High-resolution DNA content analysis of microbiopsy samples in oral lichen planus.

OBJECTIVES: DNA aneuploidy has been reported to be a predictor of poor prognosis in both premalignant and malignant lesions. In oral lichen planus (OLP), this hypothesis remains to be proved. This study aimed to determine the rate of occurrence of DNA aneuploidy in patients with OLP by high-resolution DNA flow cytometry. METHODS: Patients with OLP were consecutively enrolled. Tissue samples were subdivided for formalin fixation and routine histological assessment and for immediate storage at -20°C for later DNA ploidy analysis, which was performed by DAPI staining of the extracted nuclei and excitation with a UV lamp. The DNA aneuploid sublines were characterized by the DNA Index. RESULTS: A DNA aneuploid status was observed in two of 77 patients with OLP (2.6%). When considering the clinical aspect of the OLP lesions, both DNA aneuploid cases had a reticular clinical aspect. CONCLUSIONS: DNA aneuploidy is an uncommon event in OLP and less frequent compared to other non-dysplastic and non-OLP oral potentially malignant disorders. The extremely low rate of DNA aneuploidy could represent an occasional finding or reflect the low rate of malignant transformation observed in patients with OLP even if the real prognostic value of DNA ploidy analysis in patients with OLP remains to be confirmed.

Author Correction: Achievement of sustainable development goals through the Mediterranean diet.

Correction to: Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 89-99-DOI: 10.26355/eurrev_202312_34693 After publication and following some post-publication concerns, the authors have applied the following corrections to the galley proof. -       The conflict of interest section has been amended as follows: M.C. Medori and D. Malacarne are employees at MAGI'S LAB. K. Donato is employee at MAGI EUREGIO and MAGISNAT. M. Bertelli is president of MAGI EUREGIO, MAGISNAT, and MAGI's LAB. E. Borghetti is president at AERSAFE srl. C. Zuccato is researcher at AERSAFE srl. E. Borghetti is patent inventor (IT202100021344A1, IT202100020330A1, WO2021260537A1, WO2022259165A1). M. Bertelli is patent inventor (US20220362260A1, US20230173003A1, WO2022079498A1). D. Malacarne is patent inventor (WO2022079498A1; US20230173003A1). S. Michelini is patent inventor (US20220362260A1). M. Bertelli, S. Michelini, and K. Donato are patent applicants (Application Number: 18/516,241). M. Bertelli and K. Donato are patent applicants (Application Number: 18/466.879). M. Bertelli, K. Donato, and S. Michelini are patent applicants (Application Number: 63/495,155). The remaining authors have no conflict of interest to disclose. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34693.

Achievement of sustainable development goals through the Mediterranean diet.

The prosperity of our planet relies on the cardinal concept of sustainable development. The dietary choices of humans play a pivotal role in creating a peaceful and contented world. In this context, the Mediterranean diet (MD) has emerged as a valuable approach to accomplishing such progress, wherein the rights of all living beings are equally honored. This review aims to analyze the significance of a plant-based diet, particularly the Mediterranean diet, in attaining sustainable development goals. A comprehensive search of the literature was conducted to gather the most reliable and published scientific evidence from books and papers. Within this research endeavor, specific Sustainable Development Goals (SDGs) are individually addressed in relation to the adoption of the Mediterranean diet as a foundational nutritional paradigm. Our research findings underscore the immense importance of the MD and advocate for its worldwide implementation to accomplish sustainable development objectives. The MD emerges as the most suitable dietary option for fostering sustainability and tranquility in our world. It is crucial to prioritize the global implementation of the MD to genuinely achieve sustainable development.

Unleashing the potential of biotechnology for sustainable development.

The UN Sustainable Development Goals (SDGs) strive to eliminate poverty, preserve the planet, and promote shared prosperity through sustainable and inclusive means by 2030. This requires the implementation of a diverse set of strategies to overcome challenges and foster synergies among different SDG targets, facilitating the achievement of these ambitious goals. The aim of this review is to highlight the world's progress toward SDGs with the utilization of biotechnological advancements, including targets, strategies, synergies, and challenges. We scrutinized published research articles in peer-reviewed journals, UN reports, and scientific books that were relevant to the current topic. We identified some major challenges faced by the countries, especially developing ones, in the way of sustainable progress. These include inadequate governance, fragile states, armed conflicts, rising inequality, limited economic progress, climate change, environmental degradation, and food insecurity. Biotechnological advancements contribute to sustainable resource management, environmental conservation, and ecosystem restoration. Collaboration among countries and organizations is crucial for sharing knowledge and providing technical and financial assistance to developing nations.

Bioetics Issues of Artificial Placenta and Artificial Womb Technology.

Abstract: The worldwide infertility crisis and the increase in mortality and morbidity among infants, due to preterm births and associated complications, have stimulated research into artificial placenta (AP) and artificial womb (AW) technology as novel solutions. These technologies mimic the natural environment provided in the mother's womb, using chambers that ensure the supply of nutrients to the fetus and disposal of waste substances through an appropriate mechanism. This review aims to highlight the background of AP and AW technologies, revisit their historical development and proposed applications, and discuss challenges and bioethical and moral issues. Further research is required to investigate any negative effects of these new technologies, and ethical concerns pertaining to the structure and operation of this newly developed technology must be addressed and resolved prior to its introduction to the public sphere.

In Memory of Professor Derek Pheby.

Abstract: Professor Derek Pheby's passing in November 2022 marked a profound loss for the scientific community. Professor Derek Pheby, a stalwart figure in the fields of autoimmune diseases and bioethics, was known for his dedication to scientific research and patients' support, particularly for those affected by paraneoplastic autoimmune syndromes. Professor Pheby made significant contributions to research, especially about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). His leadership of the ME Biobank and scientific coordination of EUROMENE demonstrated his commitment to pushing boundaries and fostering international collaborations. Professor Pheby's scientific work addressed various aspects of ME/CFS, from physician education to patient needs, the development of a post-mortem tissue bank, and effective treatments. Beyond his medical career, Professor Pheby was a crucial member of the Independent Ethics Committee of MAGI, he was a poet, humanitarian, and advocate for child protection. His generosity and boundless spirit left an enduring legacy, fostering innovative research in the pursuit of combating autoimmune diseases.

Human Cloning: Biology, Ethics, and Social Implications.

Abstract: This scholarly article delves into the multifaceted domains of human cloning, encompassing its biological underpinnings, ethical dimensions, and broader societal implications. The exposition commences with a succinct historical and contextual overview of human cloning, segueing into an in-depth exploration of its biological intri-cacies. Central to this biological scrutiny is a comprehensive analysis of somatic cell nuclear transfer (SCNT) and its assorted iterations. The accomplishments and discoveries in cloning technology, such as successful animal cloning operations and advances in the efficiency and viability of cloned embryos, are reviewed. Future improvements, such as reprogramming procedures and gene editing technology, are also discussed. The discourse extends to ethical quandaries intrinsic to human cloning, entailing an extensive contemplation of values such as human dignity, autonomy, and safety. Furthermore, the ramifications of human cloning on a societal plane are subjected to scrutiny, with a dedicated emphasis on ramifications encompassing personal identity, kinship connections, and the fundamental notion of maternity. Culminating the analysis is a reiteration of the imperative to develop and govern human cloning technology judiciously and conscientiously. Finally, it discusses several ethical and practical issues, such as safety concerns, the possibility of exploitation, and the erosion of human dignity, and emphasizes the significance of carefully considering these issues.

Teaching Vaginal Hysterectomy via Simulation: Creation and Validation of the Objective Skills Assessment Tool for Simulated Vaginal Hysterectomy on a Task Trainer and Performance Among Different Levels of Trainees.

OBJECTIVES: The use of simulation-based education to train surgeons is widely accepted. Although many authors describe the use of an Objective Skills Assessment Test (OSAT) to assess performance of various surgical procedures, there is a paucity of research on use of this modality to evaluate vaginal surgery skills. We created a vaginal hysterectomy procedure-specific checklist (PSC) to complete the OSAT (which is composed of a PSC and a global rating scale [GRS]). The primary objective of this study is to evaluate the performance of a novel evaluation strategy for vaginal hysterectomy using an OSAT combining PSC and GRS. METHODS: This is a descriptive prospective study from a single institution. After orientation to the model, participants were filmed performing vaginal hysterectomy. A blinded grader scored each subject using the PSC and GRS. RESULTS: Medical students, residents, fellows, and attendings performed vaginal hysterectomy on a simulated model. Mean PSC and GRS scores increased significantly with surgeon level of experience (P < 0.001). Procedure-specific checklist scores significantly correlated with GRS scores (P < 0.001). CONCLUSIONS: The vaginal hysterectomy model and PSC have been studied across different surgeon levels using OSATs. Training programs should consider using this low-cost task trainer as a teaching tool.

Inhibition of a protein-protein interaction between INI1 and c-Myc by small peptidomimetic molecules inspired by Helix-1 of c-Myc: identification of a new target of potential antineoplastic interest.

c-Myc is a transcription modulator proto-oncogene. When overexpressed, it becomes an important contributor to the multi-hit process of malignant transformation. In two earlier papers in this journal (see refs. 19 , 20) we reported that retro-inverso peptidomimetic molecules inspired by the Helix-1 of c-Myc motif could be sequence-specific antiproliferative agents active in the low micromolar range. We also found that our peptides were not opening the four-alpha-helix Myc:Max bundle. Their antiproliferative activity in cancer cell lines needs the presence of side chains projecting outside of the bundle in the corresponding native H1 motif. This observation suggested interference with an external partner. In this study we investigated the INI1:Myc interaction. INI1 is a subunit of the SWI/SNF complex (component of the enhanceosome surrounding Myc:Max heterodimer). The INI1:Myc interaction was confirmed via pull down, ELISA, and fluorescence anisotropy assays. According to the length of INI1 fragments used, we calculated Kds ranging between 1.3x10(-6) and 4.8x10(-7) M. The three different techniques applied showed that the INI1:Myc interaction was also the target of our retro-inverso peptidomimetic molecules, which seem to bind specifically at INI1. A Myc binding, 21aa INI1 fragment (minimum interacting sequence), could inspire the synthesis of a new class of more selective c-Myc inhibitors.

Sequence specific peptidomimetic molecules inhibitors of a protein-protein interaction at the helix 1 level of c-Myc.

Our work is focused in the broad area of strategies and efforts to inhibit protein-protein interactions. The possible strategies in this field are definitely much more varied than in the case of ATP-pocket inhibitors. In our previous work (10), we reported that a retro-inverso (RI) form of Helix1 (H1) of c-Myc, linked to an RI-internalization sequence arising from the third alpha-helix of Antennapedia (Int) was endowed with an antiproliferative and proapoptotic activity toward the cancer cell lines MCF-7 and HCT-116. The activity apparently was dependent upon the presence of the Myc motif. In this work, by ala-scan mapping of the H1 portion of our molecules with D-aa, we found two amino acids necessary for antiproliferative activity: D-Lys in 4 and D-Arg in 5 (numbers refer to L-forms). In the natural hetero-dimer, these two side chains project to the outside of the four alpha-helix bundle. Moreover, we were able to obtain three peptides more active than the original lead. They strongly reduced cell proliferation and survival (RI-Int-VV-H1-E2A,S6A,F8A; RI-Int-VV-H1-S6A,F8A,R11A; RI-Int-VV-H1-S6A,F8A,Q13A): after 8 days at 10 muM total cell number was approximately 1% of the number of cells initially seeded. In these more potent molecules, the ablated side chains project to the inside in the corresponding natural four alpha-helix bundle. In the present work, we also investigated the behavior of our molecules at the biochemical level. Using both a circular dichroism (CD) and a fluorescence anisotropy approach, we noted that side chains projecting at the interior of the four alpha-helix bundle are needed for inducing the partial unfolding of Myc-H2, without an opening of the leucine zipper. Side chains projecting at the outside are not required for this biochemical effect. However, antiproliferative activity had the opposite requirements: side chains projecting at the outside of the bundle were essential, and, on the contrary, ablation of one side chain at a time projecting at the inside increased rather than decreased biological activity. We conclude that our active molecules probably interfere at the level of a protein-protein interaction between Myc-Max and a third protein of the transcription complex. Finally, CD and nuclear magnetic resonance (NMR) data, plus dynamic simulations, suggest a prevalent random coil conformation of the H1 portion of our molecules, at least in diluted solutions. The introduction of a kink (substitution with proline in positions 5 or 7) led to an important reduction of biological activity. We have also synthesized a longer peptido-mimetic molecule (RI-Int-H1-S6A,F8A-loop-H2) with the intent of obtaining a wider zone of interaction and a stronger interference at the level of the higher-order structure (enhanceosome). RI-Int-H1-S6A,F8A-loop-H2 was less active rather than more active in respect to RI-Int-VV-H1-S6A,F8A, apparently because it has a clear bent to form a beta-sheet (CD and NMR data).

Examples of uses of databases for quantitative and qualitative correlation studies between genotoxicity and carcinogenicity.

In this paper we give some examples of using databases of genotoxicity and carcinogenicity for quantitative and qualitative correlation studies between short-term tests and carcinogenicity. The quality of the databases is obviously important, but one of the major deficiencies of present databases is that they are too small. Using relatively small, different databases, different results can be obtained. With small databases it is difficult to disaggregate data for homogeneous chemical classes or other types of subsets. Using the databases of Gold (carcinogenicity) and Würgler (genotoxicity), we have investigated the carcinogenic potency of genotoxic and nongenotoxic carcinogens for different chemical classes.

Relationship between molecular connectivity and carcinogenic activity: a confirmation with a new software program based on graph theory.

For a database of 826 chemicals tested for carcinogenicity, we fragmented the structural formula of the chemicals into all possible contiguous-atom fragments with size between two and eight (nonhydrogen) atoms. The fragmentation was obtained using a new software program based on graph theory. We used 80% of the chemicals as a training set and 20% as a test set. The two sets were obtained by random sorting. From the training sets, an average (8 computer runs with independently sorted chemicals) of 315 different fragments were significantly (p < 0.125) associated with carcinogenicity or lack thereof. Even using this relatively low level of statistical significance, 23% of the molecules of the test sets lacked significant fragments. For 77% of the molecules of the test sets, we used the presence of significant fragments to predict carcinogenicity. The average level of accuracy of the predictions in the test sets was 67.5%. Chemicals containing only positive fragments were predicted with an accuracy of 78.7%. The level of accuracy was around 60% for chemicals characterized by contradictory fragments or only negative fragments. In a parallel manner, we performed eight paired runs in which carcinogenicity was attributed randomly to the molecules of the training sets. The fragments generated by these pseudo-training sets were devoid of any predictivity in the corresponding test sets. Using an independent software program, we confirmed (for the complex biological endpoint of carcinogenicity) the validity of a structure-activity relationship approach of the type proposed by Klopman and Rosenkranz with their CASE program.

Are genotoxic carcinogens more potent than nongenotoxic carcinogens?

In this report we have raised the question whether genotoxic carcinogens are more potent than nongenotoxic carcinogens when studied in long-term carcinogenicity assays in rodents. To build a large database of compounds for which both carcinogenicity and genotoxicity had been investigated, we have used a database produced by Gold and co-workers for carcinogenic potency data (975 chemicals) and a database produced by Würgler for genotoxicity data (2834 chemicals). Considering compounds positive or negative in at least three short-term tests and in at least 75% of available tests, we could define 67 genotoxic carcinogens and 46 nongenotoxic carcinogens. Carcinogenic potency of genotoxic carcinogens was about 50 times higher than carcinogenic potency of nongenotoxic carcinogens. Our results are different from the results of Tennant et al.; their database (24 genotoxic carcinogens and 12 nongenotoxic carcinogens compatible with our definition) seems to suggest that there is practically no difference in potency between genotoxic and nongenotoxic carcinogens. The two databases have only four compounds in common and are also different in terms of number of elements for different chemical classes. Nitrosocompounds, nitrogen mustards, hydrazine derivatives, and polycyclic aromatic hydrocarbons are not represented in the database of Tennant. The overall impression from our analysis is that the usefulness of short-term tests of genotoxicity could be significantly better than what has been suggested by the previous work of Tennant et al. because these tests tend to detect, at least for many important chemical classes, the most potent carcinogens. This consideration may not be valid for certain classes of chemicals.

Analysis and comparison of information and data recorded in carcinogenicity and genotoxicity databases.

The Interlab Project is a university-industry joint project recently funded by the Italian government as part of the improvement of the Italian research infrastructure; among its short-term goals are the implementation of data banks of biomedical interest and the spread of informatic tools for biomedical research. Results of both long-term assays of carcinogenicity in rodents and short-term in vitro and in vivo tests of genotoxicity are relevant for a wide body of users, ranging from carcinogenesis research laboratories to industries and governmental agencies. To evaluate the most appropriate ways of spreading information on these experiments, a detailed analysis on information recorded in available databases has been carried out. Furthermore, the contents of the most known databases have been compared, with respect to a specific compound, to evaluate both the overall reliability of these systems, compared to longer and more complex assessments carried out manually starting from bibliographic searches, and the level of concordance among them.

Computer-aided analysis of mutagenicity and cell transformation data for assessing their relationship with carcinogenicity.

Using a computer-aided approach, the tests for Salmonella mutagenicity and transformation in established cell lines were compared for the qualitative bases of their carcinogenicity predictions. For this purpose, a database of 145 chemicals was prepared in which rodent carcinogenicity data and results of the Ames' and transformation tests were available. Using a software program for connectivity analysis (previously developed and validated by us), we assayed the molecular structures of these chemicals for the presence of fragments relatable to their positive (i.e., biophores) or negative (i.e., biophobes) response to the tests in question. These fragments were then studied for their association with genotoxic and nongenotoxic carcinogenicity. The philosophy adopted was that the type and number of molecular fragments chosen by the software to describe the chemicals correctly predicted by the tests could be related to the type of carcinogenic effects to which the tests themselves were sensitive. The classifications made by the software were interpreted by human expertise and the biophores found were compared with the acknowledged structural alerts to DNA reactivity as formalized by Ashby and co-workers [(1991): Mutat Res 257:229-306; (1993): Mutat Res 286: 3-74]. The results show that, in quantitative terms, the overall ability to predict carcinogenicity is about the same for both the Salmonella and transformation tests. However, in qualitative terms the transformation test appears to be sensitive to effects that are more heterogeneous than those inducing mutation, some of which are presumably related to nongenotoxic carcinogenic activities. This study illustrates a possible, innovative model of analysis of chemical structures that, using an automated approach along with the biologist's judgment, could contribute to the detection of complementarities among short-term test endpoints.

A computerized connectivity approach for analyzing the structural basis of mutagenicity in Salmonella and its relationship with rodent carcinogenicity.

We have applied a new software program, based on graph theory and developed by our group, to predict mutagenicity in Salmonella. The software analyzes, as information in input, the structural formula and the biological activities of a relatively large database of chemicals to generate any possible molecular fragment with size ranging from two to ten nonhydrogen atoms, and detects (as predictors of biological activity) those fragments statistically associated with the biological property investigated. Our previous work used the program to predict carcinogenicity in small rodents. In the current work we applied a modified version of the program, which bases its predictions solely on the most important fragment present in a given molecule, considering as practically negligible the effects of additional less important fragments. For Salmonella mutagenicity we used a database of 551 compounds, and the program achieved a level of predictivity (73.9%) comparable to that obtained by other authors using the Computer Automated Structure Evaluation (CASE) program. We evaluated the relative contributions of biophores and biophobes to overall predictivity: biophores tended to be more important than biophobes, and chemicals containing both biophores and biophobes were more difficult to predict. Many of the molecular fragments identified by the program as being strongly associated with mutagenic activity were similar to the structural alerts identified by the human experts Ashby and Tennant. Our results tend to confirm that structural alerts useful to predict Salmonella mutagenicity are generally not very strong predictors of rodent carcinogenicity. Although the predictivity level achieved for oncogenic activity improved when the program was directly trained with carcinogenicity data, carcinogenicity as a biological endpoint was still more difficult to predict than Salmonella mutagenicity.

Molecular fragments associated with non-genotoxic carcinogens, as detected using a software program based on graph theory: their usefulness to predict carcinogenicity.

We assembled 390 chemicals with a structure non-alerting to DNA-reactivity (145 carcinogens and 245 non-carcinogens) for which rodent carcinogenicity data were available. These non-alerting chemicals were defined by the absence in their molecules of DNA-reactive (directly or after metabolic activation) alerting structures, as described by Ashby and coworkers (Mutat. Res., 204 (1988) 17-115; Mutat. Res., 223 (1989) 73-103; Mutat. Res., 257 (1991) 209-227; Mutat. Res., 286 (1993) 3-74). Using our software program based on graph theory we analyzed the compounds in order to estimate the program's ability to predict nonalerting carcinogens. Our software fragmented the structural formula of the chemicals into all possible fragments of contiguous atoms with size between 2 and 8 (non-hydrogen) atoms and learned about statistically significant fragments from a training set of chemicals. These fragments were used to predict carcinogenicity or lack thereof in a verification set of compounds. For 390 runs of the software program we used (n - 1) of the chemicals as a training set, to predict the excluded chemical at each run (as a test set). Using two different probability thresholds to select significant fragments (P = 0.05 and P = 0.125 1-tailed according to binomial distribution), we performed two analyses: in the better one (P = 0.05) 19% of the molecules tested lacked significant fragments, for the remaining 81% the observed level of accuracy of the prediction was 66.0% against an expected level of accuracy of 51.7%. The difference was highly significant (P < 0.0001). We also examined the more significant activating fragments (biophores) and discussed at length both their biological plausibility and the working hypothesis that additional alerting structures for carcinogenicity (not only those related to genotoxicity) can be detected using this type of SAR approach. This new class of alerting structures could identify subfamilies of congeneric analogs active through mechanisms of receptor mediated carcinogenesis.

Non-genotoxic factors in the carcinogenetic process: problems of detection and hazard evaluation.

In the classical two-stage models of carcinogenesis, initiation has been usually related to a DNA-damage/gene-mutation event, while promotion has been related to the non-genotoxic effects of clonal expansion of preneoplastic cells and/or modulation of cell differentiation. It is now clear that the process of carcinogenesis is linked to more than one irreversible alteration in the genome. Likewise, we can envisage that non-genotoxic events can take place after perhaps 0, 1, 2 or more irreversible alterations in the genome. Initiating and promoting activities of a chemical can be considered clearly separated in theory, but in practice, the chemicals we work with only rarely will be purely of the genotoxic or non-genotoxic type. We will discuss an empirical approach to classify genotoxic or prevalently non-genotoxic chemical carcinogens. For prevalently non-genotoxic carcinogens we will analyze what fraction of them can be detected as promoters of in vivo rat liver carcinogenesis. We will analyze carcinogenic potency of genotoxic and non-genotoxic carcinogens.

A genotoxicity study on N-acryloyl-N'-phenylpiperazine: implications of aneugenic effects in risk evaluations.

Further to a previous genotoxicity study, we analyzed sister-chromatid exchange (SCE) and DNA-repair induction (V79 and EUE cells in vitro) and DNA damage (rat liver in vivo) with regard to N-acryloyl-N'-phenylpiperazine (AcrNPP), a chemical proposed for biomaterial polymerization which contains an aromatic tertiary amine function in a piperazine cycle. This chemical induced SCEs in a dose-dependent fashion (up to approximately 3.7 times the control value), while it was negative for DNA-repair induction and weakly yet significantly positive for in vivo DNA damage (maximum increase approximately 1.4 times the control value). Taken together with our previous genotoxicity data on AcrNPP and structurally related compounds, the present results confirm that aneuploidy is a possible major effect of aromatic tertiary amines. As regards exposure to aneugenic agents, considerations on cancer risk evaluation are presented.

Drug metabolism polymorphisms as modulators of cancer susceptibility.

Recently, several molecular genetic bases of polymorphic enzyme activities involved in drug activation and detoxification have been elucidated. Many molecular epidemiology studies based on these premises have sought to gather information on the association of genetically determined metabolic variants with different risks of environmentally induced cancer. While rare alterations of tumor suppressor genes dramatically raise cancer risk for the single affected subjects, far more common and less dramatic differences in genes encoding for drug metabolism enzymes can be responsible for a relatively small, but rather frequent increase of cancer risk at the population level. This increase could be especially important in specific cases of occupational, pharmacological or environmental exposure. Examination of the current literature reveals that the most extensively investigated metabolic polymorphisms are those of P450 1A1 and P450 2D6 cytochromes, glutathione S-transferases (GSTs; M1 and, to a lesser extent, M3, P1 and T1) and N-acetyltransferases (NATs; NAT1 and NAT2). Making reference to these enzymes, we have assayed the current knowledge on the relations among polymorphisms of human xenobiotic-metabolizing enzymes and cancer susceptibilities. We have found intriguing models of susceptibility toward different types of cancer. We have reviewed and commented these models on light of the complex balance among different enzyme activities that, in each individual, determines the degree of each cancer susceptibility. Moreover, we have found techniques of molecular genetic analysis, more suitable than previous ones on phenotypic expression, now allowing better means to detect individuals at risk of cancer. According to the models presently available, a systematic screening of individuals at risk seems to make sense only in situations of well defined carcinogenic exposures and when performed by the polymorphism analysis of coordinated enzyme activities concurring to the metabolism of the carcinogen(s) in question. Genetic polymorphism analysis can allow for the detection of patients more prone to some types of specific cancers, or to the adverse effects of specific pharmaceutical agents. Considering the increasingly confirmed double-edged sword nature of metabolism polymorphism (both wild-type and variant alleles can predispose to cancer, albeit in different situations of exposure), individual susceptibility to cancer should be monitored as a function of the nature, and mechanism of action, of the carcinogen(s) to which the individual under study is known to be exposed, and with reference to the main target organ of the considered type of exposure.