UMG1/CD3ε-bispecific T-cell engager redirects T-cell cytotoxicity against diffuse large B-cell lymphoma.

UMG1 is a unique epitope of CD43, not expressed by normal cells and tissues of haematopoietic and non-haematopoietic origin, except thymocytes and a minority (<5%) of peripheral blood T lymphocytes. By immunohistochemistry analysis of tissue microarray and pathology slides, we found high UMG1 expression in 20%-24% of diffuse large B-cell lymphomas (DLBCLs), including highly aggressive BCL2high and CD20low cases. UMG1 membrane expression was also found in DLBCL bone marrow-infiltrating cells and established cell lines. Targeting UMG1 with a novel asymmetric UMG1/CD3ε-bispecific T-cell engager (BTCE) induced redirected cytotoxicity against DLBCL cells and was synergistic with lenalidomide. We conclude that UMG1/CD3ε-BTCE is a promising therapeutic for DLBCLs.

IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth.

BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappaB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKgamma, increasing availability of IKKgamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappaB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.

Reactivation of telomerase reverse transcriptase expression in cancer: the role of TERT promoter mutations.

Telomerase activity and telomere elongation are essential conditions for the unlimited proliferation of neoplastic cells. Point mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been found to occur at high frequencies in several tumour types and considered a primary cause of telomerase reactivation in cancer cells. These mutations promote TERT gene expression by multiple mechanisms, including the generation of novel binding sites for nuclear transcription factors, displacement of negative regulators from DNA G-quadruplexes, recruitment of epigenetic activators and disruption of long-range interactions between TERT locus and telomeres. Furthermore, TERT promoter mutations cooperate with TPP1 promoter nucleotide changes to lengthen telomeres and with mutated BRAF and FGFR3 oncoproteins to enhance oncogenic signalling in cancer cells. TERT promoter mutations have been recognized as an early marker of tumour development or a major indicator of poor outcome and reduced patients survival in several cancer types. In this review, we summarize recent findings on the role of TERT promoter mutations, telomerase expression and telomeres elongation in cancer development, their clinical significance and therapeutic opportunities.

The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development.

Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is universally enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein-Barr virus (EBV) LMP1, Kaposi's sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) Tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TERT gene. Specifically, viral oncoproteins have been shown to bind TERT promoter, to induce post-transcriptional alterations of TERT mRNA and to cause epigenetic modifications, which have important effects on the regulation of telomeric and extra-telomeric functions of the telomerase. Other viruses, such as herpesviruses, operate by integrating their genomes within the telomeres or by inducing alternative lengthening of telomeres (ALT) in non-ALT cells. In this review, we recapitulate on recent findings on virus-telomerase/telomeres interplay and the importance of TERT-related oncogenic pathways activated by cancer-causing viruses.

A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3ε (CD1a x CD3ε) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3ε induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3ε significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3ε is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.

The Role of circRNAs in Human Papillomavirus (HPV)-Associated Cancers.

Circular RNAs (circRNAs) are a new class of "non-coding RNAs" that originate from non-sequential back-splicing of exons and/or introns of precursor messenger RNAs (pre-mRNAs). These molecules are generally produced at low levels in a cell-type-specific manner in mammalian tissues, but due to their circular conformation they are unaffected by the cell mRNA decay machinery. circRNAs can sponge multiple microRNAs or RNA-binding proteins and play a crucial role in the regulation of gene expression and protein translation. Many circRNAs have been shown to be aberrantly expressed in several cancer types, and to sustain specific oncogenic processes. Particularly, in virus-associated malignancies such as human papillomavirus (HPV)-associated anogenital carcinoma and oropharyngeal and oral cancers, circRNAs have been shown to be involved in tumorigenesis and cancer progression, as well as in drug resistance, and some are useful diagnostic and prognostic markers. HPV-derived circRNAs, encompassing the HPV E7 oncogene, have been shown to be expressed and to serve as transcript for synthesis of the E7 oncoprotein, thus reinforcing the virus oncogenic activity in HPV-associated cancers. In this review, we summarize research advances in the biogenesis of cell and viral circRNAs, their features and functions in the pathophysiology of HPV-associated tumors, and their importance as diagnostic, prognostic, and therapeutic targets in anogenital and oropharyngeal and oral cancers.

Precision medicine in gastric cancer.

Gastric cancer (GC) is a complex disease linked to a series of environmental factors and unhealthy lifestyle habits, and especially to genetic alterations. GC represents the second leading cause of cancer-related deaths worldwide. Its onset is subtle, and the majority of patients are diagnosed once the cancer is already advanced. In recent years, there have been innovations in the management of advanced GC including the introduction of new classifications based on its molecular characteristics. Thanks to new technologies such as next-generation sequencing and microarray, the Cancer Genome Atlas and Asian Cancer Research Group classifications have also paved the way for precision medicine in GC, making it possible to integrate diagnostic and therapeutic methods. Among the objectives of the subdivision of GC into subtypes is to select patients in whom molecular targeted drugs can achieve the best results; many lines of research have been initiated to this end. After phase III clinical trials, trastuzumab, anti-Erb-B2 receptor tyrosine kinase 2 (commonly known as ERBB2) and ramucirumab, anti-vascular endothelial growth factor receptor 2 (commonly known as VEGFR2) monoclonal antibodies, were approved and introduced into first- and second-line therapies for patients with advanced/metastatic GC. However, the heterogeneity of this neoplasia makes the practical application of such approaches difficult. Unfortunately, scientific progress has not been matched by progress in clinical practice in terms of significant improvements in prognosis. Survival continues to be low in contrast to the reduction in deaths from many common cancers such as colorectal, lung, breast, and prostate cancers. Although several target molecules have been identified on which targeted drugs can act and novel products have been introduced into experimental therapeutic protocols, the overall approach to treating advanced stage GC has not substantially changed. Currently, surgical resection with adjuvant or neoadjuvant radiotherapy and chemotherapy are the most effective treatments for this disease. Future research should not underestimate the heterogeneity of GC when developing diagnostic and therapeutic strategies aimed toward improving patient survival.

Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches.

Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.

A STARD-compliant prediction model for diagnosing thrombotic microangiopathies.

Aim of the study was the definition of a predictive model for the initial diagnosis of thrombotic microangiopathies (TMA). We retrospectively collected data on all adult patients admitted to the Gemelli Hospital from 2010 to 2014. ICD-9 codes from primary diagnoses were used for TMA diagnosis. Demographic and laboratory characteristics on admission of patients with TMA were then compared with a random sample of 500 patients with other diagnoses. The prediction model was externally validated in a cohort from another hospital. Overall, 23 of 187,183 patients admitted during the study period received a primary diagnosis of TMA. LDH (OR 1.26, 95% CI 1.05, 1.63) and platelets (OR 0.96, 95% CI 0.94, 0.98) were the only independent predictors of TMA. The AUROC of the final model including only LDH and platelets was 0.96 (95% CI 0.91, 1.00). The Hosmer-Lemeshow (HL) test (p = 0.54) suggested good calibration. Our model also confirmed good discriminatory power (AUROC 0.72 95% CI 0.60, 0.84) and calibration (HL test p = 0.52) in the validation sample. We present a simple prediction model for use in diagnosing TMA in hospitalized patients. The model performs well and can help clinicians to identify patients at high risk of TMA.

Second-trimester maternal serum alpha-fetoprotein elevation and its association with adverse maternal/fetal outcome: ten years experience.

BACKGROUND: Alpha-fetoprotein (AFP) is the major serum protein in the embryonic stage and in the early fetal stage. The aim of this study was to determine any possible association between an "unexplained" elevation of maternal serum alpha-fetoprotein (MSAFP) levels in the second trimester of pregnancy and adverse maternal/fetal outcome. METHODS: A retrospective cohort study, was carried out in the University of Parma, by reviewing all triple tests that had been found positive for neural tube defect screening, showing an "unexplained" MSAFP elevation (> or =2.5 multiples of the median [MoM]), which could not be ascribed to any apparent reason. These results were compared with those of negative controls (MSAFP <2.5 MoM) in order to evaluate the course and outcome of pregnancy. Statistical analysis was performed by chi-square test, Fisher's exact test, Student's t-test, and odds ratio calculation. RESULTS: We reviewed 16,747 tests: 143 tests with high MSAFP levels were found, including 105 data already available. Out of them 21 tests were excluded from the study because of the presence of fetal malformations, chromosomal diseases, or late miscarriage. Among the 84 remaining pregnancies, 43 were significantly associated with increased rates of pregnancy pathology compared with the control group of 199 patients, with 25 complicated pregnancies. In addition, high MSAFP levels were correlated with a less favorable neonatal outcome in terms of low birth weight, Apgar score, and transfer to a neonatal intensive care unit. CONCLUSIONS: Unexplained elevation of MSAFP levels in the second trimester of pregnancy is associated with an adverse maternal/fetal outcome, possibly suggesting the need for a more strict management of pregnancies.

Blood Sampling Seasonality as an Important Preanalytical Factor for Assessment of Vitamin D Status.

BACKGROUND: The measurement of vitamin D is now commonplace for preventing osteoporosis and restoring an appropriate concentration that would be effective to counteract the occurrence of other human disorders. The aim of this study was to establish whether blood sampling seasonality may influence total vitamin D concentration in a general population of Italian unselected outpatients. METHODS: We performed a retrospective search in the laboratory information system of the University Hospital of Parma (Italy, temperate climate), to identify the values of total serum vitamin D (25-hydroxyvitamin D) measured in outpatients aged 18 years and older, who were referred for routine health check-up during the entire year 2014. RESULTS: The study population consisted in 11,150 outpatients (median age 62 years; 8592 women and 2558 men). The concentration of vitamin D was consistently lower in samples collected in Winter than in the other three seasons. The frequency of subjects with vitamin D deficiency was approximately double in samples drawn in Winter and Spring than in Summer and Autumn. In the multivariate analysis, the concentration of total vitamin D was found to be independently associated with sex and season of blood testing, but not with the age of the patients. CONCLUSIONS: According to these findings, blood sampling seasonality should be regarded as an important preanalytical factor in vitamin D assessment. It is also reasonable to suggest that the amount of total vitamin D synthesized during the summer should be high enough to maintain the levels > 50 nmol/L throughout the remaining part of the year.

A new hexapeptide from the leader peptide of rMnSOD enters cells through the oestrogen receptor to deliver therapeutic molecules.

A 24-amino acid leader peptide of a new human recombinant manganese superoxide dismutase can enter cells and carry molecules. Here, we demonstrated that six of the 24 amino acids penetrate cells through a particular gate represented by a specific amino acid sequence of the oestrogen receptor (ER). We analysed the internalization of the synthetic hexapeptide and the cytotoxic activity of the hexapeptide conjugated to cisplatin on a cell line panel. In most cell lines, the hexapeptide delivered an amount of cisplatin that was 2 to 8 times greater than that released by cisplatin when the drug was used alone. This increased delivery increases the therapeutic index of cisplatin and reduces side effects caused by a high dosage or long-term treatment times. We may consider this hexapeptide a new molecular carrier to deliver molecules with therapeutic activity into ER(+) cells for diagnostic purposes and clinical or immune therapy.

Birth season and vitamin D concentration in adulthood.

BACKGROUND: Recent evidences suggest that the season of birth may influence human development and vulnerability to develop certain diseases. METHODS: A retrospective analysis was hence carried out in the laboratory information system of the University Hospital of Parma (North-West Italy), to retrieve values of total serum vitamin D (25-hydroxyvitamin D) measured in a the whole cohort of unselected outpatients age 18 years and older referred for routine health check-up during January to December 2014. Vitamin D was then stratified according to birth season. RESULTS: The study population consisted in 11,150 unselected Italian residents (median age 62 years; 8,592 women and 2,558 men). Serum vitamin D values were found to be significantly lower in subjects born in winter than in those born in spring and summer. More specifically, winter season birth was associated with 11% increased risk of developing vitamin D deficiency later in life compared to spring birth. Daily sunlight hours at birth independently predicted vitamin D concentration in adulthood. CONCLUSIONS: The results of this large, cross-sectional retrospective investigation attest that subjects born in winter have a total vitamin D concentration in adulthood that is significantly lower than those born in seasons with longer daylight periods.

The use of S-Monovette is effective to reduce the burden of hemolysis in a large urban emergency department.

BACKGROUND: Due to the high prevalence of hemolysis in specimens received from the emergency department (ED), several strategies have been proposed to improve sample quality, but none of these seem effective to overcome the problem. In a preliminary study we showed that the use of S-Monovette blood collection system was effective to lower the risk of hemolysis in venous blood samples collected from intravenous catheters. This study was hence aimed to verify whether the replacement of a conventional vacuum system with S-Monovette may be effective to reduce the burden of hemolysis in the daily practice of a large urban ED. MATERIALS AND METHODS: The study was divided in two observational periods of 4 months each. In the former period, blood was collected from intravenous catheters using BD Vacutainer SST II Plus plastic serum tubes, whereas in the latter period the blood was drawn from intravenous catheters using S-Monovette blood tubes in aspiration mode. Sample hemolysis was automatically assessed in all serum samples by photometrical measurement. RESULTS: The total number of hemolysed serum specimens was 624/14155 (4.41%) in the first phase of the study, and 342/13319 (2.57%) in the second phase of the study (P<0.001). CONCLUSION: Results of our study confirm that the introduction of the Sarstedt S-Monovette blood tubes has reduced the hemolysis rate in the emergency department compared to the previously used BD Vacutainer® SST II Plus plastic serum tubes.

Association of Hyponatremia and Hypovitaminosis D in Ambulatory Adults.

BACKGROUND: Hyponatremia and vitamin D deficiency are frequent disorders, and both have been associated with gait disturbances, falls and fractures. The aim of this study was to evaluate the existence of an association between serum sodium and vitamin D serum levels. METHODS: We performed a retrospective investigation to establish whether hyponatremia and vitamin D deficiency may be associated in a general population of unselected outpatients. An electronic search was performed in the laboratory information systems of the Hospital of Verona and the Hospital of Parma (Italy), to retrieve combined results for total vitamin D and sodium obtained in all outpatients referred for health check-up in the year 2013. RESULTS: Combined results of vitamin D and sodium could be retrieved for 5097 outpatients (3859 females and 1238 males; mean age 64±17 years). Vitamin D deficient subjects displayed significantly lower levels of serum sodium (140 versus 141 mmol/L; p<0.001), along with a significantly higher rate of hyponatremia (6.3% versus 5.1%; p=0.037). Accordingly, hyponatremic subjects had significantly lower levels of serum vitamin D (55 versus 60 nmol/L; p=0.015), along with a significantly higher rate of vitamin D deficiency (41.8% versus 36.1%; p=0.030). A highly significant correlation was found between sodium and total vitamin D after adjustment for age and gender (p<0.001). CONCLUSIONS: The results of this study demonstrate for the first time the existence of a significant correlation between the serum levels of sodium and total vitamin D in a general population of unselected outpatients.

The burden of vitamin D deficiency in a mediterranean country without a policy of food fortification.

BACKGROUND: Vitamin D deficiency is a public healthcare issue and its correction is increasingly regarded as a cornerstone of preventive medicine. METHODS: We designed a retrospective observational study to clearly define the burden of total vitamin D (25-hydroxyvitamin D) deficiency in a supposedly healthy population of outpatients residing in two regions (Emilia Romagna and Veneto) of Northern Italy. RESULTS: 25-hydroxyvitamin D results were available for a total number of 5,096 outpatients in the two centers. The median value of 25-hydroxyvitamin D was 60 nmol/L, and was higher in women than in men (62 nmol/L versus 56 nmol/L; p<0.001). The rate of 25-hydroxyvitamin D deficiency was 36%, and was marginally but significantly higher in men than in women (40% versus 35%; p=0.003). A significant variation in the rate of 25-hydroxyvitamin D deficiency was found throughout different age ranges, exhibiting a significant increase in the elderly. CONCLUSIONS: The results of this large observational study show that the burden of 25-hydroxyvitamin D deficiency in two regions of a Mediterranean country without a policy of food fortification is as high as 36%, and this evidence represents a background for healthcare preventive measures aimed at reducing the prevalence of this condition in the general population. (www.actabiomedica.it).

Effectiveness of a computerized alert system based on re-testing intervals for limiting the inappropriateness of laboratory test requests.

OBJECTIVES: There is consolidated evidence that the burden of inappropriate laboratory test requests is very high, up to 70%. We describe here the function of a computerized alert system linked to the order entry, designed to limit the number of potentially inappropriate laboratory test requests. DESIGN AND METHODS: A computerized alert system based on re-testing intervals and entailing the generation of pop-up alerts when preset criteria of appropriateness for 15 laboratory tests were violated was implemented in two clinical wards of the University Hospital of Parma. The effectiveness of the system for limiting potentially inappropriate tests was monitored for 6months. RESULTS: Overall, 765/3539 (22%) test requests violated the preset criteria of appropriateness and generated the appearance of electronic alert. After alert appearance, 591 requests were annulled (17% of total tests requested and 77% of tests alerted, respectively). The total number of test requests violating the preset criteria of inappropriateness constantly decreased over time (26% in the first three months of implementation versus 17% in the following period; p<0.001). The total financial saving of test withdrawn was 3387 Euros (12.8% of the total test cost) throughout the study period. CONCLUSIONS: The results of this study suggest that a computerized alert system may be effective to limit the inappropriateness of laboratory test requests, generating significant economic saving and educating physicians to a more efficient use of laboratory resources.

Improving laboratory test ordering can reduce costs in surgical wards.

Background and Aim Laboratory blood tests for hospitalized patients are often overused. Excessive costs and no proof of benefit suggest re-evaluating the current approach to laboratory test ordering. The aim of the study is to improve the decision-making process of test ordering and to investigate what effect a rational, evidence-based use of laboratory test ordering in surgical wards would have on costs and healthcare resources. Methods Three-phase experimental prospective study carried out at the tertiary referral teaching hospital of Parma. Phase 1 (baseline status). The baseline status of laboratory test ordering was evaluated by recording the number of biochemical tests requested for patients undergoing elective surgery. Laboratory tests were grouped in "recommended" (RT) and "non recommended" (nRT) tests on the basis of pertinent literature. Phase 2 (improvement action): new guidelines were introduced into clinical practice. Phase 3 (feedback): Prospective data collection for first and second feedback was performed with no advance notice. Results A highly significant reduction in test ordering was found on occasion of the phases 2 and 3 of the study. The overall number of tests decreased, largely due to a decrease in the use of nRT. Conclusions Analysis was justified by the fact that most test requests proved not to be supported by clinical evidence. Inappropriate ordering of laboratory tests results in an unnecessarily high number of requests, which do not in turn improve patient management. Moreover, more appropriate, evidence-based laboratory test ordering for patients undergoing elective surgery may produce a significant reduction in costs, particularly in high-cost settings. (www.actabiomedica.it).

Fetal ontogeny and tumor expression of the early thymic antigen UN1.

UN1 antigen (Ag), a 100-120 kDa sialoglycoprotein, was initially identified on immature thymocytes (CD3(dim)), a small subpopulation of CD4(+) peripheral blood T-lymphocytes, on leukemic T-cell lines and in fetal thymus. Biochemical analysis of the Ag has identified molecular features that are characteristic of cell-membrane-associated mucin-like glycoproteins. To investigate the biological role and the potential usefulness of the Ag, we have more extensively studied the pattern of UN1 Ag expression in a panel of fetal tissues, at different gestational ages, and on adult normal and tumor specimens. In the fetal samples examined by immunohistochemistry, including intestine, liver, lung and adrenal gland, we found that UN1 Ag is widely expressed during early stages of fetal development and down-regulated during ontogenesis. Very poor or not detectable expression of UN1 Ag was found at late gestational age. Immunohistochemical, Western blot and flow cytometric analysis of a panel of normal adult tissues and benign lesions failed to find Ag expression, whereas UN1 Ag was highly detectable in a variety of cancer specimens from breast, lung, gastrointestinal, gynaecological malignancies and melanomas. Based on these data UN1 Ag, for the wide expression on fetal tissues, the down-regulation during ontogeny and the re-expression in cancer cells, may be considered a novel oncofetal Ag of interest for biological investigation and clinical applications.