Malignant Features Research Articles

DDX5 enhances HIF-1 activity by promoting the interaction of HIF-1α with HIF-1β and recruiting the resulting heterodimer to its target gene loci.

Cancer cells acquire malignant characteristics and therapy resistance by employing the hypoxia-inducible factor 1 (HIF-1)-dependent adaptive response to hypoxic microenvironment in solid tumors. Since the underlying molecular mechanisms remain unclear, difficulties are associated with establishing effective therapeutic strategies. We herein identified DEAD-box helicase 5 (DDX5) as a novel activator of HIF-1 and found that it enhanced the heterodimer formation of HIF-1α and HIF-1β and facilitated the recruitment of the resulting HIF-1 to its recognition sequence, hypoxia-response element (HRE), leading to the expression of a subset of cancer-related genes under hypoxia. This study reveals that the regulation of HIF-1 recruitment to HRE is an important regulatory step in the control of HIF-1 activity. The present study provides novel insights for the development of strategies to inhibit the HIF-1-dependent expression of cancer-related genes.

Post-transplant malignancy: Focusing on virus-associated etiologies, pathogenesis, evidence-based management algorithms, present status of adoptive immunotherapy and future directions

Modern immunosuppression has led to a decrease in rejection rates and improved survival rates after solid organ transplantation. Increasing the potency of immunosuppression promotes post-transplant viral infections and associated cancers by impairing immune response against viruses and cancer immunoediting. This review reflects the magnitude, etiology and immunological characteristics of various virus-related post-transplant malignancies, emphasizing the need for future research. A multidisciplinary and strategic approach may serve best but overall literature evidence targeting it is sparse. However, the authors attempted to provide a more detailed update of the literature consensus for the prevention, diagnosis, management and surveillance of post-transplant viral infections and associated malignancies, with a focus on the current role of adoptive immunotherapy and the way forward. In order to achieve long-term patient and graft survival as well as superior post-transplant outcomes, collaborative research on holistic care of organ recipients is imperative.

Principal Component Analysis Applied to Radiomics Data: Added Value for Separating Benign from Malignant Solitary Pulmonary Nodules.

Here, we report on the added value of principal component analysis applied to a dataset of texture features derived from 39 solitary pulmonary lung nodule (SPN) lesions for the purpose of differentiating benign from malignant lesions, as compared to the use of SUVmax alone. Texture features were derived using the LIFEx software. The eight best-performing first-, second-, and higher-order features for separating benign from malignant nodules, in addition to SUVmax (MaximumGreyLevelSUVbwIBSI184IY), were included for PCA. Two principal components (PCs) were retained, of which the contributions to the total variance were, respectively, 87.6% and 10.8%. When included in a logistic binomial regression analysis, including age and gender as covariates, both PCs proved to be significant predictors for the underlying benign or malignant character of the lesions under study (p = 0.009 for the first PC and 0.020 for the second PC). As opposed to SUVmax alone, which allowed for the accurate classification of 69% of the lesions, the regression model including both PCs allowed for the accurate classification of 77% of the lesions. PCs derived from PCA applied on selected texture features may allow for more accurate characterization of SPN when compared to SUVmax alone.

Adenocarcinoma de pulmón en felinos

Lung adenocarcinoma in felines is a lung neoplasm commonly described among the primary lung carcinomas reported in the species. Primary lung neoplasms in felines are rare, have characteristics of malignancy and tend to metastasize to intrathoracic and extrathoracic organs. Elderly cats are commonly more affected, with no predisposition by sex or breed, although the Persian breed has been reported in the literature. In veterinary medicine, metastasis to the digits, called digit-pulmonary syndrome, has been described as a condition that exclusively affects this species. Specific clinical signs are generally a dry, non-productive cough, dyspnea, tachypnea and intolerance to exercise, while non-specific systemic signs are related to the organ involved and, when present, are associated with paraneoplastic syndrome. Cats with primary lung neoplasia may be asymptomatic and primary lung disease presents as an incidental finding. The initial diagnosis may be based on a chest radiographic study, with the aim of detecting lung masses and metastases. Computed tomography has shown to be more sensitive and detect lymphadenopathy more efficiently than conventional radiography. Histopathological evaluation has proven to be the gold standard for the definitive diagnosis of primary lung neoplasms in felines. Post-mortem examination allows macroscopic evaluation of the lesion and allows for the identification of changes in other organs. Adjuvant chemotherapy treatment and surgical resection of well-differentiated lung neoplasms can offer longer survival compared to individuals diagnosed with poorly differentiated neoplasms and metastases present in other locations. The prognosis is mostly unfavorable, usually leaving only palliative care, aiming at analgesia and patient comfort.

Staging of breast cancer in the breast and regional lymph nodes using contrast-enhanced photon-counting detector CT: accuracy and potential impact on patient management.

To describe the feasibility and evaluate the performance of multiphasic photon-counting detector (PCD) CT for detecting breast cancer and nodal metastases with correlative dynamic breast MRI and digital mammography as the reference standard. Adult females with biopsy-proven breast cancer undergoing staging breast MRI were prospectively recruited to undergo a multiphasic PCD-CT using a 3-phase protocol: a non-contrast ultra-high-resolution (UHR) scan and 2 intravenous contrast-enhanced scans with 50 and 180 s delay. Three breast radiologists compared CT characteristics of the index malignancy, regional lymphadenopathy, and extramammary findings to MRI. Thirteen patients underwent both an MRI and PCD-CT (mean age: 53 years, range: 36-75 years). Eleven of thirteen cases demonstrated suspicious mass or non-mass enhancement on PCD-CT when compared to MRI. All cases with metastatic lymphadenopathy (3/3 cases) demonstrated early avid enhancement similar to the index malignancy. All cases with multifocal or multicentric disease on MRI were also identified on PCD-CT (3/3 cases), including a 4 mm suspicious satellite lesion. Four of five patients with residual suspicious post-biopsy calcifications on mammograms were detected on the UHR PCD-CT scan. Owing to increased field-of-view at PCD-CT, a 5 mm thoracic vertebral metastasis was identified at PCD-CT and not with the breast MRI. A 3-phase PCD-CT scan protocol shows initial promising results in characterizing breast cancer and regional lymphadenopathy similar to MRI and detects microcalcifications in 80% of cases. UHR and spectral capabilities of PCD-CT may allow for comprehensive characterization of breast cancer and may represent an alternative to breast MRI in select cases.

Mitochondria Transfer by Platelet-Derived Microparticles Regulates Breast Cancer Bioenergetic States and Malignant Features.

We show that the transfer of foreign mitochondria by microparticles modulates recipient cancer cell metabolic plasticity, leading to greater malignant processes.

SPOCK1, as a potential prognostic and therapeutic biomarker for lung adenocarcinoma, is associated with epithelial-mesenchymal transition and immune evasion

BackgroundThe occurrence of epithelial-mesenchymal transition (EMT) and immune evasion is considered to contribute to poor prognosis in lung adenocarcinoma (LUAD). Therefore, this study aims to explore the key oncogenes that promote EMT and immune evasion and reveal the expression patterns, prognostic value, and potential biological functions.MethodsFirstly, we identified gene modules associated with EMT and Tumor Immune Dysfunction and Exclusion (TIDE) through weighted gene co-expression network analysis (WGCNA). Next, we utilized differential analysis and machine learning to identify the key genes and validate them. Moreover, we analyzed the correlation between key genes and tumor microenvironment remodeling, drug sensitivity, as well as mutation frequency. Furthermore, we explored and validated their malignant biological characteristics through in vitro experiments and clinical samples. Finally, potential drugs for LUAD were screened based on CMap and validated through experiments.ResultsFirstly, WGCNA analysis revealed that red and green modules were highly correlated with EMT and TIDE. Among them, upregulated expression of SPOCK1 was observed in lung adenocarcinoma tissues and was associated with poor prognosis. Additionally, patients in the high SPOCK1 group showed more activation of malignant oncogenic pathways, higher infiltration of immunosuppressive components, and a higher frequency of mutations. The knockdown of SPOCK1 suppressed invasion and metastasis capabilities of lung adenocarcinoma cells, and the high expression of SPOCK1 was associated with low infiltration of CD8+ T cells. Therapeutic aspects, SPOCK1 can be a candidate indicator for drug sensitivity and CMap showed that VER-155008 was the drug candidate with the largest perturbation effect on the SPOCK1 expression profile. In vitro and in vivo experiments validated the cancer-inhibitory effect of VER-155008 in LUAD.ConclusionThis study revealed through comprehensive bioinformatics analysis and experimental analysis that SPOCK1 can promote EMT and immune escape in LUAD, and it may serve as a promising candidate prognostic biomarker and therapeutic target for LUAD.

Profiling and Bioinformatics Analyses of Hypoxia-Induced Differential Expression of Long Non-coding RNA in Glioblastoma Multiforme Cells.

Hypoxic microenvironments are intricately linked to malignant characteristics of glioblastoma multiforme (GBM). Long non-coding ribonucleic acids (lncRNAs) have been reported to be involved in the progression of GBM and closely associated with hypoxia. Nevertheless, the differential expression profiles as well as functional roles of lncRNAs in GBM cells under hypoxic conditions remain largely obscure. We explored the expression profiles of lncRNAs in hypoxic U87 cells as well as T98G cells using sequencing analysis. The effect of differentially expressed lncRNAs (DElncRNAs) was assessed through bioinformatic analysis. Furthermore, the expression of lncRNAs significantly dysregulated in both U87 and T98G cells was further validated using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Relevant cell functional experiments were also conducted. We used predicted RNA-binding proteins (RBPs) to construct an interaction network via the interaction prediction module. U87 and T98G cells showed dysregulation of 1115 and 597 lncRNAs, respectively. Gene Ontology (GO) analysis indicated that altered lncRNA expression was associated with nucleotide-excision repair and cell metabolism in GBM cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the association between dysregulated lncRNAs and the Hippo signaling pathway under hypoxia. The dysregulation of six selected lncRNAs (ENST00000371192, uc003tnq.3, ENST00000262952, ENST00000609350, ENST00000610036, and NR_046262) was validated by qRT-PCR. Investigation of lncRNA-microRNA (miRNA)-mRNA networks centered on HIF-1α demonstrated cross-talk between the six validated lncRNAs and 16 related miRNAs. Functional experiments showed the significant inhibition of GBM cell proliferation, invasion, and migration by the knockdown of uc003tnq.3 in vitro. Additionally, uc003tnq.3 was used to construct a comprehensive RBP-transcription factor (TF)-miRNA interaction network. The expression of LncRNAs was dysregulated in GBM cells under hypoxic conditions. The identified six lncRNAs might exert important effect on the development of GBM under hypoxic microenvironment.

Modulation of Epstein-Barr-Virus (EBV)-Associated Cancers by Co-Infections.

The oncogenic and persistent Epstein Barr virus (EBV) is carried by more than 95% of the human adult population. While asymptomatic in most of these, EBV can cause a wide variety of malignancies of lymphoid or epithelial cell origin. Some of these are also associated with co-infections that either increase EBV-induced tumorigenesis or weaken its immune control. The respective pathogens include Kaposi-sarcoma-associated herpesvirus (KSHV), Plasmodium falciparum and human immunodeficiency virus (HIV). In this review, I will discuss the respective tumor entities and possible mechanisms by which co-infections increase the EBV-associated cancer burden. A better understanding of the underlying mechanisms could allow us to identify crucial features of EBV-associated malignancies and defects in their immune control. These could then be explored to develop therapies against the respective cancers by targeting EBV and/or the respective co-infections with pathogen-specific therapies or vaccinations.

Symptoms and Prognoses of Patients With Breast Cancer and Malignant Wounds in Palliative Care Units: The Multicenter, Prospective, Observational EASED Study.

This study sought to investigate the symptoms and prognoses of patients with breast cancer and malignant wounds in the palliative care unit setting. This study was a sub-group analysis of a multicenter, prospective, observational study. Patients admitted to 23 palliative care units in Japan between January and December 2017 were enrolled. Data of patients with breast cancer were extracted. We compared demographic characteristics, symptoms, and prognoses by breast cancer malignant wound status. The primary outcome was overall survival. Secondary outcomes included Palliative Prognostic Index (PPI) score, malignant wound characteristics, and symptom burden. Of 1896 patients, 131 (6.9%) had breast cancer. In this cohort, 44 (33.6%) patients had malignant wounds. Most malignant wounds (88%) were on the back and chest. Malignant wounds were associated with skin redness, erosion, necrosis, or fistula. Symptoms included bleeding, exudate, odor, and pain. Twenty-eight patients (63.6%) needed dressing changes and 14 (31.8%) patients experienced bleeding. None died due to bleeding. In the malignant wounds group, 32 (72.8%) patients had used an opioid dose equivalent to 38mg of oral morphine daily, compared to 25mg by 57 (65.5%) patients in the non-malignant wounds group (P = .26). Median PPI scores at hospital admission were 4.5 vs 6.5 (P = .08). Median survival was 23 vs 21days (P = .48). Patients with malignant wounds had a distinct symptom burden profile and tended to use a higher dose of opioids. The effect of malignant wounds on survival was unclear.

Altered CELF4 splicing factor enhances pancreatic neuroendocrine tumors aggressiveness influencing mTOR and everolimus response

Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of tumors with growing incidence. Recent molecular analyses provided a precise picture of their genomic and epigenomic landscape. Splicing dysregulation is increasingly regarded as a novel cancer hallmark influencing key tumor features. We have previously demonstrated that splicing machinery is markedly dysregulated in PanNETs. Here, we aimed to elucidate the molecular and functional implications of CELF4, one of the most altered splicing factors in PanNETs. CELF4 expression was determined in 20 PanNETs, comparing tumor and non-tumoral adjacent tissue. RNA-Seq dataset was analyzed to explore CELF4-linked interrelations among clinical features, gene expression, and splicing events. Two PanNETs cell lines were employed to assess CELF4 function in vitro and in vivo. PanNETs display markedly upregulated CELF4 expression, which is closely associated to malignancy features, altered expression of key tumor players, and distinct splicing event profiles. Modulation of CELF4 influenced proliferation in vitro and reduced in vivo xenograft tumor growth. Interestingly, functional assays and RNA-Seq analysis revealed that CELF4 silencing altered mTOR signaling pathway, enhancing the effect of everolimus. We demonstrate that CELF4 is dysregulated in PanNETs, where it influences tumor development and aggressiveness, likely by modulating mTOR pathway, suggesting its potential as therapeutic target.

MiR-4270 suppresses hepatocellular carcinoma progression by inhibiting DNMT3A-mediated methylation of HGFAC promoter

Background miR-4270 is a regulatory factor has been linked with the progression of various cancers, such as nasopharyngeal carcinoma, hepatocellular carcinoma (HCC), and gastric cancer. However, the underlying mechanisms through which miR-4270 modulates HCC development are not fully understood. Methods miR-4270 expression levels were analyzed in various HCC cell lines and tissue samples. An online bioinformatics tool was then utilized to predict the miR-4270 target gene. The binding relationship between miR-4270 and its target gene DNMT3A was verified using dual-luciferase reporter and Ago2–RIP assays. Then, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays were conducted to investigate the association between DNMT3A and the hepatocyte growth factor activator (HGFAC) promoter region. To assess the methylation level of the HGFAC promoter, methylation-specific PCR (MSP) was employed. Furthermore, rescue analyses were carried out to evaluate the functional relevance of miR-4270 and HGFAC in the modulation of the malignant properties of HCC cells. Finally, HepG2 cells overexpressing miR-4270 were subcutaneously injected into nude mice to estimate the impact of miR-4270 on the xenograft tumor growth of HCC. Results A substantial miR-4270 downregulation was revealed in HCC patient samples and cell lines. miR-4270 upregulation suppressed both cell proliferation and invasion while promoting apoptosis. At the molecular level, miR-4270 was found to bind to the 3′untranslated region (3′UTR) of DNMT3A, thereby inhibiting DNMT3A-mediated methylation of the HGFAC promoter. Functional assays indicated that inhibition of miR-4270 stimulated HCC cell growth, an effect counteracted by overexpression of HGFAC. In vivo assays further verified that miR-4270 effectively suppressed the progression of HCC xenograft tumors. Conclusions miR-4270 was found to mitigate the malignant characteristics of HCC by inhibiting DNMT3A-mediated methylation of the HGFAC promoter, suggesting a potential therapeutic avenue for the management of HCC.

Incidental multiple myeloma in a patient with neuroretinitis: a case report

BackgroundNeuroretinitis is classically defined as a clinical triad of unilateral, painless vision loss, accompanied by optic disc edema and characteristic macular star formation. The causes of neuroretinitis can be categorized as infectious, non-infectious, and idiopathic, therefore differential diagnosis and careful evaluation are required, owing to the various etiologies and masqueraders.Case presentationA 54-year-old woman presented to the clinic with blurred vision in both eyes. A complete ophthalmic examination revealed optic disc edema with blurred margins and macular exudates, intraretinal edema in the temporal peripapillary area, and subretinal fluid with neurosensory retinal detachment in the macular area. Systemic laboratory investigations showed no signs of infection or inflammation. However, bone marrow suppression was suspected based on the results of the complete blood count test, and the patient was diagnosed with multiple myeloma.ConclusionAlthough neuroretinitis is rarely accompanied by hematological malignancy, it is important to be mindful of the latter because ophthalmic manifestations are a common feature of hematological malignancies and lesions occur in nearly every ocular structure.

Large intramuscular and parosteal lipoma of the upper limb: A case report and literature review

Although lipomas are the most common benign soft-tissue tumors, the intramuscular type is rare and the parosteal type is even rarer. These types of tumors can present like malignant tumors like liposarcoma. Unlike superficial lipomas, deep lipomas (intramuscular/parosteal) require magnetic resonance imaging to evaluate for and rule out malignant features. We report this patient with giant and mixed types of rarest lipomas (intramuscular and parosteal) that arise from the humeral periosteum and within the brachioradialis muscle with encasement of the radial nerve. We aimed to increase awareness to think outside the box and shed light on this giant, rarest mixed type of intramuscular and parosteal lipomas. Furthermore, it emphasizes the need for careful investigations to rule out malignant tumors like liposarcoma. Finally, many orthopedic oncology centers designate large, deep lipomas as low-grade liposarcoma due to the risk of local recurrence.

Abstract C039: Cancer labeling should be retained for prostate cancer with a Gleason score of 3+3=6 - based on genomic, transcriptomic, and proteomic aspects

Abstract Purpose: The decision to remove the cancer label for prostate cancer with a Gleason score (GS) of 3+3 relies on pathology and clinical manifestations. However, evidence at the molecular level, especially for comparing the Excluding 3 group (GS4+4, GS4+5, GS5+4 and GS5+5) and the Gleason Grade Group 1 (GG1) (GS3+3), is lacking. To address this gap, we aimed to explore the differences between these two groups at the genomic, transcriptomic, and proteomic levels. Methods: We compared the GG1 group (n=82) and Excluding 3 group (n=148) using data from the TCGA in terms of genomic alterations, including gene mutations, chromosomal structure variants, and copy number variants. Pathways were revealed by using GSEA enrichment analysis at the transcriptome level. We also conducted a quantitative whole protein analysis of prostate cancer and paraneoplastic tissues in 6 pairs of GG1 and 11 pairs of Excluding 3 groups to compare the differences at the protein level and explored the enriched pathways between them by GSEA enrichment analysis. Finally, we validated the accuracy of DIA quantification by performing immunohistochemical experiments on radical resection pathology specimens from 29 patients diagnosed with GG1 and 29 patients diagnosed with Excluding 3 group. Results: At the genomic level, we found that the mutation frequencies of GG1 and Excluding 3 group were comparable. But, the mutation frequencies of TP53, FOXA1 and PTEN were significantly higher in the Excluding 3 group than in the GG1 group , while the TMPRSS2-ERG fusion was not significantly different between the two groups. And the incidence of the p53 signaling pathway, WNT pathway, PI3K pathway, and DNA damage was significantly higher in the Excluding 3 group than in the GG1 group. For the transcriptomic level, GSEA enrichment analysis revealed that both groups were enriched for multiple tumor-related pathways. At the proteome level, with protein quantitative testing by mass spectrometry, we identified that androgen-response pathway was inhibited in the GG1 group, while DNA repair and PPAR signaling pathway was activated in the Excluding 3 group. Six differential proteins were identified which had important roles in cancer development. And immunohistochemical experiments confirmed the accuracy of quantification analysis for 3 representative proteins (DDX21, NOLC1, and TIMP1). Conclusion: The GG1 and Excluding 3 groups showed similar oncogene mutation frequencies and chromosomal structural variations. However, shared and distinct pathway alterations were observed in genomic and transcriptomic analyses, indicating common driving factors and differential influences of biological factors. Proteomic analysis identified differentially expressed proteins and enriched cancer-related pathways associated with tumor characteristics. These findings support the malignancy features of GG1 prostate cancer. Citation Format: Sijie Wen, Yinzhao Wang, Lin Qi, Hongling Yin, Xiaomei Gao, Minfeng Chen, Yi Cai. Cancer labeling should be retained for prostate cancer with a Gleason score of 3+3=6 - based on genomic, transcriptomic, and proteomic aspects [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C039.

Ossifying Fibromyxoid Tumor with Atypical Features: A Case Report and Review of Literature

Abstract Introduction/Objective Ossifying fibromyxoid tumor (OFMT) is a soft tissue neoplasm usually behaving in a benign fashion, however, it can rarely show atypical or malignant features. It most frequently occurs within the extremities and trunk. Although OFMTs are translocation-associated tumors, and very commonly associated with recurrent gene rearrangements involving the PHF1 gene, their morphologic and immunophenotypic profile can overlap with other soft tissue tumors posing a diagnostic challenge. Methods/Case Report Herein we present a case of a 23-year-old woman who had an excision of a subcutaneous shoulder mass. Grossly, the 5.3 cm mass had a thin translucent capsule and a pink, soft-cut surface with scattered calcifications. Microscopic examination revealed a well-circumscribed lesion composed of plump spindle cells with uniform oval nuclei arranged in short fascicles within a mildly collagenous background. There was prominent hemangiopericytoma-like vasculature and foci of ossification. The tumor cells contained moderate cytoplasm and showed a mild degree of nuclear atypia. Mitotic activity was up to 6 per 10 high-power fields. Immunohistochemical stains showed tumor cells are positive for Desmin, SMA, AE1/AE3 (patchy), TLE, and SATB2, while negative for CD31, CD34, S-100, C-kit, DOG-1, CD117, HMB-45, Melan-A, ALK-1, SOX10, Inhibin, and STAT6. Ki-67 proliferation index was low (1-2%). Fluorescence in situ hybridization (FISH) testing was negative for SYT and MDM2 gene amplification. FISH testing for PHF1 gene (using experimental probes) showed a break apart signal in a subset (~ 25%) of tumor cells, which is equivocal but insufficient to establish clonal interchromosomal translocation involving PHF1. Results (if a Case Study enter NA) NA Conclusion There is a histologic spectrum and morphologic overlap of OFMTs with several other soft tissue neoplasms. OFMT with atypical features (increased cellularity and mitotic activity), as in this case, may harbor the unpredictable biologic potential for recurrence and metastasis. Additional studies are required to discover a morphologic, immunohistochemical, and possibly molecular pattern that will help to differentiate OFMT subtypes.

Effect and Mechanism of NL-101 Combined with Bcl-2 Inhibitor Venetoclax in Acute Myeloid Leukemia

Background Acute myeloid leukemia (AML) is a kind of malignant clonal disease originating from hematopoietic stem cells with strong heterogeneity,with the highly recurrence rate and mortality rate.Although the application of hematopoietic stem cell transplantation and new targeted drugs has improved the prognosis of some patients in recent years, chemotherapy is still the most important treatment for AML. 50-80% of AML patients eventually relapsed after CR, with a low remission rate after relapse.There are reports that BCL-2 overexpression is a clinical feature of human hematologic malignancies that exacerbates the malignant state and drives apoptosis resistance phenotypes.Therefore, how to reduce treatment-related toxic and side effects and overcome tumor cell drug resistance is a hot and difficult topic in current AML treatment. Venetoclax (ABT-199) is an oral, selective Bcl-2 inhibitor. It showed strong anti-leukemia activity in preclinical stage, but its clinical efficacy as a single drug for AML was limited.Nl-101 (also known as EDE-S101)is a new small molecule compound formed by covalently linking the DNA damage core group of Bendamustine hydrochloride with the inhibition core group of histone deacetylase of the histone inhibitor Volinostat (also known as SAHA).Our previous study found that NL-101 single drug can reduce tumor load and prolong survival of AML mice in vivo.In this study, we used Venetoclax in combination with NL-101 to understand its efficacy and safety in vitro and in vivo, and to explore the synergies and mechanisms of action between the two drugs, providing new effective options for the treatment of AML patients. Purpose To explore the efficacy of Bcl-2 inhibitor Venetoclax (ABT-199) and a novel small molecule compound NL-101 in the treatment of acute myeloid leukemia（AML） and the related mechanisms. Experimental Design AML cell lines and primary patient samples were collected and used for cell proliferation assay. MTS colorimetric assay was used to determine the effect of Venetoclax alone or in combination with NL-101 on the growth of AML cells，the combination index (CI) was calculated to evaluate the synergistic effect of the two drugs. Cell death induced by Venetoclax alone or in combination with NL-101 was analyzed by Annexin V-FITC/ Propyl -iodide staining and flow cytometry. Western blot was used to analyze the protein expression levels of MAPK/ERK, PI3K/AK/GSK pathway members and BCL-2 family members.The MV4-11-derived xenograft mouse model was used to assess in vivo efficacy of the combination of venetoclax and NL-101. Results Venetoclax alone and in combination with NL-101 can inhibit the growth of AML cell lines and primary cells to a certain extent, and the combination of drugs has a synergistic effect. Venetoclax combined with NL-101 effectively synergistically induced apoptosis in AML cell lines and primary patient samples. Venetoclax combined with NL-101 can down-regulate the expression of pro-survival proteins in the Bcl-2 family, such as McL-1, Bcl-2, and Bcl-XL, and up-regulate the expression of pro-apoptotic proteins, such as BIM, BID, and BAX/BAK. Phosphorylated ERK, AKT, and JNK expressions were eliminated by venetoclax in combination with NL-101. In vivo results suggest that Venetoclax combined with NL-101 has the potential to treat AML. Conclusions Venetoclax combined with NL-101 can synergistically inhibit the growth and promote apoptosis of AML cell lines and primary AML cells. In vivo experiments demonstrated that Venetoclax combined with NL-101 can synergistically reduce tumor load and prolong survival time in AML mice. These results suggest that Venetoclax in combination with NL-101 is effective in the treatment of acute myeloid leukemia.

Chromosomal Instability-Driven Cancer Progression: Interplay with the Tumour Microenvironment and Therapeutic Strategies.

Chromosomal instability (CIN) is a prevalent characteristic of solid tumours and haematological malignancies. CIN results in an increased frequency of chromosome mis-segregation events, thus yielding numerical and structural copy number alterations, a state also known as aneuploidy. CIN is associated with increased chances of tumour recurrence, metastasis, and acquisition of resistance to therapeutic interventions, and this is a dismal prognosis. In this review, we delve into the interplay between CIN and cancer, with a focus on its impact on the tumour microenvironment-a driving force behind metastasis. We discuss the potential therapeutic avenues that have resulted from these insights and underscore their crucial role in shaping innovative strategies for cancer treatment.

Repeated radon exposure induced epithelial-mesenchymal transition-like transformation via disruption of p53-dependent mitochondrial function.

As a human carcinogen, radon and its progeny are the second most important risk factor for lung cancer after smoking. The tumor suppressor gene, p53, is reported to play an important role in the maintenance of mitochondrial function. In this work, we investigated the association between p53 and p53-responsive signaling pathways and radon-induced carcinogenesis. After repeated radon exposure, the malignant characteristics, cell cycle arrest, cell apoptotic rate, adenosine triphosphate (ATP) content, reactive oxygen species (ROS) level, mitochondrial DNA (mtDNA) copy number as well as indicative biomarkers involved in mitochondrial energy metabolism were evaluated in BEAS-2B cells or BALB-c mouse lung tissue. Radon exposure induced epithelial-mesenchymal transition (EMT)-like transformation in BEAS-2B cells, as indicated by increased cell proliferation and migration. Additional mitochondrial alterations, including decreased ATP content, increased ROS levels, mtDNA copy numbers, cell apoptosis, and G2/M cell cycle arrest were observed. Radon exposure caused an energy generation shift from aerobic respiration to glycolysis as reflected by increased expression of TIGAR and p53R2 proteins and decreased expression of SCO2 protein in BEAS-2B cells, and increased expression of p53, SCO2 and TIGAR proteins in mouse lung tissue, respectively. The effects of p53 deficiency on the prevention of mitochondrial dysfunction suggested a protective role of p53 in radon-induced malignant-like features in BEAS-2B cells. Repeated radon exposure induced EMT-like transformation in BEAS-2B cells via disruption of mitochondrial function. Activation of p53 and p53-responsive signaling pathways in BEAS-2B cells and BALB-c mice may confer a protective mechanism for radon-induced lung injury.

FOXM1/KIF20A axis promotes clear cell renal cell carcinoma progression via regulating EMT signaling and affects immunotherapy response

BackgroundThe correlation between FOXM1 and KIF20A has not been revealed in clear cell renal cell carcinoma (ccRCC). MethodsPublic data was downloaded from The Cancer Genome Atlas (TCGA) database. R software was utilized for the execution of bioinformatic analysis. The expression levels of specific molecules (mRNA and protein) were detected using real-time quantitative PCR (qRT-PCR) and Western blot assays. The capacity of cell growth was assessed by employing CCK8 and colony formation assay. Cell invasion and migration ability were assessed using transwell assay. ResultsIn our study, we illustrated the association between FOXM1 and KIF20A. Our results indicated that both FOXM1 and KIF20A were associated with poor prognosis and clinical performance. The malignant characteristics of ccRCC cells can be significantly suppressed by inhibiting FOXM1 and KIF20A, as demonstrated by in vitro experiments. Moreover, we found that FOXM1 can upregulate KIF20A. Then, EMT signaling was identified as the underlying pathway FOXM1 and KIF20A are involved. WB results indicated that FOXM1/KIF20A axis can activate EMT signaling. Moreover, we noticed that FOXM1 and KIF20A can affect the immunotherapy response and immune microenvironment of ccRCC patients. ConclusionsOur results identified the role of the FOXM1/KIF20A axis in ccRCC progression and immunotherapy, making it the underlying target for ccRCC.