Different Types Of Malignancies Research Articles

Abstract 4989: Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer

Abstract Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases. The CDK12/cyclin K complex regulates the elongation step of RNA transcription by phosphorylating Ser2 on the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II, and selectively affects the expression of genes, such as BRCA1 and BRCA2, involved in DNA Damage Response (DDR). CDK12 mutations as well as overexpression have been reported in different types of malignancies, making it an attractive cancer target. In this study, a series of covalent CDK12 inhibitors were designed and profiled in biochemical and cellular assays. ISM6466A was identified as a lead compound, demonstrating good in vitro efficacy, ADME properties, safety pharmacology profile (e.g., CYP, hERG), and a reasonable in vivo PK profile. Biochemically, ISM6466A exhibited reasonable selectivity over other CDKs, and inhibited cell proliferation in a panel of tumor cell lines with IC50 values in the nanomolar range (e.g., IC50 of ~100nM in the TNBC and AML cell lines, SUM149PT and MV4-11, respectively). Cell-based assays showed that ISM6466A has a selective inhibitory action for the phosphorylation of Ser2 on the CTD, but not for that of Ser5 or Ser7. Notably, ISM6466A demonstrated excellent in vivo anti-tumor efficacy in the SUM149PT breast cancer CDX model (Tumor Growth Inhibition, TGI, of 114% at 60 mg/kg QD) and in the MV4-11 AML CDX model (TGI of 95% at 30 mg/kg QD), without body weight loss. Data from an endpoint PKPD study in the MV4-11 CDX model revealed that ISM6466A inhibited phosphorylation of Ser2 on the CTD, and also inhibited DDR genes such as BRCA1 and ATR. Results from a 28-day rat DRF study revealed that the compound did not show evident signs of toxicity at the tested doses, suggesting a reasonable safety window for ISM6466A.In summary, the novel, covalent, small-molecule CDK12 inhibitor, ISM6466A, demonstrated excellent preclinical efficacy along with favorable drug-like properties. Our results underscore the therapeutic potential of ISM6466A for the treatment of cancer. Citation Format: Lihua Min, Hongfu Lu, Yihong Zhang, Jianping Wu, Xin Cai, Min Zheng, Hui Cui, Junwen Qiao, Xiao Ding, Sujata Rao, Feng Ren, Alex Zhavoronkov. Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4989.

U-shaped association between serum IGF2BP3 and T2DM: A cross-sectional study in Chinese population.

To clarify the expression of N6-methyladenosine (m6 A) modulators involved in the pathogenesis of type 2 diabetes mellitus (T2DM). We further explored the association of serum insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) levels and odds of T2DM in a high-risk population. The gene expression data set GSE25724 was obtained from the Gene Expression Omnibus, and a cluster heatmap was generated by using the R package ComplexHeatmap. Differential expression analysis for 13 m6 A RNA methylation regulators between nondiabetic controls and T2DM subjects was performed using an unpaired t test. A cross-sectional design, including 393 subjects (131 patients with newly diagnosed T2DM, 131 age- and sex-matched subjects with prediabetes, and 131 healthy controls), was carried out. The associations between serum IGF2BP3 concentrations and T2DM were modeled by restricted cubic spline and logistic regression models. Two upregulated (IGF2BP2 and IGF2BP3) and 5 downregulated (methyltransferase-like 3 [METTL3], alkylation repair homolog protein 1 [ALKBH1], YTH domain family 2 [YTHDF2], YTHDF3, and heterogeneous nuclear ribonucleoprotein [HNRNPC]) m6 A-related genes were found in islet samples of T2DM patients. A U-shaped association existed between serum IGF2BP3 levels and odds of T2DM according to cubic natural spline analysis models, after adjustment for body mass index, waist circumference, diastolic blood pressure, total cholesterol, and triglyeride. Multivariate logistic regression showed that progressively higher odds of T2DM were observed when serum IGF2BP3 levels were below 0.62 ng/mL (odds ratio 3.03 [95% confidence interval 1.23-7.47]) in model 4. Seven significantly altered m6 A RNA methylation genes were identified in T2DM. There was a U-shaped association between serum IGF2BP3 levels and odds of T2DM in the general Chinese adult population. This study provides important evidence for further examination of the role of m6 A RNA methylation, especially serum IGF2BP3 in T2DM risk assessment.

Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential.

Cisplatin (CP) is a broad-spectrum antineoplastic agent, used to treat many different types of malignancies due to its high efficacy and low cost. However, its use is largely limited by acute kidney injury (AKI), which, if left untreated, may progress to cause irreversible chronic renal dysfunction. Despite substantial research, the exact mechanisms of CP-induced AKI are still so far unclear and effective therapies are lacking and desperately needed. In recent years, necroptosis, a novel subtype of regulated necrosis, and autophagy, a form of homeostatic housekeeping mechanism have witnessed a burgeoning interest owing to their potential to regulate and alleviate CP-induced AKI. In this review, we elucidate in detail the molecular mechanisms and potential roles of both autophagy and necroptosis in CP-induced AKI. We also explore the potential of targeting these pathways to overcome CP-induced AKI according to recent advances.

Clinical and Immunologic Characteristics of Non-Hematologic Cancers in Patients with Inborn Errors of Immunity.

Inborn errors of immunity (IEI) are a heterogeneous group of inherited disorders, and almost 500 genes associated with these disorders have been identified. Defects in IEI genes lead to diverse clinical manifestations including increased susceptibility to recurrent or prolonged infections, immune dysregulation phenotypes (such as severe atopy, allergy, autoimmunity, and uncontrolled inflammation, lymphoproliferation), as well as predisposition to malignancies. Although the majority of IEI patients present hematologic cancers, the characteristics of other types of cancers are not well described in these groups of patients. By investigating 5384 IEI patients registered in the Iranian national registry the clinical and immunologic phenotypes of patients with non-hematologic cancers were compared with other malignant and non-malignant patients. Solid tumors were reported <20% of malignant IEI patients (n = 27/144 patients) and appeared to be very heterogeneous by type and localization as well as molecular defects (mainly due to DNA repair defect resulted from ATM deficiency). The correlation between the type of malignancy and survival status was remarkable as patients with non-hematologic cancers survive higher than IEI patients with hematologic cancers. Our findings showed that different types of malignancy could be associated with specific entities of IEI. Therefore, the education of physicians about the risk of malignancies in IEI is required for personalized treatment and appropriate management of patients.

Different Tumor Types Share a Common Nuclear Map of Chromosome Territories.

Different tumor types are characterized by unique histopathological patterns including distinctive nuclear architectures. I hypothesized that the difference in nuclear appearance is reflected in different nuclear maps of chromosome territories, the discrete regions occupied by individual chromosomes in the interphase nucleus. To test this hypothesis, I used interchromosomal translocations (ITLs) as an analytical tool to map chromosome territories in 11 different tumor types from the TCGA PanCancer database encompassing 6003 tumors with 5295 ITLs. For each chromosome I determined the number and percentage of all ITLs for any given tumor type. Chromosomes were ranked according to the frequency and percentage of ITLs per chromosome. The ranking showed similar patterns for all tumor types. Chromosomes 1, 8, 11, 17, and 19 were ranked in the top quarter, accounting for 35.2% of 5295 ITLs, whereas chromosomes 13, 15, 18, 21, and X were in the bottom quarter, accounting for only 10.5% ITLs. The correlation between the chromosome ranking in the total group of 6003 tumors and the ranking in individual tumor types was significant, ranging from P < .0001 to .0033. Thus, contrary to my hypothesis, different tumor types share a common nuclear map of chromosome territories. Based on the large number of ITLs in 11 different types of malignancy one can discern a shared pattern of chromosome territories in cancer and propose a probabilistic model of chromosomes 1, 8, 11, 17, 19 in the center of the nucleus and chromosomes 13, 15, 18, 21, X at the periphery.

The significance of preoperative thrombocytosis in ovarian cancer patients

The presence of an increased number of platelets has been demonstrated to be significantly associated with the presence of different types of malignancies, especially when it comes to gynecological cancers and seems to be associated with a poorer prognosis. This fact has been widely studied in order to better understand the physiopathology of the phenomenon, the impact on the overall outcomes and to validate new therapeutic lines for such cases. The aim of the current paper is to review the most important studies conducted on this issue.

Cancer risks in rheumatoid arthritis patients who received immunosuppressive therapies: Will immunosuppressants work?

Exploring the cancer risks of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARDs) can help detect, evaluate, and treat malignancies at an early stage for these patients. Thus, a comprehensive analysis was conducted to determine the cancer risk of RA patients using different types of DMARDs and analyze their relationship with tumor mutational burdens (TMBs) reflecting immunogenicity. A thorough search of PubMed, EMBASE, Web of Science, and Medline was conducted up to 20 August 2022. Standardized incidence ratios (SIRs) were constructed with a random-effect model to determine risks for different types of malignancies in comparison with the general population. We also analyzed the correlation between SIRs and TMBs using linear regression (LR). From a total of 22 studies, data on 371,311 RA patients receiving different types of DMARDs, 36 kinds of malignancies, and four regions were available. Overall cancer risks were 1.15 (SIR 1.15; 1.09-1.22; p < 0.001) and 0.91 (SIR 0.91; 0.72-1.14; p = 0.402) in RA populations using conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs), respectively. RA patients taking csDMARDs displayed a 1.77-fold lung cancer risk (SIR 1.77; 1.50-2.09; p < 0.001), a 2.15-fold lymphoma risk (SIR 2.15; 1.78-2.59; p < 0.001), and a 1.72-fold melanoma risk (SIR 1.72; 1.26-2.36; p = 0.001). Correlation coefficients between TMBs and SIRs were 0.22 and 0.29 from those taking csDMARDs and bDMARDs, respectively. We demonstrated a cancer risk spectrum of RA populations using DMARDs. Additionally, TMBs were not associated with elevated cancer risks in RA patients following immunosuppressive therapy, which confirmed that iatrogenic immunosuppression might not increase cancer risks in patients with RA. Changes were similar in cancer risk after different immunosuppressive treatments, and there was a lack of correlation between SIRs and TMBs. These suggest that we should look for causes of increased risks from the RA disease itself, rather than using different types of DMARDs.

Adipositas aus viszeralonkologischer Perspektive

Up to 40% of all adults worldwide are overweight or obese. Besides the established obesity-related comorbidities, such as type 2 diabetes mellitus, hypertension or NAFLD (non-alcoholic fatty liver disease), the focus of interest is shifting towards the influence of increased body weight as a risk factor for the development of malignant diseases. For more than 20 different types of malignancies, interactions between increased body weight and cancer risk have been established. Pathophysiological influences of obesity on carcinogenesis are diverse, including factors such as chronic inflammation, hyperinsulinaemia and insulin resistance, various changes in growth factor and changes in sex hormones. In cohorts of visceral oncology patients, malignancies such as colorectal carcinomas, hepatocellular carcinomas, adenocarcinomas of the pancreas, oesophageal and gastric carcinomas are also linked to an increased disease risk with increasing body weight. Since obesity must be considered a preventable or at least treatable cause of cancer, this review examines the influence of obesity in the field of visceral oncology, examining the effects of obesity on tumour prevalence, prevention and diagnostic testing, as well as its influence on treatment and prognosis. Furthermore, this review explores the current evidence on the influence of bariatric surgery on the prevalence of these obesity associated tumours. For example, in the case of colorectal carcinomas, the evidence base following bariatric surgery is mixed, painting an inhomogeneous picture. On the other hand, significantly lower prevalence of pancreatic adenocarcinoma and hepatocellular carcinomas is to be noted. The latter effect can be explained by the decrease in non-alcoholic fatty liver disease (NAFLD) associated with weight loss. Despite the justified concern that bariatric procedures (especially gastric sleeve resection) lead to increased prevalence of malignancies of the oesophageal junction, the currently available epidemiological data does not seem to identify a relevant increase in the incidence of these malignancies.

Identification of eIF6 as a prognostic factor that drives tumor progression and predicts arsenic trioxide efficacy in lung adenocarcinoma

BackgroundLung cancer is the leading cause of cancer-related mortality worldwide. Dysregulation of mRNA translation can contribute to the development and progression of cancer whilst also having an impact on the prognosis of different types of malignancies. Eukaryotic translation initiation factors (eIFs) have been reported to serve a key role in the initiation of mRNA translation. However, little was known about the association between eIF6 and lung adenocarcinoma (LUAD) progression. We aimed to elucidate the roles of eIF6 in LUAD tumorigenesis.MethodsBioinformatic analysis was conducted to assess the clinical significance of eIF6 in LUAD. CCK-8, colony formation assays were used to evaluate the biological roles of eIF6. The subcutaneous model was used to assess the in vivo roles of eIF6.ResultsIn the present study, it was found that eIF6 expression was significantly higher in LUAD samples compared with that in normal lung tissues. Higher expression levels of eIF6 were found to be associated with more advanced clinical stages of LUAD and poorer prognoses in patients with LUAD. Subsequently, overexpression of eIF6 was demonstrated to promote LUAD cell proliferation, migration and invasion, which are features of metastasis, in vitro. By contrast, inhibition of eIF6 induced cell cycle arrest and apoptosis in LUAD cells. Further bioinformatics analysis and experimental assays revealed that eIF6 expression positively correlated with the mRNA expression of stemness-associated genes in LUAD cells. Targeting eIF6 suppressed the sphere formation capacity of LUAD cells. In addition, data from the subcutaneous xenograft model in vivo also suggested that eIF6 deficiency could significantly delay tumor growth and improve the prognosis of mice. Targeting eIF6 rendered LUAD cells sensitive to arsenic trioxide treatment.ConclusionThe present study suggest that eIF6 can serve as a prognostic biomarker and a potential therapeutic target for patients with LUAD.

Comprehensive Analysis Reveals PTK6 as a Prognostic Biomarker Involved in the Immunosuppressive Microenvironment in Breast Cancer.

The significant mortality rate that is currently experienced by female breast cancer (BC) patients highlights the importance of locating potent and dependable biomarkers in BC patients. Over the past few years, a number of studies have demonstrated that PTK6 was dysregulated in a variety of cancers. However, its expression and the clinical importance it may have in patients with BC have not been explored. Based on datasets from the TCGA database and GTEx database, we studied the expressions and functions of PTK6 across 33 different kinds of cancer. In this study, we investigated the differential expression of PTK6 in tumor tissue compared to nontumor tissue as well as in various stages of cancer. ROC assays were used to conduct an investigation into the diagnostic potential of PTK6 in BC. After that, the Kaplan-Meier method, univariate analysis, and multivariate analysis were carried out in order to investigate the PTK6 gene's potential prognostic significance in patients with BC. ssGSEA was utilized in order to conduct an investigation of the immune infiltration. In this study, we discovered that the expressions of PTK6 were significantly raised in the majority of different types of malignancies, including BC. The diagnostic value of PTK6 expression was validated by ROC tests, demonstrating an AUC greater than 0.7. A positive PR, ER, and HER2 status was found to be related with high expression levels of PTK6. According to the results of a survival analysis, patients who had a high level of PTK6 expression had a shorter overall survival time than those who had a low level of PTK6 expression. Besides, we observed that PTK6 expressions were positively correlated with the abundance of NK CD56bright cells and Th17 cells and negatively correlated with that of Th1 cells, macrophages, B cells, T cells, aDC, DC, cytotoxic cells, Tem, TFH, NK CD56dim cells, Treg, and Tgd. In conclusion, PTK6 expression was found to be linked with the clinical phenotype of BC, and as a result, this finding may have consequences for the diagnosis, prognosis, and treatment of individuals with BC.

Multiple Cancer Combating by Natural Bioactives: A Review

Background: Significant progress in the field of anticancer research has led to a rise in the study of bioactive chemicals with potential anticancer effects. Still, many bioactive natural chemicals must be investigated in order to generate more effective anti-cancer therapeutics. Outline: There have been many attempts to treat cancer, and this review summarizes many bioactive substances obtained from nature that have the ability to fight against different types of malignancies with minimal harm, based on diverse research. Polyphenolic flavonoids, carotenoid (fucoxanthin), tannin, and other notable natural bioactive with anticancer potential were examined and reviewed systematically with an eye toward their significance in many types of cancer treatment. Conclusion: Throughout the text, it was concluded that the natural bioactive play a very prominent role in combating different types of cancer, and the information related to the bioactive role in cancer treatment over the last 10 years was gathered from several research and review articles. The material kept in this paper can act as a template for future research in expressing the more beneficial role of other bioactive in acting as an adjuvant in chemotherapy practice for prevention and treatment of various cancer additionally with no or minimal adverse effects which are prominent with the conventional drugs used for the treatment of cancer.

Let-7 microRNAs Are Possibly Associated with Perineural Invasion in Colorectal Cancer by Targeting IGF Axis.

Increased insulin-like growth factor (IGF) axis activity is associated with the development and progression of different types of malignancies, including colorectal cancer (CRC). MicroRNAs (miRNAs) belonging to the let-7 family have been reported to target genes involved in this axis and are known as tumor suppressors. In this study, in silico bioinformatic analysis was performed to assess miRNA–mRNA interactions between eight miRNAs belonging to the let-7 family and genes involved in the IGF signaling pathway, coding for receptors and substrates. miRNAs’ expression analysis revealed that hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let- 97 7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, and hsa-let-7g-5p were significantly down-regulated in 25 CRC tumoral tissues (T) compared to the corresponding adjacent peritumoral tissues (PT). Moreover, our results showed an upregulation of miR-let-7e-5p in CRC tissues with mutations in KRAS codon 12 or 13, and, for the first time, found a specific dysregulation of let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, and let-7i-5p in CRC with perineural invasion. Our results sustain the relationship between the IGF axis, let-7 miRNAs, and CRC and suggest an association between the expression of these miRNAs and perineural invasion.

To Study the Prevalence and Severity of Anemia in Solid Malignancy Patients

Background: Anemia in solid malignancy may be due to tumor-associated bleeding, hemolysis, hypersplenism, reduced production of EPO, nutritional deficiencies, bone marrow failure and toxicity associated with therapies which increases the mortality. Aim: To study the prevalence and severity of anemia in solid malignancy patients. Methods: Hospital based -cross sectional study done on patients above 18 years with solid malignancy with elevated C-reactive protein level (CRP). Sample size was 50.Complete blood count, peripheral smear and CRP were measured. Results: Among 50 patients, the overall prevalence of anemia in solid malignancy with elevated CRP was 100%. The mean hemoglobin was lower in female patients 8.2 ± 1.40 g/dl (mean±SD) compared with male patients 8.4 ± 2.01g/dl (mean±SD). 62% patients were having elevated CRP value ranges from 0.6mg/dl to 1 mg/dl with a mean hemoglobin of 8.3 ± 1.32 (mean±SD) and 38% were having CRP of more than 1mg/dl with a mean hemoglobin of 8.1 ± 1.02 (mean±SD). Among the different types of malignancy, colorectal and gynecological tract group were found to have low mean hemoglobin value of 7.8 ± 1.04 (mean±SD) and 7.9 ± 1.13 (mean±SD).Most of them were having moderate anemia (70%) and normocytic normochromic anemia (78%). Conclusion: The overall prevalence of anemia in solid malignancy patients with elevated inflammatory marker like CRP was 100%. Most of them were having moderate anemia (70%), normocytic normochromic type (78%). Keywords: Anemia, Solid malignancy, Hemoglobin.

Abstract PO031: Cannabidiol inhibits cell viability and induces apoptosis in hepatocellular carcinoma cell lines: The interplay between apoptosis and autophagy

Abstract Hepatocellular carcinoma (HCC) is the most common model of liver cancer representing approximately 75% of all liver cancer types. In HCC, a complex molecular interplay involving multiple signaling pathways such as β-catenin, STAT3, and S6k1 signals have found attributed to the development of HCC. The hindrance of such signals has been recorded as a robust therapeutic tool in many different types of malignancies. Cannabinoids (CBDs) have been emphasized with its promising therapeutic properties against numerous types of cancers. Recently, we reported that CBD has been recognized for its wide spectrum therapeutic activity as an anti-cancer for both ER (+) and Triple (-) human breast cancer cells. Herein, to investigate the antitumor activity of CBD on HCC viability and proliferation, two different liver cancer cell lines, Hep-G2 and Hep-3B, were used. Cells were treated with different concentrations of CBD increasingly and the protein expression levels of oncogenic and pro-survival signals β-catenin, STAT3 and S6K1 were detected, using the western blotting analysis. In both cell lines, CBD inhibited cell survival in a dose dependent manner as observed by Wst-1 assay and induced apoptosis, showing a significant enhancement of caspase-3 activity as well as histone release, and DNA fragmentation. Cells viability inhibition was confirmed by the morphological changes that was detected after CBD treatment for 48h. Furthermore, CBD-induced apoptosis was accompanied by down-regulation of pro-survival oncogenic expression of β-catenin, STAT3 and S6K1 in the both cell lines comparing to the untreated control cells. The crosstalk between the autophagic and apoptotic signaling pathways was also investigated and we found that beclin1 is essential for CBD-mediated apoptosis in HepG2 cells. In addition, CBD enhances the interaction between beclin1 and Vps34 that inhibits the association between beclin1 and Bcl-2, triggers the translocation of BID to the mitochondria, releases cytochrome c to the cytosol, and finally activates the intrinsic apoptotic pathway in HepG2 cells. CBD increased the generation of reactive oxygen species (ROS) and using ROS inhibitors significantly decrease the induction of apoptosis and autophagy. All in all, our data revealed an intricate interplay between apoptosis and autophagy in CBD-treated HCC cell lines, suggesting that CBD treatment induces an interplay among β-catenin, STAT3 and S6K1 in favor of apoptosis induction in both Hep-G2 and Hep-3B cells, introducing CBD as a promising treatment for different liver cancer subtypes. Citation Format: Islam Yahiya, Kamal Kandiel, Ahmed Sultan. Cannabidiol inhibits cell viability and induces apoptosis in hepatocellular carcinoma cell lines: The interplay between apoptosis and autophagy [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO031.

High sustained virologic response rate after 8 weeks of direct-acting antivirals in cancer patients with chronic hepatitis C virus.

There is no prospective data on 8 weeks of direct-acting antivirals (DAA) therapy with glecaprevir/pibrentasvir (GLE/PIB) or ledipasvir/sofosbuvir (LDV/SOF) in hepatitis C virus (HCV)-infected patients with different types of malignancies. This study evaluated the efficacy and safety with 8 weeks of DAA therapy in cancer patients with chronic HCV infection. Patients treated with DAAs at our center during 2014-2021 were included in a prospective observational study. Efficacy (sustained virologic response at 12 weeks; SVR12) and safety [adverse events and clinically significant drug-drug interactions (DDIs)] were assessed. We included 47 patients. Most were men (29; 62%), white (33; 70%), non-cirrhotic (45; 96%), and with HCV genotype 1 (38; 85%). None of the patients had HCC. The SVR12 rate was 96% (45/47; 95% CI: 86-99%) for the entire study cohort, 100% [17/17; 95% CI: 82-100%] for the patients treated with GLE/PIB and 93% [28/30; 95% CI: 79-98%] for the patients treated with LDV/SOF. Fisher's exact test showed no significant difference in SVR12 rates between the regimens (P = 0.53). No patients had serious adverse events (grade 3-4) or treatment discontinuation. Among the 17 patients who received concomitant cancer therapy, no DDIs occurred. Eight weeks of DAA therapy is highly effective and safe in HCV-infected patients with different types of malignancies and may grant access to investigational cancer therapy, broadening treatment options.

Identification of ISCA1 as novel immunological and prognostic biomarker for bladder cancer.

BackgroundIron-sulfur cluster assembly 1 (ISCA1) has a significant effect on respiratory complexes and energy metabolism. Although there is some evidence that ISCA1 gene expression impacts energy metabolism and consequently has a role in tumorigenesis and cancer metastasis in different types of malignancies, no systematic pan-cancer study of the ISCA1 has been conducted. As a result, we sought to investigate ISCA1’s predictive value in 33 cancer types as well as its possible immunological function.MethodsWe included the pan-cancer expression profile dataset and clinical data from the public database. Firstly, the single-sample Gene Set Enrichment Analysis (ssGSEa) approach was employed for analyzing the immune link in pan-cancer, while the limma package was utilized for analyzing the differential expression in cancer species. Subsequently, ciberport, MCP-counter, TIMER2, quanTIseq, and xCELL were employed for analyzing bladder cancer (BLCA)’s immune infiltration. Least absolute shrinkage and selection operator (Lasso) were employed for choosing the best gene to develop the immune risk scoring model.Results ISCA1 gene expression was positively related to four immune signatures (chemokine, immunostimulator, MHC, and receptor) in BLCA. Samples of BLCA were sorted into two groups by the best cut-off of ISCA1 expression degree. The group with a high level of ISCA1 expression had a higher risk, suggesting that the ISCA1 gene was a risk factor in BLCA, and its high expression resulted in a poorer prognosis. Additionally, it was noted that ISCA1 was positively linked with these immune checkpoints. Moreover, there was a considerable positive link between ISCA1 and different immune properties in subgroups with different immune checkpoint inhibiting responses. Finally, an immune risk scoring model was made and it showed a better score in comparison to that of TIDE.Conclusion ISCA1 can be a prognostic marker for a variety of cancers, particularly BLCA. Its high level of expression has a deleterious impact on the prognosis of BLCA patients. This strongly shows that ISCA1 is a significant prognostic factor for BLCA and that it could be used as a new prognostic detection target and treatment approach.

Identification of NEK7 inhibitors: structure based virtual screening, molecular docking, density functional theory calculations and molecular dynamics simulations

NEK7 is a NIMA related-protein kinase that plays a crucial role in spindle assembly and cell division. Dysregulation of NEK7 protein leads to development and progression of different types of malignancies including colon and breast cancers. Therefore, NEK7 could be considered as an attractive target for anti-cancer drug discovery. However, few efforts have been made for the development of selective inhibitors of NIMA-related kinase but still no FDA approved drug is known to selectively inhibit the NEK7 protein. Dacomitinib and Neratinib are two Enamide derivatives that were approved for treatment against non-small cell lung cancer and breast cancer respectively. Drug repurposing is a time and cost-efficient method for re-evaluating the activities of previously authorized medications. Thus, the present research involves the repurposing of two FDA-approved medications via comprehensive in silico approach including Density functional theory (DFTs) studies which were conducted to determine the electronic properties of the Dacomitinib and Neratinib. Afterward, binding orientation of selected drugs inside NEK7 activation loop was evaluated through molecular docking approach. Selected drugs exhibited potential molecular interactions engaging important amino acid residues of active site. The docking score of Dacomitinib and Neratinib was –30.77 and –26.78 kJ/mol, respectively. The top ranked pose obtained from molecular docking was subjected to Molecular Dynamics (MD) Simulations for investigating the stability of protein-ligand complex. The RMSD pattern revealed the stability of protein-ligand complex throughout simulated trajectory. In conclusion, both drugs displayed inhibitory efficacy against NEK7 protein and provide a prospective therapy option for malignant malignancies linked with NEK7.

In-hospital prognosis of malignancy-related pulmonary embolism: an analysis of the national inpatient sample 2016-2018.

A substantial proportion of patients with malignancy develop pulmonary embolism (PE), which significantly worsens the prognosis and ranks as one of the leading causes of mortality in these patients. This retrospective study aimed to examine prognosis of PE in 17 different types of malignancies. All hospitalizations for a primary diagnosis of PE, were identified from the National Inpatient Sample from 2016 to 2018 and divided into those with and without malignancies. Propensity score matching was performed with malignancy as the dependent variable and 23 clinically relevant covariates. Malignancy was stratified into 17 different types of cancer, for which the odds of in-hospital mortality were calculated. After propensity score matching, 82,970 hospitalizations for PE each were allocated into those with and without malignancy groups. PE in all types of malignancies had significantly higher odds of in-hospital mortality compared to PE without malignancy (OR 2.27, 95% CI 2.03-2.54). When stratified to types, esophageal cancer (OR 4.05, 95% CI 2.77-5.92) was associated with the highest odds of in-hospital mortality, followed by gastric (OR 3.41, 95% CI 2.25-5.16) and ovarian cancer (OR 2.95, 95% CI 2.12-4.13). On sensitivity analysis, only PE in esophageal and lung cancer was associated with higher odds of in-hospital mortality compared to PE in all other malignancies combined. Hospitalizations for PE in patients with malignancy were associated with higher odds of in-hospital mortality than those without malignancy. Esophageal cancer had the highest odds of in-hospital mortality, followed by gastric, ovarian, and lung cancer.

Beta-adrenergic receptor blockers and hepatocellular carcinoma survival: a systemic review and meta-analysis.

Preclinical data have revealed that beta-adrenergic stimulation can affect the growth and progression of different types of malignancies. Beta-adrenergic receptor blockers have been associated with improved survival in patients with many types of cancer. We performed a meta-analysis to investigate the association between beta-blocker use and hepatocellular carcinoma (HCC) prognosis. In this meta-analysis, a full search was conducted using PubMed, the Cochrane library and Embase to identify all relevant studies published up to May 2021. Available hazard ratios (HRs) were extracted for overall survival (OS), cancer-specific survival (CSS) and pooled using a random-effects meta-analysis. Four studies involving 7252 patients with HCC met the inclusion criteria and were included in the systemic review. Three studies that reported OS data of 5148 patients were included in the meta-analysis. The random-effects model showed that beta-blocker use was associated with significantly improved OS in HCC (HR = 0.69, 95% CI = 0.54-0.88, P = 0.0031), without significant heterogeneity (I2 = 41%; Q = 6.42, P = 0.18). This meta-analysis suggested that beta-blocker use can be associated with prolonged OS of patients with HCC.

Abstract 846: Transcriptional regulation of Aurora-B kinase expression in B-cell acute lymphoblastic leukemia (B-ALL)

Abstract The Aurora kinases are serine/threonine kinases that are essential for mitosis. Aurora-B kinase is a component of the chromosomal passenger complex (CPC), chromosome condensation, the spindle-assembly checkpoint, and for cytokinesis. The activity of Aurora-B is essential for cellular division and proliferation. Inhibition of Aurora-B is cytotoxic, and inhibitor of Aurora-B - Barasertib (AZD1152) has been tested in clinical trials against different types of malignancies, including leukemia. However, regulation of Aurora-B expression is still largely unknown. Here, we present evidence that expression of Aurora-B in B-cell acute lymphoblastic leukemia (B-ALL) is regulated at the transcriptional level by Ikaros, a transcription factor and tumor suppressor protein. Analysis of global chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) in several B-ALL primary human B-ALL cells and cell lines, showed a strong enrichment of Ikaros at the promoter of the Aurora-B gene. Ikaros functions as a tumor suppressor protein and deletion of Ikaros is associated with development of high-risk B-ALL. Ikaros binding to Aurora-B promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP) in primary B-ALL cells. The role of Ikaros in regulating Aurora-B transcription in B-ALL was tested using gain-of-function and loss-of-function experiments. Overexpression of Ikaros in human B-ALL was associated with strongly reduced transcription and overall expression of Aurora-B. Ikaros knock-down with shRNA results in increased expression of Aurora-B in B-ALL. Since Ikaros function in B-ALL is negatively regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 can regulate expression of Aurora-B in B-ALL. Overexpression of CK2 via retroviral transduction resulted in increased expression of the Aurora-B gene. Increased expression of CK2 was associated with a loss of Ikaros binding to the Aurora-B gene promoter. Molecular inhibition of CK2 using shRNA resulted in reduced expression of Aurora-B in human B-ALL. Inhibition of CK2 was associated with increased Ikaros binding at the Aurora-B promoter. Ikaros knock-down abolished downregulation of Aurora-B expression in B-ALL cells following treatment with CK2 inhibitors. These data demonstrate that CK2 and Ikaros are critical regulators of Aurora-B expression in B-ALL. In conclusion, these results indicate that expression of the Aurora-B gene in B-ALL is regulated by the CK2-Ikaros signaling axis and provide a novel insight into mechanisms that regulate mitosis in leukemia. Citation Format: Yali Ding, Chunhua Song, Joseph Schramm, Soumya Maru, Daniel Bogus, Dhimant H. Desai, Arati K. Sharma, Chandrika Gowda, Sinisa Dovat. Transcriptional regulation of Aurora-B kinase expression in B-cell acute lymphoblastic leukemia (B-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 846.