N6-methyladenosine facilitates arsenic-induced neoplastic phenotypes of human bronchial epithelial cells by promoting miR-106b-5p maturation.

Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N6-methyladenosine (m6A) modification is known to modulate pri-miRNA processing. However, whether m6A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m6A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5 µM arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m6A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m6A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m6A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What's more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m6A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.

Integrative radiomics clustering analysis to decipher breast cancer heterogeneity and prognostic indicators through multiparametric MRI.

Breast cancer diagnosis and treatment have been revolutionized by multiparametric Magnetic Resonance Imaging (mpMRI), encompassing T2-weighted imaging (T2WI), Diffusion-weighted imaging (DWI), and Dynamic Contrast-Enhanced MRI (DCE-MRI). We conducted a retrospective analysis of mpMRI data from 194 breast cancer patients (September 2019 to October 2023). Using 'pyradiomics' for radiomics feature extraction and MOVICS for unsupervised clustering. Interestingly, we identified two distinct patient clusters associated with significant differences in molecular subtypes, particularly in Luminal A subtype distribution (p = 0.03), estrogen receptor (ER) (p = 0.01), progesterone receptor (PR) (p = 0.04), mean tumor size (p < 0.01), lymph node metastasis (LNM) (p = 0.01), and edema (p < 0.01). Our study emphasizes mpMRI's potential in breast cancer by using radiomics-based cluster analysis to categorize tumors, uncovering heterogeneity, and aiding in personalized treatment strategies.

TM7SF2-induced lipid reprogramming promotes cell proliferation and migration via CPT1A/Wnt/ß-Catenin axis in cervical cancer cells.

Cervical cancer poses a serious threat to women's health globally. Our previous studies found that upregulation of TM7SF2, which works as an enzyme involved in the process of cholesterol biosynthesis expression, was highly correlated with cervical cancer. However, the mechanistic basis of TM7SF2 promoting cervical cancer progression via lipid metabolism remains poorly understood. Therefore, quantification of fatty acids and lipid droplets were performed in vitro and in vivo. The protein-protein interaction was verified by Co-IP technique. The mechanism and underlying signaling pathway of TM7SF2 via CPT1A associated lipid metabolism in cervical cancer development were explored using Western blotting, IHC, colony formation, transwell assay, and wound healing assay. This study reported that overexpression of TM7SF2 increased fatty acids content and lipid droplets both in vivo and in vitro experiments. While knockout of TM7SF2 obviously attenuated this process. Moreover, TM7SF2 directly bonded with CPT1A, a key enzyme in fatty acid oxidation, and regulated CPT1A protein expression in cervical cancer cells. Notably, the proliferation and metastasis of cervical cancer cells were elevated when their CPT1A expression was upregulated. Then, rescue assay identified that CPT1A overexpressed could enhance the cell viability and migration in TM7SF2-knockout cells. Furthermore, depletion of TM7SF2 significantly inhibited WNT and ß-catenin proteins expression, which was enhanced by CPT1A-overexpressed. The proliferation and migration of cervical cancer cells were reversed in CPT1A-overexpressed cells with the treatment of MSAB, an inhibitor of Wnt/ß-Catenin pathway. This study put forward an idea that TM7SF2-induced lipid reprogramming promotes proliferation and migration via CPT1A/Wnt/ß-Catenin axis in cervical cancer, underlying the progression of cervical cancer.

Single-cell RNA sequencing of cervical exfoliated cells reveals potential biomarkers and cellular pathogenesis in cervical carcinogenesis.

Cervical cancer (CC) is a common gynecological malignancy. Despite the current screening methods have been proved effectively and significantly decreased CC morbidity and mortality, deficiencies still exist. Single-cell RNA sequencing (scRNA-seq) approach can identify the complex and rare cell populations at single-cell resolution. By scRNA-seq, the heterogeneity of tumor microenvironment across cervical carcinogenesis has been mapped and described. Whether these alterations could be detected and applied to CC screening is unclear. Herein, we performed scRNA-seq of 56,173 cervical exfoliated cells from 15 samples, including normal cervix, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and malignancy. The present study delineated the alteration of immune and epithelial cells derived during the cervical lesion progression. A subset of lipid-associated macrophage was identified as a tumor-promoting element and could serve as a biomarker for predicting the progression of LSIL into HSIL, which was then verified by immunofluorescence. Furthermore, cell-cell communication analysis indicated the SPP1-CD44 axis might exhibit a protumor interaction between epithelial cell and macrophage. In this study, we investigated the cervical multicellular ecosystem in cervical carcinogenesis and identified potential biomarkers for early detection.

Predictive value of triple negative breast cancer based on DCE-MRI multi-phase full-volume ROI clinical radiomics model.

BACKGROUND: Since no studies compared the value of radiomics features of distinct phases of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting triple-negative breast cancer (TNBC). PURPOSE: To identify the optimal phase of DCE-MRI for diagnosing TNBC and, in combination with clinical factors, to develop a clinical-radiomics model to well predict TNBC. MATERIAL AND METHODS: This retrospective study included 158 patients with pathology-confirmed breast cancer, including 38 cases of TNBC. The patients were randomly divided into the training and validation set (7:3). Eight radiomics models were built based on eight DCE-MR phases, and their performances were evaluated using receiver operating characteristic curve (ROC) and DeLong's test. The Radscore derived from the best radiomics model was integrated with independent clinical risk factors to construct a clinical-radiomics predictive model, and evaluate its performance using ROC analysis, calibration, and decision curve analyses. RESULTS: WHO classification, margin, and T2-weighted (T2W) imaging signals were significantly correlated with TNBC and independent risk factors for TNBC (P<0.05). The clinical model yielded areas under the curve (AUCs) of 0.867 and 0.843 in the training and validation sets, respectively. The radiomics model based on DCEphase7 achieved the highest efficacy, with an AUC of 0.818 and 0.777. The AUC of the clinical-radiomics model was 0.936 and 0.886 in the training and validation sets, respectively. The decision curve showed the clinical utility of the clinical-radiomics model. CONCLUSION: The radiomics features of DCE-MRI had the potential to predict TNBC and could improve the performance of clinical risk factors for preoperative personalized prediction of TNBC.

TRAIL-driven targeting and reversing cervical cancer radioresistance by seleno-nanotherapeutics through regulating cell metabolism.

Recently, radioresistance has become a major obstacle in the radiotherapy of cervical cancer. To demonstrate enhanced radiosensitization against radioresistant cervical cancer, radioresistant cervical cancer cell line was developed and the mechanism of radioresistance was explored. Due to the overexpression of (death receptor 5, DR5) in cervical cancer, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-overexpressed cervical cancer cell membrane-camouflaged Cu2-xSe nanomedicine (CCMT) was designed. Since the CCMT was encapsulated with TRAIL-modified cell membrane, it represented high target to cervical cancer cell and immune evasion. Furthermore, Cu2-xSe had the ability to scavenge glutathione (GSH) and produce ·OH with excess H2O2 in the tumor microenvironment. The presence of CCMT combined with radiation therapy could effectively increase the 1O2 produced by X-rays. In vitro and in vivo studies elaborated that CCMT exhibited excellent radiosensitization properties to reverse radiotolerance by scavenging GSH and promoting DNA damage, apoptosis, mitochondrial membrane potential damage and metabolic disruption. Collectively, this study suggested that the development of TRAIL-overexpressed cell membrane-camouflaged Cu2-xSe nanomedicine could advance future cervical cancer treatment and minimize the disadvantages associated with radiation treatment.

Selenium promotes immunogenic radiotherapy against cervical cancer metastasis through evoking P53 activation.

Radiotherapy is still the recommended treatment for cervical cancer. However, radioresistance and radiation-induced side effects remain one of the biggest clinical problems. Selenium (Se) has been confirmed to exhibit radiation-enhancing effects for cancer treatment. However, Se species dominate the biological activities and which form of Se possesses better radiosensitizing properties and radiation safety remains elusive. Here, different Se species (the valence state of Se ranged from - 2, 0, +4 to + 6) synergy screen was carried out to identify the potential radiosensitizing effects and radiation safety of Se against cervical cancer. We found that the therapeutic effects varied with the changes in the Se valence state. Sodium selenite (+4) displayed strong cancer-killing effects but also possessed severe cytotoxicity. Sodium selenate (+6) neither enhanced the killing effects of X-ray nor possessed anticancer activity by its alone treatment. Although nano-selenium (0), especially Let-SeNPs, has better radiosensitizing activity, the - 2 organic Se, such as selenadiazole derivative SeD (-2) exhibited more potent anticancer effects and possessed a higher safe index. Overall, the selected Se drugs were able to synergize with X-ray to inhibit cell growth, clone formation, and cell migration by triggering G2/M phase arrest and apoptosis, and SeD (-2) was found to exhibit more potent enhancing capacity. Further mechanism studies showed that SeD mediated p53 pathway activation by inducing DNA damage through promoting ROS production. Additionally, SeD combined with X-ray therapy can induce an anti-tumor immune response in vivo. More importantly, SeD combined with X-ray significantly inhibited the liver metastasis of tumor cells and alleviated the side effects caused by radiation therapy in tumor-bearing mice. Taken together, this study demonstrates the radiosensitization and radiation safety effects of different Se species, which may shed light on the application of such Se-containing drugs serving as side effects-reducing agents for cervical cancer radiation treatment.

Emerging role of mesenchymal stromal cells in gynecologic cancer therapy.

Mesenchymal stromal cells (MSCs) show considerable promise in regenerative medicine with superior anti-fibrotic, immunomodulatory, and angiogenic functions. More recently, discovered with the tumor tropism, MSCs have been exploited as the basis of targeted cancer therapy. In this scenario, MSCs can directly home to tumor tissues and play anti-tumor properties. In addition, MSCs, MSC-derived exosomes and MSC-derived membranes are often developed as carriers for precisely delivering cytotoxic agents to cancer sites, including chemotherapeutic drugs, therapeutic genes, or oncolytic viruses. However, it has revealed the tumorigenic risk of MSCs as an important component within the tumor microenvironment, hampering the translation of MSC-based cancer therapies into clinical settings. Therefore, in this review, we introduce the specific tumor-tropic ability of MSCs and underlying mechanisms. We also summarize the current application of MSC-based therapeutic approaches in treating gynecologic cancers, mainly including cervical, ovarian, and endometrial cancers. Moreover, we discuss the main challenges that the current MSC-based cancer therapies are facing.

Therapeutic application of manganese-based nanosystems in cancer radiotherapy.

Radiotherapy is an important therapeutic modality in the treatment of cancers. Nevertheless, the characteristics of the tumor microenvironment (TME), such as hypoxia and high glutathione (GSH), limit the efficacy of radiotherapy. Manganese-based (Mn-based) nanomaterials offer a promising prospect for sensitizing radiotherapy due to their good responsiveness to the TME. In this review, we focus on the mechanisms of radiosensitization of Mn-based nanosystems, including alleviating tumor hypoxia, increasing reactive oxygen species production, increasing GSH conversion, and promoting antitumor immunity. We further illustrate the applications of these mechanisms in cancer radiotherapy, including the development and delivery of radiosensitizers, as well as their combination with other therapeutic modalities. Finally, we summarize the application of Mn-based nanosystems as contrast agents in realizing precision therapy. Hopefully, the present review will provide new insights into the biological mechanisms of Mn-based nanosystems, as well as their applications in radiotherapy, in order to address the difficulties and challenges that remain in their clinical application in the future.

The functions of lncRNAs in the HPV-negative cervical cancer compared with HPV-positive cervical cancer.

Cervical cancer is one of the most common female malignancies. Human papillomaviruses (HPV) are the main causative agents of virtually all cervical carcinomas. Nevertheless, emerging evidence has demonstrated that a small proportion of cervical cancer patients are HPV negative. Long noncoding RNAs (lncRNAs) have been identified to play a crucial role in cervical cancer development. Here, this review describes the incidence and development of HPV-negative cervical cancer. Moreover, HPV-negative cervical cancers are more likely diagnosed at non-squamous type, older ages, more advanced stage and metastases, and associated with poorer prognosis as compared to HPV-positive cervical cancer. Furthermore, the significant role and functions of lncRNAs underlying HPV-negative cervical cancer is clarified.

Erratum: Nucleic acids and proteins carried by exosomes of different origins as potential biomarkers for gynecologic cancers.

[This corrects the article DOI: 10.1016/j.omto.2021.12.005.].

Nucleic acids and proteins carried by exosomes of different origins as potential biomarkers for gynecologic cancers.

Exosomes are extracellular vesicles with a diameter of 30-150 nm that function in mediating intercellular communication and intercellular material exchange. The liposomal membrane of exosomes protects the cargo carried by exosomes from degradation and assists in transporting cargo to recipient cells to regulate a variety of physiological and pathological processes. The incidence of gynecologic cancers is increasing annually, which is extremely harmful to the lives and health of women because such cancers are challenging to detect at the early stage. Recently, exosomes have emerged as novel biomarkers for diagnosing and predicting the development of gynecologic cancers. In particular, non-coding RNAs (microRNAs [miRNAs], long non-coding RNAs [lncRNAs], and circular RNAs [circRNAs]) carried by exosomes have been extensively investigated in gynecologic cancers. Therefore, the purpose of this review is to focus on the potential roles of exosomes of different origins in ovarian cancer, cervical cancer, and endometrial cancer, which will help to determine the molecular mechanism of carcinogenesis.

Insight into the role of multiple signaling pathways in regulating cancer stem cells of gynecologic cancers.

Mounting evidence has demonstrated that a myriad of developmental signaling pathways, such as the Wnt, Notch, Hedgehog and Hippo, are frequently deregulated and play a critical role in regulating cancer stem cell (CSC) activity in human cancers, including gynecologic malignancies. In this review article, we describe an overview of various signaling pathways in human cancers. We further discuss the developmental roles how these pathways regulate CSCs from experimental evidences in gynecologic cancers. Moreover, we mention several compounds targeting CSCs in gynecologic cancers to enhance the treatment outcomes. Therefore, these signaling pathways might be the potential targets for developing targeted therapy in gynecologic cancers.

Applications of Multi-omics Approaches for Exploring the Molecular Mechanism of Ovarian Carcinogenesis.

Ovarian cancer ranks as the fifth most common cause of cancer-related death in females. The molecular mechanisms of ovarian carcinogenesis need to be explored in order to identify effective clinical therapies for ovarian cancer. Recently, multi-omics approaches have been applied to determine the mechanisms of ovarian oncogenesis at genomics (DNA), transcriptomics (RNA), proteomics (proteins), and metabolomics (metabolites) levels. Multi-omics approaches can identify some diagnostic and prognostic biomarkers and therapeutic targets for ovarian cancer, and these molecular signatures are beneficial for clarifying the development and progression of ovarian cancer. Moreover, the discovery of molecular signatures and targeted therapy strategies could noticeably improve the prognosis of ovarian cancer patients.

Clinicopathological Features and Survival of Adolescent and Young Adults with Cervical Cancer.

PURPOSE: To explore clinicopathological characteristics and their prognostic value among young patients with cervical cancer (who are aged ≤25 years old). METHODS: The Surveillance, Epidemiology, and End Results Program (SEER) database was used to extract data on cervical cancer patients. They were then stratified by age as young women (≤25 years old) and old women (26-35 years old) and analyzed for clinicopathology characteristics and treatment modalities. Prognosis was analyzed using Kaplan-Meier survival curve, as well as hazard ratios using Cox regression modeling. The nomogram was developed based on Cox hazards regression model. RESULTS: Compared to 26-35 years old women, patients aged ≤25 years tended to be white ethnicity, unmarried, had earlier stage of disease. There was also a better prognosis among younger cohort. Grade, FIGO stage, histologic subtypes, and surgical modalities influenced the survival outcomes of young patients. Among young cohorts, surgery prolonged the survival time of IA-IIA stage patients while surgical and non-surgical management presented no statistically prognostic difference among patients at IIB-IVB stage. Besides, the nomogram which constructed according to Cox hazards regression model which contained independent prognosis factors including FIGO stage, surgery type, and histologic type of tumor can robustly predict survival of young patients. CONCLUSION: Cervical cancer patients ≤25 years old were uncommon and lived longer than the older patients. Among these young patients at IA-IIA stage, surgical treatment could be more effective at preventing death than non-surgery. The nomogram could perfectly predict the prognosis of young adults and adolescents with cervical cancer.

TM7SF2 regulates cell proliferation and apoptosis by activation of C-Raf/ERK pathway in cervical cancer.

Transmembrane 7 superfamily member 2 (TM7SF2) coding an enzyme involved in cholesterol metabolism has been found to be differentially expressed in kinds of tissues. Nevertheless, the role of TM7SF2 in the regulation of growth and progression among various cancers is unclear. In this study, the immunohistochemistry (IHC) assay, real-time RT-PCR and western blotting analysis were used to determine the TM7SF2 expression in cervical cancer tissues. Next, we used multiple methods to determine the ability of cell proliferation, migration, invasion, apoptosis, and cell cycle in cervical cancer cells after TM7SF2 modulation, such as CCK8 assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry. Our results revealed that upregulation of TM7SF2 facilitated cell proliferation and metastasis, suppressed cell apoptosis and prevented G0/G1 phase arrests in C33A and SiHa cells. Consistently, the opposite effects were observed after TM7SF2 knockout in cervical cancer cells. Further, we found that TM7SF2 participated in promoting tumorigenesis and progression via activation of C-Raf/ERK pathway in cervical cancer, which can be partly reversed by Raf inhibitor LY3009120. Moreover, TM7SF2 overexpression contributed to enhancement of xenograft tumor growth in vivo. Our findings indicated that TM7SF2 plays a vital role in tumor promotion by involving in C-Raf/ERK activation. Therefore, TM7SF2 could serve as a therapeutic target in future cervical cancer treatment.

The role of lncRNAs and circRNAs in the PD-1/PD-L1 pathway in cancer immunotherapy.

Cancer immunotherapy has recently shown promising antitumor effects in various types of tumors. Among all immune checkpoints, the PD-1/PD-L1 pathway plays an important role in the immune evasion of tumor cells, making it a potent target in antitumor immunity. Accordingly, antibodies targeting the PD-1/PD-L1 pathway have been developed to attack tumor cells; however, resistance to immune therapy remains to be solved. Hence, identification of the underlying modulators of the PD-1/PD-L1 pathway is of significant importance to understand the mechanisms of antitumor immunotherapy. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been identified to regulate the PD-1/PD-L1 pathway, leading to participation in the immune response and immunotherapy. Therefore, this review focuses on the functions of lncRNAs and circRNAs in regulation of the PD-1/PD-L1 axis in tumorigenesis and tumor progression. We hope this review will stimulate research to supply more precise and effective cancer immune checkpoint therapies for a large number of tumors.

E26 transformation-specific variant 4 as a tumor promotor in human cancers through specific molecular mechanisms.

E26 transformation-specific (ETS) variant 4 (ETV4) is an important transcription factor that belongs to the ETS transcription factor family and is essential for much cellular physiology. Recent evidence has revealed that ETV4 is aberrantly expressed in many types of tumors, and its overexpression is related to poor prognosis of cancer patients. Additionally, increasing studies have identified that ETV4 promotes cancer growth, invasion, metastasis, and drug resistance. Mechanistically, the level of ETV4 is regulated by some post-translation modulations in a broad spectrum of cancers. However, little progress has been made to comprehensively summarize the critical roles of ETV4 in different human cancers. Hence, this review mainly focuses on the physiological functions of ETV4 in various human tumors. In addition, the molecular mechanisms of ETV4-mediated cancer progression were elucidated, including how ETV4 modulates its downstream signaling pathways and how ETV4 is regulated by some factors. On this basis, the present review may provide a valuable therapeutics strategy for future cancer treatment by targeting ETV4-related pathways.

ALKBH5 promotes cadmium-induced transformation of human bronchial epithelial cells by regulating PTEN expression in an m6A-dependent manner.

Cadmium is a carcinogenic heavy metal that poses a severe threat to human beings. The underlying mechanism, however, remains elusive. N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in mRNA that regulates RNA metabolism. Emerging evidence shows that m6A is involved in the pathogenesis of various cancers. In this study, human bronchial epithelial BEAS-2B cells were transformed by exposing to 2 µM of cadmium for 20 weeks to investigate the role of m6A in cadmium carcinogenesis. We found the level of m6A in mRNA was significantly decreased in cadmium-transformed BEAS-2B cells, and this change was regulated by m6A demethylase ALKBH5. ALKBH5 was significantly upregulated in the middle and late stages of cell transformation at week 8, 12, 16 and 20. Knockdown of ALKBH5 in cadmium-transformed cells alleviated cell proliferation, migration, invasion, and anchorage-independent growth, but co-transfection with ALKBH5 siRNA and PTEN siRNA restored the inhibitory effects of ALKBH5 knockdown on those transformation properties. ALKBH5 decreased the m6A level of PTEN mRNA, resulting in its instability and reduction of PTEN protein expression. These results indicate that ALKBH5-mediated demethylation m6A at PTEN mRNA is involved in cadmium-induced cell transformation. Our study provides a new perspective for the involvement of m6A modification in cadmium carcinogenesis.

A novel circular RNA, circPUS7 promotes cadmium-induced transformation of human bronchial epithelial cells by regulating Kirsten rat sarcoma viral oncogene homolog expression via sponging miR-770.

Cadmium is a human carcinogen, which induces cancers by mechanisms that are not fully understood. Induction of oxidative stress, apoptosis resistance, genotoxic effects, and epigenetic modulations have been indicated to regulate cadmium-induced carcinogenesis. Circular RNAs are epigenetic regulators that have been recognized to play essential roles in carcinogenesis. Yet, the involvement of circular RNAs in cadmium carcinogenesis remains unclear. In this study, a novel circular RNA, circPUS7, was identified and described for the first time. CircPUS7 was significantly upregulated at week 12, 16, and 20 during the cadmium-induced transformation of human bronchial epithelial BEAS-2B cells. Knockdown of circPUS7 in cadmium-transformed BEAS-2B (T-BEAS-2B) cells significantly attenuated transformation markers including cell proliferation, migration, invasion, and anchorage-independent growth. Moreover, circPUS7 promoted malignant phenotypes by competitively binding with miR-770. Overexpression of miR-770 significantly inhibited the transformation properties of T-BEAS-2B cells while inhibition of miR-770 potently reversed the inhibitory effects of circPUS7 knockdown in proliferation, migration, invasion, and anchorage-independent growth of the T-BEAS-2B cells. Kirsten rat sarcoma viral oncogene homolog (KRAS), which was increased synchronically with circPUS7 during cadmium-induced cell transformation, was regulated by circPUS7 through sponging miR-770. In summary, our findings demonstrate that circPUS7 promotes cadmium-induced cell transformation through sponging miR-770 to regulate KRAS expression, providing a new perspective with the involvement of circular RNAs to further understand the mechanisms of cadmium carcinogenesis.