19 (IC50 = 22.84 ± 0.62 μM), 24 (IC50 = 35.1 ± 0.82 μM) and 15 (IC50 = 40.03 ± 1.06 μM) showed an excellent 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, better than the standard butylatedhydroxyanisole (BHA) (IC50 = 44.6 ± 0.6 μM). Likewise, two compounds 16 (IC50 = 4.3 ± 1.3 μM) and 20 (IC50 = 6.6 ± 1.6 μM) showed oxidative burst scavenging activity better than the standard drug ibuprofen (IC50 = 11.2 ± 1.9 μM). Some synthesized compounds showed good to moderate toxicity against prostate cancer (PC-3) cell lines. This study has identified potent antioxidants and good cytotoxic agents with the potential to further investigate.

Stereotactic radiosurgery of radioresistant glioblastomas. The ways of overcoming radioresistance of hypoxic tumors

Background. Taking into account high degree of resistance of glioblastoma to radiation therapy, and also low overall survival rates of patients, it is necessary to develop improved methods of treating this pathology, in particular, complex combined treatment with radiation therapy and radiosensitizers.&#x0D; Purpose – to assess the effectiveness of radiosensitization of hypoxic tumors in radiosurgical treatment of glioblastomas; to increase non-recurrent and overall survival rate of patients. Materials and methods. Stereotactic radiosurgery (SRS) of glioblastoma was performed in 106 patients (average age – 53 years), 66 males (62,26%) and 40 females (37,73%). The average dose was 18 Gy in a single-fraction SRS, and 32 Gy (7 Gy per fraction) in multi-fraction SRS. The average volume tumor was 29 cm3 . The treatment group consisted of 66 patients who underwent SRS with radiosensitization. 40 patients made up the control group and underwent SRS without radiosensitization.&#x0D; Results. Median overall survival (MOS) was 20 months in the group with radiosensitization, whereas in the control group it was 12 months. 10-month recurrence-free period after radiosurgery was observed in 95,4% of the patients of the group with radiosensitization and in 70,6% of the patients of the control group. MOS after SRS was similar between the patients with wild-type IDH tumors and patients with tumors with IDH mutation (10,0 months and 11,0 months respectively), and also between the patients with MGMT-methylated tumors and patients with MGMT-nonmethylated tumors (11,2 and 10,2 months respectively). Among all the treated patients, in 20 of them (16,6%) side radiation effects after SRS were observed, and in 9 patients (7,5%) radiation necrosis developed in 3 to 16 months after SRS. The signs of moderate toxicity in the form of vomiting were observed in 6,6% of the patients of the subgroup with metronidazole. There were no signs of toxicity in the subgroup with nimorazole.&#x0D; Conclusions. Radiosensitization improves rates of overall survival by 53,3% and recurrence-free survival by 24,8 % in performing SRS of hypoxic radioresistant glioblastomas. Nimorazole and metronidazole are powerful radiosensitizers which increase radiosensitivity of tumor cells through enhancing oxygen saturation of hypoxic cells. In order to determine indications for performing SRS with radiosensitization and periods for performing an SRS session we must take into consideration the result of an oxygen test (level of oxygen saturation of the tumor), the peak of signal intensity in the zone of active tumor growth and the peak of saturation of the whole tumor volume.

3-Methylmethcathinone (3-MMC) Poisonings: Acute Clinical Toxicity and Time Trend Between 2013 and 2021 in the Netherlands

The synthetic cathinone 3-methylmethcathinone (3-MMC, or metaphedrone) has recently gained popularity. We studied the numbers of 3-MMC poisonings over time and the clinical effects following poisonings with 3-MMC. We performed a retrospective study on the numbers of self-reported 3-MMC poisonings to the Dutch Poisons Information Center (DPIC) from 2013 to June 2021. For poisonings reporting 3-MMC only, the symptoms were extracted and the Poisoning Severity Score (PSS) was determined. From 2016 to June 2019, a prospective cohort study on poisonings reporting only 3-MMC was performed, in which details on the clinical courses were collected through telephone interviews. From 2013 to June 2021, the DPIC was consulted on 184 3-MMC poisonings. The number of poisonings increased from 1 in 2013 to 70 in the first half of 2021. In 84 poisonings with only 3-MMC (46%), sympathomimetic symptoms were commonly reported, including tachycardia (n=29, 35%), hypertension (n=17, 20%), and agitation (n=16, 19%). The initial PSS was usually minor (n=37, 44%) to moderate (n=39, 46%). Five patients (6%) experienced severe effects, including 3 patients experienced severe hypertension (systolic blood pressure >180 mmHg; n=3) and nonfatal cardiac arrest (n=1). Sympathomimetic symptoms (n=8) were also reported in the prospective cohort study. The percentage of moderate poisonings increased (n=6, 75%), and 1 (13%) severe poisoning was observed. Analytical confirmation of 3-MMC exposure was performed in 2 cases. The number of 3-MMC poisonings reported to the DPIC has increased over time. Most poisonings with 3-MMC resulted in moderate toxicity and involved sympathomimetic effects, while severe effects were observed in 5 cases.

Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni.

Neglected tropical diseases (NTDs), including trypanosomiasis, leishmaniasis, and schistosomiasis, result in a significant burden in terms of morbidity and mortality worldwide every year. Current antiparasitic drugs suffer from several limitations such as toxicity, no efficacy toward all of the forms of the parasites’ life cycle, and/or induction of resistance. Histone-modifying enzymes play a crucial role in parasite growth and survival; thus, the use of epigenetic drugs has been suggested as a strategy for the treatment of NTDs. We tested structurally different HDACi 1–9, chosen from our in-house library or newly synthesized, against Trypanosoma cruzi, Leishmania spp, and Schistosoma mansoni. Among them, 4 emerged as the most potent against all of the tested parasites, but it was too toxic against host cells, hampering further studies. The retinoic 2′-aminoanilide 8 was less potent than 4 in all parasitic assays, but as its toxicity is considerably lower, it could be the starting structure for further development. In T. cruzi, compound 3 exhibited a single-digit micromolar inhibition of parasite growth combined with moderate toxicity. In S. mansoni, 4’s close analogs 17–20 were tested in new transformed schistosomula (NTS) and adult worms displaying high death induction against both parasite forms. Among them, 17 and 19 exhibited very low toxicity in human retinal pigment epithelial (RPE) cells, thus being promising compounds for further optimization.