Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway.

The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-ß and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.

A systematic review on deep learning-based automated cancer diagnosis models.

Deep learning is gaining importance due to its wide range of applications. Many researchers have utilized deep learning (DL) models for the automated diagnosis of cancer patients. This paper provides a systematic review of DL models for automated diagnosis of cancer patients. Initially, various DL models for cancer diagnosis are presented. Five major categories of cancers such as breast, lung, liver, brain and cervical cancer are considered. As these categories of cancers have a very high percentage of occurrences with high mortality rate. The comparative analysis of different types of DL models is drawn for the diagnosis of cancer at early stages by considering the latest research articles from 2016 to 2022. After comprehensive comparative analysis, it is found that most of the researchers achieved appreciable accuracy with implementation of the convolutional neural network model. These utilized the pretrained models for automated diagnosis of cancer patients. Various shortcomings with the existing DL-based automated cancer diagnosis models are also been presented. Finally, future directions are discussed to facilitate further research for automated diagnosis of cancer patients.

Level of non-conventional lipid parameters and its comparative analysis with TSH in subclinical hypothyroidism.

OBJECTIVES: The objective of this study is to estimate lipid parameters in subclinical hypothyroidism and correlate it with TSH. METHODS: Forty newly diagnosed cases of subclinical hypothyroidism and Forty age and gender-matched healthy controls were recruited for the study. Blood samples were collected from them and serum lipid profile (i.e. HDL, LDL, TG, serum total cholesterol) of the subjects was estimated by standard photometric methods in a fully auto-analyzer (MINDRAY BS-300) using commercially available kits and VLDL cholesterol was calculated using the Friedewald's formula. While serum Ox-LDL, Lipoprotein A, Apolipoprotein A1 and Apo B were estimated by using commercial kit based on enzyme-linked immmunosorbent assay. RESULTS: The parameters such as Oxidized low-density lipoprotein (Ox-LDL), lipoprotein (a), apolipoprotein A1, apolipoprotein B and small dense lipoprotein (sd LDL) were significantly increased in subclinical hypothyroid cases when compared with the control subjects (p<0.0001). In present study results showed significant positive correlations of serum thyroid stimulating hormone (TSH) with Ox-LDL (r=0.85, p<0.01), sd LDL (r=0.71, p<0.01). CONCLUSIONS: The present study focuses on the role of Ox-LDL, sd-LDL Lipoprotein A, Apolipoprotein A1 and Apo B that are sensitive indicators of atherogenic dyslipidemia in subclinical hypothyroidism and can serve as a better & novel risk factor for CAD.

Functional Transnasal Endoscopic Conjunctivorhinostomy.

The various surgical options for lacrimal tract reconstruction include canaliculodacryocystorhinostomy; fundal transposition; Conjunctivodacrocystorhinostomy with Jones tube; and in extreme cases conjunctivo-rhinostomy (CR) for total lacrimal bypass. The first three require partial lacrimal tract presence/ integrity while CR is indicated when the canaliculi and/or sac are nonfunctional. This report describes a novel technique of minimally invasive CR through a predominantly endoscopic endonasal approach and further discusses its advantages over other established techniques.

A Study on the Serum γ-Glutamyltranspeptidase and Plasma Osteopontin in Alcoholic Liver Disease.

Background Alcoholic liver disease (ALD) is a major source of alcohol-related morbidity and mortality. Heavy drinkers and alcoholics may progress from fatty liver to alcoholic hepatitis to cirrhosis. The enzyme γ-glutamyltranspeptidase (GGT) is a membrane-bound glycoprotein which catalyzes the transfer of the γ-glutamyl group from γ-glutamyl peptides to other peptides, amino acids, and water. Serum GGT activity mainly attributed to hepatobiliary system and thus is an important marker of ALD. Hence the present study is conducted to estimate and correlate the levels of GGT and osteopontin (OPN) in ALD. Aims and Objectives The objective of this study is to estimate and correlate the levels of GGT and OPN in ALD. Materials and Methods Sixty clinically diagnosed cases of ALD and sixty age- and gender-matched healthy controls were recruited for the study. Blood samples were collected from them and serum aspartate aminotransferase, serum alanine transaminases (ALTs), serum ALP levels, and plasma OPN levels were measured. Estimation of serum aspartate transaminases (AST), ALTs, and alkaline phosphatase (ALP) was assayed by standard photometric methods in autoanalyzer ERBA-XL (EM-200) using commercially available kits. OPN was estimated by using commercial kit based on enzyme-linked immunosorbent assay. Results The parameters of the liver function tests such as AST, ALT, and ALP were significantly increased in patients with ALD ( p < 0.001) when compared with the healthy control subjects. In the present study, significantly increased levels of γ-glutamyl transferases and OPN were found in patients with ALD ( p < 0.001) when compared with the control subjects. OPN showed significant positive correlations with AST ( r = 0.76, p < 0.001), ALT ( r = 0.64, p < 0.001), ALP ( r = 0.68, p < 0.001), and GGT ( r = 0.61, p < 0.001). Conclusion The present study focuses on the role of GGT and OPN that are sensitive indicators of liver cell injury and are most helpful in recognizing hepatocellular diseases such as ALD, hepatitis, and liver cirrhosis. Hence, the pattern of the GGT and OPN levels elevation can be helpful diagnostically.

Homology Modelling, Molecular Docking and Molecular Dynamics Simulation Studies of CALMH1 against Secondary Metabolites of Bauhinia variegata to Treat Alzheimer's Disease.

Calcium homeostasis modulator 1 (CALHM1) is a protein responsible for causing Alzheimer's disease. In the absence of an experimentally designed protein molecule, homology modelling was performed. Through homology modelling, different CALHM1 models were generated and validated through Rampage. To carry out further in silico studies, through molecular docking and molecular dynamics simulation experiments, various flavonoids and alkaloids from Bauhinia variegata were utilised as inhibitors to target the protein (CALHM1). The sequence of CALHM1 was retrieved from UniProt and the secondary structure prediction of CALHM1 was done through CFSSP, GOR4, and SOPMA methods. The structure was identified through LOMETS, MUSTER, and MODELLER and finally, the structures were validated through Rampage. Bauhinia variegata plant was used to check the interaction of alkaloids and flavonoids against CALHM1. The protein and protein-ligand complex were also validated through molecular dynamics simulations studies. The model generated through MODELLER software with 6VAM A was used because this model predicted the best results in the Ramachandran plot. Further molecular docking was performed, quercetin was found to be the most appropriate candidate for the protein molecule with the minimum binding energy of -12.45 kcal/mol and their ADME properties were analysed through Molsoft and Molinspiration. Molecular dynamics simulations showed that CALHM1 and CALHM1-quercetin complex became stable at 2500 ps. It may be seen through the study that quercetin may act as a good inhibitor for treatment. With the help of an in silico study, it was easier to analyse the 3D structure of the protein, which may be scrutinized for the best-predicted model. Quercetin may work as a good inhibitor for treating Alzheimer's disease, according to in silico research using molecular docking and molecular dynamics simulations, and future in vitro and in vivo analysis may confirm its effectiveness.

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed ß,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Integrated Blockchain-Deep Learning Approach for Analyzing the Electronic Health Records Recommender System.

Blockchain is a recent revolutionary technology primarily associated with cryptocurrencies. It has many unique features including its acting as a decentralized, immutable, shared, and distributed ledger. Blockchain can store all types of data with better security. It avoids third-party intervention to ensure better security of the data. Deep learning is another booming field that is mostly used in computer applications. This work proposes an integrated environment of a blockchain-deep learning environment for analyzing the Electronic Health Records (EHR). The EHR is the medical documentation of a patient which can be shared among hospitals and other public health organizations. The proposed work enables a deep learning algorithm act as an agent to analyze the EHR data which is stored in the blockchain. This proposed integrated environment can alert the patients by means of a reminder for consultation, diet chart, etc. This work utilizes the deep learning approach to analyze the EHR, after which an alert will be sent to the patient's registered mobile number.

Inhibition of Oxidized Nucleotide Sanitation By TH1579 and Conventional Chemotherapy Cooperatively Enhance Oxidative DNA Damage and Survival in AML.

Currently, the majority of patients with acute myeloid leukemia (AML) still die of their disease due to primary resistance or relapse toward conventional reactive oxygen species (ROS)- and DNA damage-inducing chemotherapy regimens. Herein, we explored the therapeutic potential to enhance chemotherapy response in AML, by targeting the ROS scavenger enzyme MutT homolog 1 (MTH1, NUDT1), which protects cellular integrity through prevention of fatal chemotherapy-induced oxidative DNA damage. We demonstrate that MTH1 is a potential druggable target expressed by the majority of patients with AML and the inv(16)/KITD816Y AML mouse model mimicking the genetics of patients with AML exhibiting poor response to standard chemotherapy (i.e., anthracycline & cytarabine). Strikingly, combinatorial treatment of inv(16)/KITD816Y AML cells with the MTH1 inhibitor TH1579 and ROS- and DNA damage-inducing standard chemotherapy induced growth arrest and incorporated oxidized nucleotides into DNA leading to significantly increased DNA damage. Consistently, TH1579 and chemotherapy synergistically inhibited growth of clonogenic inv(16)/KITD816Y AML cells without substantially inhibiting normal clonogenic bone marrow cells. In addition, combinatorial treatment of inv(16)/KITD816Y AML mice with TH1579 and chemotherapy significantly reduced AML burden and prolonged survival compared with untreated or single treated mice. In conclusion, our study provides a rationale for future clinical studies combining standard AML chemotherapy with TH1579 to boost standard chemotherapy response in patients with AML. Moreover, other cancer entities treated with ROS- and DNA damage-inducing chemo- or radiotherapies might benefit therapeutically from complementary treatment with TH1579.

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.

COVID-19 Public Opinion: A Twitter Healthcare Data Processing Using Machine Learning Methodologies.

The COVID-19 pandemic has shattered the whole world, and due to this, millions of people have posted their sentiments toward the pandemic on different social media platforms. This resulted in a huge information flow on social media and attracted many research studies aimed at extracting useful information to understand the sentiments. This paper analyses data imported from the Twitter API for the healthcare sector, emphasizing sub-domains, such as vaccines, post-COVID-19 health issues and healthcare service providers. The main objective of this research is to analyze machine learning models for classifying the sentiments of people and analyzing the direction of polarity by considering the views of the majority of people. The inferences drawn from this analysis may be useful for concerned authorities as they work to make appropriate policy decisions and strategic decisions. Various machine learning models were developed to extract the actual emotions, and results show that the support vector machine model outperforms with an average accuracy of 82.67% compared with the logistic regression, random forest, multinomial naïve Bayes and long short-term memory models, which present 78%, 77%, 68.67% and 75% accuracy, respectively.

MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells.

T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not up-regulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1low phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1high and MTH1low activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.

MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematologic cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin-CD34+CD38-), which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the preclinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rationale to investigate the clinical usefulness of TH1579 in AML in an ongoing clinical phase I trial. SIGNIFICANCE: The MTH1 inhibitor TH1579 is a potential novel AML treatment, targeting both blasts and the pivotal leukemic stem cells while sparing normal bone marrow cells.

Diagnostic measures comparison for ovarian malignancy risk in Epithelial ovarian cancer patients: a meta-analysis.

Epithelial ovarian cancer has become the most frequent cause of deaths among gynecologic malignancies. Our study elucidates the diagnostic performance of Risk of Ovarian Malignancy Algorithm (ROMA), Human epididymis secretory protein 4 (HE4) and cancer antigen (CA125). To compare the diagnostic accuracy of ROMA, HE-4 and CA125 in the early diagnosis and screening of Epithelial Ovarian Cancer. Literature search in electronic databases such as Medicine: MEDLINE (through PUBMED interface), EMBASE, Google Scholar, Science Direct and Cochrane library from January 2011 to August 2020. Studies that evaluated the diagnostic measures of ROMA, HE4 and CA125 by using Chemilumincence immunoassay or electrochemiluminescence immunoassay (CLIA or ECLIA) as index tests. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). We included 32 studies in our meta-analysis. We calculated AUC by SROC, pooled estimated like sensitivity, specificity, likelihood ratio, diagnostic odds ratio (DOR), Tau square, Cochran Q through random effect analysis and meta-regression. Data was retrieved from 32 studies. The number of studies included for HE4, CA125 and ROMA tests was 25, 26 and 22 respectively. The patients with EOC were taken as cases, and women with benign ovarian mass were taken as control, which was 2233/5682, 2315/5875 and 2281/5068 respectively for the markers or algorithm. The pooled estimates of the markers or algorithm were sensitivity: ROMA (postmenopausal) (0.88, 95% CI 0.86-0.89) > ROMA (premenopausal) 0.80, 95% CI 0.78-0.83 > CA-125(0.84, 95% CI 0.82-0.85) > HE4 (0.73, 95% CI 0.71-0.75) specificity: HE4 (0.90, 95% CI 0.89-0.91) > ROMA (postmenopausal) (0.83, 95% CI 0.81-0.84) > ROMA (premenopausal) (0.80, 95% CI 0.79-0.82) > CA125 (0.73, 95%CI 0.72-0.74), Diagnostic odd's ratio ROMA (postmenopausal) 44.04, 95% CI 31.27-62.03, ROMA (premenopausal)-18.93, 95% CI 13.04-27.48, CA-125-13.44, 95% CI 9.97-18.13, HE4-41.03, 95% CI 27.96-60.21 AUC(SE): ROMA (postmenopausal) 0.94(0.01), ROMA (premenopausal)-0.88(0.01), HE4 0.91(0.01), CA125-0.86(0.02) through bivariate random effects model considering the heterogeneity. Our study found ROMA as the best marker to differentiate EOC from benign ovarian masses with greater diagnostic accuracy as compared to HE4 and CA125 in postmenopausal women. In premenopausal women, HE4 is a promising predictor of Epithelial ovarian cancer; however, its utilisation requires further exploration. Our study elucidates the diagnostic performance of ROMA, HE4 and CA125 in EOC. ROMA is a promising diagnostic marker of Epithelial ovarian cancers in postmenopausal women, while HE4 is the best diagnostic predictor of EOC in the premenopausal group. Our study had only EOC patients as cases and those with benign ovarian masses as controls. Further, we considered the studies estimated using the markers by the same index test: CLIA or ECLIA. The good number of studies with strict inclusion criteria reduced bias because of the pooling of studies with different analytical methods, especially for HE4. We did not consider the studies published in foreign languages. Since a few studies were available for HE4 and CA125 in the premenopausal and postmenopausal group separately, data were inadequate for sub-group analysis. Further, we did not assess these markers' diagnostic efficiency stratified by the stage and type of tumour due to insufficient studies.

Comparison between two intravitreal injection techniques with respect to fluid reflux, intraocular pressure, and therapeutic effect.

CONTEXT: Effect of fluid reflux on intraocular pressure (IOP) and therapeutic benefits. AIMS: The aim of this study is to compare two intravitreal injection techniques in terms of fluid reflux, short-term IOP changes, and therapeutic effect. SETTINGS AND DESIGN: A prospective, double-blinded, randomized interventional study. SUBJECTS AND METHODS: Sixty eyes were randomly allocated to two groups (direct intravitreal injection technique and oblique intravitreal injection technique). IOP was measured before and immediately after the injection of 0.1 ml comprising of bevacizumab (1.25 mg/0.05 ml) and dexamethasone (0.2 mg/0.05 ml) and then at 30 min after the injection. Occurrence and amount of vitreous reflux were recorded. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) were assessed preinjection and 6 weeks postinjection. RESULTS: IOP (mmHg ± standard deviation) increased significantly immediately after injection to 24.30 ± 3.02 (direct intravitreal injection) and 31.50 ± 3.49 (oblique intravitreal injection). These pressure rise differed significantly between both groups (mean difference: 7.2, P < 0.0001). Thirty minutes after injection, there was no significant difference in IOP increase between the groups. Occurrence and amount of fluid reflux were significantly higher with direct intravitreal injection. There was no significant difference in BCVA and CMT outcome between both groups. CONCLUSIONS: Direct intravitreal injection technique has lower rise in IOP and higher incidence of fluid reflux than the oblique intravitreal technique. Fluid reflux does not cause a therapeutic compromise in terms of BCVA or CMT changes, so the reflux fluid must be the vitreous not the drug. Thus, direct injection technique seems to be the preferred technique.

NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis.

Patients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC. SIGNIFICANCE: This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.

Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma.

Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.