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Human papillomaviruses (HPVs) account for more than 30% of cancer cases, with definite identification of the oncogenic role of viral E6 and E7 genes. However, the identification of high-risk HPV genotypes has largely relied on lagged biological exploration and clinical observation, with types unclassified and oncogenicity unknown for many HPVs. In the present study, we retrieved and cleaned HPV sequence records with high quality and analyzed their genomic compositional traits of dinucleotide (DNT) and DNT representation (DCR) to overview the distribution difference among various types of HPVs. Then, a deep learning model was built to predict the oncogenic potential of all HPVs based on E6 and E7 genes. Our results showed that the main three groups of Alpha, Beta, and Gamma HPVs were clearly separated between/among types in the DCR trait for either E6 or E7 coding sequence (CDS) and were clustered within the same group. Moreover, the DCR data of either E6 or E7 were learnable with a convolutional neural network (CNN) model. Either CNN classifier predicted accurately the oncogenicity label of high and low oncogenic HPVs. In summary, the compositional traits of HPV oncogenicity-related genes E6 and E7 were much different between the high and low oncogenic HPVs, and the compositional trait of the DCR-based deep learning classifier predicted the oncogenic phenotype accurately of HPVs. The trained predictor in this study will facilitate the identification of HPV oncogenicity, particularly for those HPVs without clear genotype or phenotype. [ABSTRACT FROM AUTHOR]

As the initial point for digestion, the balance of oral microorganisms plays an important role in maintaining local and systemic health. Oral dysbiosis, or an imbalance in the oral microbial community, may lead to the onset of various diseases. The presence or abnormal increase of microbes in the oral cavity has attracted significant attention due to its complicated relationship with oral cancer. Oral cancer can remodel microbial profiles by creating a more beneficial microenvironment for its progression. On the other hand, altered microbial profiles can promote tumorigenesis by evoking a complex inflammatory response and affecting host immunity. This review analyzes the oncogenic potential of oral microbiome alterations as a driver and biomarker. Additionally, a potentially therapeutic strategy via the reversal of the oral microbiome dysbiosis in oral cancers has been discussed. [ABSTRACT FROM AUTHOR]

Background: Abnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain. Methods: The FABD-deficient adenovirus vectors Ad-BCR/ABL△FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright‒Giemsa staining and haematoxylin and eosin (HE) staining. Results: We report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice. Conclusions: These findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL. [ABSTRACT FROM AUTHOR]

As one of the most important avian immunosuppressive and neoplastic diseases, Marek's disease (MD), caused by oncogenic Marek's disease virus (MDV), has caused huge economic losses worldwide over the past five decades. In recent years, MD outbreaks have occurred frequently in MD-vaccinated chicken flocks, but the key pathogenic determinants and influencing factors remain unclear. Herein, we analyzed the pathogenicity of seven newly isolated MDV strains from tumor-bearing chickens in China and found that all of them were pathogenic to chicken hosts, among which four MDV isolates, SDCW01, HNXZ05, HNSQ05 and HNSQ01, were considered to be hypervirulent MDV (HV-MDV) strains. At 73 days of the virus infection experiment, the cumulative incidences of MD were 100%, 93.3%, 90% and 100%, with mortalities of 83.3%, 73.3%, 60% and 86.7%, respectively, for the four viruses. The gross occurrences of tumors were 50%, 33.3%, 30% and 63.3%, respectively, accompanied by significant hepatosplenomegaly and serious atrophy of the immune organs. Furthermore, the immune protection effects of four commercial MD vaccines against SDCW01, CVI988, HVT, CVI988+HVT, and 814 were explored. Unexpectedly, during the 67 days of post-virus challenge, the protection indices (PIs) of these four MD vaccines were only 46.2%, 38.5%, 50%, and 28%, respectively, and the birds that received the monovalent CVI988 or HVT still developed tumors with cumulative incidences of 7.7% and 11.5%, respectively. To our knowledge, this is the first demonstration of the simultaneous comparison of the immune protection efficacy of multiple commercial MD vaccines with different vaccine strains. Our study revealed that the HV-MDV variants circulating in China could significantly break through the immune protection of the classical MD vaccines currently widely used. For future work, there is an urgent need to develop novel, more effective MD vaccines for tackling the new challenge of emerging HV-MDV strains or variants for the sustainable control of MD. [ABSTRACT FROM AUTHOR]

In recent years, outbreaks of Marek's disease (MD) have been frequently reported in vaccinated chicken flocks in China. Herein, we have demonstrated that four Marek's disease virus (MDV) isolates, HN502, HN302, HN304, and HN101, are all pathogenic and oncogenic to hosts. Outstandingly, the HN302 strain induced 100% MD incidence, 54.84% mortality, and 87.10% tumor incidence, together with extensive atrophy of immune organs. Pathotyping of HN302 was performed in comparison to a standard very virulent (vv) MDV strain Md5. We found that both CVI988 and HVT vaccines significantly reduced morbidity and mortality induced by HN302 or Md5 strains, but the protection indices (PIs) provided by these two vaccines against HN302 were significantly lower (27.03%) or lower (33.33%) than that against Md5, which showed PIs of 59.89% and 54.29%, respectively. These data suggested that HN302 possesses a significant higher virulence than Md5 and at least could be designated as a vvMDV strain. Together with our previous phylogenetic analysis on MDV-1 meq genes, we have presently suggested HN302 to be a typical highly virulent MDV variant belonging to an independent Chinese branch. To our knowledge, this is the first report to provide convincible evidence to identify a pathogenic MDV variant strain with a higher virulence than Md5 in China, which may have emerged and circulating in poultry farms in China for a long time and involved in the recent MD outbreaks. [ABSTRACT FROM AUTHOR]

Objective: New therapeutic approaches are needed to improve the prognosis of glioblastoma (GBM) patients. Methods: With the objective of identifying alternative oncogenic mechanisms to abnormally activated epidermal growth factor receptor (EGFR) signalling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We then conducted gain of function as well as genetic and pharmocological inhibition assays in GBM patient‐derived cell lines to functionnally validate our finding. Results: We identified that growth hormone receptor (GHR) signalling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of suppressor of cytokine signalling 2 (SOCS2) expression due to SOCS2 promoter hypermethylation. In GBM patient‐derived cell lines, GHR signalling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro and promotes tumourigenesis, tumour growth, and tumour invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro. Conclusion: This study pioneers a new field of investigation to improve the prognosis of GBM patients. [ABSTRACT FROM AUTHOR]

Objective: This study aims to explore the effects of miR-342-3p on liver cancer stem cells (LCSC) and related mechanism. Methods: LCSC were sorted using immunomagnetic beads and flow cytometry was used to determine CD133+ and CD133− sorted cells. The self-renewal ability and growth ability of LCSC were measured by tumor spheroid formation assay and soft agar colony formation assay. Protein and mRNA expressions of CD44, ALDH1, Bmi1, Sox2 and Oct4 were detected by western blot and quantitative PCR. The relationship between miR-342-3p and HDAC7 was analyzed by dual-luciferase assay. The acetylation level of H3 protein was measured by acetyl Lysine antibody. Results: miR-342-3p overexpression in LCSC lead to lower tumor volume, reduced tumor spheroid formation and agar colony formation rates, as well as lower mRNA and protein expressions of CD44, ALDH1, Bmi1, Sox2, and Oct4. Dual-luciferase reporter assay confirmed HDAC7 as a target gene of miR-342-3p. Inhibition of HDAC7 or overexpression of PTEN suppressed the carcinogenicity and stemness of LCSC. PTEN expression was increased in sh-HDAC7 group and decreased in pcDNA3.1-HDAC7 group. HDAC7 promoted H3 deacetylation and inhibited PTEN expression. Overexpression of HDAC7 or silencing of PTEN could reverse the inhibitory effect of overexpression of miR-342-3p on LCSC carcinogenicity and cell stemness. Conclusion: MiR-342-3p inhibited LCSC oncogenicity and cell stemness by promoting PTEN and inhibiting HDAC7. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are emerging biomarkers in biological processes and the role of miR‐495‐3p has been identified in melanoma, while the detailed molecular mechanisms remain to be further explored. We aim to explore the effect of histone deacetylase 3 (HDAC3) and miR‐495‐3p on epithelial‐mesenchymal transition (EMT) and oncogenicity of melanoma cells by regulating tumour necrosis factor receptor‐associated factor 5 (TRAF5). Levels of HDAC3, miR‐495‐3p and TRAF5 in melanoma tissues and pigmented nevus tissues were determined, and the predictive roles of HDAC3 and miR‐495‐3p in prognosis of melanoma patients were measured. The melanoma cells were screened and transfected with relative oligonucleotides and plasmids, and the expression of HDAC3, miR‐495‐3p and TRAF5, and phenotypes of melanoma cells were gauged by a series of assays. The relations between HDAC3 and miR‐495‐3p, and between miR‐495‐3p and TRAF5 were confirmed. HDAC3 and TRAF5 were increased while miR‐495‐3p was decreased in melanoma cells and tissues, and the low expression of miR‐495‐3p as well as high expression of HDAC3 indicated a poor prognosis of melanoma patients. Inhibited HDAC3 elevated miR‐495‐3p to suppress EMT and oncogenicity of melanoma cells by reducing TRAF5. HDAC3 particularly bound to miR‐495‐3p and TRAF5 was the target gene of miR‐495‐3p. Our results revealed that down‐regulated HDAC3 elevates miR‐495‐3p to suppress malignant phenotypes of melanoma cells by inhibiting TRAF5, thereby repressing EMT progression of melanoma cells. This study may provide novel targets for melanoma treatment. [ABSTRACT FROM AUTHOR]

Purposes: Long intergenic non-protein coding RNA 525 (LINC00525), a long noncoding RNA, has been implicated in the carcinogenesis and progression of many human cancer types. However, the detailed roles of LINC00525 in chordoma and the underlying mechanisms are not fully understood. Here, we aimed to determine whether LINC00525 could modulate the oncogenicity of chordoma cells and to elucidate in detail the molecular events underlying these tumor-promoting activities. Methods: Reverse-transcription quantitative polymerase chain reactions were performed to assess LINC00525 expression in chordoma. The effects of LINC00525 silencing on chordoma cell proliferation, apoptosis, migration, and invasiveness in vitro and tumor growth in vivo were respectively tested using CCK-8 assay, flow cytometry, migration and invasion assays, and xenograft experiments. Results: High LINC00525 expression levels were detected in chordoma tissues. The proliferative, migratory, and invasive abilities of chordoma cells in vitro and their tumor growth in vivo were suppressed by the LINC00525 knockdown, whereas apoptosis was induced by it. Mechanistically, LINC00525 acted as a molecular sponge of microRNA-505-3p (miR-505-3p) and upregulated the expression of high mobility group box 1 (HMGB1), which is directly targeted by miR-505-3p. Rescue assays indicated that increasing the output of miR-505-3p–HMGB1 axis attenuated the effects of LINC00525 depletion on chordoma cells. Conclusion: LINC00525, a pro-oncogenic long noncoding RNA, promotes chordoma progression by regulating the miR-505-3p–HMGB1 axis. The LINC00525–miR-505-3p–HMGB1 pathway may be a novel therapeutic target in chordoma. [ABSTRACT FROM AUTHOR]

The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed. [ABSTRACT FROM AUTHOR]

A heterozygous point mutation of p53 gene at codon 280 from AGA to ACA (R280T) frequently occurs in nasopharyngeal carcinoma (NPC) cell lines, and about 10% NPC tissues. However, the role of this mutation in the pathogenesis of NPC remains unclear. In this study, we generated p53 knockout (KO) NPC cell lines from CNE2 cells carrying heterozygous p53 R280T (p53-R280T) mutation and C666-1 cells carrying wild-type p53 by CRISPR-Cas9 gene editing system, and found that KO of heterozygous p53-R280T significantly decreased NPC cell proliferation and increased NPC cell apoptosis, whereas KO of wild-type p53 had opposite effects on NPC cell proliferation and apoptosis. Moreover, KO of heterozygous p53-R280T inhibited the anchorage-independent growth and in vivo tumorigenicity of NPC cells. mRNA sequencing of heterozygous p53-R280T KO and control CNE2 cells revealed that heterozygous p53-R280T mutation activated PI3K-Akt signaling pathway. Moreover, blocking of PI3K-Akt signaling pathway abolished heterozygous p53-R280T mutation-promoting NPC cell proliferation and survival. Our data indicate that p53 with heterozygous R280T mutation functions as an oncogene, and promotes the oncogenicity of NPC cells by activating PI3K-Akt signaling pathway. [ABSTRACT FROM AUTHOR]

The use of diagnostic imaging involving ionising radiation may be necessary in pregnancy and requires an assessment of the most appropriate and safest imaging modality which will provide the necessary information balanced with the potential risks to the mother and fetus. In most cases, this will involve a potential fetal radiation dose well below 50 mGy. At these doses, there is no risk of lethality, genetic damage/epigenetic change, teratogenicity, growth impairment or sterility. Older epidemiological data indicating a potential increased cancer risk have been contradicted by newer data and better understanding of the biology of low dose radiation. The linear no-threshold rule has been challenged by many and more realistic estimates of oncogenicity risk along with the potential risks of contrast agents are summarised in this review. Imaging in the pregnant population is increasing in both the number of examinations performed and the number of patients being imaged, with the greatest increase being computed tomography scans. Counselling and obtaining informed consent for imaging that involves radiation requires the clinician to communicate with the woman and her family a realistic estimate of the potential radiation dose to herself and her fetus, to describe and quantitate the risks of this estimated dose, to outline the benefits of the imaging procedure and to respond to any questions or concerns. As almost all diagnostic imaging involves doses below the 50 mGy threshold, clinically indicated investigations should not be withheld during pregnancy. All allied staff must also be well informed to ensure the patient receives a consistent message about the risks and benefits of the proposed test. [ABSTRACT FROM AUTHOR]

Purpose: Several microRNAs (miRNAs) that are aberrantly expressed in glioblastoma multiforme (GBM) play a significant role in GBM formation and progression. The expression profile and functions of miR-559 in GBM remain unclear. Here, we quantified the expression and investigated the involvement of miR-559 in the oncogenicity of GBM cells in vitro and in vivo. Material and methods: Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) was carried out to determine miR-559 expression in GBM tissues and cell lines. A series of functional assays was performed to evaluate the effects of miR-559 overexpression on GBM cell proliferation, apoptosis, migration, and invasion in vitro and on GBM tumor growth in vivo. The regulatory mechanisms of miR-559 action in GBM cells were then explored. Results: The expression of miR‑559 was lower in GBM tissues and cell lines and significantly correlated with the Karnofsky performance score and tumor size among patients with GBM. Exogenous miR‑559 expression inhibited GBM cell proliferation, migration, and invasion and promoted apoptosis. MiR-559 overexpression decreased tumor growth in vivo. Mechanistic experiments confirmed metadherin (MTDH) as a direct target gene of miR-559 in GBM. Silencing of MTDH induced effects similar to those of miR-559 upregulation in GBM cells, whereas MTDH expression restoration attenuated the antitumor effects of miR‑559 in GBM cells. Protein kinase B (AKT) in the phosphatase and tensin homolog (PTEN)–AKT signaling pathway was found to be deactivated in GBM cells after upregulation of miR-559 both in vitro and in vivo. Conclusion: MiR-559 acts as a tumor suppressor in GBM cells in vitro and in vivo, at least in part through the downregulation of MTDH and inhibition of AKT in the PTEN–AKT pathway. Therefore, targeting the miR-559–MTDH axis may be a promising therapeutic strategy for patients with GBM. [ABSTRACT FROM AUTHOR]

Human papillomavirus 58 (HPV58) ranks the second or third in East Asian cervical cancers. Current studies on HPV58 are scarce and focus on the prototype. Previously, we identified the three most common circulating HPV58 E7 strains contained amino acid alterations: G41R/G63D (51%), T20I/G63S (22%) and T74A/D76E (14%) respectively. Among them, the T20I/G63S variant (V1) had a stronger epidemiological association with cervical cancer. We therefore suggested that V1 possessed stronger oncogenicity than the other two variants. Here, we performed phenotypic assays to characterize and compare their oncogenicities with HPV58 E7 prototype. Our results showed that overexpression of V1 conferred a higher colony‐forming ability to primary murine epithelial cells than prototype (P < 0.05) and other variants, implicating its higher immortalising potential. Further experiments showed that both V1 and prototype enhanced the anchorage‐independent growth of NIH/3T3 cells (P < 0.001), implicating their stronger transforming power than the two other variants. Moreover, they possessed an increased ability to degrade pRb (P < 0.001), which is a major effector pathway of E7‐driven oncogenesis. Our work represents the first study to compare the oncogenicities of HPV58 E7 prototype and variants. These findings deepened our understanding of HPV58 and might inform clinical screening and follow‐up strategy. [ABSTRACT FROM AUTHOR]

Artemin (ARTN) is a member of glial cell linederived neurotrophic factor (GDNF) family of ligands, and its signaling is mediated via a multi-component receptor complex including the glycosylphosphatidylinositolanchored GDNF family receptors a (GFRa1, GFRa3) and RET receptor tyrosine kinase. The major mechanism of ARTN action is via binding to a non-signaling co-receptor. The major function of ARTN is to drive the molecule to induce migration and axonal projection from sympathetic neurons. It also promotes the survival, proliferation and neurite outgrowth of sympathetic neurons in vitro. ARTN triggers oncogenicity and metastasis by the activation of the AKT signaling pathway. Recent studies have reported that the expression of ARTN in hepatocellular carcinoma is associated with increased tumor size, quick relapse and shorter survival. Furthermore, ARTN promotes drug resistance such as antiestrogens, doxorubicin, fulvestrant, paclitaxel, tamoxifen and trastuzumab. Moreover, ARTN also stimulates the radio-therapeutic resistance. This review highlights the proposed roles of ARTN in cancer cells and discusses recent results supporting its emerging role as an oncogenic, metastatic and drug-resisting agent with a special focus on how these new insights may facilitate rational development of ARTN for targeted therapies in the future. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus-1 (HTLV-1) is the first pathogenic human retrovirus identified in 1979 by the Gallo group. HTLV-1 causes fatal T-cell leukemia (adult T cell leukemia) and a progressive myelopahy (HTLV-1-associated myelopathy/tropical spastic paraparesis, HAM/TSP) and other disorders. Since the discovery of HTLV-1, several other microorganisms are demonstrated to cause cancer in humans. In this article, we investigated the oncogenic capacity of HTLV-1, in comparison with those of other oncoviruses and one oncobacterium (Helicobacter pylori, H. Pylori) based on published literature. We conclude here that HTLV-1 is one of the most and may be the most carcinogenic among them and arguably one of the most potent of the known human carcinogens. This fact has not been noted before and is particularly important to justify why we need to study HTLV-1 as an important model of human viral oncogenesis. [ABSTRACT FROM AUTHOR]

GalNAc-transferase-7 (GALNT7) is essential for the regulation of cell proliferation and has been implicated in tumorigenesis. However, the role of GALNT7 in the development and progression of nasopharyngeal carcinoma (NPC) remains unclear. Our previous study showed that GALNT7 was a putative target of miR-494, which was confirmed by luciferase reporter assay. In the present study, we demonstrated that in vitro knockdown of GALNT7 significantly inhibited the proliferation, colony formation, migration, and invasion of NPC-derived cells. In vivo tumorigenicity assay showed that miR-494 and GALNT7-small interfering RNA (siRNA) reduced tumor growth in nude mice. Taken together, our results provided new evidence for an oncogenic role of GALNT7 in NPC. [ABSTRACT FROM AUTHOR]

We propose a method for determining the criticality of residual host cell DNA, which is characterized through two attributes, namely the size and amount of residual DNA in biopharmaceutical product. By applying a mechanistic modeling approach to the problem, we establish the linkage between residual DNA and product safety measured in terms of immunogenicity, oncogenicity, and infectivity. Such a link makes it possible to establish acceptable ranges of residual DNA size and amount. Application of the method is illustrated through two real-life examples related to a vaccine manufactured in Madin Darby Canine Kidney cell line and a monoclonal antibody using Chinese hamster ovary (CHO) cell line as host cells. [ABSTRACT FROM PUBLISHER]

Cancer is the greatest challenge to human health in our era. Perturbations of receptor tyrosine kinase (RTK) function contribute to a large chunk of cancer etiology. Current evidence supports that mutations in RTKs mediate receptor dimerization and result in ligand-independent kinase activity and tumorigenesis, indicating that mutation-introduced receptor dimerization is a critical component of oncogenesis RTK mutations. However, there are no specialized reviews of this important principle. In the current review, we discuss the physiological and harmless RTK function and subsequently examine mutation-introduced dimerization of RTKs and the role of these mutations in tumorigenesis. We also summarize the protein structure characteristics that are important for dimerization and introduce research methods and tools to predict and validate the existence of oncogenic mutations introduced by dimerization in RTKs. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma is an embryonic neoplasm originating from the neural crest with cellular heterogeneity as one of its oncobiological characteristics. This study was undertaken to determine whether human neuroblastoma contains stem cell-like cells. Methods: Twenty patients with neuroblastoma who have been treated in our hospital since January 2005 were divided into pre-operative chemotherapy (10 patients) and non-chemotherapy (10) groups. Tumor specimens of the patients were taken and paraffin sections were made. The expressions of stem cell markers CD133, ABCG2, CD117 and nestin were immunohistochemically detected in the specimens. Neuroblastoma cells were stained with Hoechst 33342 and PI. The side population (SP) cells were analyzed by the fluorescence-activated cell sorter. The disparity drug resistance to cisplatin (DDP) of SP and non-SP cells was measured with MTT colorimetric assay. The oncogenicity of SP and non-SP cells was identified in nude mice. Results: There was no significant difference in the expression intensity of CD117 and nestin between the two groups of specimens ( P>0.05). There was a significant difference between the two groups in terms of the expression intensity of CD133 and ABCG2 ( P<0.05). The SP cells accounted for 0.2%-1.3% of the total human neuroblastoma cells and were decreased to 0.1%-0.5% after verapamil treatment. The SP and non-SP cells showed disparity in cell growth experiment and drug resistance to DDP. Oncogenicity experiment revealed that nude mice could erupt tumor by an injection of l×10 SHSY5Y and WIV SP cells. However, the nude mice could not form tumor by an injection of l×10 non-SP cells. Conclusion: Neuroblastoma might contain cancer stem cell-like cells. [ABSTRACT FROM AUTHOR]

B7-H4 is expressed in a variety of tumor cells and functions as a negative regulator of T cells. However, clarification is needed as to whether B7-H4 mediates tumorigenesis through mechanisms, such as apoptosis, in addition to mediating tumor immune escape. We investigate the mechanisms involved in enhanced oncogenicity and the inhibition of apoptosis by B7-H4 in pancreatic cancer cells. Short interfering RNAs (siRNAs) specific for B7-H4 were evaluated for their ability to knockdown B7-H4 mRNA and protein expression in pancreatic cancer cells and the most effective siRNA was selected for investigating the effect of B7-H4 gene silencing in a number of functional assays. The inhibition of B7-H4 increased cell-cell adhesion and decreased the formation of pseudopodia. It also increased the expression of E-cadherin and decreased the expression of vimentin and CD44. B7-H4 siRNA inhibited cell proliferation, colony formation and migration of pancreatic cancer cells. Moreover, increased apoptosis in pancreatic cancer cells following B7-H4 silencing was demonstrated in vitro by using flow cytometry and in a xenograft tumor model and was associated with increased caspase activity and decreased Erk1/2 phosphorylation both in vitro and in vivo. Loss of B7-H4 function thus prevents tumor growth through many processes, including the induction of apoptosis and inhibition of the Erk1/2 signaling pathway indicating that B7-H4 is a cancer promoter and a potentially important therapeutic target. B7-H4 inhibition might offer an exciting opportunity to inhibit the progression of human pancreatic cancers. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a clonal hematologic malignancy characterized by the BCR-ABL protein. BCR-ABL is a constitutively active tyrosine kinase and plays a critical role in the pathogenesis of CML. Imatinib mesylate, a selective tyrosine kinase inhibitor, is effective in CML, but drug resistance and relapse occur. The coiled-coil (CC) domain located in BCR mediates BCR-ABL tetramerization, which is essential for the activation of tyrosine kinase and transformation potential of BCR-ABL. CC domain is supposed to be a therapeutic target for CML. We purified a TAT-CC protein competively binding with the endogenous CC domain to reduce BCR-ABL kinase activity. We found that TAT-CC co-located and interacted with BCR-ABL in Ba/F3-p210 and K562 cells. It induced apoptosis and inhibited proliferation in these cells. It increased the sensitivity of these cells to imatinib and reduced the phosphorylation of BCR-ABL, CRKL and STAT5. We confirmed that TAT-CC could attenuate the oncogenicity of Ba/F3-p210 cells and diminish the volume of K562 solid tumor in mice. We conclude targeting the CC may provide a complementary therapy to inhibit BCR-ABL oncogenicity. [ABSTRACT FROM AUTHOR]

As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastineassociated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage. [ABSTRACT FROM AUTHOR]

As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastine-associated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage. [ABSTRACT FROM AUTHOR]

Marek's disease virus (MDV) is an oncogenic herpesvirus that causes malignant lymphomas in chickens. Recent field isolates of MDV have tended to exhibit increasing virulence, and MDV strains are currently classified into four categories based on their relative virulence. Meq, a putative MDV oncoprotein, resembles the Jun/Fos family of basic leucine zipper (bZIP) transcription factors and can regulate the expression of viral and cellular genes as a homodimer or as a heterodimer with a variety of bZIP family proteins. MDV isolates display distinct diversity and point mutations in Meq, which may contribute to changes in the transcriptional activities of Meq and subsequently, to observed increases in MDV oncogenicity. In this study, we introduced mutations into the meq gene and used dual luciferase reporter assays to analyze the transcriptional activities of the resulting Meq proteins to determine whether distinct mutations in Meq could be responsible for differences in transcriptional activity among MDV strains. A proline-to-alanine substitution at position 217, the second position of one of the proline direct repeats in the transactivation domain, enhanced the transactivation activity of Meq. In addition, we found that two substitutions at positions 283 and 320 affected transactivation activity. These results suggest that the distinct diversity of and point mutations in the Meq proteins are responsible for differences in transactivation activity among MDV strains. [ABSTRACT FROM AUTHOR]

Background: Based on the severity and prognostic condition of respective cancers caused by them, papilloma viruses are classified into high, medium, and low risk groups using E6 and E7 viral proteins. Nowadays, different methods of modeling in clinical medicine are used for diagnosis of diseases and evaluation of their molecular characteristics. Among the new methods of modeling, fuzzy systems are of particular importance in various fields of science. The aim of this study was to use a new intelligent Adaptive Nero Fuzzy Inference System (ANFIS) for predicting human papilloma virus oncogenicity based on a number of biochemical properties of E7 protein. Materials and Methods: In this study, using ANFIS model, a new model was developed for predicting oncogenicity of papilloma virus isolated from patients. The process of training and testing was performed using a set of available published filed data and several statistical and graphical criteria. Accordingly, through provision of needed biochemical and biophysical data on E7 gens from the existing data, this model was developed. The results of this model were, then, validated by the authentic published data. Results: Based on the results, the developed model is capable of predicting papilloma virus oncogenicity efficiently. R2 and RMSE values in training stage were 0.99 and 101.18, respectively. In the testing stage, however, they stood at 0.94 and 173.8, respectively. Conclusion: Based on the findings, the use of ANFIS model significantly improves the accuracy of estimating virus oncogenicity phenomenon. The methodology presented in this study is a new approach in estimating viral oncogenicity and can successfully be combined with other mathematical models for model updating in real conditions. [ABSTRACT FROM AUTHOR]

The polyisocyanates of 1,6-hexamethylene diisocyanate (HDI) find widespread commercial use as components of paints and in the formulation of light-stable polyurethane coating materials. This 2-year study assessed the oncogenicity of the diisocyanate monomer HDI in male and female Fischer-344 rats exposed 6 h/day, 5 days/week to mean analytical air concentrations of 0, 0.005, 0.025, and 0.164 ppm HDI. During the in-life phase, transient eye irritation was observed in 0.164 ppm males, and a slight body weight decrease (5%) in the 0.164 ppm females during the second year of exposure. There were no exposure-related effects on mortality. Compound-related, non-neoplastic histopathologic changes were limited to the respiratory tract and changes were characterized by epithelial tissue reaction to the acute irritant properties of HDI vapor. For tissues of the nasal cavity, the major histopathologic findings were degeneration of the olfactory epithelium characterized by destruction of the epithelial architecture often with narrowing or atrophy and occasional focal erosion or ulceration. In addition, there was variable degeneration of the respiratory epithelium with hyperkeratosis of the epithelium, epithelial and mucus secretory cell hyperplasia, squamous metaplasia, chronic-active inflammation, and errosive or ulcerative changes. These tissue effects along with a statistically significant decrease in body weight of female rats demonstrated attainment of a maximum tolerated dose. There was no evidence of progression of these changes in the nasal epithelium to neoplasia nor evidence of any compound-related neoplastic lesions for any of the other tissues examined. Therefore, it is concluded that HDI did not show a carcinogenic potential in this study. [ABSTRACT FROM AUTHOR]

The synthetic retinoic acid analog, 9-cis-UAB30 [(2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2, 4,6-octatrienoic acid], is a specific ligand for the retinoid X receptor. Murine oncogenicity and pharmacokinetics studies were performed as part of the preclinical development of 9-cis-UAB30 for breast cancer chemoprevention. In the oncogenicity study, TSG-p53(+/-) (p53 knockout) mice (25 per sex per group) received daily gavage exposure to 9-cis-UAB30 doses of 0 (control), 30, 100, or 300 mg/kg/d for 6 months. Positive controls received p-cresidine (400 mg/kg/d) for 6 months. 9-cis-UAB30 had no biologically significant effects on survival, body weight, body weight gain, clinical signs, hematology, or clinical chemistry but induced dose-related hepatomegaly in both sexes and decreased thymus weights in high-dose females. Gross and microscopic pathology provided no evidence of 9-cis-UAB30 toxicity or oncogenicity; by contrast, p-cresidine induced urinary bladder neoplasms in more than 60% of male and female mice. It was concluded that 9-cis-UAB30 is not oncogenic in p53(+/-) mice. In the pharmacokinetics study, C57BL/6 mice received daily gavage exposure to 9-cis-UAB30 (100 or 300 mg/kg/d) for 1 or 7 days. Pharmacokinetic parameters were similar after 1 and 7 days of dosing. Dose-related peak plasma levels of 9-cis-UAB30 were seen between 0.25 and 3 hours; volume of distribution was comparable at both dose levels. Increases in area under the curve were less than proportional to dose and were associated with an increased rate of apparent clearance and decreased elimination half-life. These results suggest decreased absorption and/or possible induction of clearance mechanisms. Enzyme induction may underlie the hepatomegaly seen in mice treated with 9-cis-UAB30 for 6 months in the oncogenicity study. [ABSTRACT FROM AUTHOR]

Animal models are widely used to study the biological behavior of human tumors in vivo. Murine immunodeficient models are used to test novel human anti-tumor therapies, and humanized mice are employed to study immunotherapeutic protocols. We find that human melanoma cell lines lose HLA class I surface expression after growth in immunodeficient mice and that this phenomenon occurs frequently and is reproducible. This HLA loss is due to a coordinated down-regulation of APM and HLA heavy chain expression at the transcriptional level. It is produced by epigenetic modifications and can be reversed by treatment with histone deacetylase inhibitors or IFN-gamma. These HLA alterations only appear during in vivo growth and not during successive in vitro passages. Interestingly, these new tumor variants with HLA class I loss show higher tumorigenicity per se and may represent a more advanced state of the original tumor. Lack of MHC class I expression on tumor cells represents a frequent escape mechanism from the immune response. Our results indicate that tumor variants with alterations in MHC can also appear in vivo after the immunoescape phase in the absence of anti-tumor immune response. Our findings suggest that any studied parameter, i.e., HLA expression, of malignant cells in xenograft models, has to be evaluated before and after growth in immunodeficient mice, in order to design more appropriate immunotherapy and chemotherapy treatments against tumor cells growing in vivo. [ABSTRACT FROM AUTHOR]

We report that artemin, a member of the glial cell line-derived neurotrophic factor family of ligands, is oncogenic for human mammary carcinoma. Artemin is expressed in numerous human mammary carcinoma cell lines. Forced expression of artemin in mammary carcinoma cells results in increased anchorage-independent growth, increased colony formation in soft agar and in three-dimensional Matrigel, and also promotes a scattered cell phenotype with enhanced migration and invasion. Moreover, forced expression of artemin increases tumor size in xenograft models and leads to highly proliferative, poorly differentiated and invasive tumors. Expression data in Oncomine indicate that high artemin expression is significantly associated with residual disease after chemotherapy, metastasis, relapse and death. Artemin protein is detectable in 65% of mammary carcinoma and its expression correlates to decreased overall survival in the cohort of patients. Depletion of endogenous artemin with small interfering RNA, or antibody inhibition of artemin, decreases the oncogenicity and invasiveness of mammary carcinoma cells. Artemin is therefore oncogenic for human mammary carcinoma, and targeted therapeutic approaches to inhibit artemin function in mammary carcinoma warrant consideration.Oncogene (2009) 28, 2034–2045; doi:10.1038/onc.2009.66; published online 13 April 2009 [ABSTRACT FROM AUTHOR]

There are no published cancer studies of methanol-exposed cohorts. Genotoxicity studies do not suggest carcinogenic activity from methanol exposure. Oncogenicity studies of methanol were conducted by inhalation for ~20 hrs/day at up to 1000 ppm in F344 rats and B6C3F1 mice (NEDO), and by incorporation into drinking water at up to 20,000 ppm in Sprague-Dawley rats (Ramazzini Foundation, by Soffritti et al.). No increased neoplasms were found in the NEDO rat and mouse inhalation studies, even at air levels (up to 1000 ppm for >19 hours/day, 7 days/week) that caused 10-fold increased blood methanol levels. The maximum dose level was 600 mg/kg/day. The breakdown of methanol to formaldehyde in rats is saturated at doses above 600 mg/kg according to Horton et al. Thus, higher inhalation exposure concentrations are not expected to lead to tumors in rats or mice. In the Soffritti et al. study there was excessive early mortality, and lung pathology (inflammation, dysplasia, or neoplasm) was present in 87–94% of those dying anytime in the study. Soffritti et al. reported lympho-immunoblastic lymphoma. There are no historical control data to which this study can be compared because this diagnosis is not used by any other pathologist in animal studies. Lung infections probably played a role in formation of the lesions called lympho-immunoblastic lymphoma in the Ramazzini methanol study. The data from genotoxicity studies, the inhalation and drinking water oncogenicity studies of methanol in rats and mice, and mode of action considerations support a conclusion that methanol is not likely to be carcinogenic in humans. [ABSTRACT FROM AUTHOR]

Expression of homeobox A1 (HOXA1) results in oncogenic transformation of immortalized human mammary epithelial cells with aggressive tumor formation in vivo. However, the mechanisms by which HOXA1 mediates oncogenic transformation is not well defined. To identify molecules that could potentially be involved in HOXA1-mediated oncogenic transformation, microarray analysis was utilized to characterize and compare the gene expression pattern in response to forced expression or depletion of HOXA1 in human mammary carcinoma cells. Gene expression profiling identified that genes involved in the p44/42 mitogen-activated protein (MAP) kinase activation pathway (GRB2, MAP kinase kinase (MEK1) and SDFR1) or p44/42 MAP kinase-regulated genes (IER3, EPAS1, PCNA and catalase) are downstream expression targets of HOXA1. Forced expression of HOXA1 increased GRB2 and MEK1 mRNA and protein expression and increased p44/42 MAP kinase phosphorylation, activity and Elk-1-mediated transcription. Use of a MEK1 inhibitor demonstrated that increased p44/42 MAP kinase activity is required for the HOXA1-mediated increase in cell proliferation, survival, oncogenicity and oncogenic transformation. Thus, modulation of the p44/42 MAP kinase pathway is one mechanism by which HOXA1 mediates oncogenic transformation of the human mammary epithelial cell.Oncogene (2007) 26, 3998–4008. doi:10.1038/sj.onc.1210180; published online 8 January 2007 [ABSTRACT FROM AUTHOR]

A comprehensive analysis of the TP53 gene and its protein status was carried out on a panel of 56 colorectal cancer cell lines. This analysis was based on a combination of denaturing HPLC mutation screening of all exons of the p53 gene, sequencing the cDNA, and assessing the function of the p53 protein by assaying the induced expression of phosphorylated p53 and p21 after exposing cells to γ-rays. In a few cases where there was no production of p53 message nor evidence of functional p53 protein, all of the p53 exons were sequenced directly. Thirteen of the 56 cell lines had functional p53, 21 lines had missense mutations (one of which made no detectable protein), 4 lines produced no p53 transcripts, and the remaining 18 lines carried truncating TP53 mutations. Thus, our results showed a relatively high frequency of TP53 mutations (76.8%) in our cell lines, with almost half of the mutations being truncating mutations. This is a rather higher frequency of such mutations than usually reported. Of the 18 cell lines with truncating mutations, 12 had detectable truncated protein based on Western blot analysis, whereas no protein was detected in the remaining 6 cell lines. Our data provide a valuable source of TP 53 mutations for further studies and raise the question of the extent to which truncating mutations may have dominant negative effects, even when no truncated protein can be detected by standard methods. [ABSTRACT FROM AUTHOR]

Seirogan, an herbal medicine containing wood creosote (tablets, 10.0%w/w), has been developed and marketed for almost a century in various countries for the control of acute diarrhea and treatment of associated symptoms, such as abdominal cramping. Wood creosote (CAS no. 8021–39–4) is a mixture of simple phenolic compounds, including guaiacol and creosol and related compounds, and is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen. In the current study, the oncogenic potential of wood creosote was assessed in a 96/103-week oral gavage study in Sprague-Dawley rats. Groups of 60 rats/sex received wood creosote at dose levels of 20, 50, or 200 mg/kg body weight [bw]/day. An additional group of rats received the vehicle, 0.5% carboxymethylcellulose in deionized, distilled water, at the same dose volume as the treatment groups (10 ml/kg) and served as the controls. Treatment-related decreases in survival, body weight, and food consumption, as well as increased incidences of clinical signs that included rales, decreased activity, and salivation, were noted at 200 mg/kg bw/day when compared with the control group. There was an increased incidence of reddened and edematous lungs in rats from the 200 mg/kg bw/day group that died during the study. The lung findings were suggestive of test article aspiration during dose administration or agonal aspiration preceding and possibly resulting in death, especially because these observations were not seen in animals that survived to scheduled sacrifice. Additionally, phenols are generally recognized as having corrosive properties. There were no changes in clinical pathology and no increases in neoplastic or non-neoplastic lesions, excluding the lung findings, related to treatment with wood creosote at any dose level. Although the results of this study indicate that the maximum tolerated dose of wood creosote was met or exceeded at 200 mg/kg bw/day, there was no evidence of oncogenicity at any dose level. The lack of any evidence of oncogenicity supports the safety profile of the active ingredient in Seirogan, wood creosote. [ABSTRACT FROM PUBLISHER]

Autologous dermal fibroblasts after propagation in cell culture were used for face soft tissue augmentation. Twenty patients aged 37–61 years with facial rhytides and atrophic scars were treated with autologous fibroblasts from cell culture. Significant sustained clinical improvement was observed. Cells of early passages (4, 5, 6) were used for injection. The study showed that cultured fibroblasts were functionally active and produced large quantities of type I collagen. In vitro studies of scar formation potency of injectable fibroblasts showed that these cells possessed normal collagen gel contraction capacity. In vivo experiments showed that cultured fibroblasts exhibited no oncogenic properties and induced no tumors in nude mice. [ABSTRACT FROM AUTHOR]

Polyox Water Soluble Resins (CAS No. 25322–68–3) are high-molecular-weight polymers of ethylene oxide in a variety of viscosity grades. They are widely used in cosmetic formulations, as pharmaceutical excipients, and food contact applications. The potential for absorption and long-term toxicity (including oncogenicity) from peroral dosing was investigated using an N-10 grade with an average molecular weight of about 100,000 daltons. A subchronic (13-week) toxicity study with up to 3% Polyox N-10 in the diet of Fischer 344 rats showed slight increases in food consumption, body weight, and body weight gain. A dose-related increase in liver weight was observed, but this was not associated with any histopathology, and morphometric analysis showed no alteration in the number or size of the hepatocytes. Because of the lack of correlative pathology findings, the liver weight increase was considered not to be deleterious, but a secondary response to increased food consumption. A chronic (2-year) toxicity/oncogenicity study with up to 2% Polyox N-10 in the diet of Fischer 344 rats showed no effect with respect to clinical signs, body and organ weights, clinical pathology, urinalysis, and neoplastic and non-neoplastic pathology. Pharmacokinetic and material balance studies showed essentially complete recoveries (99% in males, 104% in females) from the excreta, with nearly all the radiolabel being eliminated in the feces (98% in males, 101% in females) in Fischer 344 rats given an oral dose of 14C-labelled Polyox N-10. Recoveries from the urine, expired air, blood, and other tissues were negligible (<1%). In conclusion, Polyox N-10 given orally is not absorbed from the gastrointestinal tract, and does not produce long-term and chronic toxicity, including oncogenicity. [ABSTRACT FROM PUBLISHER]

Polyox Water Soluble Resins (CAS No. 25322-68-3) are highmolecular-weight polymers of ethylene oxide in a variety of viscosity grades. They are widely used in cosmetic formulations, as pharmaceutical excipients, and food contact applications. The potential for absorption and long-term toxicity (including oncogenicity) from peroral dosing was investigated using an N-10 grade with an average molecular weight of about 100,000 daltons. A subchronic (13-week) toxicity study with up to 3% Polyox N-10 in the diet of Fischer 344 rats showed slight increases in food consumption, body weight, and body weight gain. A dose-related increase in liver weight was observed, but this was not associated with any histopathology, and morphometric analysis showed no alteration in the number or size of the hepatocytes. Because of the lack of correlative pathology findings, the liver weight increase was considered not to be deleterious, but a secondary response to increased food consumption. A chronic (2-year) toxicity/oncogenicity study with up to 2% Polyox N-10 in the diet of Fischer 344 rats showed no effect with respect to clinical signs, body and organ weights, clinical pathology, urinalysis, and neoplastic and non-neoplastic pathology. Pharmacokinetic and material balance studies showed essentially complete recoveries (99% in males, 104% in females) from the excreta, with nearly all the radiolabel being eliminated in the feces (98% in males, 101% in females) in Fischer 344 rats given an oral dose of [sup 14]C-labelled Polyox N-10. Recoveries from the urine, expired air, blood, and other tissues were negligible (< 1%). In conclusion, Polyox N-10 given orally is not absorbed from the gastrointestinal tract, and does not produce long-term and chronic toxicity, including oncogenicity. [ABSTRACT FROM AUTHOR]

Autologous dermal fibroblasts after propagation in cell culture were used for face soft tissue augmentation. Twenty patients aged 37–61 years with facial rhytides and atrophic scars were treated with autologous fibroblasts from cell culture. Significant sustained clinical improvement was observed. Cells of early passages (4, 5, 6) were used for injection. The study showed that cultured fibroblasts were functionally active and produced large quantities of type I collagen. In vitro studies of scar formation potency of injectable fibroblasts showed that these cells possessed normal collagen gel contraction capacity. In vivo experiments showed that cultured fibroblasts exhibited no oncogenic properties and induced no tumors in nude mice. [ABSTRACT FROM AUTHOR]

As part of a comparative chronic toxicity/oncogenicity study of different Aroclors (1016, 1242, 1254, and 1260), neurotoxicity was assessed in male and female Sprague-Dawley rats using functional observational battery (FOB) and motor activity tests, and histopathologic evaluation of selected nervous system tissues. Doses varied by Aroclor and ranged from 25 to 200 ppm in the diet. Animals were evaluated prior to initiation of dosing and at 13, 26, 39, and 52 weeks of exposure. Clinical signs, body weights, and feed consumption were evaluated weekly. Data analysis of FOB and motor activity results revealed several instances where Aroclor-treated groups were different from control. However, these were considered incidental, as they lacked any consistent dose- or time-related pattern that would suggest Aroclor-induced neurotoxicity. The nonremarkable findings during each of the four assessments were supported by the absence of any treatment-related clinical signs or mortality. Decreased body weight gain was evident in the male 100 ppm Aroclor 1254 dose group and in all female Aroclor 1254 dose groups late in the study (when a linear relationship was assumed between body weight and time), correlating with decreased feed consumption. Although a variety of incidental, spontaneous, degenerative changes were found in nervous tissue evaluated histopathologically, these changes were seen with similar incidence and severity in treated and control groups. No lesions were found that could be attributed to Aroclor-related neurotoxicity. In summary, 52 weeks of exposure to Aroclors 1016, 1242, 1254, or 1260 mixed in the diet did not yield any functional or morphologic changes indicative of PCB-induced neurotoxicity. [ABSTRACT FROM PUBLISHER]

Chronic toxicity and/or oncogenicity studies were conducted in rats, mice, and dogs with the insect repellent DEET. DEET was mixed in the diet and administered to CD* rats for two years at concentrations that corresponded to dosage levels of 10, 30 or 100 mg/kg/day for males and 30, 100, or 400 mg/kg/day for females; to CD*-1 mice for 18 months at dosage levels of 250, 500, or 1000 mg/kg/day; and to dogs for one year, via gelatin capsules, at dosage levels of 30, 100, or 400 mg/kg/day. In the rodent studies, each group consisted of 60 animals of each sex, and two concurrent independent control groups, each containing 60 animals/sex were included in each study. Each group in the dog study consisted of four male and four female dogs and one control group was included in the study. Treatment-related effects were observed at the highest dose level in all three studies. For rats, the effects included decreases in body weight and food consumption and an increase in serum cholesterol in females only. In mice, the effects observed were decreases in body weight and food consumption in both sexes. The effects observed in dogs included increased incidences of emesis and ptyalism, and levels of transient reduction in hemoglobin and hematocrit, increased alkaline phosphatase (males only), decreased cholesterol, and increased potassium. One male dog in the high-dose group also exhibited ataxia, tremors, abnormal head movements, and/or convulsions on several occasions during the study. The highest no-observed-effect levels (NO-ELs) for rats, mice and dogs were determined to be 100, 500, and 100 mg/kg/day, respectively. No specific target organ toxicity or oncogenicity was observed in any of the studies. [ABSTRACT FROM PUBLISHER]

Groups of 70 male and 70 female Charles River CD (Sprague-Dawley-derived) rats were exposed whole body to styrene vapor at 0, 50, 200, 500, or 1000 ppm 6 h/day 5 days/week for 104 weeks. The rats were observed daily, body weights and food and water consumption were measured periodically, and a battery of hematologic and clinical pathology examinations was conducted at weeks 13, 26, 52, 78, and 104. Nine or 10 rats per sex per group were necropsied after 52 weeks of exposure and the remaining survivors were necropsied after 104 weeks. Control and high-exposure rats received a complete histopathologic examination, while target organs, gross lesions, and all masses were examined in the lower exposure groups. Styrene had no effect on survival in males, but females exposed to 500 or 1000 ppm had a dose-related increase in survival. Levels of styrene in the blood at the end of a 6-h exposure during week 95 were proportional to exposure concentration. Levels of styrene oxide in the blood of rats exposed to 200 ppm or greater styrene were proportional to styrene exposure concentration. There were no changes of toxicologic significance in hematology, clinical chemistry, urinalysis, or organ weights. Males exposed to 500 or 1000 ppm gained less weight than the controls during the first year and maintained the difference during the second year. Females exposed to 200, 500, or 1000 ppm gained less weight during the first year; those exposed to 500 or 1000 ppm continued to gain less during months 13–18. Styrene-related non-neoplastic histopathologic changes were confined to the olfactory epithelium of the nasal mucosa. There was no evidence that styrene exposure caused treatment-related increases of any tumor type in males or females or in the number of tumor-bearing rats in the exposed groups compared to controls. In females, there were treatment-related decreases in pituitary adenomas and mammary adenocarcinomas. Based on an overall evaluation of eight onco-genicity studies, there is clear evidence that styrene does not induce Cancer in rats. [ABSTRACT FROM PUBLISHER]

2,4-Dichlorophenoxybutyric acid (2,4-DB) is principally used in the United States on peanuts, soybeans, and alfalfa. In Europe, it is used on cereals, undersown cereals, lucerne (alfalfa), clover, and clover mixtures. Doses in the 2-year chronic/oncogenicity rat study were 0, 60, 600, and 1800 ppm. No evidence of an oncogenic potential for 2,4-DB was evident and the study clearly established a NOEL of 2.48 mg/kg/day (60 ppm, males) and 3.23 mg/kg/day (60 ppm, females), as well as an MTD of 78.0 (1800 ppm, males) and 110.6 mg/kg/day (1800 ppm, females), for chronic effects of 2,4-DB in the rat Doses in the 18-month mouse oncogenicity study were 0, 25, 250, and 750 ppm. No oncogenic effect was noted in the study. In summary, the findings of these studies indicate low chronic toxicity of 2,4-DB and the lack of oncogenic response to 2,4-DB following chronic dietary exposure of 2,4-DB in the rat and mouse. [ABSTRACT FROM PUBLISHER]

The results of oncogenicity studies of β-cyclodextrin in inbred Fischer 344 rats and CD-1 outbred mice are presented. Chronic feeding of β-cyclodextrin to Fischer 344 rats and CD-1 mice did not cause any treatment related carcinogenic effects. The only toxic effect was seen in mice as macroscopic distension of the large intestine with soft or fluid contents, histologically associated with the mucosa covered by mucous secretion containing exfoliated cells, and mucosal flattening and intestinal gland atrophy. Despite these observations, no differences between control and treated groups were observed concerning mortality, clinical observations or body weight and food consumption. [ABSTRACT FROM AUTHOR]

Three rat ventral prostate (RVP) cell lines transformed after in vitro treatment with cadmium chloride (CdCl) and one control untreated cell line were tested for tumorigenicity in newborn rats. All three cadmium-transformed RVP cell lines induced tumors at the site of inoculation in 95-100% of animals. The fibroblastoid RVP56Cd cell line induced sarcomas, whereas the epithelial cell lines RVP47-3G and RVP47-3F produced highly differentiated squamous cell carcinomas. About 20% of animals injected with RVP47-3G developed lung and splenic metastases. The tumors could be further passaged into young rats. The sarcomas had a hyperdiploid modal chromosome number similar to that of the RVP56Cd cell line. Carcinomas induced by the RVP47-3G cell line had a large proportion of stromal metaphases. The modal chromosome number of these carcinomas was in the hypertriploid-hypotetraploid range, similar to that of the parental cell line. These results demonstrate that treatment of RVP cells with CdCl in vitro results in neoplastic transformation. Since both fibroblastoid and epithelial prostate cells have undergone transformation, it seems possible that cadmium acted as a carcinogen without cell specificity. The susceptibility of these cells to the carcinogenic effect may be related to their resistance to cadmium. In the process of neoplastic transformation induced by CdCl in RVP epithelial cells changes of squamous metaplasia occur, and probably precede acquisition of tumorigenicity. [ABSTRACT FROM AUTHOR]

The association of human papillomavirus type 57 (HPV-57) with premalignant and malignant tumors of the nasal cavity was previously reported (Wu et al., Lancet 341, 522, 1993). We determined the complete nucleotide sequence of HPV-57b (GenBank 37537), which was molecularly cloned from a benign fungiform papilloma, and compared it with other HPV types and HPV-57a, which was cloned from an inverted papilloma of the maxillary sinus by de Villiers et al. (Virology 171, 248. 1989). Comparative and phylogenetic analysis of amino acid sequences of the HPV-57b oncogenes E5, E6, and E7 were performed with HPV-6, 11, 16, and 18. Phylogenetic trees using the Jotun-Hein algorithm indicated a closer relationship of HPV-57b E5 and E7 with corresponding genes of HPV-18. Signature pattern analysis of these two oncogenes was also in agreement with a closer relatedness to HPV-16 and 18 oncogenes, which are associated with a high risk for malignant progression. Compared with 7861 bp of HPV-57a, HPV-57b had 7868 bp as well as differences in the restriction enzyme sites and the open reading frames, including at least five additional ones. To investigate the oncogenic potential of HPV-57b, NIH 3T3 and REF52 cells were cotransfected with two plasmids: pKP54.HPV-57b, which contains the HPV-57b genome, and pMT.neo. 1, which confers resistance to G418. After selection in culture medium containing G418, 58% of the G418 NIH 3T3 colonies and 47% of the G418 REF52 colonies exhibited morphological transformation. These results indicate that the transcriptional regulatory elements and the oncoproteins of HPV-57b are active in vitro to induce cellular transformation, as are other high-risk HPV types. [ABSTRACT FROM AUTHOR]

The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. In this review, we provide an extensive description of the main biological functions of p38 and focus on recent studies that have addressed its role in cancer. Furthermore, we provide an updated overview of therapeutic strategies targeting p38 in cancer and promising alternatives currently being explored. [ABSTRACT FROM AUTHOR]

Bovine collagen is an acceptable agent for vocal cord medialization; however, it produces only a temporary effect. As a foreign protein bovine collagen is susceptible to host collagenase and can induce immune response. Autologous collagen has become recently available, but it is less effective as a medialization agent. The study examines human skin fibroblasts growing in culture. Human skin bioptates were taken from the retroauricular area. Fibroblasts in culture were tested for scar contractility and ability to produce type I collagen (by flow cytometry with labeled antibodies). After five passages in culture the cells produced normal type I collagen, exhibited normal contractility, and did not induce no tumors in nude mice. [ABSTRACT FROM AUTHOR]

Bovine collagen is an acceptable agent for vocal cord medialization; however, it produces only a temporary effect. As a foreign protein bovine collagen is susceptible to host collage-nase and can induce immune response. Autologous collagen has become recently available, but it is less effective as a medialization agent. The study examines human skin fibroblasts growing in culture. Human skin bioptates were taken from the retroauricular area. Fibroblasts in culture were tested for scar contractility and ability to produce type I collagen (by flow cytometry with labeled antibodies). After five passages in culture the cells produced normal type I collagen, exhibited normal contractility, and did not induce no tumors in nude mice. [ABSTRACT FROM AUTHOR]