Toxic Agents Research Articles

Cyanide and Cyanogenic Compounds—Toxicity, Molecular Targets, and Therapeutic Agents

Cyanide (CN) is a well-known mitochondrial poison. CN poisoning may result from acute or long-term exposure to a number of CN compounds. Recent insight into the chemical affinities of the CN anion has increased our understanding of its toxicity and the mechanisms of antidotal actions, which, together with information on various exposure sources, are reviewed in the present article. A literature search in Scopus, Embase, Web of Science, PubMed, and Google Scholar for the period 2001–2024 revealed that the CN anion after exposure or degradation of CN compounds is distributed to vulnerable copper and iron-containing targets, especially in mitochondria, thus blocking the electron transport chain. Intake of cyanogenic compounds may exert subacute or chronic toxic effects, also because of the interaction with cobalt in vitamin B12. Antidotal agents exert their effects through the affinity of CN for cobalt- or iron-containing compounds. Research on CN interactions with metalloproteins may increase our insight into CN toxicity and efficient antidotal regimens.

Construction and 3D Printing of Multiscale Silk Fiber‐Cellulose Composite Networks Based on Ionic Liquids

AbstractMicroscopic defects in the amorphous regions of natural cellulose affect the mechanical properties of their materials. After dissolution and regeneration, cellulose's mechanical properties are still insufficient for application in advanced materials. Conventional compounding and crosslinking techniques with toxic crosslinking agents are not only cumbersome, but also have limited performance enhancement in cellulose materials Therefore, much attention has been paid to designing and developing more straightforward and efficient cellulose reinforcement technologies. Herein, an in situ multiscalarization strategy is used to form multiscale silk fiber‐cellulose composites (MS‐C) by the gradual nanosizing of silk fibers (SF) under heating in a 1‐butyl‐3‐methylimidazolium chloride solution of cellulose (Cel‐BmimCl). MS‐C are constructed from micro and nano SF, fibroin chains, and cellulose molecules into a multidimensional network. Due to its advantage of multiscale structure, MS‐C has excellent mechanical properties, the tensile strength and Young's modulus, which are 123.06% and 91.68% higher than that of pure regenerated cellulose after 5h heating treatment. Besides, MS‐C has good biocompatibility and can be molded or 3D printed with direct ink writing, showing broad application prospects in medical, bioengineering, and other fields. This multiscale enhancement strategy can also be extended to the research and application of biopolymers such as natural polysaccharides or proteins.

Magnetic Hercules Swarm for Precise and Effective Deep Biofilm Eradication

AbstractOver the past decade, significant advancements in micro‐nano robots have enabled non‐invasive operations in hazardous, confined environments, particularly targeting persistent bacterial biofilms in hard‐to‐reach areas. However, many of these robots are limited by poor magnetic properties, hindering their effectiveness against biofilms. This study proposes a novel strategy using a swarm with strong magnetic effects (Hercules swarm) combined with near‐infrared (NIR) light for effective biofilm eradication. Carbonyl iron particles coated with polydopamine (CI@PDA), averaging ≈3 µm in diameter, demonstrate clustering and significant magneto‐force under a rotating magnetic field due to their large magnetic saturation. This enables the Hercules swarm to achieve rapid delivery (100 mm s−1), efficient cargo transport (carrying twice its own weight), and effective catheter clearance (1 mm min−1). The controllable motion and high photothermal activity enable precise biofilm eradication without toxic agents. The aggregation of magnetic particles into chains and their rotation are explored by improved particle dynamic model. Simulations also reveal enhanced fluid convection and mechanical pressure around the particle chain. Due to its easy operation, straightforward controllability, and environmental compatibility, the magnetic Hercules swarm emerges as a promising treatment modality for eliminating biofilms entrenched within intricate, narrow, and convoluted medical implants or industrial conduits.

Nanoplatforms for Magnetic-Photo-Heating of Thermo-Resistant Tumor Cells: Singular Synergic Therapeutic Effects at Mild Temperature.

A self-assemble amphiphilic diblock copolymer that can incorporate iron oxide nanocubes (IONCs) in chain-like assemblies as heat mediators for magnetic hyperthermia (MHT) and tuneable amounts of IR780 dye as agent for photothermal therapy (PTT) is developed. MHT-heating performance of photobeads in viscous media have the same heat performances in water at magnetic field conditions of clinical use. Thanks to IR780, the photobeads are activated by infrared laser light within the first biological window (808nm) with a significant enhancement of photo-stability of IR780 enabling the raise of the temperature at therapeutic values during multiple PTT cycles and showing unchanged optical features up to 8 days. Moreover, the photobeads fluorescent signal is preserved once internalized by glioblastoma multiforme (GBM) cells. Peculiarly, the photobeads are used as toxic agents to eradicate thermo-resistant GBM cells at mild heat, as low as 41°C, with MHT and PTT both of clinical use. Indeed, a high U87 GBM cell mortality percentage is obtained only with dual MHT/PTT while each single treatment dose not provide the same cytotoxic effects. Only for the combined treatment, the cell death mechanism is assigned to clear sign of apoptosis as observed by structural/morphological cell studies and enhanced lysosome permeability.

Effective Use of Euphorbia milii DCM Root Extract Encapsulated by Thermosensitive Immunoliposomes for Targeted Drug Delivery in Prostate Cancer Cells

The delivery of anticancer drugs using nanotechnology is a promising approach aimed at improving the therapeutic efficacy and reducing the toxicity of chemotherapeutic agents. Liposomes were prepared using HSPC: DSPE–PEG–2000: DSPE–PEG2000–maleimide in the ratio of 4:1:0.2 and conjugated with a PSA antibody. Euphorbia milii extract (EME), doxorubicin (Dox), and docetaxel (Doc) encapsulated in temperature–sensitive immunoliposomes were investigated for their activities against the prostate cancer LNCap and DU145 cell lines. Organic extracts of EME leaves, roots, and stems were screened against both cell lines, inhibiting more than 50% of cell culture at concentrations of 10 μg/mL. The immunoliposomes incorporating the EME and docetaxel were active against the LNCap cells when exposed to heat at 39–40 °C. The liposomes not exposed to heat were inactive against the LNCap cells. The developed heat-sensitive immunoliposomes used for the delivery of both the EME and chemotherapeutic agents was able to successfully release the entrapped contents upon heat exposure above the phase transition temperature of the liposome membrane. The heat-sensitive immunoliposomes conjugated with a PSA antibody encapsulated the extract successfully and showed better cell antiproliferation efficacy against the prostate cancer cell lines in the presence of heat.

8-Anilino-1-naphthalenesulfonate-Conjugated Carbon-Coated Ferrite Nanodots for Fluoromagnetic Imaging, Smart Drug Delivery, and Biomolecular Sensing

Background: Superparamagnetic properties and excitation independence have been incorporated into carbon-decorated manganese ferrite nanodots (MnFe@C) to introduce an economical and safer multimodal agent for use in both T1-T2 MRI and fluorescence-based imaging to replace the conventional highly toxic heavy metal contrast agents. Methods: The surface conjugation of 8-anilino-1-naphthalenesulfonate (ANS) to MnFe@C nanodots (ANS-MnFe@C) enhances both longitudinal and transverse MRI relaxation, improves fluorescence for optical imaging, and increases protein detection sensitivity, showing higher multimodal efficacy in terms of molar relaxivity, radiant efficiencies, and fluorescence sensitivity compared to MnFe@C. Results: The band gap energy was determined using Tauc’s equation to be 3.32 eV, while a 72% quantum yield demonstrated that ANS-MnFe@C was highly fluorescent, with the linear range and association constant calculated using the Stern–Volmer relation. The synthesized ANS-MnFe@C demonstrated excellent selectivity and sensitivity for bovine serum albumin (BSA), with a nanomolar detection limit of 367.09 nM and a broad linear range from 0.015 to 0.225 mM. Conclusions: In conclusion, ANS-MnFe@C holds ease of fabrication, good biocompatibility, as assessed in A375 cells, and an effective pH-sensitive doxorubicin release profile to establish anticancer activity in lung cancer cell line (A549), highlighting its potential as an affordable therapeutic agent for multimodal imaging, drug delivery, and protein sensing.

Efficient electroporation in primary cells with PEDOT:PSS electrodes.

Precise and efficient delivery of macromolecules into cells enhances basic biology research and therapeutic applications in cell therapies, drug delivery, and personalized medicine. While pulsed electric field electroporation effectively permeabilizes cell membranes to deliver payloads without the need for toxic chemical or viral transduction agents, conventional bulk electroporation devices face major challenges with cell viability and heterogeneity due to variations in fields generated across cells and electrochemistry at the electrode-electrolyte interface. Here, we introduce the use of microfabricated electrodes based on the conducting polymer poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS), which substantially increases cell viability and transfection efficiency. As a proof of concept, we demonstrate the enhanced delivery of Cas9 protein, guide RNA, and plasmid DNA into cell lines and primary cells. This use of PEDOT:PSS enables rapid modification of difficult-to-transfect cell types to accelerate their study and use as therapeutic platforms.

Facile fabrication of green and sustainable gelatin-based aerogels for marine oil spill recovery

Efficient and rapid cleanup of marine oil spills is crucial for environmental protection and resource recovery. Biomass aerogel has a broad application prospect in oil spill treatment, but is often limited by the complex preparation process and the use of toxic cross-linking agents. In this study, the hydrophobic gelatin-based aerogels (HGAs) were simply prepared for marine oil spill recovery based on self-crosslinking of gelatin, bubbles produced by surfactants and high-speed stirring, and chemical vapor deposition using methyl trichlorosilane (MTCS). The results showed that the HGAs exhibited a three-dimensional porous structure with a water contact angle of 131.6°. Their adsorption capacities for various oils and organic solvents ranged from 60.4 to 146.5 g/g, which was linearly related to the oil density and depended on the number of pores within the material. The oil adsorption by the HGAs reached equilibrium within 30 s, following the pseudo-second-order kinetic model and the HGAs were highly stable in different temperature, pH, and salinity conditions. Simple squeezing can recover 80 % of the spilled oil, and retain 86 % of the initial adsorption capacity after 10 adsorption-squeeze cycles. Additionally, the HGAs had an excellent continuous oil-water separation performance, demonstrating significant potential and practicability in marine oil spill recovery.

FT-IR detection of DMMP on TiO2-Modified porous silicon substrates

In this study, we present a new chemical sensor based on a functionalized porous silicon and sensitive to dimethyl methyl phosphonate (DMMP), a simulant of sarin gas, known as one of the most toxic warfare agents. The porous silicon was prepared by anodising a boron-doped p-Si (100) wafer. A metal oxide TiO2 layer was then deposited by thermal evaporation of Ti and oxidized under atmospheric conditions to form a TiO2 film which was used as a reactive coating. The characterization of the PSi and TiO2/PSi films was investigated using SEM, EDX and XPS spectroscopies. The results indicated that the TiO2 was well incorporated on the surface and slightly inside the porous silicon layer. FT-IR studies were then carried out before and after exposure to DMMP and the detection performance was compared with PSi. The results obtained showed that our surfaces have the ability to detect DMMP down to 0.5 ppm compared to uncoated PSi layer. We have also shown that a TFA pre-treatment of our TiO2 modified PSi, prior the exposure to DMMP, is crucial for increasing its sensitivity and that our sensor can be reused several times with a simple hexane cleaning step, a key criterion for routine applications.

A study on the effectiveness of (+)-usnic acid as oral toxic sugar bait against adult male and female Anopheles gambiae

BackgroundDespite the application of various tools for the control of vectors of Plasmodium falciparum, malaria remains the major killer disease in sub-Saharan Africa accounting for up to 90% of deaths due to the disease. Due to limitations of the useage of chemical insecticides such as resistance, negative impact on the environment and to nontarget organisms, the World Health Organization (WHO) requires that affected countries find alternative vector control tools. This study evaluated the effectiveness of ( +)-usnic acid (UA) as an insecticide through oral administration to male and female Anopheles gambiae as an alternative or additional active ingredient to be used in toxic sugar bait.Methods( +)-usnic acid was diluted using acetone at 5, 10, and 15 mg/ml concentrations in three replicates. A 5 ml mixture of 2% food dye and 10% sugar using chlorine-free water mixed with the dilutions of the ( +)-usnic acid and negative control was made containing 2% food dye and 10% sugar solution. The preparations were soaked on a ball of cotton wool and placed over the net of a cup. 5 male and 5 non-blood-fed female newly hatched starved An. gambiae Kisumu strain were introduced together into a cup and monitored for knockdown and mortalities after 4, 24 48, and 72 h. The data were analysed using a multiple linear regression model using the lm function, a base R function and a posthoc test were conducted on the significant main effects and interaction terms using the emmeans function from the emmeans R package. All analyses were performed in RStudio using base R (version 4.3.3).ResultsThere was high mortality of both male and female An. gambiae after ingestion of the toxic sugar bait. 15 mg/ml usnic acid caused the highest mortality (50%) within the first 4 h compared to 5 and 10 mg/ml ( +)-UA. There was a decline in the mortality rate with increased exposure time from 24 to 72 h, however, there was a significant difference in mortality at 5, 10 and 15 mg/ml. Acute toxicity was associated with ingestion of 15 mg/ml after 24 h. 72 h post-mortality was lower in all concentrations than in the control. High mortality was observed among females over the first 4 h (60%) compared to males (40%) due to higher feeding rate of the toxic agent. The proportion of dead males and females was equal after 24 h while after 48 h, the proportion of dead males was high.There was a significantly lower mortality rate after 72 h for both males and females (0 to 13.3%). Compared to all the treatments, high mortality of males was observed.ConclusionsThe results of this study indicate that ( +)-UA when administered as oral sugar bait to An. gambiae has insecticidal properties and is a suitable ingredient to be used as a toxic agent in the novel attractive toxic sugar bait for the control of malaria vectors. ( +)-UA may be an alternative active ingredient as toxic bait in the effort to reduce and eliminate the transmission of Plasmodium falciparum in Africa.

Surface acoustic wave platform integrated with ultraviolet activated rGO-SnS2 nanocomposites to achieve ppb-level dimethyl methylphosphonate detection at room-temperature

Dimethyl methylphosphonate (DMMP) is commonly used as an alternative for demonstrating to detect sarin, which is one of the most toxic but odorless chemical nerve agents. Among various types of DMMP sensors, those utilizing surface acoustic wave (SAW) technology provide notable advantages such as wireless/passive monitoring, digital output, and a compact, portable design. However, key challenges for SAW-based DMMP sensors operated at room temperature lies in simultaneous enhancement of sensitivities and reduction of detection limits. In this study, we developed a binary material strategy by combining reduced graphene oxide (rGO) and tin disulfide (SnS2) with (100)-facets orientation as sensing layers of SAW device for DMMP detection utilized at room temperature. Ultraviolet (UV) light was applied to activate the sensitive film and reduce the sensor's response time. The developed SAW DMMP sensor demonstrated a superior sensitivity (−1298.82 Hz/ppm), a low detection limit of 50 ppb, and a hysteresis below 1.5%, along with fast response/recovery time (39.2 s/28.4 s), excellent selectivity, long-term stability and repeatability. The formation of shrub-like rGO-SnS2 heterojunctions with abundant surface defects and large specific surface areas, high-energy (100) crystalline surfaces of SnS2, and photogenerated carriers generated by UV irradiation were pinpointed as the crucial sensing mechanisms. These factors collectively enhanced adsorption and reaction dynamics of DMMP molecules.

Ambidextrous approach in action: Mg(OMe)2-doped hierarchical porous zirconium MOFs for decontaminating toxic chemical agents in nonbuffered systems

Utilizing a ligand-truncation strategy, a hierarchically porous structure was engineered within MOF-808, designated as HP-MOF-808. Furthermore, Mg(OMe)2 doping yielded HP-MOF-808@Mg(OMe)2, materials with both hierarchical porosity and basic character, for decontamination of two types of toxic chemical agents in nonbuffered solutions. In aqueous solution, the HP-808-2 exhibited decontamination rate constants for dimethyl-4-nitrophenyl phosphate (DMNP) and the nerve agent soman (GD) that were 3.13 and 1.98 times higher than MOF-808, respectively. The decontamination half-lives of HP-808-2@Mg(OMe)2 1:2 for DMNP and GD were further reduced by 13.87 and 36.82 times compared to HP-808-2. The material retains its decontamination efficacy for DMNP even after 60-days exposure in air and maintains structural integrity in solvents devoid of labile hydrogen for at least 24 h. In methanol, HP-808-2@Mg(OMe)2 achieved 100% DMNP decontamination in 25 min, outperforming HP-808-2 at 31.8%, marking it as the fastest DMNP decontamination material in methanol. Theoretical simulations confirmed the experimental findings, clearly demonstrating the energy changes during reactions with various nucleophiles and revealing the degradation process and mechanism of DMNP on the active sites of MOFs. Moreover, these materials rapidly degraded 2-chloroethyl ethyl sulfide (CEES) through hydrolysis, dehydrohalogenation, and heterolytic cleavage, demonstrating great potential for dual decontamination of toxic chemical agents in unbuffered systems.

METTL3-regulated m6A modification of lncRNA E230001N04Rik is involved in myofibroblast differentiation in arsenic-induced pulmonary fibrosis through promoting senescence of lung epithelial cells

Arsenic is a toxic agent that causes respiratory damage. Long non-coding RNAs (lncRNAs) are non-coding transcripts that adsorb specific miRNAs and regulate biological processes of human diseases. N6-Methyladenosine (m6A) is an internal modification of RNAs. However, there are few reports about lncRNAs and m6A modifications as co-regulators of pulmonary fibrosis. For 6 months, C57BL/6 mice were given water containing 0, 10, or 20 ppm arsenite. meRIP-seq and lncRNA-seq analyses showed that the m6A levels of the lncRNA E230001N04Rik were higher, and the levels of E230001N04Rik itself were lower in the high-dose arsenite group than in the controls. Murine lung epithelial 12 (MLE12) cells, exposed to 8 μM arsenite for 8 passages, had elevated METTL3 and miR-20b-3p and low E230001N04Rik. Arsenite induced cellular senescence, as demonstrated by secretion of factors related to the senescence-associated secretory phenotype (SASP). Arsenite-treated MLE12 cells co-cultured with primary lung fibroblasts (PLFs) caused myofibroblast differentiation. These data show that METTL3 reduces E230001N04Rik expression via controlling its m6A levels, which regulate miR-20b-3p and mediate the senescence of alveolar epithelial cells (AECs). Thereby, E230001N04Rik is involved in the arsenite-induced myofibroblast differentiation and in pulmonary fibrosis. These observations provide a prospective mechanism for chronic pulmonary disease caused by arsenite.

A novel route to produce metal or ceramic parts in space: local debinding and sintering of powdered filaments

AbstractIn-space manufacturing of polymer feedstocks has already been shown using the widely investigated filament extrusion additive manufacturing (AM) technology. Yet, polymers are only a small piece of the puzzle, and there is a growing demand to locally source metal and ceramic parts. In this manuscript, we propose a cost-effective method for in-orbit manufacturing of metal and ceramic multi-material components using highly packed powdered filaments, which need to be shaped, debinded, and sintered in sequential steps. Traditional debinding and sintering of material extrusion (MEX) AM parts are known to be time-consuming and require complex post-processing, often involving toxic debinding agents. To overcome this, a low-intensity infrared diode laser and an induction heater are coupled to a hybrid MEX system to allow full processing in situ, within the same volume. The results show that the main binder matrix can be removed across the 3D volume of the part via laser ablation of the polymeric mass, even for multi-material metal–ceramic composites. The sintered geometries further densify efficiently within the bulk due to the high-energy concentration of the induction sintering treatment, providing short processing times. Debinding and sintering locally, in the same machine, offer a simple and effective way to produce space hardware in situ, avoiding the use of consumables or part transportation to bulky equipment.

A Study to Assess the Effectiveness of Video Assisted Teaching Programme on Knowledge, Attitude and Practice Regarding Renal Rehabilitation among Patients with Chronic Kidney Disease Who are Admitted in the Mamata General and Super Specialty Hospital, at Khammam, Telanagana

ABSTRACT Background: Kidneys are one of the vital organs in the human body. Kidneys perform vital functions like excretion of waste products, maintenance of water balance, thus maintaining the homeostasis. In addition, kidneys perform many other functions such as role in Homeostasis, Production of Erythrocyte, Endocrine function, Regulation of Blood Sugar and regulation of Blood Calcium level. Because the kidney performs a wide variety of functions, the effects of loss of renal function not only in kidney but also in other organ systems.Hemo dilaysis is used for clients with acute or irreversible renal failure and fluid and electrolyte imbalances. It is usually the treatment of choice when toxic agents, such as barbiturates after an over dose need to be removed quickly. The availability of the treatment for clients with end stage renal failure (ESRF) has become more prevalent. The population receiving hemo dilaysis now represents a wide cross-section of age rehabilitative potential of socio-economic status. Materials and Methods: For the present study, quantitative Evaluative Approach ,Pre – Experimental research design, one group pretest and one group post test design.The study was conducted in the Mamata General and super specialty Hospital at Khammam, Telangana. Results: The above table shows that the pre test mean knowledge score is 10.05 and standard deviation is 3.77 where as post test mean score is 18.02 and standard deviation is 3.36 and mean difference is 7.97, the paired ‘t’ test calculated value is 14.89, which is greater than table value with df value of 79at (p<0.05) level. Conclusion: The main study was conducted in Mamata general and super specialty hospital, at Khammam, Telanagana . The sample sizes 30. The sample was selected by using non probability of convenient sampling technique among those fulfill the criteria.

The evolution of new and emerging occupational health and safety risks: A qualitative review.

Work itself and occupational health and safety (OHS) have evolved through industrial revolutions and will also continue to evolve in the future. The aim of this qualitative literature review was to examine how the scientific discussion on new and emerging risks (NERs) related to OHS has evolved in recent decades in developed and newly industrialized countries. A search of the Scopus database yielded 34 articles published before 2000 and from 2020 onwards. A review of the articles identified NERs themes related to changes in work patterns, changing workforce and growth in some sectors, climate change, new materials or increased use of materials, new technology and technological development, and viruses. In both article collection periods, possible adverse OHS effects discussed included musculoskeletal disorders, exposure to toxic agents, chemical compounds and hazardous materials, increased stress, increased likelihood of errors and accidents, psychosocial problems, mental fatigue, and increases in work-related illnesses and accidents. The articles published during both periods discussed similar themes. The main differences were regarding specific time-related cases, such as climate change and COVID-19. Based on the findings of this review, points to consider in OHS management and future studies are discussed.

12347 Cholesterol Biosynthesis Inhibitor Ro 48-8071 Suppresses Growth Of Triple-negative Breast Cancer Cells By Inducing Apoptosis And Suppressing Angiogenesis

Abstract Disclosure: Y. Liang: None. S.M. Hyder: None. Triple-negative breast cancers (TNBC) lack ER, PR and Her2neu, proteins that are commonly targeted in breast cancer therapies. Women who suffer from TNBC have limited treatment options and are administered toxic chemotherapeutic agents. They have poor prognosis due to the emergence of drug-resistant cells that lead to tumor metastasis. New non-toxic therapeutic strategies to control TNBC progression, and prevent metastasis are urgently needed. Cholesterol is an essential structural and functional component of cell membranes necessary for tumor growth and progression. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy since tumor cells grow rapidly, and need a greater supply of cholesterol. We targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor growth. RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors but its effect on TNBC is not known. Pharmacological doses of RO potently reduced the viability of both MDA-MB-231 and BT20 TNBC cells in a dose dependent manner (1-50 μM). IC50 values for loss of cell viability was approximately 10 μM for both cell lines following 48 h exposure to RO. Doses close to the IC50 for OSC (1-10 nM) also reduced cell viability following exposure of TNBC cells to RO for a week. Importantly, RO had no effect on the viability of normal human mammary cells. FACS analysis revealed that RO dose-dependently induced apoptosis of TNBC cell lines in vitro. In vivo, administration of 5-10 mg/kg RO to mice with BT-20 TNBC cell-derived xenografts (100 mm3) inhibited tumor growth with no apparent toxicity. Immunohistochemical analysis of tumor tissues at the end of treatment showed that RO increased TUNEL expression, suggesting that the in vivo effects of RO were also exerted through mechanisms affecting apoptosis. Furthermore, IHC of tumor sections showed that RO also reduced levels of the angiogenic markers VEGF and CD-31 (blood vessels) in vivo, indicating that suppression of angiogenesis is also part of the mechanism through which RO exerts its anti-tumor effects. We conclude that RO is a potent inhibitor of TNBC and that its anti-tumor effects involve mechanisms that induce apoptosis and suppress angiogenesis. Presentation: 6/2/2024

Protective effect of aspirin and gentisic acid, a plant-derived phenolic acid, on acrylamide-induced neurotoxicity by inhibiting apoptosis and autophagy.

Acrylamide (ACR) is a toxic agent for humans and animals. Gentisic acid, anaspirinmetabolite, has antioxidant activity. Therefore, the present study investigated the probable protective effects of aspirin and gentisic acid on ACR-induced neurotoxicity in PC12 cells and rats. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the effects of aspirin and gentisic acid (1.25, 2.5, 5 µM) on ACR (5 mM) toxicity. Male Wistar rats were randomly divided into 13 groups: (1) Control group, (2) ACR (50 mg/kg, 11 days, i.p.), (3-5) ACR + aspirin (25, 50, 75 mg/kg, 11 days, p.o.), (6-8) ACR + gentisic acid (25, 50, 75 mg/kg, 11 days, p.o.), (9) ACR + vitamin E (200 mg/kg, every other day, i.p.), (10, 11) Aspirin (75, 100 mg/kg, 11 days, p.o.), (12, 13) Gentisic acid (75, 100 mg/kg, 11 days, p.o.). Behavioral tests were assessed on the final day of the study. In the cerebral cortex, malondialdehyde (MDA), glutathione (GSH), cleaved-caspase-3, and microtubule-associated protein 1A/1B-light chain 3 (LC3) protein levels were evaluated. When compared with the ACR group, aspirin (2.5, 5 µM) and gentisic acid (2.5 µM) significantly enhanced cell viability. In comparison to the control group, ACR induced severe motor impairment, elevated MDA, cleaved-caspase-3, LC3 II/I ratio, and decreased GSH levels in the cerebral cortex of rats. ACR-induced changes were significantly reversed by aspirin and gentisic acid (25 mg/kg). Oxidative stress, apoptosis, and autophagy play important roles in the neurotoxicity of ACR. Aspirin and gentisic acid significantly reduced ACR-induced toxicity by inhibiting the mentioned mechanisms.

Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparib

Loss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through allele-specific therapies. To discover frequently lost genes with prevalent LoF alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity. We identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids. Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment. This work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113).

FcγR3A polymorphism influences natural killer cell activation and response to anti-PD-L1 (avelumab) in gestational trophoblastic neoplasia

BackgroundLow-risk gestational trophoblastic neoplasia (GTN) are currently receiving monochemotherapy as first-line therapy. In the case of a resistance, a second-line mono- or polychemotherapy is proposed. As an alternative to these toxic and historic chemotherapy agents, the efficacy of the anti-PD-L1 monoclonal antibody (avelumab) was assessed in the TROPHIMMUN phase II trial Cohort A. Avelumab yielded a 53% cure rate with an acceptable tolerance profile, including normal further pregnancy and delivery. Beyond the blockade of PD-1/PD-L1 interactions, avelumab effect could rely on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by FcγR3A-expressing natural killer (NK) cells. ObjectiveThis translational study aimed at testing whether ADCC is involved in avelumab efficacy on GTN and if FcγR3A affinity polymorphism could help predicting the response to avelumab in GTN. Study DesignThe expression of PD-L1 by the tumor and the phenotype of NK cells infiltrating GTN were verified by performing transcriptomic and proteomic analyses. Then, JEG-3 choriocarcinoma cells were cocultured with human NK cells in presence and absence of avelumab. The impact of FcγR3A functional polymorphism was assessed on the activation status of NK cells and the viability of JEG-3 choriocarcinoma cells. Finally, the data from TROPHIMMUN trial were reanalyzed to determine the impact of the FcγR3A polymorphism of patients on their response to avelumab. ResultsWe confirmed that FcγR3A+ NK cells infiltrated PD-L1-expressing GTN. In vitro, avelumab-coated JEG-3 choriocarcinoma cells induced NK cell activation, which promoted the destruction of JEG-3 cells. NK cell activation was abolished when the Fc portion of avelumab was removed, demonstrating the importance of Fcγ receptor in this process. Using this model of ADCC, we demonstrated that high-affinity FcγR3A polymorphism on NK cells was associated with better in vitro response to avelumab. In line with this result, patients from the TROPHIMMUN trial homozygous for the high affinity FcγR3A polymorphism had better clinical response to avelumab. ConclusionsOur work demonstrates that ADCC contributes to the therapeutic effect of avelumab in GTN and that the individual patient response is impacted by the FcγR3A polymorphism. The FcγR3A polymorphism could be used as a biomarker to identify patients diagnosed with monochemoresistant GTN who are most likely to respond to avelumab.