Lethal Toxicity Research Articles

Ruxolitinib Rescues Mice from Lethal Interferon Beta Toxicity and TLS

Introduction. Oncolytic Vesicular Stomatitis Virus expressing human interferon beta and the sodium iodide symporter reporter gene (VSV-hIFNβ-NIS) is in Phase 1 clinical testing for systemic administration in patients with relapsed multiple myeloma, acute myeloid leukemia and T cell lymphoma (NCT03017820). Local production of interferon β enhances virotherapy by activating the immune system, and restricts viral replication in normal cells by activating IFN induced antiviral responses. Thus, the virus propagates efficiently in IFN non-responsive cancer cells but is constrained in IFN responsive cells. Cancer cells that are defective in their viral sensing and IFN response pathways are exquisitely sensitive to VSV-IFNβ-NIS oncolysis, cumulating in tumor lysis syndrome and IFNβ induced toxicity in the MPC-11 mouse plasmacytoma model. Here, we evaluated the feasibility of using ruxolitinib, a clinically approved Jak1/2 inhibitor, to rescue mice from virotherapy induced TLS and IFNβ toxicity.Methods. To characterize IFNβ toxicity in the absence of TLS , varying levels of mIFNβ were achieved in the blood of mice by intramuscular injection of an AAV1 vector encoding mIFNβ. For the virotherapy-associated TLS and IFNβ toxicity model, Balb/c mice with subcutaneous MPC-11 murine plasmacytoma were given one intravenous administration of VSV-mIFNβ-NIS. To determine whether the Jak/STAT inhibitor ruxolitonib could impact IFNβ toxicity, mice were treated with ruxolitinib (2 mg/dose by oral gavage) given twice a day for 10 days. All mice were monitored for adverse clinical signs andtumor size. Plasma IFNβ levels, CBC and comprehensive clinical chemistry panels were analyzed at necropsy.Results. There was a dose dependent increase in plasma IFNβ levels with increasing doses of AAV1-mIFNβ given intramuscularly to mice. Adverse clinical signs were seen in mice given high doses of AAV1-mIFNβ. There was a good correlation between IFNβ and AST or ALT levels. High circulating levels of IFNβ resulted in elevation in transaminases, thrombocytopenia, anemia and lymphopenia. IFN receptor defective mice were completely resistant to these toxic effects even with blood levels of >80,000 pg/ml IFNβ. Nontumor bearing Balb/c mice were shown to tolerate high IV doses of VSV-mIFNβ-NIS with transient lymphopenia and transaminases. In Balb/c mice with IFN nonresponsive MPC-11 tumors that support robust viral replication, VSV-mIFNβ-NIS therapy was highly effective for tumor control, but resulted in TLS and IFNβ toxicity, requiring early euthanasia of mice. Mice given VSV and a neutralizing anti-IFNR antibody did not show any adverse clinical signs due to IFNβ toxicity but control of tumor growth was significantly impaired in comparison to virus treatment alone. In contrast combination treatment of mice VSV and ruxolitinib resulted in reversal of lethal IFNβ toxicity without loss of effective tumor control.Conclusions. Our data demonstrate that ruxolitinib reverses the toxicity of IFNβ seen following highly efficacious VSV-IFNβ-NIS virotherapy in the MPC-11 plasmacytoma model. Clinical evaluation of this promising combination is warranted. [Display omitted] DisclosuresPeng:Vyriad: Equity Ownership; Imanis Life Sciences: Employment, Equity Ownership. Russell:Vyriad: Equity Ownership; Imanis Life Sciences: Equity Ownership.

Effects of fragrance compounds on growth of the silkworm Bombyx mori.

Due to the contamination and biological toxicity of some fragrance compounds, the environmental and ecological problems of such compounds have attracted more and more attention. However, studies of the toxicity of fragrance compounds for insects have been limited. The toxicity of 48 fragrance compounds for the silkworm Bombyx mori were investigated in this study. All of the fragrance compounds examined had no acute toxicity for B. mori larvae, but eight of them (menthol, maltol, musk xylene, musk tibeten, dibutyl sulfide, nerolidol, ethyl vanillin, and α-amylcinnamaldehyde) exhibited chronic and lethal toxicity with LC50 values from 20 to 120 µM. In a long-term feeding study, musk tibeten, nerolidol, and musk xylene showed significant growth regulatory activity. They were also extremely harmful to the cocooning of B. mori, resulting in small, thin, and loose cocoons. Two important insect hormones, namely, juvenile hormone (JH) and 20-hydroxyecdysone (20-E), were quantified in hemolymph following chronic exposure to musk tibeten, nerolidol, and musk xylene, respectively. Musk tibeten significantly increased JH titer and decreased the 20-E titer in hemolymph, and musk xylene had a significant inhibitory effect on JH titer and increased 20-E titer. Although nerolidol had no effect on hormone levels, exogenous JH mimic nerolidol increased the physiological effects of JH and significantly slowed the growth rate of B. mori larvae. The results showed that these fragrance compounds could interfere with the insect endocrine system, leading to death and abnormal growth. The risk to insects of residual fragrance compounds in the environment is worthy of attention.

Lethal and Sublethal Effects of Conventional and Organic Insecticides on the Parasitoid Trissolcus japonicus, a Biological Control Agent for Halyomorpha halys.

The egg parasitoid Trissolcus japonicus is a natural enemy of Halyomorpha halys, a polyphagous invasive pest in Europe and North and South America. Integration of chemical and biological control tactics could facilitate effective and sustainable integrated pest management programs. This study was conducted to assess (i) the lethal effects of field rates, (ii) the sublethal effects of maximum and half field rates, and (iii) the lethal effects of different routes of exposure of three organic and two conventional insecticides against T. japonicus. Maximum field rates of spinosad and sulfoxaflor resulted in acute lethal toxicity to adult T. japonicus 1 week after residual contact exposure. Maximum and half field rates of pyrethrins, the mixture of azadirachtin and pyrethrins, and clothianidin caused sublethal effects to female wasps through residual contact exposure. Furthermore, all insecticides caused acute lethal effects 1 week after ingestion by unmated female wasps. Taken together, these results suggest that careful planning is necessary to ensure compatibility between biological and chemical control for H. halys. The insecticides evaluated in this study varied in toxicity to T. japonicus and should be used with caution to conserve this natural enemy for biological control of H. halys.

Is the Concurrent Use of Sorafenib and External Radiotherapy Feasible for Advanced Hepatocellular Carcinoma? A Meta-Analysis.

Simple SummaryConcurrent chemotherapy and external radiation is a commonly used method for cancer treatment. However, concurrent application of sorafenib and external radiotherapy has not been commonly used in clinical practice due to the possible risk of excessive complication. The results of this meta-analysis suggest that concurrent treatment might be a feasible option, and treatment targeting metastatic lesion or vessel involvement is particularly recommended.We evaluate the feasibility of a concurrent application of sorafenib and external beam radiation therapy (EBRT) for advanced hepatocellular carcinoma (HCC). PubMed, Embase, Medline, and Cochrane Library were searched up to 9 April 2021. The primary endpoint was grade ≥3 complications, and the secondary endpoint was overall survival (OS). Subgroup analyses were performed for studies with the EBRT targets, intrahepatic vs. non-intrahepatic lesions (e.g., extrahepatic metastases or malignant vessel involvement only). Eleven studies involving 512 patients were included in this meta-analysis. Pooled rates of gastrointestinal, hepatologic, hematologic, and dermatologic grade ≥3 toxicities were 8.1% (95% confidence interval (CI): 4.8–13.5, I2 = ~0%), 12.9% (95% CI: 7.1–22.1, I2 = 22.4%), 9.1% (95% CI: 3.8–20.3, I2 = 51.3%), and 6.8% (95% CI: 3.8–11.7, I2 = ~0%), respectively. Pooled grade ≥3 hepatologic and hematologic toxicity rates were lower in studies targeting non-intrahepatic lesions than those targeting intrahepatic lesions (hepatologic: 3.3% vs. 17.1%, p = 0.041; hematologic: 3.3% vs. 16.0%, p = 0.078). Gastrointestinal and dermatologic grade ≥3 complications were not significantly different between the subgroups. Regarding OS, concurrent treatment was more beneficial than non-concurrent treatment (odds ratio: 3.3, 95% CI: 1.3–8.59, p = 0.015). One study reported a case of lethal toxicity due to tumor rupture and gastrointestinal bleeding. Concurrent treatment can be considered and applied to target metastatic lesions or local vessel involvement. Intrahepatic lesions should be treated cautiously by considering the target size and hepatic reserve.

Lethal toxicity assessment of castor bean (Ricinus communis) seed as fish toxicant and its residual effect on water quality in aquaculture

Lethal toxicity assessment of castor bean (Ricinus communis) seed as fish toxicant and its residual effect on water quality in aquaculture

Pre-therapeutic dihydropyridimidine dehydrogenase (DPD) deficiency screening: Impact on fluoropyrimidine dose reduction at the second chemotherapy cycle and on early severe toxicity.

3096 Background: DPD deficiency screening before fluoropyrimidine is a matter of debate. To avoid lethal toxicity, French authorities impose DPD screening before fluoropyrimidine-based chemotherapy by dosing uracilemia since April 2019. Methods: We have included all consecutive adult patients receiving 5-fluorouracil (5-FU) or capecitabin from April 2019 to January 2020 in 6 cancer centers. During the study period, different methods for screening had been applied: DPYD complete sequencing, phenotype (uracilemia and/or dihydrouracilemia/uracilemia ratio - UH2/U -) or both. All sceening tests were conducted in the same laboratory. Association between the method of DPD screening and fluoropyrimidine dose reduction at second chemotherapy cycle or on severe ≥grade 3 early toxicity (between first and second cycle) was evaluated using multivariate logistic regression. Concordance between genotype and phenotype for DPD deficiency was explored using Cohen Kappa test. Results: We included 597 patients, the median age was 63 (range, 55-77). The most prevalent cancers were digestive (68.3%), head and neck (19.4%) and breast (9.2%). 12.3% of patients received capecitabine and 87.3% received polychemotherapy. DPD deficiency screening was done for most of patients (n=519, 86.9%). DPD screening method consisted in full sequencing of DPYP (n=41; 7.9%), phenotype analysis (n=44, 8.5%) or both (n=424, 83.6%). We did not identify any complete DPD deficiency. Uracilemia was dosed for 467 patients, the median was 6.5 ng/mL and for 21 patients (4.5%) uracilemia was > 16 ng/mL and/or UH2/U <6, suggesting DPD deficiency. Severe early toxicities were observed for 82 patients (14%), with two patients presenting grade 5 toxicity. Overall DPD screening and method of DPD screening were not associated with fluoropyrimidine dose reduction at second cycle or early severe toxicity. In multivariate analysis, the only predictor for fluoropyrimidine reduction at second cycle (n = 125 patients) was polychemotherapy (OR=2.8; p=0.012). Kappa between uracilemia and UH2/U was 0.23 (poor concordance). Kappa between DPYP sequencing and uracilemia or UH2/U was 0.09 (very poor concordance). Conclusions: No DPD deficiency screening method was associated with dose adaptation at second cycle or early severe toxicity. The optimal strategy for DPD screening requires further clinical evaluation.

Lethal, behavioral, growth and developmental toxicities of alkyl-PAHs and non-alkyl PAHs to early-life stage of brine shrimp, Artemia parthenogenetica

Alkyl-PAHs are the predominant form of PAHs in crude oils which are supposed to demonstrate different toxicities compared to non-alkyl PAHs. Little information is available about the toxicity of alkyl-PAHs on marine Artemia. This study addressed and compared the lethal, behavioral, growth and developmental toxicities of three alkyl-PAHs, namely 3-methyl phenanthrene (3-mPhe), retene (Ret) and 2-methyl anthracene (2-mAnt), to their non-alkyl forms, phenanthrene (Phe) and anthracene (Ant) using Artemia parthenogenetica (nauplii, <24 h) as test organism following a 48 h and a 7 d of exposure, respectively. Benzo-a-pyrene (Bap) was selected as a reference toxicant for the comparison with the above alkyl-PAHs and non-alkyl PAHs. Results showed that for all tested endpoints, A. parthenogenetica nauplii had the highest sensitivity to Bap while Ant had no significant effect on nauplii survival or development within given concentrations. Considering the aqueous freely dissolved PAH concentrations, the 48 h-LC50 (survival), 48 h-EC50 (immobility) and 7 d-LC10 (survival) of Bap were calculated as 0.321, 0.285 and 0.027 μg/L, respectively, which were twofold to fivefold lower than those of Phe, 3-mPhe, Ret, Ant and 2-mAnt. A higher acute toxicity of alkyl-PAHs (3-mPhe and 2-mAnt) than their non-alkyl forms (Phe and Ant) was observed. Not limited to Phe, the common non-polar narcotic mode of action was also observed for Bap, 3-mPhe, Ret and 2-mAnt, which was evident by the inhibited mobility of nauplii. The decreased body lengths were found for all PAH treatments compared to the solvent control, whereas instar retardations were only found in nauplii exposed to Bap, Phe and Ret. Our findings emphasized the sensitivity differences of A. parthenogenetica nauplii to selected alkyl PAHs and non-alkyl PAHs and confirmed the application of lethal, behavioral and growth indicators in the toxicity evaluation of selected PAHs other than Ant. However, the distinct toxicities of these PAHs suggested other toxic modes of action may play more important roles apart from narcotic mode of action and need to be elucidated in future studies. In addition, a strong correlation between the body length and the instar of A. parthenogenetica nauplii was observed for each PAH exposure, suggesting that body length can be representative for both growth and developmental indicators during biological monitoring of PAH pollution in marine environment.

Determination of medium lethal dose (LD50) and acute toxicity of formulation Cytoreg®, an ionic mixture of strong and weak acids

A series of toxicological and pharmacological tests were started in the bioterium of the University of Los Andes, in order to evaluate a new formulation for therapeutic purposes. The present work reports the results found regarding the LD50 and the acute toxicity of this formulation produced by Cytorex of Venezuela, S.A. The new formulation supplied in liquid form, containing a variety of acid atoms whose conjugated bases have different electrical charges. It constitutes an ion transport complex of positively charged cations and negatively charged anions in high concentrations that help regulate mitochondrial and cellular metabolism and utilizes the inorganic fluoride ion (HF) as the main active compound, as referred to by the supplier. All the concentrations described in this work are referred to hydrofluoric acid (HF), which is the active compound of the formulation. Conventional pharmacological methods were used and it was found that the average lethal dose in rats resulted in 44.83 mg/Kg, and of 0.82ml/Kg. At the concentration of minimum dose of 0,49 mL/Kg of weight, the surviving animals did not present apparent macroscopic lesions at necropsy.

Impact of Cypermethrin 25% EC and pH on Certain Haematological Parameters of Cyprinid Fish Puntius javanicus

In present study an attempt has been made to investigate the combined impact of sub lethal toxicity of Cypermethrin 25% EC and pH on certain blood parameters of Puntius javanicus. Adult fish were exposed to sublethal concentration (0.36 µg/L) of cypermethrin 25% EC in different pH water i.e. pH 5, pH 6, pH 7, pH 8.5 and pH 9.5 for 15 days. Significant changes in red blood cell (RBCs) count, total white blood cells (WBCs), haemoglobin % (Hb%), haematocrit value, total serum protein and blood glucose level were observed in fish exposed to sub-lethal concentration of cypermethrin. Significant decrease in red blood cell (RBCs) count, haemoglobin % (Hb %), haematocrit value and total serum protein content were found in fish exposed to sub-lethal concentration of cypermethrin in pH 5, pH 6 and pH 9.5, compared to fish exposed to sub-lethal concentration of cypermethrin in pH 7. A significant increase in these parameters were documented in fish exposed to sub-lethal concentration of cypermethrin in pH 8.5, compared to fish exposed to sub-lethal concentration of cypermethrin in pH 7. On the other hand a significant increase of total white blood cells (WBCs) and blood glucose level were recorded in fish subjected to sub-lethal concentration of cypermethrin in pH 5, pH 6 and pH 9.5, compared to fish exposed to sub-lethal concentration of cypermethrin in pH 7. Values of these parameters were decreased significantly in fish exposed to sub-lethal concentration of cypermethrin in pH 8.5, compared to fish exposed to sub-lethal concentration of cypermethrin in pH 7. The values of all studied blood parameters in fish subjected to sub-lethal concentration of cypermethrin in pH 8.5 were almost found to retain the values of control group (pH 7, without toxicant).

Combined lethal toxicities of pesticides with similar structures to Caenorhabditis elegans are not necessarily concentration additives

Studies have shown that the mixture toxicity of compounds with similar modes of action (MOAs) is usually predicted by the concentration addition (CA) model. However, due to the lack of toxicological information on compounds, more evidence is needed to determine whether the above conclusion is generally applicable. In general, the same type of compounds with similar chemical structures have similar MOAs, so whether the toxicities of the mixture of these compounds are additive needs to be further studied. In this paper, three types of pesticides with similar chemical structures (three organophosphoruses, two carbamates and two neonicotinoids) that may have similar MOAs were selected and five binary mixture systems were constructed. For each system, five mixture rays with different concentration ratios were designed by the direct equipartition ray design (EquRay) method. The mortality of Caenorhabditis elegans was regarded as the endpoint for the toxicity exposure to single pesticides and binary mixtures. The combined toxicities were evaluated simultaneously using the CA model, isobologram and combination index. The structural similarity of the same type of pesticides was quantitatively analyzed according to the MACCS molecular fingerprint and the slope of dose-response curve at pEC50. The results show that the toxicities of neonicotinoid mixtures and carbamate mixtures are almost antagonistic. The entire mixture system of dichlorvos and dimethoate produced synergism, and four of the five mixture rays of dimethoate and methamidophos induced antagonism, while among the mixture rays of dichlorvos and methamidophos, different concentrations showed different interaction types. The results of structural similarity analysis show that the size of structural similarity showed a certain quantitative relationship with the toxicity interaction of mixtures, that is, the structural similarity of the same type of pesticides may show an additive action in a certain range.

Spectroscopic, density functional theory, cytotoxicity and antioxidant activities of sulfasalazine and naproxen drugs combination

In this study, we reported preparation and characterization of a new nano product consisting of the combination of two anti-inflammatory drugs: naproxen and sulfasalazine (Sulfoxen) where both are currently used for the treatment of inflammatory disorders. The nano combination product and its structural characterization were obtained by the Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRPD), Thermogravimetric analysis (TGA), Differential scanning calorimetry (DSC), Dynamic light scattering (DLS), Atomic force microscopy (AFM), and Field emission scanning electron microscopy (FE-SEM), respectively.The hydrogen bonding between the COOH groups of naproxen (NPX) and sulfasalazine (SSZ) drugs were evaluated by the experimental and theoretical spectra. FESEM and AFM techniques represent that the most particles of Sulfoxen have a solid dense cubical or cuboidal structure and they also have size range of 50–100 nm. The objective was to prepare the nano-formulation of the Sulfoxen with improved antioxidant properties with respect to the two compounds administered separately. We have evaluated the anti-cancer effect of Sulfoxen in comparison to sulfasalazine and naproxen drugs on MCF-7 and KYSE30 cell lines. Interestingly, exposure of the zebrafishes to Sulfoxen (12.5 mM) did not exhibit lethal toxicity compared to the control groups. Therefore, Sulfoxen could contribute to more studies for the possible future clinical use.

Radiation Increases Bioavailability of Lisinopril, a Mitigator of Radiation-Induced Toxicities.

There are no FDA-approved drugs to mitigate the delayed effects of radiation exposure that may occur after a radiological attack or nuclear accident. To date, angiotensin-converting enzyme inhibitors are one of the most successful candidates for mitigation of hematopoietic, lung, kidney, and brain injuries in rodent models and may mitigate delayed radiation injuries after radiotherapy. Rat models of partial body irradiation sparing part of one hind leg (leg-out PBI) have been developed to simultaneously expose multiple organs to high doses of ionizing radiation and avoid lethal hematological toxicity to study the late effects of radiation. Exposures between 9 and 14 Gy damage the gut and bone marrow (acute radiation syndrome), followed by delayed injuries to the lung, heart, and kidney. The goal of the current study is to compare the pharmacokinetics (PK) of a lead angiotensin converting enzyme (ACE) inhibitor, lisinopril, in irradiated vs. nonirradiated rats, as a step toward licensure by the FDA. Methods: Female WAG/RijCmcr rats were irradiated with 12.5–13 Gy leg-out PBI. At day 35 after irradiation, during a latent period for injury, irradiated and nonirradiated siblings received a single gavage (0.3 mg, 0.6 mg) or intravenous injection (0.06 mg) of lisinopril. Plasma, urine, lung, liver and kidney levels of lisinopril were measured at different times. PK modeling (R package) was performed to track distribution of lisinopril in different compartments. Results: A two-compartment (central plasma and periphery) PK model best fit lisinopril measurements, with two additional components, the gavage and urine. The absorption and renal clearance rates were similar between nonirradiated and irradiated animals (respectively: ratios 0.883, p = 0.527; 0.943, p = 0.605). Inter-compartmental clearance (from plasma to periphery) for the irradiated rats was lower than for the nonirradiated rats (ratio 0.615, p = 0.003), while the bioavailability of the drug was 33% higher (ratio = 1.326, p < 0.001). Interpretation: Since receptors for lisinopril are present in endothelial cells lining blood vessels, and radiation induces vascular regression, it is possible that less lisinopril remains bound in irradiated rats, increasing circulating levels of the drug. However, this study cannot rule out changes in total amount of lisinopril absorbed or excreted long-term, after irradiation in rats.

Comparisons of segment-specific toxicity of platinum-based agents and cadmium using S1, S2, and S3 cells derived from mouse kidney proximal tubules

Renal toxicants such as cisplatin and cadmium cause segment-specific damages in kidney proximal tubules. Recently, we established an in vitro experimental system for evaluating segment-specific toxicity and transport of chemicals using immortalized S1, S2, and S3 cells derived from the S1, S2, and S3 regions of mouse kidney proximal tubules. In the present study, we examined the toxicity and accumulation of cisplatin, carboplatin, oxaliplatin, and cadmium in S1, S2, and S3 cells. We found that not only cisplatin but also carboplatin and oxaliplatin exhibited higher lethal toxicity in S3 cells than in S1 and S2 cells. At sublethal doses, cisplatin showed delayed induction of Kim-1 and clusterin on days 3 and 6, which may reflect the latent renal toxicity of cisplatin in vivo. The high sensitivities of S3 cells to the platinum-based agents were not due to the high accumulation of Pt in S3 cells. Exposure to cadmium resulted in similar toxicity among these cells, suggesting that S3 cells were not sensitive to any renal toxicants. Thus, the utilization of S1, S2, and S3 cells may provide a useful tool for the in vitro evaluation of the proximal tubule segment-specific toxicity of chemicals.

Toxic effects in Aphanomyces brasiliensis and zebrafish embryos caused by oomyceticides.

In fish farming, high losses occur during egg incubation and larviculture due to diseases caused by oomycetes. This study aimed to identify the oomycete species that occurs in zebrafish Danio rerio eggs and to evaluate the oomyceticidal effect of copper sulfate, bronopol and methylene blue on the mycelial growth of this organism, as well as to determine the lethal and sublethal toxicity of these compounds in embryos of D. rerio. The isolates were cultivated in yeast-starch medium to determine the concentration necessary to inhibit mycelial growth by 50% (IC50) and 100% (minimum oomyceticidal concentration) after a 96 h exposure to these compounds. In addition, tests with D. rerio eggs were conducted to determine the lethal concentrations for 50% of the organisms (96h-LC50), and the concentrations that inhibited 17% of the eggs hatching (96h-IC17) after 96 h. The organism responsible for the mortality of D. rerio eggs was classified by classical and molecular methods as Aphanomyces brasiliensis, representing the first report of this pathogen in zebrafish eggs. IC50 values could be determined for both bronopol and copper sulfate, whereas methylene blue had low effectiveness against the oomycete. Copper showed high toxicity to D. rerio eggs at low concentrations, while methylene blue and bronopol toxicity was low and similar to each other. The use of bronopol at a concentration of 4.8 mg l-1 for the treatment of zebrafish eggs allows controlling the pathology without causing deleterious effects to the treated organisms.

Capital and Chlordecone Poisoning in the French Caribbean Islands of Guadeloupe and Martinique: A Thesis on Crimes of the Market

ABSTRACT Guadeloupe and Martinique, two French overseas territories located in the Caribbean, are today facing serious public health crises; particularly, the highest rates of prostate cancer in the world. These crises resulted from the French colonial policy of primitive accumulation, which authorized two decades of the use of a carcinogenic pesticide, chlordecone (a.k.a. Kepone), by French settler farmers to control banana weevil pests. This was despite evidence of its lethal toxicity. Deploying the theoretical arguments of Market Criminology, this paper discusses the current health crises in both islands and the political economy of predation which created them as criminal. This is in sync with a growing body of literature which contextualizes preventable market-generated harms as criminal.

Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors

SummaryUtilizing T cells expressing chimeric antigen receptors (CARs) to identify and attack solid tumors has proven challenging, in large part because of the lack of tumor-specific targets to direct CAR binding. Tumor selectivity is crucial because on-target, off-tumor activation of CAR T cells can result in potentially lethal toxicities. This study presents a stringent hypoxia-sensing CAR T cell system that achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by inadequate oxygen supply. Using murine xenograft models, we demonstrate that, despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate unlimited expansion of the CAR T cell target repertoire for treating solid malignancies.

Antimicrobial, Cytotoxicity, Acute Oral Toxicity, and Qualitative Phytochemical Screening of the Aqueous and Methanolic Stem-Bark Extracts of Croton megalocarpus Hutch. (Euphorbiaceae)

Microbial infections are feared to cause over 10 million deaths by the year 2050, whereby 50% of the global burden squarely lies in less developed countries of Africa and Asian continents. The current drugs have suffered resistance by previously susceptible strains, are associated with severe side effects, among other therapeutic and economic drawbacks, hence the need for alternatives. Despite the widespread usage of medicinal plants by over 80% of the global population to treat common ailments, including microbial infections, only a few have been empirically validated. Croton megalocarpus is used to treat microbial-associated infections like pneumonia and typhoid among the Agikuyu community of Kenya. However, its healing claims and safety have not been evaluated empirically to date, hence this study. We investigated the antimicrobial, cytotoxicity, acute oral toxicity, and qualitative phytochemical composition of the aqueous and methanolic stem bark extracts of C. megalocarpus. The disk diffusion and broth microdilution techniques described by the Clinical Laboratory Standards Institute (CLSI) were adopted for antimicrobial assays. The acute oral toxicity effects of the studied plant extracts were evaluated according to the Organisation of Economic Co-operation and Development (OECD) guideline document number 425. The brine shrimp lethality assay technique was used to appraise the cytotoxic effects of the studied plant extracts. Qualitative phytochemical screening was performed following standard procedures. The results revealed that all the studied plant extracts had varied antimicrobial effects on selected microbial strains and showed MIC values of &lt;1000 µg/ml indicating their antimicrobial potential. Moreover, the studied plant extracts had LC50 values of &gt;100 µg/ml and &gt;2000 mg/Kg bw in the brine shrimp lethality and acute oral toxicity assays, respectively, demonstrating their safety. Antimicrobial- associated phytocompounds were detected in the studied plant extracts suggesting they were responsible for the reported bioactivity. Further studies to establish the specific mode(s) of antimicrobial action, toxicological, and safety should be performed. Furthermore, antimicrobial investigations of the studied plant extracts on other clinically significant microbial strains and the isolation, characterization, and optimization of antimicrobials from the studied plant extracts should be done.

Influence of Ph on The Lethal Toxicity of Phenol, Para Chlorophenol And Pentaclorophenol to Freshwater Fish Gambusia Affinis

Phenol and Phenolic compounds has several sources including industrial wastes, coal , wood distillation, road tars, petroleum refining, chemical and plastics manufacture, domestic sewage discharges, natural sources such as plant material decay and leaching from coal and oil deposits enter natural water system and affect the fish and other aquatic organisms , So the static renewal bioassays were done to study the influence of pH on the lethal toxicity of phenol, para chlorophenol and pentachlorophenol to the freshwater fish Gambusia affinis. The studies shows that phenol, para chlorophenol and pentachlorophenol decreased their toxicity as the pH increased to the said fish .The24,48,72 and 96 hours LC50 values were found to be 48.0,45.0, 43.0 and 41.0 mg/l at pH 6.0 and at pH 7.5 the 24,48,72 and 96 hours LC50 values were 50.0, 48.0, 46.0 and 44.0 mg/l respectively for the fish exposed to phenol, And at pH 6.0 the 24,48,72 and 96 hours LC 50 values were 24.0, 21.0, 19.0, 17.0 mg/l and at pH 7.5 the 24, 48, 72 and 96 hours were 30.0, 28.0, 25.0 and 22.0 mg/l respectively for the fish exposed to para chlorophenol .The LC50 values at 24,48,72 and 96 hours at pH 6.0 were 0.12, 0.10, 0.09 and 0.07 mg/l respectively and at pH 7.5 The LC50 values were 1.23, 1.19, 1.15 and 1.11 mg/l respectively for the fish Gambusia affinis.

Study of Phytochemical, Antibacterial Activity and Toxicity on Acetone Extract Seed LeersiaHexandraSw

The Sayat-sayat(LeersiahexandraSw) plant is a plant used in traditional medicine by the Batak Karo people in North Sumatra. This study aims to examine the phytochemical content, antibacterial activity and cytotoxic test of acetone extract of L.hexandraSw seeds. Phytochemical tests include tests for alkaloids, flavonoids, saponins, tannins and steroids. Antibacterial tests were carried out against Propionibacterium acnesATCC (27853), Escherichia coli ATCC 25922, Bacillus cereus ATCC 1178, Salmonella enterica ATCC 14028 with the paper disc diffusion method M02-A11 (CLSI) and continued with the determination of MIC and MBC using the microdilution method M07-A9 (CLSI). The toxicity test used the Brint Shrimp Lethality Toxicity (BSLT) method using Artemia Salina Leach shrimp larvae. The results of phytochemical screening showed that the acetone extract of the L.hexandraSw seeds contained alkaloids, flavonoids and terpenoids. The results of the antibacterial activity test showed the best activity against B. cereus ATCC 1178 and S. enterica ATCC 14028 with an inhibition zone in the range of 8.4-8.6mm, with MIC and MBC values of 625 μg/mL. The results of the toxicity test are toxic and potentially bioactive.

Long-Term Liver Expression of an Apolipoprotein A-I Mimetic Peptide Attenuates Interferon-Alpha-Induced Inflammation and Promotes Antiviral Activity.

Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.