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Fatty acid–binding proteins (FABPs) play a pivotal role in the metabolism of fatty acids and are expressed in a tissue-specific manner. FABP1 is most abundantly expressed in the liver where it accounts for about 10% of the total cytosolic protein and is thought to have diagnostic utility. To comprehensively determine FABP1 expression in normal and neoplastic tissues, a tissue microarray containing 17,071 samples from 150 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Among normal tissues, a strong FABP1 immunostaining was observed in hepatocytes, proximal tubuli of the kidney and epithelium of small intestine, appendix, and the colorectum. FABP1 positivity was found in 24 of 150 tumor categories, including 17 tumor categories with at least 1 strongly positive case. The highest FABP1 positivity rates were seen in colorectal adenomas (86%), in colorectal adenocarcinomas (71.1%), and in hepatocellular carcinomas (65.3%), followed by mucinous carcinoma of the ovary (34.6%), cholangiocarcinoma (21.6%), and various adenocarcinomas from the digestive tract (10–23%). Eleven additional entities had positivity rates between 0.2 and 6.5%. FABP1 staining was not seen in 169 primary adenocarcinomas of the lung. In colorectal cancer, reduced FABP1 expression was linked to poor-grade, right-sided tumor location, microsatellite instability (p < 0.0001 each), and absence of BRAF V600E mutations (p = 0.001), but unrelated to pT and pN status. FABP1 expression has considerably high tumor specificity. As FABP1 expression was virtually absent in adenocarcinomas of the lung, FABP1 immunohistochemistry might be particularly helpful to assist in the identification of metastatic colorectal or gastrointestinal adenocarcinoma to the lung. [ABSTRACT FROM AUTHOR]

Though the incidence of several cancers in Western societies is regulated wisely, some cancers such as breast, lung, and colorectal cancer are currently rising in many low- and middle-income countries due to increased risk factors triggered by societal and development problems. Surgery, chemotherapy, hormone, radiation, and targeted therapies are examples of traditional cancer treatment approaches. However, multiple short- and long-term adverse effects may also significantly affect patient prognosis depending on treatment-associated clinical factors. More and more research has been carried out to find new therapeutic agents in natural products, among which the bioactive compounds derived from plants have been increasingly studied. Naringin and naringenin are abundantly found in citrus fruits, such as oranges and grapefruits. A variety of cell signaling pathways mediates their anti-carcinogenic properties. Naringin and naringenin were also documented to overcome multidrug resistance, one of the major challenges to clinical practice due to multiple defense mechanisms in cancer. The effective parameters underlying the anticancer effects of naringenin and naringin include GSK3β inactivation, suppression of the gene and protein activation of NF-kB and COX-2, JAK2/STAT3 downregulation, downregulation of intracellular adhesion molecules-1, upregulation of Notch1 and tyrocite-specific genes, and activation of p38/MAPK and caspase-3. Thus, this review outlines the potential of naringin and naringenin in managing different types of cancers. [ABSTRACT FROM AUTHOR]

The zinc finger and BTB (broad-complex, tramtrack and bric a brac) domain containing protein 7A (ZBTB7A) is a pleiotropic transcription factor that plays an important role in various stages of cell proliferation, differentiation, and other developmental processes. ZBTB7A is a member of the POK family that directly and specifically binds to short DNA recognition sites located near their target genes thereby acting as transcriptional activator or repressor. ZBTB7A overexpression has been associated with tumorigenesis and metastasis in various human cancer types, including breast, prostate, lung, ovarian, and colon cancer. However in some instances downregulation of ZBTB7A results in tumor progression, suggesting its role as a tumor suppressor. ZBTB7A is involved with complicated regulatory networks which include protein–protein and protein-nucleic acid interactions. ZBTB7A involvement in cancer progression and metastasis is perhaps enabled through the regulation of various signaling pathways depending on the type and genetic context of cancer. The association of ZBTB7A with other proteins affects cancer aggressiveness, therapeutic resistance and clinical outcome. This review focuses on the involvement of ZBTB7A in various signaling pathways and its role in cancer progression. We will also review the literature on ZBTB7A and cancer which could be potentially explored for its therapeutic implications. [ABSTRACT FROM AUTHOR]

Bisphenol A [BPA; (CH3)2C(C6H4OH)2] is a synthetic chemical used as a precursor material for the manufacturing of plastics and resins. It gained attention due to its high chances of human exposure and predisposing individuals at extremely low doses to diseases, including cancer. It enters the human body via oral, inhaled, and dermal routes as leach-out products. BPA may be anticipated as a probable human carcinogen. Studies using in vitro cell lines, rodent models, and epidemiological analysis have convincingly shown the increasing susceptibility to cancer at doses below the oral reference dose set by the Environmental Protection Agency for BPA. Furthermore, BPA exerts its toxicological effects at the genetic and epigenetic levels, influencing various cell signaling pathways. The present review summarizes the available data on BPA and its potential impact on cancer and its clinical outcome. [ABSTRACT FROM AUTHOR]

RAS mutation is the most frequent oncogenic alteration in human cancers. KRAS is the most frequently mutated followed by NRAS. The emblematic KRAS mutant cancers are pancreatic, colorectal, lung adenocarcinomas and urogenital cancers. KRAS mutation frequencies are relatively stable worldwide in various cancer types with the one exception of lung adenocarcinoma. The frequencies of KRAS variant alleles appears cancer type specific, reflecting the various carcinogenic processes. In addition to point mutation KRAS, allelic imbalances are also frequent in human cancers leading to the predominance of a mutant allele. KRAS mutant cancers are characterized by typical, cancer-type-specific co-occurring mutations and distinct gene expression signatures. The heterogeneity of KRAS mutant primary cancers is significant, affecting the variant allele frequency, which could lead to unpredictable branching development in metastases. Selection of minute mutant subclones in the primary tumors or metastases during target therapies can also occur frequently in lung or colorectal cancers leading to acquired resistance. Ultrahigh sensitivity techniques are now routinely available for diagnostic purposes, but the proper determination of mutant allele frequency of KRAS in the primary or metastatic tissues may have larger clinical significance. [ABSTRACT FROM AUTHOR]

A hydrolytically stable mesoporous Gd(III)-MOF {[Gd2(TATAB)2]·6 DMF}n (1) has been successfully prepared by reaction of Gd(NO3)3·6H2O with a flexible ligand 4,4′,4′′-s-triazine-1,3,5-triyltri-p-aminobenzoate (H3TATAB) under solvothermal conditions. Further, the nanostructure 1 could be obtained via an ultrasonic treatment method. Nitrogen adsorption measurements revealed the presence of mesoporosity as well as a moderate high BET surface areas in the activated nanostructure 1 (1a), which was further used in the 5-Fu loading with the uptake capacity of 47 wt%. Meanwhile, the controlled release of 5-Fu in a simulated human body with liquid phosphate-buffered saline solution was realized. In the biological study, the anti-proliferation activity of 5-Fu@1a on A549 human non-small lung cancer (NSCLC) cells after 5-Fu@1a exposure was evaluated by the CCK-8 preformation. The effect of 5-Fu@1a on A549 NSCLC cell migration and invasion ability was detected by transwell assay. The mechanism was revealed by the detection of the NLRP3 inflammasome activation level in A549 through western blot and ELISA assay. For further explore the inhibitory effect of 5-Fu@1a, the anti-tumor ability was evaluated in the in vivo xenograft model. [ABSTRACT FROM AUTHOR]

The human DNA damage response (DDR) is a complex signaling network constituting many factors responsible for the preservation of genomic integrity. Human polyomaviruses (HPyVs) are able to harness the DDR machinery during their infectious cycle by expressing an array of tumor (T) antigens. These molecular interactions between human polyomavirus T antigens and the DDR create conditions that promote viral replication at the expense of host genomic stability to cause disease as well as carcinogenesis in the cases of the Merkel cell polyomavirus and BK polyomavirus. This review focuses on the six HPyVs with disease association, emphasizing strain-dependent differences in their selective manipulation of the DDR. Appreciation of the HPyV–DDR interface at a molecular scale is conducive to the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Numerous studies on the nature of neoplastic growth have demonstrated that oncogenic viruses may be one of the factors causing cancer. According to various estimates, 10–20% of all human cancers are caused by viruses. For example, the Epstein–Barr virus (EBV), hepatitis B and C viruses, human papillomavirus (HPV), human T-lymphotropic virus type 1 (HTLV-1), human herpesvirus type 8 (HHV-8), and Merkel cell polyomavirus were implicated in initiating tumors. At the same time, the long period between viral infection and the manifestation of cancer significantly complicates the search for a causal relationship between the presence of a virus in the human organism and the malignant transformation. For this reason, the role of certain viruses in the initiation of neoplastic processes in humans remains an unresolved issue. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 therapy are now FDA-approved treatment options for different cancer types. However, the therapeutic efficacy of ICIs varies substantially among cancer types and patients, and only a limited proportion of cancer patients benefit clinically from ICIs. To improve the therapeutic efficacy of cancer treatments involving ICI, the mechanisms of response to ICIs and the heterogeneous pattern of immune checkpoint receptor expression need to be better understood. Here, we review recent studies on ICIs in human cancer, providing the necessary basis for the rational design of immunotherapy and for appropriate patient selection. [ABSTRACT FROM AUTHOR]

Taxol or paclitaxel, an approved drug by the Food and Drug Administration, is being used for the treatment of human cancers. This study aimed to isolate and determine different species of native endophytic fungi from Iranian Taxus baccata (yew) plants located in the northern forests of Iran. To do so, a novel molecular screening approach was performed for 50 isolated endophytic fungi through amplification of exon No. 1 of taxadine synthase as a key gene in taxol production pathway. We used effective colony-polymerase chain reaction technique for rapid screening of potent taxol-producing fungi instead of genomic DNA extraction. Production of taxol was performed in batch culture by selected fungi individually and produced taxol was assayed quantitatively by high-performance liquid chromatography using standard taxanes. We found that only six fungi could produce taxol and baccatin III. Interestingly, after 7 days of incubation, the highest level of taxol was found to be 129 and that of baccatin 139.2 mg/kg dw for two native isolated Cladosporium sp. named F1 and F3. The fungal taxols could decrease cell viability in MTT assay same as commercial taxol. The fungal taxols semi-quantitatively showed antimitotic effects on MCF-7 cells as human breast cancer cell line. The expression of bcl-2 anti-apoptotic gene, in contrast to bax pro-apoptotic gene, significantly decreased after treatment by standard and fungal taxols. As fungal taxol was produced simpler than other methods and could significantly affect viability and specific genes expression profile, it is recommended that using of taxol-producing fungi from Iranian yew could be a safe and confident procedure to overcome challenges of using other methods. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition (EMT) is a crucial developmental process by which epithelial cells undergo a mesenchymal phenotypic change. During EMT, epigenetic mechanisms including DNA methylation and histone modifications are involved in the regulation of EMT-related genes. The epigenetic gene silencing of the epithelial marker E-cadherin has been well characterized. In particular, three major transcriptional repressors of E-cadherin, Snail, ZEB, and Twist families, also known as EMT-inducing transcription factors (EMT-TFs), play a crucial role in this process by cooperating with multiple epigenetic modifiers. Furthermore, recent studies have identified the novel epigenetic modifiers that control the expression of EMT-TFs, and these modifiers have emerged as critical regulators of cancer development and as novel therapeutic targets for human cancer. In this review, the diverse functions of EMT-TFs in cancer progression, the cooperative mechanisms of EMT-TFs with epigenetic modifiers, and epigenetic regulatory roles for the expression of EMT-TFs will be discussed. [ABSTRACT FROM AUTHOR]

MicroRNAs are a family of small noncoding RNAs, regulating gene expression at the post-transcriptional level and playing a crucial role as potential biomarkers and targets for many types of cancer. Our attention was given to electrochemical and spectral studies of miR-34a-5p, related to head and neck and also prostate cancer. Voltammetric experiments on a hanging mercury drop electrode and circular dichroic spectroscopic experiments in buffer solutions were performed in the range of pH from 3 to 6 and from 3 to 8, respectively. The miRNA and its DNA sequential analogues (miDNA) provided interesting and significantly different results. A comparison of miRNA and both miDNA (U) and (T) showed the effect of substitution of ribose to deoxyribose, and structural diversity of nucleic acids was confirmed by both electrochemical and spectral methods. It emerged that a single substitution of ribose to deoxyribose (equivalent to miRNA→miDNA (U)) leads on to the formation of a second guanine oxidation peak, and an RNA molecule in contrast to DNA analogues offers circular dichroic spectra of higher variability (indicating more terminal structures) and a more observable dependence on pH in the range of 3-6. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that function by base pairing with messenger RNAs, thereby regulating protein expression. Functional studies indicate that miRNAs are involved in the regulation of almost every biological pathway. Moreover, changes in miRNA expression are associated with several human pathologies, including cancer. Dysregulation and aberrant expression of microRNA-100 (miR-100) have been reported to be involved in tumorigenesis and tumor progression of several cancer types, suggesting that miR-100 might serve as a diagnostic and/or prognostic marker for human malignancy. In this review, we summarize the potential application of miR-100 in cancer treatment and as a new molecular marker for cancer prognosis and diagnosis. We will provide a brief introduction to miR-100 and discuss its role as a non-invasive biomarker and a potential therapeutic target in human cancers. [ABSTRACT FROM AUTHOR]

The activity of the proteasome, a polyfunctional enzymatic complex, is known to undergo changes during cancer development. This phenomenon is probably caused by the changes in subunit composition of proteasomes. In this work, we studied the chymotrypsin-like activity of proteasomes; their subunit composition; and their association in breast cancer, head and neck squamous cell carcinoma, endometrial cancer, renal cancer, bladder cancer, stomach cancer, and colorectal cancer. The increase in proteasome activity was revealed in most cancer tissues compared with adjacent tissues, except for the renal cell carcinoma. Changes in proteasome activity in cancer tissues compared with correspondent normal tissues observed in combination with an increased expression of immune subunits and/or proteasome activator PA28β associated with activity of 20S proteasome. In breast cancer, head and neck squamous cell carcinoma, bladder cancer, stomach cancer, and colorectal cancer, we additionally found the higher expression of Rpt6 subunit of the 19S-subunit in 26S proteasome. Correlations between chymotrypsin-like proteasome activity and subunit expressions were found in human cancer tissues. Thus, we suggest that proteasome activation and changes in its subunit composition play an important role in cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Background IMC-18F1 (icrucumab), a human monoclonal antibody against vascular endothelial growth factor receptor-1 (VEGFR-1), potently inhibits ligand-dependent phosphorylation of VEGFR-1 and downstream signaling, making icrucumab an attractive candidate for antitumor activity. Objectives The primary objective was to determine the safety profile and maximum tolerated dose of icrucumab in patients with advanced solid tumors that were previously unresponsive to standard therapy or for which no standard therapy was available. Methods In this open-label, dose-escalation, Phase 1 study, patients received icrucumab intravenously weekly at 2, 3, 6, and 12 mg/kg (Cohorts 1-4), every other week (q2w) at 15 mg/kg (Cohort 5), or every third week at 20 mg/kg (Cohort 6). Patients received icrucumab until evidence of progressive disease or other withdrawal criteria were met. Results Twenty-six patients received icrucumab. The most common adverse events were fatigue, nausea, peripheral edema, anemia, dyspnea, and vomiting. No dose-limiting toxicities (DLTs) were observed in Cohorts 1-5. Two DLTs were observed in Cohort 6 (anemia and hyponatremia), and enrollment was stopped. No patient demonstrated an immunogenic response. Overall, icrucumab exhibited nonlinear pharmacokinetics at doses >6 mg/kg. Six patients (23.1 %) achieved stable disease with median duration of 11.1 weeks (range = 10.3-18.7 weeks); tumor types were thyroid, melanoma, colorectal (3 patients), and small-cell lung cancers. Conclusions Icrucumab was safely administered weekly at doses of 2-12 mg/kg and q2w at a dose of 15 mg/kg with no DLTs. Based on achievement of stable disease, icrucumab has potential for antitumor activity against advanced solid tumors. [ABSTRACT FROM AUTHOR]

Identification and characterization of the important roles microRNAs (miRNAs) perform in human cancer is an increasingly active research area. Unfortunately, prediction of miRNA target genes remains a challenging task to cancer researchers. Current processes are time-consuming, error-prone, and subject to biologists' limited prior knowledge. Therefore, we propose a domain-specific knowledge base built upon Ontology for MicroRNA Targets (OMIT) to facilitate knowledge acquisition in miRNA target gene prediction. We describe the ontology design, semantic annotation and data integration, and user-friendly interface and conclude that the OMIT system can assist biologists in unraveling the important roles of miRNAs in human cancer. Thus, it will help clinicians make sound decisions when treating cancer patients. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NRs) play pivotal roles in cell growth, proliferation, differentiation and homeostasis. Recent progress demonstrates that NR is tightly linked to human disease such as cancer, diabetes and obesity. Here we explore NR expression profiles in human tissue using systematic approaches. NR gene profiles reveal that individual NR has its own gene expression signature depending on tissue type. Of many organs, NRs expression is enriched in liver. Expression of many NRs was significantly changed in liver cancer. Notably, NR0B2/SHP expression level was significantly decreased in human liver cancer but not in normal liver. In addition, expression of SHP is well associated with good prognosis. SHP gene network analysis based on microarray data in liver cancer shows that SHP regulates cell proliferation and metabolism related gene sets. Our systematic approaches suggest that loss of SHP expression in liver might be key genetic events during hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Protein kinase C epsilon (PKCɛ), a novel calcium-independent PKC isoform, has been shown to be a transforming oncogene. PKCɛ-mediated oncogenic activity is linked to its ability to promote cell survival. However, the mechanisms by which PKCɛ signals cell survival remain elusive. We found that signal transducers and activators of transcription 3 (Stat3), which is constitutively activated in a wide variety of human cancers, is a protein partner of PKCɛ. Stat3 has two conserved amino-acid (Tyr705 and Ser727) residues, which are phosphorylated during Stat3 activation. PKCɛ interacts with Stat3α isoform, which has Ser727, and not with Stat3β isoform, which lacks Ser727. PKCɛ–Stat3 interaction and Stat3Ser727 phosphorylation was initially observed during induction of squamous cell carcinomas and in prostate cancer. Now we present that (1) PKCɛ physically interacts with Stat3α isoform in various human cancer cells: skin melanomas (MeWo and WM266-4), gliomas (T98G and MO59K), bladder (RT-4 and UM-UC-3), colon (Caco-2), lung (H1650), pancreatic (PANC-1), and breast (MCF-7 and MDA:MB-231); (2) inhibition of PKCɛ expression using specific siRNA inhibits Stat3Ser727 phosphorylation, Stat3-DNA binding, Stat3-regulated gene expression as well as cell invasion; and (3) PKCɛ mediates Stat3Ser727 phosphorylation through integration with the MAPK cascade (RAF-1, MEK1/2, and ERK1/2). The results indicate that PKCɛ-mediated Stat3Ser727 phosphorylation is essential for constitutive activation of Stat3 and cell invasion in various human cancers. [ABSTRACT FROM AUTHOR]

Viruses are associated with 15–20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy. [ABSTRACT FROM AUTHOR]

Gene expression profiling has emerged as powerful technique for studying the mechanisms of tumor genesis and development. Seroreactivity profiling of tumor antigens is a more recent technique that further contributes to the understanding of tumors and that offers itself for noninvasive tumor diagnosis. We performed expression profiling of 55 000 transcripts and expressed-sequence-tags for 24 meningiomas and related these data to autoantibody profiles of more than 50 antigens immunogenic in the autologous patients. The expression values of antigens in WHO grade I meningioma were significantly higher if the patients' sera reacted with these antigens as confirmed by a two-tailed Wilcoxon–Mann–Whitney test. Specifically, KIAA1344 that was previously identified as frequent antigen marker in meningioma, showed increased expression if antigens against KIAA1344 were detected in autologous patients. Our study is the first to combine genome-wide expression signatures and comprehensive seroreactivity patterns toward a more complete view on tumor immunology, especially concerning the overall role of the level of gene expression on the immunogenicity of meningioma antigens.Gene Therapy (2009) 16, 184–189; doi:10.1038/gt.2008.130; published online 14 August 2008 [ABSTRACT FROM AUTHOR]

Hypomethylation of repeated elements in the genome is a common feature of human cancer, however, the direct consequences of this epigenetic defect for cancer biology are still largely unknown. Telomeres are specialized chromatin structures at the ends of eukaryotic chromosomes formed by tandem repeats of G-rich sequences and associated proteins, which have an essential role in chromosome end protection and genomic stability. Telomeric DNA repeats cannot be methylated, however, the adjacent subtelomeric DNA is heavily methylated in humans. Here, we show that the methylation status of subtelomeric DNA repeats negatively correlates with telomere length and telomere recombination in a large panel of human cancer cell lines. These findings suggest that tumor telomere length and integrity can be influenced by epigenetic factors. Finally, we show that treatment of human cancer cell lines with demethylating drugs results in hypomethylation of subtelomeric repeats and increased telomere recombination, which in turn may facilitate telomere elongation. All together, these findings suggest that tumor telomere length and integrity can be influenced by the epigenetic status of cancer cells.Oncogene (2008) 27, 6817–6833; doi:10.1038/onc.2008.289; published online 1 September 2008 [ABSTRACT FROM AUTHOR]

RAF kinases entered the limelight when our understanding of the genetic nature of cancer was much less defined and the seminal importance of proto-oncogenes as components of intracellular signaling pathways was just beginning to be recognized. Following the discovery of the v-RAF oncogene and the subsequent description of the c-RAF-1 gene by the group of Ulf Rapp, the last 20 years have seen the dissection of the signaling pathways in which RAF kinases function, and the cellular processes they control. The recent demonstration of mutations in B-RAF and C-RAF in human tumors marked the return of RAF kinases to their roots as oncogenes. The availability of small molecular weight inhibitors has fueled the hope for new therapeutic approaches. Despite the deep insights gained through the work of many laboratories, the past has left us with sufficient controversy and plenty of open questions to keep RAF research as interesting as ever. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptor-α (PPARα), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPARα is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPARα occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPARα agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPARα also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPARα. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPARα target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPARα in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPARα agonist-induced hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

The therapeutic effect of intratumoural application of Interleukin-2 (IL-2) was studied in patients with stage III–IV nasopharyngeal carcinoma (NPC) that received radiotherapy. Patients with stage III–IV NPC receiving a standard treatment of 7,000 cGy external beam irradiation have a mean disease-free survival of about 1.5 years. In this paper, we describe ten of these patients who were treated with additional peritumoural and intratumoural injections with 3×104 U IL-2 on 5 days in weeks 2, 4, and 6 of the 7-weeks’ irradiation period. This combined treatment group was compared with a historical group of patients treated with standard irradiation alone. Local IL-2 therapy showed a marked clinical and statistical significant improvement of disease-free survival. After 5 years, 63% of the IL-2 treated patients were disease-free versus 8% of the control patients. These results suggest that the therapeutic results of radiotherapy can be significantly improved by combining it with local IL-2 treatment. To our knowledge, this is the first clinical report showing that local IL-2 therapy is effective against an infiltrative and locally metastasizing tumour in human patients. [ABSTRACT FROM AUTHOR]

S100 proteins belong to the EF-hand Ca2+-binding protein family and are involved in the regulation of a variety of cellular processes. Individual S100 proteins are expressed in cell- and tissue-specific manners, and functional deterioration of S100 proteins leads to a number of human diseases, including cancer. We previously demonstrated that S100C/A11 was translocated to nuclei and inhibited DNA synthesis in human keratinocytes when exposed to high Ca2+. In the present study we examined the effects of synthetic partial peptides of S100C/A11 on human carcinoma cell lines. Only an N-terminal peptide with 19 amino acid residues (MAK19) showed cytotoxicity to the cell lines in dose- and time-dependent manners when introduced into cells by flanking the HIV-TAT protein transduction domain (TAT-MAK19). Pulse field electrophoresis revealed that DNA of the treated cells was partially degradated. Annexin V, a marker of cellular apoptosis, was detected in the cells treated with TAT-MAK19 by immunostaining and flow cytometry. The induction of apoptotic cell death was apparently independent of p53, p21WAF1/CIP1, and caspase activity, but treatment with TAT-MAK19 resulted in partial translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. These results indicate that MAK19 induces apoptosis in human cell lines and may therefore lead to the establishment of a new molecular target for the treatment of human cancer. [ABSTRACT FROM AUTHOR]

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We have previously reported that loss of p53 tumor suppressor protein results in centrosome hyperamplification, which leads to aberrant mitosis and chromosome instability. Since p53 is either deleted or mutated in human cancers at a high frequency, we investigated whether human cancers showed centrosome hyperamplification. Screening of advanced stage breast ductal carcinomas and squamous cell carcinomas of the head and neck (SCCHN) revealed that centrosome hyperamplification is frequent in both tumor types. Moreover, through the analyses of p53 in SCCHN samples by direct sequencing and by loss-of-heterozygosity test, we found that p53 mutations correlated with occurrence of centrosome hyperamplification. However, in some cases, we observed centrosome hyperamplification in tumors that retained wild-type p53. These tumors contained high levels of Mdm2. Since Mdm2 can inactivate p53 through physical association, we investigated whether Mdm2 overexpression induced centrosome hyperamplification. We found that Mdm2 overexpression, like loss of p53, induced centrosome hyperamplification and chromosome instability in cultured cells. [ABSTRACT FROM AUTHOR]

Modal DNA values of tumours from various sites may exhibit (1) a diploid-near diploid distribution, (2) an exponential distribution in the tetraploid to triploid range, or (3) a log-normal distribution in the triploid to tetraploid range. Examples of these various types of distribution are non-Hodgkin's lymphoma (1), aneuploid prostate carcinoma (2), aneuploid colon, breast, cervix and testicular carcinomas (3). These differences indicate dissimilarities in tumour development. In aneuploid tumours from the same site both tetraploid exponential and triploid-tetraploid log-normal distributions may occur. In bladder carcinoma these are related to grade. Modal DNA values in tumours are 10% higher than would be expected from modal chromosome numbers. This difference seems not to be due to a relative increase in large-sized chromosomes or due to technical shortcomings. Chromosome studies also show the possibility of the existence of near diploid malignant cells in grossly aneuploid tumours. Modal DNA values are connected with functional tumour properties by the proportion of S-phase cells. The significance of the latter is exemplified by follow-up of patients with bladder and cervix carcinoma. [ABSTRACT FROM AUTHOR]

Studies of human hematologic malignancies have provided sufficient data not only for the identification of nonrandom abnormalities of whole chromosomes, but also for determination of the specific chromosome regions involved. In clonal aberrations leading to an excess of chromosome No. 1, or a partial excess of No. 1, trisomy for bands 1q25 to 1q32 was noted in the myeloid cells obtained from every one of 35 patients who had various disorders, such as acute leukemia, polycythemia vera, or myelofibrosis. Similar chromosome changes were a consistent finding in various solid tumors as well. This rearrangement was not the result of a particularly fragile site in that region of the chromosome, since the break points in reciprocal translocations that involve No. 1 occurred almost exclusively in the short arm. The nonrandom chromosome changes found in neoplastic cells can now be correlated with the gene loci on these chromosomes or chromosome segments as an attempt is made to identify specific genes that might be related to malignancy. [ABSTRACT FROM AUTHOR]

A series of human colonic epithelial cell lines have been cultured from a single patient: LS-180 the original adenocarcinoma, LS-174T a trypsinized variant, and normal colonic tissue. The malignant cells, 20 to 40 µm in diameter and oval to polygonal, exhibited characteristics of normal colonic mucosal cells, namely, abundant microvilli prominent in secretory cells, and the presence of intracytoplasmic mucin vacuoles. The cultured adenocarcinoma cells, but not normal, demonstrated neoplastic properties by producing high levels of carcinoembryonic antigen (CEA) and by the ability to be propagated in hamster cheek pouches and in immunodeprived mice. The CEA production by the newly established line LS-180 released 900 times more CEA per cell into the culture medium and bore 30 times more cell-associated material than the established line, HT-29. These cell lines may permit detection of distinctive chemical, physiological, pharmacologic, and immunologic characteristics of neoplastic colonic cells. [ABSTRACT FROM AUTHOR]

The PA of GC, CC, and RC extracts was assayed by the recalcification of human normal or F VII-DP, and the PA of normal tissue was also determined. The PA of normal tissue was higher than that of the cancer tissues in all groups of specimens. Substitution of normal plasma by F VII-DP resulted in significant depression of the PA and the differences in the PA between the normal and cancer tissue samples disappeared. Preincubation of normal and cancer tissue extracts with the cysteine proteinase inhibitors, mercuric chloride and iodoacetamide, did not affect the PA of these extracts. We conclude that the PA of the investigated cancer extracts is factor VII-dependent and can be related to the presence of tissue factor within cancer tissue. [ABSTRACT FROM AUTHOR]

Cases of cancer notified to the Danish Cancer Registry during the period 1970 to 1984 in the age groups 16 to 66 years have been linked to information on employment kept on file in the nationwide Supplementary Pension Fund since 1964. Industrial hygienists classified industrial groups as defined by the Pension Fund with regard to exposure to wood dust, and a list of industries with major exposure to wood dust was defined. The risk for cancer of the respiratory system and the gastrointestinal tract was evaluated by means of a proportional cancer incidence analysis. A fourfold increase in risk for sinonasal cancer was found among men involved in the manufacture of wooden furniture, and a twofold increase in risk for gastric cancer was seen in all of the component industries of basic wood-processing. In contrast, no excess of gastric cancer could be detected in men working in the manufacture of wooden building materials and wooden furniture, and a risk below unity was seen for those in carpentry and joinery. The elevated risk for gastric cancer in some wood-processing industries is probably due to social factors also common to men in agriculture and manufacturing. The absence of an increased risk for gastric cancer in trades in which a high risk for sinonasal cancer is seen indicates that wood dust is not of aetiological importance for gastric cancer. No excess of total lung cancer or of the adenocarcinoma subtype was seen in any of the wood-processing industries. [ABSTRACT FROM AUTHOR]

The ability of RPMI4788 cells, a human colon cancer cell line, to produce experimental metastases in the lung, intraperitoneal cavity, and liver was studied in nude mice. Injection of 2×10 tumor cells into the tail vein of nude mice produced metastatic lung tumors, and an intraportal injection of 5×10 cells produced metastatic liver tumors. An intraabdominal carcinomatosis with ascites was formed after an i.p. injection of 5×10 tumor cells. The nude mice with lung metastasis or intraabdominal carcinomatosis always died within a few weeks. Macroscopic observation showed that the number of lung metastatic nodules on day 21 after tumor inoculation was 311.3±78.2 (mean±SD) in BALB/C nude mice, and 187.5±26.7 in ICR nude mice. In survival experiments, the mice with intraabdominal carcinomatosis showed a mean survival of 29.0±1.7 (mean±SD) days in BALB/C nude mice and 43.6±6.1 days in ICR nude mice. These novel experimental models of metastases in nude mice produced by injection of RPMI4788 cells had high reproducibility and may be useful not only for the study of the metastatic process but also for testing anticancer drugs. [ABSTRACT FROM AUTHOR]

The concept of immunotherapy is evolving from nonspecific, haphazard stimulation of the immune apparatus to more specific and controlled manipulation of the immune system. IL-2 gives the opportunity to exert influence on the cellular immune system. Why LAK cells are able to lyse tumor cells and leave normal cells intact is not known. How LAK cells behave after reinfusion is not known; are they able to migrate to tumor sites? Can improvements be made in scheduling in order to decrease toxicity and to enhance efficacy? But first of all, the question arises whether the tremendous efforts required by adoptive transfer, in terms of toxicity, logistics, and money, are outweighed by the therapeutic results. For clinical practice inside the frontier of oncology, continuous infusion of IL-2 at an intermediate dose is a quite attractive option in finding a balance between efforts and results. [ABSTRACT FROM AUTHOR]

This paper describes a mechanism which permits somatic cells to generate random mutations in the complete absence of cell proliferation. Knowledge of the existence of this mechanism should provide us with the basis for a better understanding of a number of important biological phenomena, and in particular may help to explain the origins of many human cancers. [ABSTRACT FROM AUTHOR]

H1° histones were purified by preparative sodium dodecyl sulfate polyacrylamide gel electrophoresis from human lung carcinoma (line DMS79), human hepatoblastoma (HepG2), human adult lung and human adult and fetal liver. The purified human H1° histones were analyzed for their amino acid composition and terminal residues. The comparative analysis of the amino acid compositions of the different human H1° histones showed that: (a) all the H1° preparations have the characteristically high lysine content associated with a low arginine content, which distinguishes outer histones from core histones; (b) H1° is distinguishable from other H1 histones by the presence of methionine and histidine; (c) H1° histones from human adult, fetal and cancer cells are very similar in amino acid composition, and in cancer cells the level of the H1° histone is not inversely related with cell growth rate nor with the expression of the α-fetoprotein gene. [ABSTRACT FROM AUTHOR]