Irreversible DNA Damage Research Articles

Core-Shell Nanoparticles with Sequential Drug Release Depleting Cholesterol for Reverse Tumor Multidrug Resistance.

Multidrug resistance (MDR) facilitates tumor recurrence and metastasis, which has become a main cause of chemotherapy failure in clinical. However, the current therapeutic effects against MDR remain unsatisfactory, mainly hampered by the rigid structure of drug-resistant cell membranes and the uncontrolled drug release. In this study, based on a sequential drug release strategy, we engineered a core-shell nanoparticle (DOX-M@CaP@ATV@HA) depleting cholesterol for reverse tumor MDR. DOX-M@CaP@ATV@HA could accurately target tumor cells due to the active targetability of hyaluronic acid (HA) toward CD44 receptors. The calcium phosphate (CaP) shell was cleaved in the lysosomal acidic environment so that the cholesterol-lowering drug atorvastatin (ATV) was rapidly released to diminish cholesterol and P-glycoprotein (P-gp) level on the membrane, thereby boosting tumor cell drug uptake. Next, doxorubicin (DOX) was gradually released from the hydrophobic core of the mPEG-DSPE micelle, inflicting irreversible DNA damage and triggering apoptosis. The nanosystem was proven both in vitro and in vivo to reverse MDR effectively and exhibited a remarkable therapeutic efficacy on drug-resistant tumors with high biosafety. In conclusion, DOX-M@CaP@ATV@HA effectively reverses MDR via cholesterol depletion, which provides an innovative strategy for tumor MDR treatment.

Intestinal inflammation, oxidative damage, and pathogenesis of intestinal Cryptosporidium in juvenile Asian sea bass (Lates calcarifer)

AbstractPiscine intestinal Cryptosporidium infection is a known cause of severe illness and mortality in juvenile Asian sea bass, with inflammation playing a central role. This inflammation triggers the generation of reactive oxygen species (ROS), leading to irreversible DNA damage and activation of apoptosis pathways. However, the specific impact of inflammation on ROS production, DNA damage, and apoptosis in this context remains unclear. This study investigated the pathogenic role of inflammation and ROS in causing DNA damage and cell apoptosis in piscine intestinal cryptosporidiosis. Forty‐four intestinal samples from 60‐ and 90‐day juvenile Asian sea bass were divided into four groups based on Cryptosporidium infection status. Histopathological evaluation and immunofluorescent analysis were conducted to assess ROS production, DNA damage, and cellular apoptosis markers. Results showed significantly higher inflammatory cell infiltration, intracellular ROS production, DNA damage, and cellular apoptosis in 60‐day infected fish compared to 90‐day infected fish. These findings underscore distinct responses in juvenile Asian sea bass to piscine intestinal cryptosporidiosis, highlighting severe inflammation, oxidative DNA damage, and cellular apoptosis, particularly in younger fish.

A Nucleophilicity-Engineered DNA Ligation Blockade Nanoradiosensitizer Induces Irreversible DNA Damage to Overcome Cancer Radioresistance.

During fractionated radiotherapy, DNA damage repair intensifies in tumor cells, culminating in cancer radioresistance and subsequent radiotherapy failure. Despite the recent development of nanoradiosensitizers targeting specific DNA damage repair pathways, the persistence of repair mechanisms involving multiple pathways remains inevitable. To address this challenge, a nucleophilicity-engineered DNA ligation blockade nanoradiosensitizer (DLBN) comprising Au/CeO2 heteronanostructure modified with trans-acting activator of transcription peptides is reported, which targets and inhibits the DNA ligation inside cancer cell nuclei via heterointerface-mediated dephosphorylation of DNA, a crucial step in overcoming cancer radioresistance. First, the Schottky-type heteronanostructure of cancer cell nucleus-targeting DLBN effectively intensifies radiation-induced DNA damage via catalase-mimetic activity and radiation-triggered catalytic reactions. Notably, by leveraging Au/CeO2 heterointerface, DLBN spontaneously dissociates H2O to hydroxide, a nucleophile with higher nucleophilicity, thereby exhibiting remarkable dephosphorylation capability at DNA nicks through facilitated nucleophilic attack. This enables the blockade of DNA ligation, a pivotal step in all DNA damage repair pathways, effectively interrupting the repair process. Consequently, DLBN resensitizes radioresistant cells by overcoming therapy-induced radioresistance, leading to a substantial accumulation of unrepaired DNA damage. These findings offer insight into the dephosphorylation of DNA within nuclei, and underscore the potential of heteronanostructure-based nanoradiosensitizer to block DNA ligation against therapy-induced radioresistance.

Neighboring Effect-Initiated Supramolecular Nanocomplex with Sequential Infiltration as Irreversible Apoptosis Inducer for Synergetic Chemo-Immunotherapy.

Chemotherapy-based combination regimens are recommended as first-line treatment for colorectal cancer. However, multidrug resistance (MDR) and limited drug infiltration in tumor microenvironment remain critical challenges. Herein, a pH/redox dual activated supramolecular DAS@CD-OxPt (IV) nanoparticles (NPs) via host-guest molecular recognition to achieve relay drugs delivery of active oxaliplatin (OxPt (IV)) and Src inhibitor dasatinib (DAS) between tumor cells is developed. DAS@CD-OxPt (IV) NPs exhibit prolonged circulation in the blood and intra-tumoral retention. Triggered by the endo/lysosome (pH 5.0), flexible DAS@CD-OxPt (IV) NPs exhibited proton-driven in situ assembly to form nanofiber in tumor cells. Dual chemotherapeutic agents released from DAS@CD-OxPt (IV) NPs synergistically cause irreversible DNA damage by blocking p53-mediated DNA repair. Supramolecular nanofibers can further serve as the "ammunition depot" to continuously release drugs from dying cells and transport them into neighboring tumor cells, leading to domino-like cell death and enhanced immunogenicity. Furthermore, DAS@CD-OxPt (IV) NPs combined with immune checkpoint blockade (ICB) therapy strikingly suppress CT26 tumor growth and pulmonary metastasis.

Predisposal of Interferon Regulatory Factor 1 Deficiency to Accumulate DNA Damage and Promote Osteoarthritis Development in Cartilage.

Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation. OA progression was examined in wild-type and Irf1-/- mice using histologic assessments and microcomputed tomography analysis of whole-joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase-accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ-H2AX foci and senescence-associated beta-galactosidase activity. Our genome-wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon-responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down-regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post-traumatic OA in mice. IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.

Loss of miR-101-3p in melanoma stabilizes genomic integrity, leading to cell death prevention

Malignant melanoma remains the most lethal form of skin cancer, exhibiting poor prognosis after forming distant metastasis. Owing to their potential tumor-suppressive properties by regulating oncogenes and tumor suppressor genes, microRNAs are important player in melanoma development and progression. We defined the loss of miR-101-3p expression in melanoma cells compared with melanocytes and melanoblast-related cells as an early event in tumor development and aimed to understand the tumor suppressive role of miR-101-3p and its regulation of important cellular processes. Reexpression of miR-101-3p resulted in inhibition of proliferation, increase in DNA damage, and induction of apoptosis. We further determined the nuclear structure protein Lamin B1, which influences nuclear processes and heterochromatin structure, ATRX, CASP3, and PARP as an important direct target of miR-101-3p. RNA sequencing and differential gene expression analysis after miR-101-3p reexpression supported our findings and the importance of loss of mir-101-3p for melanoma progression. The validated functional effects are related to genomic instability, as recent studies suggest miRNAs plays a key role in mediating this cellular process. Therefore, we concluded that miR-101-3p reexpression increases the genomic instability, leading to irreversible DNA damage, which leads to apoptosis induction. Our findings suggest that the loss of miR-101-3p in melanoma serves as an early event in melanoma progression by influencing the genomic integrity to maintain the increased bioenergetic demand.

Integrating a Biomineralized Nanocluster for H2S-Sensitized ROS Bomb against Breast Cancer.

Nanomaterial-assisted chemodynamic therapy (CDT) has received considerable attention in recent years. It outperforms other modalities by its distinctive reactive oxygen species (ROS) generation through a nonexogenous stimulant. However, CDT is limited by the insufficient content of endogenous hydrogen peroxide (H2O2). Herein, a biodegradable MnS@HA-DOX nanocluster (MnS@HA-DOX NC) was constructed by in situ biomineralization from hyaluronic acid, to enlarge the ROS cascade and boost Mn2+-based CDT. The acid-responsive NCs could quickly degrade after internalization into endo/lysosomes, releasing Mn2+, H2S gas, and anticancer drug doxorubicin (DOX). The Fenton-like reaction catalyzed by Mn2+ was amplified by both H2S and DOX, producing a mass of cytotoxic ·OH radicals. Through the combined action of gas therapy (GT), CDT, and chemotherapy, oxidative stress would be synergistically enhanced, inducing irreversible DNA damage and cell cycle arrest, eventually resulting in cancer cell apoptosis.

Biodegradable copper peroxide decorated hollow polydopamine nanocomposite as effective chloroperoxidase delivery carrier for enhancing enzyme dynamic therapy via self-activated cascade reactions

Recently, enzyme dynamic therapy (EDT) has gained enormous attraction in cancer therapy. However, the efficiency of EDT is still largely restricted by the inefficient delivery efficiency of chloroperoxidase (CPO) and the insufficient hydrogen peroxide (H2O2) content in the tumor microenvironment (TME). In the present work, a biodegradable cupper peroxide decorated hollow polydopamine nanocomposite (HPDCP) with surface functionalization of PEGlated tumor targeting peptide RGD (PEG-RGD) was designed for effective CPO delivery. The resultant nanosystem of HPDCP@CPO@PEG-RGD displayed high CPO delivery efficiency to breast tumors without comprising the enzyme activity. Moreover, the nanosystem can dissociate rapidly in acidic TME by supplying substantial H2O2 and simultaneously releasing Cu2+ and CPO, followed by initiating self-activated cascade reactions. At the one hand, the self-supplied H2O2 greatly enhanced the singlet oxygen (1O2) generation via the CPO-mediated enzyme dynamic reaction. At the other hand, substantial hydroxyl radical (•OH) was produced via the Cu2+-driven Fenton reaction for chemodynamic therapy (CDT). Therefore, the anticancer efficiency of EDT was significantly enhanced due to the synergistic EDT/CDT effect. Mechanism study revealed that 1O2/•OH generated by HPDCP@CPO@PEG-RGD synergistically inhibited breast cancer cells by firstly causing severe lipid peroxidation, followed by triggering mitochondria-mediated apoptosis and causing irreversible DNA damage by inhibiting the expression of DNA repair enzyme poly (ADP-ribose) polymerase 1 (PARP-1).

Distribution and accumulation of Cadmium in different trophic levels affecting Serangium japonicum, the predatory beetle of whitefly Bemisia tabaci, biologically, physiologically and genetically: An experimental study

Cadmium (Cd) is a heavy metal that is of great concern in agroecosystems due to its toxicity to plants, herbivores, carnivores, and human beings. The current study evaluated the allocation and bioaccumulation of Cd from soil to cotton plants, cotton plants to herbivore pests, and herbivorous pests to a natural enemy predator. When soil was spiked with 100 mg/kg Cd, results demonstrated that cotton roots accumulated more Cd than the stems and leaves. The bioaccumulation of Cd was less in 4th instar larvae, pupa, and adults of Serangium japonicum than in Bemisia tabaci adults. The bioaccumulation in S. japonicum elongated the immature development period and reduced adult longevity, oviposition days, fertility, and total pre-oviposition duration. The net reproduction of S. japonicum was also reduced, as was female mature weight and feeding potential; as a result, Cd exposure could reduce the future population size compared to uncontaminated populations. There was decreased activity of the antioxidant enzymes (SOD, CAT, and POD) and energy-conserving lipids (glycogen, triglyceride, and total cholesterol) in Cd-contaminated S. japonicum compared to controls. The detoxifying enzyme activity of GST and P450 increased while AChE activity did not change. The qRT-PCR research showed that SOD1, CAT, POD, glycogen, and triglyceride gene expression was higher than in controls, whereas detoxification gene expression did not change. Our results indicate that Cd exposure has a physiological trade-off between its adverse effects on life history traits and elevated detoxification and antioxidation of S. japonicum, which could result from gene expression alteration. Further studies are needed to assess whether Cd exposure causes irreversible DNA damage in S. japonicum.

IKS03, a Novel CD19-Targeted Antibody Drug Conjugate, Induces Target Dependent In Vivo Cell Killing of B-Cell Lymphoma Xenografts By DNA Crosslinking

CD19 is widely expressed in B-cell non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). IKS03 is a CD19-targeting antibody drug conjugate (ADC) with a novel linker payload design for tumor-selective payload release. Site-specific conjugation using farnesyltransferase-catalysed ConjuALL technology to a DNA crosslinking agent yields a homogenous ADC with drug-to-antibody ratio (DAR) of 2. To minimize systemic release of the highly potent payload in human plasma, IKS03 incorporates a linker specifically cleavable by the lysosomal enzyme beta-glucuronidase. In addition, the payload is a pro-drug with a protecting moiety cleavable by the same enzyme. Therefore, following CD19-dependent binding and uptake, IKS03 requires intracellular lysosomal processing in the target cell to both release and fully activate the free pyrrolobenzodiazepine (PBD) dimer payload which induces DNA crosslinking, blocks DNA replication and ultimately leads to tumor selective cell death. In vivo efficacy was evaluated in CD19-expressing preclinical human xenograft models representing different subtypes of B-NHL. IKS03 was highly active against Farage and OCI-LY10 DLBCL xenografts as well as Granta-519 MCL xenografts in SCID mice with durable tumor regressions observed following treatment with a single dose of 0.1 to 0.3 mg/kg. Likewise, in a Ramos lymphoma model a single IKS03 dose of 0.3 mg/kg significantly inhibited tumor growth. IKS03 demonstrated greater in vivo efficacy than the clinical benchmark ADCs polatuzumab vedotin and loncastuximab tesirine approved for the treatment of patients with B-cell non-Hodgkin lymphomas. PBD cytotoxic agents have been described to induce DNA crosslinking leading to DNA damage. To demonstrate that IKS03 in vivo activity is the result of targeted payload release, Ramos xenografts were established in immunodeficient mice and treated with up to 1 mg/kg of IKS03 in comparison with a non-targeted ADC utilizing the same linker payload format. Tumors were excised at 1 day and 3 days post-treatment and assessed for the presence of phospho-H2AX positive foci, a marker of DNA damage, by immunohistochemistry. IKS03 treatment increased both frequency and staining intensity of nuclear phospho-H2AX foci in Ramos xenografts in a dose- and time-dependent manner. In contrast, the non-targeted control ADC did not result in any changes as compared to a vehicle control. This confirms the specific induction of DNA damage in CD19 positive lymphomas as a pharmacodynamic response to IKS03 treatment in vivo. In conclusion, IKS03 is highly effective in an array of preclinical MCL and DLBCL xenograft models at doses that are well tolerated. In vivo, IKS03 treatment increased the level of phospho-H2AX indicative of irreversible DNA damage in a target-dependent manner. This is consistent with the proposed mechanism of action of CD19-mediated delivery of a PBD payload specifically to B-cell tumors. Clinical investigation in patients with advanced B-Cell Non-Hodgkin Lymphomas is being initiated (NCT05365659).

Unraveling the relationship among inflammatory responses, oxidative damage, and host susceptibility to Opisthorchis viverrini infection: A comparative analysis in animal models.

Opisthorchis viverrini infection-induced inflammation contributes to cholangiocarcinoma (CCA) development in humans and animals. Inflammation generates free radicals, such as reactive oxygen species and reactive nitrogen species (RNS), which damage the host's DNA. However, only 5% of O. viverrini-infected individuals develop malignancy, suggesting that variations in the inflammatory response of individuals to the parasite may influence susceptibility. Due to limitations in studying human susceptibility, we used an animal model to investigate the profiles of inflammatory reactions, oxidative burst, and irreversible DNA damage. This study aimed to explore the potential role of inflammation and RNS in causing DNA damage that may predispose susceptible hosts and non-susceptible animal models to cancer development in O. viverrini infection. This experimental study was conducted on 30 Syrian golden hamsters (OV-H) and 30 BALB/c mice (OV-M) infected with O. viverrini, representing susceptible and non-susceptible models, respectively. Five animals per group were examined at six predetermined time points during the experiment. Biliary tract samples were systematically investigated using histopathological evaluation for inflammatory cell infiltration and immunohistochemical staining for RNS production and markers of DNA damage, including nitrotyrosine and 8-hydroxy-2'-deoxyguanosine. These features were quantified and compared among the experimental groups. Mann-Whitney U-test was used for statistical analysis, with p < 0.05 considered statistically significant. The comparison revealed that the OV-M group exhibited significantly earlier and higher rates of inflammatory cell infiltration during the acute phase, whereas the OV-H group exhibited chronic and more severe inflammation (p < 0.020). Intracellular RNS production and DNA damage were closely associated with the inflammatory response. This study demonstrates differential responses in susceptible and non-susceptible models of O. viverrini infection regarding disease onset and duration, as well as intracellular RNS production and DNA damage caused by inflammation. Persistent inflammation generated oxidatively damaged DNA, which is a distinct pathological characteristic of susceptible hosts and may be critical for CCA development.

Neo-functionalization in Saccharomyces cerevisiae: a novel Nrg1-Rtg3 chimeric transcriptional modulator is essential to maintain mitochondrial DNA integrity.

In Saccharomyces cerevisiae, the transcriptional repressor Nrg1 (Negative Regulator of Glucose-repressed genes) and the β-Zip transcription factor Rtg3 (ReTroGrade regulation) mediate glucose repression and signalling from the mitochondria to the nucleus, respectively. Here, we show a novel function of these two proteins, in which alanine promotes the formation of a chimeric Nrg1/Rtg3 regulator that represses the ALT2 gene (encoding an alanine transaminase paralog of unknown function). An NRG1/NRG2 paralogous pair, resulting from a post-wide genome small-scale duplication event, is present in the Saccharomyces genus. Neo-functionalization of only one paralog resulted in the ability of Nrg1 to interact with Rtg3. Both nrg1Δ and rtg3Δ single mutant strains were unable to use ethanol and showed a typical petite (small) phenotype on glucose. Neither of the wild-type genes complemented the petite phenotype, suggesting irreversible mitochondrial DNA damage in these mutants. Neither nrg1Δ nor rtg3Δ mutant strains expressed genes encoded by any of the five polycistronic units transcribed from mitochondrial DNA in S. cerevisiae. This, and the direct measurement of the mitochondrial DNA gene complement, confirmed that irreversible damage of the mitochondrial DNA occurred in both mutant strains, which is consistent with the essential role of the chimeric Nrg1/Rtg3 regulator in mitochondrial DNA maintenance.

Phosphorothioated amino-AS1411 aptamer functionalized stealth nanoliposome accelerates bio-therapeutic threshold of apigenin in neoplastic rat liver: a mechanistic approach

Hepatocellular carcinoma (HCC) is a leading cause of death globally. Even though the progressive invention of some very potent therapeutics has been seen, the success is limited due to the chemotherapeutic resistance and recurrence in HCC. Advanced targeted treatment options like immunotherapy, molecular therapy or surface-engineered nanotherapeutics could offer the benefits here owing to drug resistance over tumor heterogenicity. We have developed tumor-sensing phosphorothioate and amino-modified aptamer (AS1411)-conjugated stealth nanoliposomes, encapsulating with apigenin for precise and significant biodistribution of apigenin into the target tumor to exploit maximum bio-therapeutic assistances. The stable aptamer functionalized PEGylated nanoliposomes (Apt-NLCs) had an average vesicle size of 100–150 nm, a smooth surface, and an intact lamellarity, as ensured by DLS, FESEM, AFM, and Cryo-TEM. This study has specified in vitro process of optimum drug (apigenin) extrusion into the cancer cells by nucleolin receptor-mediated cellular internalization when delivered through modified AS1411 functionalized PEGylated nanoliposomes and ensured irreversible DNA damage in HCC. Significant improvement in cancer cell apoptosis in animal models, due to reduced clearance and higher intratumor drug accumulation along with almost nominal toxic effect in liver, strongly supports the therapeutic potential of aptamer-conjugated PEGylated nanoliposomes compared to the nonconjugated formulations in HCC. The study has established a robust superiority of modified AS1411 functionalized PEGylated nanoliposomes as an alternative drug delivery approach with momentous reduction of HCC tumor incidences.Graphical

THE CERIUM OXIDE GENERATED RADICAL ELIMINATION PROPERTIES OF PEG-NANOCERIA

Reactive oxygen species (ROS) have been linked to cellular degeneration, irreversible DNA damage, and various diseases. Cerium oxide nanoparticles have shown promising medical applications for their SOD mimetic activity to catalyze the breakdown of various ROS. Increasing the biocompatibility, longevity of residence, and rate of internalization of nanoceria are essential to increase its range of biomedical applications. Polyethylene glycol’s (PEG) hydrophilic, nonimmunogenic, and antioxidative properties make it an ideal coating for increasing cerium nanoparticle’s applicability. Gelatin’s low cost and versatility have made it widely employed as an antioxidant drug carrier in a variety of physiological systems. Because of gelatin’s susceptibility to ROS denaturation and well-researched structure, it is a useful tool for assessing conformational damage in applications that involve acute oxidative stress. PEG-nanoceria of various molar weights was synthesized from Ce (III) nitrate and incorporated into gelatin hydrogels that were exposed to hydrogen peroxide to provide oxidative stress damage. This study aims to assess changes to gelatin conformation were assessed using Fourier transform infrared spectroscopy. PEGNanoceria showed radical damage mitigation in hydrogels as evident by the decreased change in transmittance over its nonPEG counterpart. There was notably exceptional damage mitigation in the amide A and amide II regions. These promising findings suggest more research should be done to examine polymer-coated nanoceria’s antioxidative properties in more biologically relevant models.

Restoration of DNA integrity and the cell cycle by electric stimulation in planarian tissues damaged by ionizing radiation.

Exposure to high levels of ionizing γ radiation leads to irreversible DNA damage and cell death. Here, we establish that exogenous application of electric stimulation enables cellular plasticity and the re-establishment of stem cell activity in tissues damaged by ionizing radiation. We show that subthreshold direct current stimulation (DCS) rapidly restores pluripotent stem cell populations previously eliminated by lethally γ-irradiated tissues of the planarian flatworm Schmidtea mediterranea. Our findings reveal that DCS enhances DNA repair, transcriptional activity, and cell cycle entry in post-mitotic cells. These responses involve rapid increases in cytosolic Ca2+ concentration through the activation of L-type Cav channels and intracellular Ca2+ stores, leading to the activation of immediate early genes and ectopic expression of stem cell markers in post-mitotic cells. Overall, we show the potential of electric current stimulation to reverse the damaging effects of high-dose γ radiation in adult tissues. Furthermore, our results provide mechanistic insights describing how electric stimulation effectively translates into molecular responses capable of regulating fundamental cellular functions without the need for genetic or pharmacological intervention.

RETRACTED ARTICLE: Hybrid high performance intelligent computing approach of CACNN and RNN for skin cancer image grading

Skin cancer is defined as unregulated cell proliferation due to irreversible DNA damage. Melanoma is one kind of skin cancer generated by melanocytes, which could result in serious health issues. Early detection of this skin cancer based on image processing assist therapists in its treatment. Computational pathology has the unique capability of spatially dissecting specific interfaces on digitized histology images. The main objective of this research is to classify skin cancer using a deep learning model. This work proposes a hybrid context-aware convolutional neural network with recurrent neural network (CA-CNN-RNN) based on skin cancer histology images. This model encodes the local representation of the histological images into high-dimensional features and hence aggregates the features by considering their spatial configuration for performing final classification. The dataset for this work is made up of H&E-stained images from the database of The Cancer Genome Atlas. Using the hybrid CA-CNN-RNN model, the experiment on histological image of melanoma disease was performed and validated with several classification models like DarkNet-53, VGG-19, ResNet50, and Inception. The data set is utilized to evaluate the model in order to provide results, which are analyzed using parameters like as accuracy, precision, recall, and F1-score. The experimental analysis reveals that the CA-CNN-RNN performed better with the DarkNet-53 model. The proposed model achieved 97.14 accuracy, 96.49 precision, 98.21 recall, and 96.50 f-score.

Exposure to environmental concentrations of natural pyrethrins induces hepatotoxicity: Assessment in HepG2 cell lines and zebrafish models

Natural pyrethrins are one variety of botanical pesticide, and are commonly used in organic and ecological agriculture. However, the hepatotoxicity of natural pyrethrins is unknown. In this study, the impact of natural pyrethrins on human HepG2 cells, which are prominent cell model for toxic-induced hepatotoxicity evaluations, was investigated in accordance with the ROS production and the mechanism of DNA damage and repair. And we report the liver toxicity of natural pyrethrins in zebrafish. Our result revealed a significant increase in ROS production, suggesting oxidative stress. Besides, the most notable genotoxic effect of oxidation-induced DNA damage was observed for natural pyrethrins, as detected by neutral comet assay and γH2AX/8-oxoG staining. As revealed by the results, oxidative DNA damage is responsible for the cytotoxic exposure of natural pyrethrins to HepG2 cells in humans. The observed damage is chronic toxicity, which may cause irreversible DNA damage and more severe toxic effects on human HepG2 cells. This can account for the complicated response to DNA impairment. Visual observations of zebrafish liver and oil red staining also demonstrated that natural pyrethrins induced liver degeneration, liver size changes and liver steatosis in zebrafish. In conclusion, the health of humans can be endangered by natural pyrethrins as a result of hepatotoxicity.

Reactive Oxygen Species in Acute Lymphoblastic Leukaemia: Reducing Radicals to Refine Responses.

Acute lymphoblastic leukaemia (ALL) is the most common cancer diagnosed in children and adolescents. Approximately 70% of patients survive >5-years following diagnosis, however, for those that fail upfront therapies, survival is poor. Reactive oxygen species (ROS) are elevated in a range of cancers and are emerging as significant contributors to the leukaemogenesis of ALL. ROS modulate the function of signalling proteins through oxidation of cysteine residues, as well as promote genomic instability by damaging DNA, to promote chemotherapy resistance. Current therapeutic approaches exploit the pro-oxidant intracellular environment of malignant B and T lymphoblasts to cause irreversible DNA damage and cell death, however these strategies impact normal haematopoiesis and lead to long lasting side-effects. Therapies suppressing ROS production, especially those targeting ROS producing enzymes such as the NADPH oxidases (NOXs), are emerging alternatives to treat cancers and may be exploited to improve the ALL treatment. Here, we discuss the roles that ROS play in normal haematopoiesis and in ALL. We explore the molecular mechanisms underpinning overproduction of ROS in ALL, and their roles in disease progression and drug resistance. Finally, we examine strategies to target ROS production, with a specific focus on the NOX enzymes, to improve the treatment of ALL.

Can microorganisms develop resistance against light based anti-infective agents?

Recently, there have been increasing numbers of publications illustrating the potential of light-based antimicrobial therapies to combat antimicrobial resistance. Several modalities, in particular, which have proven antimicrobial efficacy against a wide range of pathogenic microbes include: photodynamic therapy (PDT), ultraviolet light (UVA, UVB and UVC), and antimicrobial blue light (aBL). Using these techniques, microbial cells can be inactivated rapidly, either by inducing reactive oxygen species that are deleterious to the microbial cells (PDT, aBL and UVA) or by causing irreversible DNA damage via direct absorption (UVB and UVC). Given the multi-targeted nature of light-based antimicrobial modalities, it has been hypothesised that resistance development to these approaches is highly unlikely. Furthermore, with the exception of a small number of studies, it has been found that resistance to light based anti-infective agents appears unlikely, irrespective of the modality in question. The concurrent literature however stipulates, that further studies should incorporate standardised microbial tolerance assessments for light-based therapies to better assess the reproducibility of these observations.

Melflufen Therapy for Relapsed Refractory Multiple Myeloma (RRMM) Patients Refractory to Daratumumab and/or Pomalidomide: A Report on Early Efficacy

Melflufen Therapy for Relapsed Refractory Multiple Myeloma (RRMM) Patients Refractory to Daratumumab and/or Pomalidomide: A Report on Early Efficacy