The burden of leukemia in the Kingdom of Saudi Arabia: 15 years period (1999-2013).

BACKGROUND: Leukemia is a malignant neoplasm that arises from hematopoietic cells. The number of leukemia cases has dramatically increased from 297,000 to 437, 033 cases worldwide. As result, the the Saudi Cancer Registry ramked leukemia as the 5th type of cancer cases among both genders in Saudi Arabia. Data on the trend and incidence of leukemnia in Saudi Arabia is lacking. This study aims to report the trend and incidence of leukemia in Saudi Arabia using available data from the Saudi Cancer Registry (SCR), as a population-based cancer registry in the country over a period of 15 years (1999-2013). METHODS: Data of registered leukemia cases between years 1999-2013 were retrieved from the Saudi Council of Health, Saudi Cancer Registry. Data were coded using the International Classification of Diseases for Oncology (ICD-O). Main and essential variables were retrieved such as age, sex, years of incidence, residency, and histopathological type of leukemia. RESULTS: A total of 8712 cases of leukemia were analyzed in this study, 57.2% were males and 42.8% were females. Around 33.6% of cases were from the central region of Saudi Arabia. The most diagnosed type of leukemia was the Precursor B-cell lymphoblastic leukemia (18.7%), followed by Precursor cell lymphoblastic leukemia, NOS (17.3%) with equal percentage of reported cases between males and females in these subsets. CONCLUSION: Ove a period of 15 years, the trend of leukemia showed the likelihood of increase in rate particularly in males with highest incidence reported from the central region of Saudi Arabia which needs more investigation. Resources for diagnosis and treatment should be planned with more orientation toward the accurate diagnosis of leukemia to minimize the number of "none specific diagnosis".

A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH).

Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene-1(AEG-1)/metadherin in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1ΔHEP ). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1ΔHEP mice were protected from high-fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and wild-type (WT) mice that developed steatosis upon feeding HFD. In-depth molecular analysis unraveled that inhibition of peroxisome proliferator-activated receptor alpha activity resulting in decreased fatty acid ß-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 small interfering RNA provided marked protection from HFD-induced NASH in WT mice. CONCLUSION: AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466-480).

Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1 Protein) Promotes Hepatocarcinogenesis by Inhibiting Monoglyceride Lipase (MGLL).

Staphylococcal nuclease and tudor domain containing 1 (SND1) is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC), and functions as an oncogene. This study was carried out to identify novel SND1-interacting proteins to better understand its molecular mechanism of action. SND1-interacting proteins were identified by a modified yeast two-hybrid assay. Protein-protein interaction was confirmed by co-immunoprecipitation analysis. Monoglyceride lipase (MGLL) expression was analyzed by quantitative RT-PCR, Western blot, and immunohistochemistry. MGLL-overexpressing clones were analyzed for cell proliferation and cell cycle analysis and in vivo tumorigenesis in nude mice. MGLL was identified as an SND1-interacting protein. Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. MGLL expression was detected in normal human hepatocytes and mouse liver, although it was undetected in human HCC cell lines. An inverse correlation between SND1 and MGLL levels was identified in a human HCC tissue microarray as well as in the TCGA database. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression and a marked decrease in tumor growth in nude mouse xenograft assays. MGLL overexpression inhibited Akt activation that is independent of enzymatic activity of MGLL and overexpression of a constitutively active Akt rescued cells from inhibition of proliferation and restored normal cell cycle progression. This study unravels a novel mechanism of SND1 function and identifies MGLL as a unique tumor suppressor for HCC. MGLL might function as a homeostatic regulator of Akt restraining its activation.

Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC).

Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3'-triiodothyronine (T3) with normal l-thyroxine (T4) levels, is associated with malignancy. Decreased activity of type I 5'-deiodinase (DIO1), which converts T4 to T3, contributes to NTIS. T3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-κB activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-κB. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T3-mediated gene regulation was analyzed in human HCC cells, with overexpression or knockdown of AEG-1, and primary hepatocytes from AEG-1 transgenic (Alb/AEG-1) and AEG-1 knock-out (AEG-1KO) mice. Serum T3 and T4 levels were checked in Alb/AEG-1 mice and human HCC patients. AEG-1 and DIO1 levels in human HCC samples were analyzed by immunohistochemistry. AEG-1 inhibited T3-mediated gene regulation in human HCC cells and mouse hepatocytes. AEG-1 overexpression repressed and AEG-1 knockdown induced DIO1 expression. An inverse correlation was observed between AEG-1 and DIO1 levels in human HCC patients. Low T3 with normal T4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-κB were identified to play a role in AEG-1-mediated down-regulation of DIO1. AEG-1 thus might play a role in NTIS associated with HCC and other cancers.

Identification of Novel Genes and Pathways of Ovarian Cancer Using a Comprehensive Bioinformatic Framework.

Ovarian cancer (OC) is a significant contributor to gynecological cancer-related deaths worldwide, with a high mortality rate. Despite several advances in understanding the pathogenesis of OC, the molecular mechanisms underlying its development and prognosis remain poorly understood. Therefore, the current research study aimed to identify hub genes involved in the pathogenesis of OC that could serve as selective diagnostic and therapeutic targets. To achieve this, the dataset GEO2R was used to retrieve differentially expressed genes. The study identified a total of five genes (CDKN1A, DKK1, CYP1B1, NTS, and GDF15) that were differentially expressed in OC. Subsequently, a network analysis was performed using the STRING database, followed by the construction of a network using Cytoscape. The network analyzer tool in Cytoscape predicted 276 upregulated and 269 downregulated genes. Furthermore, KEGG analysis was conducted to identify different pathways related to OC. Subsequently, survival analysis was performed to validate gene expression alterations and predict hub genes, using a p-value of 0.05 as a threshold. Four genes (CDKN1A, DKK1, CYP1B1, and NTS) were predicted as significant hub genes, while one gene (GDF15) was predicted as non-significant. The adjusted P values of said predicted genes are 2.85E - 07, 5.49E - 06, 4.28E - 07, 1.43E - 07, and 3.70E - 07 for CDKN1A, DKK1, NTS, GDF15, and CYP1B1 respectively; additionally 6.08, 5.76, 5.74, 5.01, and 4.9 LogFc values of the said genes were predicted in GEO data set. In a boxplot analysis, the expression of these genes was analyzed in normal and tumor cells. The study found that three genes were highly expressed in tumor cells, while two genes (CDKN1A and DKK1) were more elevated in normal cells. According to the boxplot analysis for CDKN1A, 50% of tumor cells ranged between approx 3.8 and 5, while 50% of normal cells ranged between approx 6.9 and 7.9, which is greater than tumor cells. This shows that in normal cells, the CYP1B1 has a high expression level according to the GEPIA boxplot; addtionally the boxplot for DKK1 indicated that 50% of tumor cells ranged between approx 0 and 0.5, which was less than that of normal cells which ranged between approx 0.3 and 0.9. It shows that DKK1 is highly expressed in normal genes. Overall, the current study provides novel insights into the molecular mechanisms underlying OC. The identified hub genes and drug candidate targets could potentially serve as alternative diagnostic and therapeutic options for OC patients. Further research is needed to investigate the clinical significance of these findings and develop effective interventions that can improve the prognosis of patients with OC.

The diagnostic yield of CGH and WES in neurodevelopmental disorders.

Background: Neurodevelopmental disorders are a group of conditions characterized by developmental delays leading to abnormal brain functions. The methods of diagnosis and treatment of these conditions are complicated, and their treatment involves a combination of various forms of therapy. In recent years, the development of high-resolution technologies has played an important role in revealing the microdeletions, microduplications, and single-nucleotide variants of the chromosomes and how they are linked to the development of neurodevelopmental disorders. The wide implementation and application of molecular methodologies have started to shed light on the functional importance of using the appropriate methods in detecting these genetic variations that are categorized as either pathogenic or benign. The study aimed to compare the diagnostic yield of comparative hybridization (CGH) and whole exome sequencing (WES) in neurodevelopmental disorders among children attending the King Abdullah Specialist Children Hospital, Riyadh, Saudi Arabia. Methods: A retrospective study was conducted between 2015 and 2018 on 105 patients diagnosed with neurodevelopmental disorders through array-based CGH (Array-CGH) and WES. Results: In a sample of 105 patients, 16% was the hit rate of copy number variations (CNVs). WES was requested for CNV-negative patients (n = 79), of which 30% was the hit rate of pathogenic or likely pathogenic single-nucleotide variants. There was a difference in the diagnostic yield between CGH (16%) and WES (30%). Conclusion: WES was a better approach than Array-CGH to detect various DNA mutations or variants. Our findings could guide clinicians, researchers, and testing laboratories select the most cost-effective and appropriate approach for diagnosing their patients.

Knowledge and attitude of pregnant women in the Kingdom of Saudi Arabia toward Noninvasive prenatal testing: A single center study.

BACKGROUND: Noninvasive prenatal testing (NIPT) is a screening tool for chromosomal aneuploidies. Prior knowledge of NIPT is an inherent factor in the decision-making process. We assessed the knowledge and attitude of pregnant women related to prenatal testing with a particular focus on NIPT. METHODS: A prospective cross-sectional study, using a culturally validated questionnaire, was conducted with 342 pregnant women of whom 74.9% consented for prenatal screening. Mean age and gestational weeks ± standard deviation was 31 ± 5 and 26 ± 11, respectively. RESULTS: A positive/very positive attitude was observed to ultrasound, followed by FCT, NIPT, and lastly to CVS. More than half of the participants (56.1%) had no previous knowledge of NIPT. A reaching significance association was detected between education and knowledge of NIPT. Significant association was detected between risk for aneuploidy and knowledge of NIPT. The majority (74%) indicated their willingness to perform the test. The effect and value of society on the pregnant women to make a decision regarding NIPT was negligible. CONCLUSION: The pregnant women in the current study displayed a lack of knowledge and awareness regarding prenatal screening, particularly the NIPT. We recommend that pregnant women receive adequate counseling regarding prenatal screening to increase their awareness and knowledge of prenatal testing, including NIPT.

Erythritol modulates the polarization of macrophages: Potential role of tumor necrosis factor-α and Akt pathway.

Low-calorie sweeteners are substitutes for sugar and frequently used by patients with cardiometabolic diseases. Erythritol, a natural low-calorie sugar alcohol, was linked to cardiometabolic diseases in several recent metabolomics studies. However, the characterization of its role in disease development is lacking. Macrophage polarization orchestrates the immune response in various inflammatory conditions, most notably cardiometabolic disease. Therefore, the physiological effects of Erythritol on THP-1 macrophages were investigated. We observed an increased cellular abundance of proinflammatory M1 macrophages, characterized by CD11c, TNF-α, CD64, CD38, and HLA-DR markers and decreased anti-inflammatory M2 macrophages, characterized by mannose receptor CD206. The, Erythritol increased ROS generation, and the activation of the AKT pathway, cytosolic calcium overload, and cell cycle arrest at the G1 phase. Concomitantly, an increased population of necroptotic macrophages was observed. In conclusion, we provide evidence that Erythritol induced the proinflammatory phenotype in THP-1 macrophages and this was associated with an increased population of necroptotic macrophages. PRACTICAL APPLICATIONS: This assessment provides evidence of the effects of Erythritol on macrophages, particularly THP-1-derived macrophages. Our results support the role of Erythritol in driving the inflammation that is associated with cardiometabolic diseases and provide insights in the role of Erythritol as an inducer of necroptosis in THP-1 derived macrophages that could be associated the disease.

Viridiflorol induces anti-neoplastic effects on breast, lung, and brain cancer cells through apoptosis.

All active natural molecules are not fully exploited as therapeutic agents, causing delays in the advancement of anticancer drug discovery. Viridiflorol is a natural volatile element that may work as anti-cancer compound. We tested the anticancer properties of viridiflorol at different concentrations ranging from 0.03 to 300 µM in vitro on three cancer cells including breast (MCF-7), lung (A549) and brain (Daoy). The cancer cells responses were documented after treatment using MTT and Annexin V assays. Viridiflorol showed cytotoxic effects against all tested cell lines, reducing cell viability in a concentration-dependent manner with variable IC50 values. Daoy and A549 cell lines were more sensitive to viridiflorol when compared with temozolomide and doxorubicin, respectively. Viridiflorol demonstrated the highest anticancer activity against the Daoy cells with an estimated IC50 of 0.1 µM followed by MCF-7 at 10 µM, and A549 at 30 µM. In addition, upon exposure to concentrations ranging from 30 µM to 300 µM of viridiflorol, early and late apoptotic cell death was induced in a concentration dependent manner in Daoy (55.8%-72.1%), MCF-7 (36.2%-72.7%) and A459 (35%-98.9%) cell lines, respectively. In conclusion, viridiflorol demonstrates cytotoxic and apoptotic ability in three different cancer cell lines (brain, breast and lung).

SARS-CoV-2 Coronavirus Spike Protein-Induced Apoptosis, Inflammatory, and Oxidative Stress Responses in THP-1-Like-Macrophages: Potential Role of Angiotensin-Converting Enzyme Inhibitor (Perindopril).

A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNFα and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 µM reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1α and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNFα and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 µM) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 µM) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process. Graphical: Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).

Translation and cross-cultural validation of the non-invasive prenatal testing questionnaire in Arabic.

OBJECTIVES: To translate and cross-culturally adapt a Swedish questionnaire to Arabic to assess the awareness of pregnant women in Saudi Arabia regarding the availability of an accurate and safe prenatal screening procedure. METHODS: The study was conducted at the Obstetrics and Gynecology Clinic, King Abdulaziz Medical City, Riyadh, Saudi Arabia between December 2018 to April 2019. The non-invasive prenatal testing (NIPT) questionnaire, translated and validated in Arabic. Cronbach's alpha reliability testing was carried out to validate the Arabic version of the questionnaire. The sample size was 100 pregnant women, at any gestational period, from 20 to 44 years old. This is a prospective cross-sectional. RESULTS: An Arabic translated, and culturally validated questionnaire related to the attitudes, knowledge, and self-perceived probability of delivering a child with chromosomal abnormality.  Conclusion: We translated and validated the NIPT questionnaire to assess the attitude and awareness of pregnant women regarding the availability of the NIPT.

Enhancing azithromycin antibacterial activity by encapsulation in liposomes/liposomal-N-acetylcysteine formulations against resistant clinical strains of Escherichia coli.

E. coli is an Enterobacteriaceae that could develop resistance to various antibiotics and become a multi-drug resistant (MDR) bacterium. Options for treating MDR E. coli are limited and the pipeline is somewhat dry when it comes to antibiotics for MDR bacteria, so we aimed to explore more options to help in treating MDR E. coli. The purpose of this study is to examine the synergistic effect of a liposomal formulations of co-encapsulated azithromycin and N-acetylcysteine against E. coli. Liposomal azithromycin (LA) and liposomal azithromycin/N-acetylcysteine (LAN) were compared to free azithromycin. A broth dilution was used to measure the MIC and MBC of both formulations. The biofilm reduction activity, thermal stability measurements, stability studies, and cell toxicity analysis were performed. LA and LAN effectively reduced the MIC of E. coli SA10 strain, to 3 µg/ml and 2.5 µg/ml respectively. LAN at 1 × MIC recorded a 93.22% effectiveness in reducing an E. coli SA10 biofilm. The LA and LAN formulations were also structurally stable to 212 ± 2 °C and 198 ± 3 °C, respectively. In biological conditions, the formulations were largely stable in PBS conditions; however, they illustrated limited stability in sputum and plasma. We conclude that the formulation presented could be a promising therapy for E. coli resistance circumstances, providing the stability conditions have been enhanced.

Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma.

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp), inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC. Cancer Res; 77(12); 3306-16. ©2017 AACR.

Tetraspanin 8 mediates AEG-1-induced invasion and metastasis in hepatocellular carcinoma cells.

Astrocyte-elevated gene-1 (AEG-1) positively regulates tumor progression and metastasis. Here, we document that AEG-1 upregulates transcription of the membrane protein tetraspanin 8 (TSPAN8). Knocking down TSPAN8 in AEG-1-overexpressing human hepatocellular carcinoma (HCC) cells markedly inhibited invasion and migration without affecting proliferation. TSPAN8 knockdown profoundly abrogated AEG-1-induced primary tumor and intrahepatic metastasis in an orthopic xenograft model in athymic nude mice. Coculture of TSPAN8 knockdown cells with human umbilical vein endothelial cells (HUVEC) markedly inhibited HUVEC tube formation indicating that inhibition of angiogenesis might cause reduction in primary tumor size. TSPAN8 inhibition might be a potential therapeutic strategy for metastatic HCC.

The role of AEG-1 in the development of liver cancer.

AEG-1 is an oncogene that is overexpressed in all cancers, including hepatocellular carcinoma. AEG-1 plays a seminal role in promoting cancer development and progression by augmenting proliferation, invasion, metastasis, angiogenesis and chemoresistance, all hallmarks of aggressive cancer. AEG-1 mediates its oncogenic function predominantly by interacting with various protein complexes. AEG-1 acts as a scaffold protein, activating multiple protumorigenic signal transduction pathways, such as MEK/ERK, PI3K/Akt, NF-κB and Wnt/ß-catenin while regulating gene expression at transcriptional, post-transcriptional and translational levels. Our recent studies document that AEG-1 is fundamentally required for activation of inflammation. A comprehensive and convincing body of data currently points to AEG-1 as an essential component critical to the onset and progression of cancer. The present review describes the current knowledge gleaned from patient and experimental studies as well as transgenic and knockout mouse models, on the impact of AEG-1 on hepatocarcinogenesis.

Role of the staphylococcal nuclease and tudor domain containing 1 in oncogenesis (review).

The staphylococcal nuclease and tudor domain containing 1 (SND1) is a multifunctional protein overexpressed in breast, prostate, colorectal and hepatocellular carcinomas and malignant glioma. Molecular studies have revealed the multifaceted activities of SND1 involved in regulating gene expression at transcriptional as well as post-transcriptional levels. Early studies identified SND1 as a transcriptional co-activator. SND1 is also a component of RNA-induced silencing complex (RISC) thus mediating RNAi function, a regulator of mRNA splicing, editing and stability, and plays a role in maintenance of cell viability. Such diverse actions allow the SND1 to modulate a complex array of molecular networks, thereby promoting carcinogenesis. Here, we describe the crucial role of SND1 in cancer development and progression, and highlight SND1 as a potential target for therapeutic intervention.

Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model.

Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality and poor prognosis. Oncogenic transcription factor Late SV40 Factor (LSF) plays an important role in promoting HCC. A small molecule inhibitor of LSF, Factor Quinolinone Inhibitor 1 (FQI1), significantly inhibited human HCC xenografts in nude mice without harming normal cells. Here we evaluated the efficacy of FQI1 and another inhibitor, FQI2, in inhibiting endogenous hepatocarcinogenesis. HCC was induced in a transgenic mouse with hepatocyte-specific overexpression of c-myc (Alb/c-myc) by injecting N-nitrosodiethylamine (DEN) followed by FQI1 or FQI2 treatment after tumor development. LSF inhibitors markedly decreased tumor burden in Alb/c-myc mice with a corresponding decrease in proliferation and angiogenesis. Interestingly, in vitro treatment of human HCC cells with LSF inhibitors resulted in mitotic arrest with an accompanying increase in CyclinB1. Inhibition of CyclinB1 induction by Cycloheximide or CDK1 activity by Roscovitine significantly prevented FQI-induced mitotic arrest. A significant induction of apoptosis was also observed upon treatment with FQI. These effects of LSF inhibition, mitotic arrest and induction of apoptosis by FQI1s provide multiple avenues by which these inhibitors eliminate HCC cells. LSF inhibitors might be highly potent and effective therapeutics for HCC either alone or in combination with currently existing therapies.