Altered Gene Research Articles

Serum tsncRNAs reveals novel potential therapeutic targets of Salvianolic Acid B on atherosclerosis

BackgroundSalvianolic Acid B (SalB) has been proven to delay the progression of atherosclerosis. The therapeutic mechanisms of this compound are unclear. A novel class of short non-coding RNAs, pre-transfer RNA and mature transfer RNA (tsncRNAs) may regulate gene expression. TsncRNAs-sequencing revealed novel therapeutic targets for SalB. This is the first study focusing on tsncRNAs to treat atherosclerosis using SalB. PurposeTo explore the potential mechanism of SalB treating atherosclerosis through tsncRNAs. MethodsFive groups of mice were created at random: control group (CON), atherosclerosis model group (MOD), SalB with high dose-treated group (SABH), SalB with low dose-treated group (SABL), and Simvastatin-treated group (ST). Aortic sinus plaque, body weight and inflammatory cytokines were evaluated. The Illumina NextSeq equipment was used to do expression profiling of tsncRNAs from serum. The targets of tsncRNAs were then predicted using tRNAscan and TargetScan. The KEGG pathway and GO analysis were utilized to forecast the bioinformatics analysis. Potential tsncRNAs and associated mRNAs were validated using quantitative real-time PCR. ResultstRF-Glu-CTC-014 and tRF-Gly-GCC-074 were markedly increased by SalB with high dose treatment and validated with quantitative real-time PCR. Two mRNAs SRF and Arrb related to tRF-Glu-CTC-014 changed consistently. GO analysis revealed that the altered target genes of the selected tsncRNAs were most enriched in protein binding and cellular process. Moreover, KEGG pathway analysis demonstrated that altered target genes of tsncRNAs were most enriched in MAPK signaling pathway. ConclusionSalB can promote the expression of tRF-Glu-CTC-014 to treat atherosclerosis.

Real-world assessment of comprehensive genome profiling impact on clinical outcomes: A single-institution study in Japan.

Comprehensive genome profiling (CGP) has revolutionized healthcare by offering personalized medicine opportunities. However, its real-world utility and impact remain incompletely understood. This study examined the extent to which CGP leads to genomically matched therapy and its effectiveness. We analyzed data from advanced solid tumor patients who underwent CGP panel between December 2019 and May 2023 at the Osaka International Cancer Institute. Patient demographics, specimen details, and expert panel assessments were collected. Turnaround time (TAT) and genomically matched therapy outcomes were analyzed. Gene alterations and their co-occurrence patterns were also assessed. Among 1437 patients, 1096 results were available for analysis. The median TAT was 63 [28-182] days. There were 667 (60.9%) cases wherein recommended clinical trials were presented and there were 12 (1.1%) cases that could be enrolled in the trial and 25 (2.3%) cases that could lead to therapies under insurance reimbursement. The median progression free survival of the trial treatment was 1.58 months (95% CI: 0.66-4.37) in clinical trials and 3.66 months (95% CI: 2.14-7.13) in treatment under insurance. Pathologic germline variants were confirmed in 15 patients (1.3%). Co-alteration of CDKN2A, CDKN2B, and MTAP was significantly observed in overall population. The effectiveness of the genomically matched therapy based on the CGP panel was unsatisfactory. Expansion of clinical trials and utilization of remote clinical trials are required to ensure that the results of the CGP panel can be fully returned to patients.

Multifaceted Understandings of Cancer: A Review of Disease Mechanisms and Therapies

Abstract: Cancer is a condition in which aberrant cells continue to divide uncontrollably, causing tissue to be destroyed. Different cancer stages have been identified by researchers, suggesting that a number of gene alterations are involved in the etiology of cancer. Unusual cell proliferation is brought on by these gene alterations. A crucial role in the acceleration of cell proliferation is played by genetic diseases brought on by heredity or hereditary factors. Its diagnosis and treatment have historically been regarded as two of the most important and significant clinical concerns. Depending on the nature and stage of the tumor, numerous ways to its corrective therapy have been established. Numerous biomolecules derived from plants are crucial for the treatment of the disease. In this review, we focus on specific aspects to give a brief overview of the major problems, including their etiology, therapies that are available, herbal alternates, available vaccines and relevant biomarkers. It was felt that much work needs to be done on combination therapy development and platform optimization.

A bHLH transcription factor AaMYC2-type positively regulates glandular trichome density and artemisinin biosynthesis in Artemisia annua.

Artemisinin-based combinational therapies (ACTs) constitute the first line of malaria treatment. However, due to its trichome-specific biosynthesis, low concentration, and poor understanding of regulatory mechanisms involved in artemisinin biosynthesis and trichome development, it becomes very difficult to meet the increased demand for ACTs. Here, we have reported that a bHLH transcription factor, AaMYC2-type, plays an important role in regulating GST development and artemisinin biosynthesis in Artemisia annua. AaMYC2-type encodes a protein that is transcriptionally active and localised to the nucleus. It is prominently expressed in aerial parts like leaves, stems, inflorescence and least expressed in roots. AaMYC2-type expression is significantly increased under different hormonal treatments. In transgenic overexpression lines, AaMYC2-type OE, a significant increase in the expression of trichome development and artemisinin biosynthesis genes was observed. While in knockdown lines, Aamyc2-type, expression of trichome development and artemisinin biosynthesis genes were significantly reduced. Yeast one-hybrid assay clearly shows that the AaMYC2-type directly binds to the E-boxes in the promoter regions of ADS and CYP71AVI. The SEM microscopy depicted the number of trichomes elevated from 11 mm-2 in AaMYC2-type OE lines to 6.1 mm-2 in Aamyc2-type. The final effect of the alteration in biosynthetic and trichome developmental genes was observed in the accumulation of artemisinin. In the AaMYC2-type OE, the artemisinin content was 12 mg g-1DW, which was reduced to 3.2 mg g-1DW in the Aamyc2-type. Altogether, the above findings suggest that the AaMYC2-type play a dual regulating role in controlling both trichome developmental and artemisinin biosynthetic genes.

Transcriptomic Analysis of Cardiac Tissues in a Rodent Model of Coronary Microembolization.

Coronary microembolization (CME) can result in cardiac dysfunction, severe arrhythmias, and a reduced coronary flow reserve. Impairment of mitochondrial energy metabolism has been implicated in the progression and pathogenesis of CME; however, its role remains largely undetermined. This study aimed to explore alterations in mitochondria-related genes in CME. A rat model of CME was successfully established by injecting plastic microspheres into the left ventricle. The cardiac tissues of the two groups were sequenced and mitochondrial functions were assessed. Using RNA-Seq, together with GO and KEGG enrichment analyses, we identified 3822 differentially expressed genes (DEGs) in CME rats compared to control rats, and 101 DEGs were mitochondria-related genes. Notably, 36 DEGs were up-regulated and 65 DEGs were down-regulated (CME vs control). In particular, the oxidative phosphorylation (OXPHOS) and mitochondrial electron transport were obviously down-regulated in the CME group. Functional analysis revealed that CME mice exhibited marked reductions in ATP and mitochondrial membrane potential (MMP), by contrast, the production of reactive oxygen species (ROS) was much higher in CME mice than in controls. Protein-protein interaction (PPI) and quantitative PCR (qPCR) validation suggested that eight hub genes including Cmpk2, Isg15, Acsl1, Etfb, Ndufa8, Adhfe1, Gabarapl1 and Acot13 were down-regulated in CME, whereas Aldh18a1 and Hspa5 were up-regulated. Our findings suggest that dysfunctions in mitochondrial activity and metabolism are important mechanisms for CME, and mitochondria-related DEGs may be potential therapeutic targets for CME.

Sex- and age-associated factors drive the pathophysiology of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity. Sex and age affect MASLD prevalence and pathophysiology. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex-associated and age-associated mechanisms underlying the pathophysiology remain poorly understood. This knowledge gap limits the development of personalized sex-specific and age-specific drug treatments. Young (7wk) and aged (52wk) male and female mice were fed a high-fat diet (HFD) or low-fat diet. Liver metabolome (>600 molecules) and transcriptome profiles were analyzed. Male and female mice fed an HFD developed obesity, glucose intolerance, and hepatic steatosis. However, fasting blood glucose, insulin, and serum alanine aminotransferase levels were higher in males fed an HFD, indicating a more severe metabolic disease. In addition, males showed significant increases in liver diacylglycerides and glycosylceramides (known mediators of insulin resistance and fibrosis), and more changes in the transcriptome: extracellular matrix organization and proinflammatory genes were elevated only in males. In contrast, no major increase in damaging lipid classes was observed in females fed an HFD. However, aging affected the liver to a greater extent in females. Acylcarnitine levels were significantly reduced, suggestive of changes in fatty acid oxidation, and broad changes in the transcriptome were observed, including reduced oxidative stress response gene expression and alterations in lipid partitioning genes. Here, we show distinct responses to an HFD between males and females. Our study underscores the need for using both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals.

Age and Sex Affects the Frequency and Mutation Type of FGFR2 Alterations in Cholangiocarcinoma

PURPOSE FGFR2 alterations are infrequent but currently represent the most common targetable mutation in cholangiocarcinoma. We performed a large-scale genomic analysis to assess associations between FGFR2 and other driver gene alterations in cholangiocarcinoma with patient demographics. METHODS Clinical and molecular data for patients with intrahepatic cholangiocarcinoma were abstracted from the Foundation Medicine (FMI) and Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) genomic databases. The Chi-squared test was used to assess the association between sex and alterations in driver genes. FGFR2 fusion partners were analyzed using descriptive statistics. RESULTS Across both FMI (N = 7,859) and GENIE (N = 1,395) cohorts, FGFR2 rearrangements were more frequent in female than male patients with cholangiocarcinoma (odds ratio, 1.69 and 2.45). By contrast, FGFR2 missense mutations, TP53 mutations, and KRAS mutations were not associated with sex. Stratifying patients by age groups showed that FGFR2 rearrangements were specifically enriched in younger ages (<45 years). Although the most common FGFR2 fusion partners were shared across both sexes, a subset of fusion partners was recurrent and uniquely associated with female or male patients. CONCLUSION FGFR2 rearrangements but not other driver alterations in cholangiocarcinoma are concentrated in young female patients, where the prevalence reached nearly 20% across two large patient cohorts. These results suggest that the molecular basis of FGFR2 rearrangements may be distinct between sexes. These results indicate the importance of genetic testing in cholangiocarcinoma, particularly for younger patients, and suggest that patient recruitment strategies in trials for FGFR2-targeting therapies should seek to reduce barriers to enhance the enrollment of young female patients.

Zoledronic acid-treated rats show altered jaw histology and gene expression in non-exposed MRONJ

BackgroundDiagnosis and management of medication-related osteonecrosis of the jaws (MRONJ) prior to clinical exposure induced by trauma may lead to improved patient management. Currently, few studies have examined early histologic and molecular MRONJ-related changes in the jaws. PurposeThis study aimed to identify histological and gene expression changes in the maxilla and mandible of Sprague-Dawley (SD) rats after zoledronic acid (ZA) treatment. Study Design, Setting, and SampleThis was an in-vivo animal study. The experiments were conducted in the laboratory at the Stomatology Hospital of Tianjin Medical University. A total of 12 SD rats were included. Predictor variableThe predictor variable was ZA exposure. Twelve SD rats were divided into two groups: experimental (n = 6) and control (n = 6), and they were intraperitoneally injected with ZA and saline, respectively. Main outcome variableThe outcome variables were histological and molecular changes. The maxilla, mandible, and ilium bone tissue samples were examined using Masson's trichrome and hematoxylin-eosin staining. Gene expression changes were identified using transcriptome sequencing, Kyoto encyclopedia of genes and genomes (KEGG), and gene interactome network analysis. The key changes were validated using the quantitative real-time polymerase chain reaction and immunohistochemistry. CovariatesNone. AnalysesThe t-test, Chi-square test, and Fisher's exact probability method were used for statistical analyses using the Statistical package for the social sciences software (version 26.0). ResultsAll animals remained healthy during the experiments. Histological staining revealed that the percentage of empty bone lacunae in the maxilla and mandible was significantly higher than that in the ilium (P < 0.01). In total, 552 genes were screened using transcriptome sequencing. The sonic hedgehog (Shh) signaling pathway was highly enriched. The key gene for the Shh interaction was distal-less homeobox 5 (Dlx-5). The Shh, Dlx-5, and bone morphogenetic protein 2 genes and protein expression levels in the maxilla and mandible were higher in the experimental group than in the control group (P < 0.05). Conclusions and RelevanceMRONJ-induced osteonecrosis and gene expression changes precede trauma-induced clinical changes in the SD rat model. These findings may provide additional support for timely and clinically early diagnosis and intervention.

P02-36 In vitro monogenic liver disease models using iPSC-derived hepatocytes demonstrate an altered CYP450 gene expression profile compared to wild-type cells

P02-36 In vitro monogenic liver disease models using iPSC-derived hepatocytes demonstrate an altered CYP450 gene expression profile compared to wild-type cells

Prognostic Impact of Postoperative Recurrence in Patients With Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable gene alterations in non-small cell lung cancer (NSCLC). In Japan, approximately 40% of patients who undergo surgical resection for non-squamous NSCLC have EGFR mutations. However, no long-term studies have been conducted including a large number of EGFR-positive NSCLC patients with postoperative recurrence (PR). We conducted a retrospective observational study of the data of EGFR-positive NSCLC patients with PR who had undergone surgery at the Shizuoka Cancer Center between October 2002 and November 2017. We evaluated post-recurrence overall survival (PRS) and postoperative overall survival (POS) using the Kaplan-Meier method and identify any associations between the clinical variables at recurrence and PRS using univariate and multivariate analysis. We enrolled 162 patients. The median observation time for PRS was 4.95 years (range, 0.82-13.25) and POS was 5.81 years (range, 2.84-16.71). The median PRS was 5.17 years (95% confidence interval [CI], 3.90-5.61) and POS was 7.07 years (95% CI, 5.88-8.01). Univariate analysis identified male sex (median PRS: 3.32 vs. 5.39 years; p < 0.05), bone metastasis (median PRS: 2.43 vs. 5.33 years; p < 0.05), and central nervous system (CNS) metastasis (median PRS: 3.05 vs. 5.39 years; p < 0.05) and multivariate analysis identified bone metastasis (hazard ratio [HR], 2.01; 95% CI, 1.23-3.28; p < 0.05) and CNS metastasis (HR, 1.84; 95% CI, 1.14-2.98; p < 0.05) as poor prognostic factors. The pattern of recurrence (oligo vs. non-oligo recurrence) was not a prognostic factor. Logistic regression analysis revealed the association between sex and the presence bone/CNS metastasis at recurrence. Our data may help visualize future prospects and determine the timing of osimertinib initiation. New treatment strategies need to be developed for patients with bone/CNS metastasis at the first recurrence.

CDK4 gene copy number increase and concurrent genetic changes in acral melanoma of a Chinese cohort

Acral melanoma (AM) is the most common subtype of melanoma in Asian population. Abnormalities in the p16-cyclin D1-CDK4 signalling pathway play a crucial role in the development and progression of AM. However, the alterations of CDK4 gene copy number in AM are underreported. In this study, we investigated CDK4 gene copy number and concurrent molecular changes in a Chinese cohort with AM, in aim of exploring CDK4 gene alterations and its significance in AM. We examined copy number alterations of CDK4 with fluorescence in situ hybridisation (FISH) in 31 patients with AM. Six patients with CDK4 high-level copy number increase were examined by next-generation sequencing to detect concurrent molecular changes. Using FISH, 12 (12/31, 38.7%) cases showed CDK4 copy number increase, with 6 (6/31, 19.4%) low-level copy number increase and 6 (6/31, 19.4%) high-level copy number increase. Five of six CDK4 low-level copy number increase cases were accompanied by polysomy of chromosome 12, while one case was not. Two of six CDK4 high-level copy number increase cases were accompanied by polysomy of chromosome 12, while four cases were not. CDK4 copy number increase was significantly correlated with younger patient age. In six CDK4 high-level copy number increase cases, one case was found to be accompanied by NRAS mutation, one case was accompanied by HER2 mutation, one case was accompanied by BCL2L11 mutation ​and one case was accompanied by BRAF, HER2 and BCL2L11 mutations. Our study confirmed the presence of CDK4 copy number increase in AM cases. Detecting CDK4 copy number increase by FISH can be reliable in the diagnosis of AM. Some CDK4 copy number increases are the results of polysomy of chromosome 12. CDK4 high-level copy number increase coexists with other pathogenic mutations in AM. CDK4 appears to be a promising target for AM treatment and is expected to be combined with other targeted therapies.

2020TiP SOGUG-NEOWIN: A phase II, open-label, multi-centre trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) and FGFR gene alterations

2020TiP SOGUG-NEOWIN: A phase II, open-label, multi-centre trial evaluating the efficacy and safety of erdafitinib (ERDA) monotherapy and ERDA and cetrelimab (CET) as neoadjuvant treatment in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) and FGFR gene alterations

Rapid molecular profiling utilising minimal quantities of endobronchial ultrasound-guided aspirates for the detection of Epidermal Growth Factor Receptor, KRAS, ALK, ROS1, RET, NTRK and MET gene alterations from patients with non-small-cell lung carcinomas on the Biocartis Idylla™ platform.

Comprehensive molecular analysis for patients with non-small-cell lung carcinoma (NSCLC) is essential for managing modern targeted therapies. This study sought to establish the feasibility of utilising real-time PCR to perform rapid and comprehensive profiling on minimal amounts of endobronchial ultrasound-guided (EBUS) aspirates as a fast, tissue-sparing route of predictive profiling. A volume of 500 μL of EBUS aspirate and fixative from patients with NSCLC was decanted, and 80 μL (<1% of total specimen received) was utilised for analysis. Biocartis Idylla™ cartridges for epidermal growth factor receptor (EGFR) mutations, KRAS mutations and a GeneFusion cartridge (ALK, ROS1, RET, NTRK1/2/3 rearrangements & MET 14 exon skipping) were analysed for each case to provide molecular data on the main clinically relevant targets as per UK guidelines. A total of 62 cases were included; all of which had successful DNA analysis (EGFR and KRAS cartridges). RNA analysis (GeneFusion cartridge) was successful for 42 of 51 (82%) with initial approach, with 11 of 11 (100%) achieving a successful result with modified protocol. In all, 23 KRAS mutations (37%), 5 EGFR mutations (8%) and 1 ROS fusion (2%) were identified. Average time from specimen receipt to molecular read-out was 5 h. Real-time PCR utilising the Idylla™ platform is rapid, utilises minimal amounts of tissue and provides accurate results. We propose this is a useful ancillary method to utilise alongside next-generation sequencing (NGS) in cases of urgent clinical requirement or EBUS aspirates with inadequate quantities of tissue for NGS.

1461P Analysis of MET gene alterations in cfDNA samples from a phase II study of savolitinib in patients (pts) with MET-amplified gastroesophageal junction adenocarcinomas or gastric cancer (GEJ/GC)

1461P Analysis of MET gene alterations in cfDNA samples from a phase II study of savolitinib in patients (pts) with MET-amplified gastroesophageal junction adenocarcinomas or gastric cancer (GEJ/GC)

1626P Incidence of hematologic toxicities in the homologous recombination repair (HRR)-deficient population of the TALAPRO-2 trial and their potential association with germline vs somatic origin of HRR gene alterations

1626P Incidence of hematologic toxicities in the homologous recombination repair (HRR)-deficient population of the TALAPRO-2 trial and their potential association with germline vs somatic origin of HRR gene alterations

Acquired gene alterations in patients treated with ribociclib plus endocrine therapy or endocrine therapy alone using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials

A prior pooled analysis of the MONALEESA-2, -3, and -7 trials identified baseline markers predictive of sensitivity or resistance to ribociclib plus endocrine therapy (ET). We report the results of an analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples across the MONALEESA trials. Paired baseline and EOT ctDNA samples from MONALEESA-2, -3, and -7 were sequenced using a targeted next-generation sequencing panel. Genes with an EOT alteration prevalence of >5% were included. A McNemar test was performed on paired samples and adjusted for multiple testing to control the false discovery rate. A Bayesian mixed-effects model was used to adjust for ctDNA fraction at both time points and for study differences. The analysis included 523 paired samples. At EOT, 21 genes had a >5% alteration prevalence. A trend for higher ctDNA fraction at EOT vs baseline (P=0.08) was observed. Prevalence of alterations was higher at EOT vs baseline in RB1, SPEN, TPR, PCDH15, and FGFR2 in the ribociclib arm; PBRM1 in the placebo arm; and ESR1 in both arms. The mixed-effects model demonstrated that the same trends for increased prevalence of these alterations at EOT were observed after adjusting for ctDNA fraction and that the increased rate of RB1 and SPEN alterations at EOT were specific to ribociclib plus ET. Analysis of ESR1 indicated a similar increase at EOT in both arms. The most common acquired ESR1 mutations at EOT included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC. The prevalence of PIK3CA hotspot mutations at baseline and EOT was similar. This analysis identified acquired gene alterations in patients with HR+/HER2- advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-CDK4/6 inhibitor setting.

Comprehensive genomic profiling in multiple cancer types: A comparative analysis of the National Biobank Consortium of Taiwan and clinical practice cohorts

BackgroundThis retrospective study analyzed tumor tissue profiling data to assess the potential of comprehensive genomic profiling (CGP) for patient care across diverse solid tumors. Material and methodsPatients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with a null immunophenotype and esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included. One cohort was a part of the National Biobank Consortium of Taiwan project, whereas the other consisted of patients undergoing routine clinical practice. Tumor samples were subjected to CGP using FoundationOne®CDx, with therapeutic implications determined using OncoKB classification. ResultsFoundationOne®CDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients with evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancers. Based on CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7–35.5 months) and 10.6 months (95% CI, 8.1–13.1 months; hazard ratio, 0.28, 95% CI, 0.14–0.55, p < 0.001), respectively. ConclusionsThis study provides comprehensive insights into the genomic profiles of diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice.

Molecular Analysis of Renal/Adrenal Angiosarcomas Reveals High Frequency of Recurrent Genetic Alterations.

Angiosarcomas of the kidney and adrenal gland are rare, highly aggressive vascular neoplasms. Their genomic profile has not been systematically studied to date. We report the clinicopathologic and molecular features of six angiosarcomas centered in the kidney/adrenal gland. All patients were male adults, ranging from 58 to 77 years of age. Tumor sizes ranged from 2.5 to 22.5 cm. Half of the cases demonstrated hot spot mutations in the KDR gene, while one-third demonstrated mutations in the PIK3CA gene; both of these gene alterations being previously described, preferentially in breast angiosarcomas. In addition, two cases each demonstrated BRIP1 gene amplification, CTNNB1 and ETV6 mutations, which have not been previously reported in angiosarcoma. Notably, molecular studies were critical in establishing the correct diagnoses in three cases: one was an epithelioid angiosarcoma originally misdiagnosed as metastatic adenocarcinoma to the adrenal gland, the second was a vasoformative angiosarcoma that mimicked hemangioma, and the third was a collision tumor between a high-grade angiosarcoma and a chromophobe renal cell carcinoma which was originally diagnosed as a sarcomatoid renal cell carcinoma. In summary, angiosarcomas of the kidney and adrenal gland have a high frequency of recurrent genetic alterations, some of them being shared with other angiosarcoma subtypes, while other appear to be novel. In particular, activating hot spot KDR and PIK3CA mutations represent potential therapeutic targets for these highly aggressive cancers.

Hydroquinidine Demonstrates Remarkable Antineoplastic Effects on Non-small Cell Lung Cancer Cells.

Despite recent progress in drug development, lung cancer remains a complex disease that poses a major public health issue worldwide, and new therapeutic strategies are urgently needed because of the failure of standard treatments. Ion channels play a critical role in various cellular processes that regulate cell proliferation, differentiation, and cell death. The potential of ion channel modulators as tumor growth suppressors has been highlighted in recent studies. Therefore, we hypothesized that hydroquinidine (HQ), a previously understudied potassium channel modulator, might have anticarcinogenic activity against A549 cells. The anticancer potential of HQ was investigated using various wellestablished in vitro assays. HQ significantly decreased colony formation and tumorigenicity and exhibited a significant anti-migratory effect in A549 cells. Our results demonstrated that HQ significantly inhibited the growth of cancer cells by decreasing the proliferation rate while increasing cell death. The altered gene expression profile in response to treatment with HQ was consistent with the observed cellular effects. Incubation of cells with HQ resulted in the downregulation of genes involved in cell division and survival, while genes promoting cell cycle arrest and apoptosis were upregulated. Our findings suggest that HQ has the potential to limit lung cancer growth as a novel potent anticarcinogenic agent. However, more investigations are needed to gain further insight into the mechanism of action of HQ and to evaluate its efficacy in invivo models.

Mendelian randomization reveals potential causal relationships between cellular senescence-related genes and multiple cancer risks

Cellular senescence is widely acknowledged as having strong associations with cancer. However, the intricate relationships between cellular senescence-related (CSR) genes and cancer risk remain poorly explored, with insights on causality remaining elusive. In this study, Mendelian Randomization (MR) analyses were used to draw causal inferences from 866 CSR genes as exposures and summary statistics for 18 common cancers as outcomes. We focused on genetic variants affecting gene expression, DNA methylation, and protein expression quantitative trait loci (cis-eQTL, cis-mQTL, and cis-pQTL, respectively), which were strongly linked to CSR genes alterations. Variants were selected as instrumental variables (IVs) and analyzed for causality with cancer using both summary-data-based MR (SMR) and two-sample MR (TSMR) approaches. Bayesian colocalization was used to unravel potential regulatory mechanisms underpinning risk variants in cancer, and further validate the robustness of MR results. We identified five CSR genes (CNOT6, DNMT3B, MAP2K1, TBPL1, and SREBF1), 18 DNA methylation genes, and LAYN protein expression which were all causally associated with different cancer types. Beyond causality, a comprehensive analysis of gene function, pathways, and druggability values was also conducted. These findings provide a robust foundation for unravelling CSR genes molecular mechanisms and promoting clinical drug development for cancer.