Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

The transcriptome analysis of cleft lip/palate-related PTCH1 variants in GMSM-K cells show carcinogenic potential

Cancer progression involves the sonic hedgehog(SHH)pathway,in which the receptor PTCH1 actives the downstream pathways.Dysfunction of PTCH1 can lead to nevoid basal cell carcinoma Syndrome(NBCCs)including neoplastic disease and congenital disorder.To evaluate the relationship between PTCH1 and cancer,we applied the CRISPR/Cas9 system to knock out PTCH1 in oral nontumorous epithelial cells(GMSM-K).Then we screened six PTCH1 variants associated with cleft lip/palate(CL/P),one of the congenital disorders in NBCCs,and generated PTCH1 variant and wild-type recombinant PTCH1^(−/−)GMSM-K cell lines.Transcriptome sequencing was conducted in these cell lines.The results revealed that differentially expressed genes(DEGs)in PTCH1^(−/−)GMSM-K were enriched in extracellular compartments,contributing epithelial diseases by pathway enrichment analysis.RT-PCR confirmed that KRT34,KRT81,KRT86,PDGFB,and WNT10B genes,associated with extracellular compartments were highly expressed in PTCH1^(−/−).The Kyoto Encyclopedia of Genes and Genomes analysis also suggested that DEGs are closely related to focal adhesion,transcriptional misregulation,and proteoglycans in breast and gastric cancers.Comparative analysis of samples revealed that the CL/P-associated PTCH1 variants A443G and V908G are potentially carcinogenic.These findings provide new insights into the carcinogenic potential of PTCH1 dysfunction.

CHEMICAL“CARCINOGENS”,AS MODULATORS OF INTER-CELLULAR COMMUNICATION,ARE MITOGENS,NOT MUTAGENS.

Although mutations clearly play a role in themulti-stage process of carcinogenesis,a challengewll be made to the paradigm that most chemical"carcinogens" act via mutagenic activity("carcinogens as mutagens").Control ofproliferation and differentiation within andbetween tissues is mediated by

Dietary Intake, Carcinogenic and Non-Carcinogenic Risk Potentials of Lead, Cadmium, Mercury and Arsenic Exposure via Consumption of Dried Crayfish in Calabar, Nigeria

Intense pressure from both onshore and offshore oil exploration and exploitation activities, together with the accompanying urbanization and industrialization has resulted in massive contamination of land and water resources in Niger Delta, Nigeria. Whereas crayfish is very sensitive to contaminant in the aquatic environment and constitute an important part of human diet, its quality and safety from environmental pollutant is of serious health concern. Evaluation of dietary intake, potential carcinogenic and non-carcinogenic risk of lead, cadmium, mercury and arsenic exposure via consumption of dried crayfish purchased from major markets in Calabar, Nigeria was carried out between June and August 2021. Thirty-six composite samples of dried crayfish purchased from 180 vendors were used for the study. Heavy metals concentrations were determined using Atomic Absorption Spectrophotometer (Model AA-6800, Japan) after wet digestion. Metals concentrations (Mg/kg) were of the ranges 0.02 - 0.24, 0.14 - 0.86, 0.32 - 0.72, 0.04 - 0.19 for Pb, Cd, Hg and As respectively. The mean content of cadmium and mercury exceeded FAO/ WHO and Commission of European Communities maximum levels for crustaceans. Average Estimated Daily Intake for each of the metals was found to be above the recommended daily intake level except for arsenic. The average estimated daily intake values for Cd and Hg were also above the tolerable upper intake level. Average Target Hazard Quotient of all the metals and Hazard Index of all the markets were below 1.00. The Incremental Lifetime Cancer Risk of the metals was greater than the standard tolerable regulatory risk (10-4) for carcinogens. Consumption of crayfish purchased from major markets in Calabar could pose a range of carcinogenic and non-carcinogenic human health risks.

Role of bacteria in carcinogenesis, with special reference to carcinoma of the gallbladder

Carcinoma of the gallbladder (CaGB) is the fifth commonest gastrointestinal tract cancer and is endemic in several countries. The interplay of genetic susceptibility, infections, and life style factors has been proposed to be responsible for carcinogenesis of gallbladder. Persistence of infection leading to chronic inflammation, and production of certain toxins and metabolites with carcinogenic potentials, by certain bacteria has been speculated to be involved in the transformation of the gallbladder epithelium. Therefore, any bacteria that have evolved to acquire both of the above carcinogenic mechanisms can cause cancer. Salmonella typhi has been found to be prominently associated with CaGB. Chronic typhoid carriage (persistence) and production of mediators of chronic infl ammation and a genotoxic toxin (cytotoxic distending toxin, CdtB) are also known for this bacterium. Furthermore, the natural concentrating function of the gallbladder might amplify the carcinogenic effect of the mediators of carcinogenesis. In addition to S. typhi, certain species of Helicobacter (H. bilis and H. hepaticus) and Escherichia coli have also been implicated in carcinogenesis. As the isolation rate is verypoor with the presently available culture techniques, the existence of bacteria in a viable but non-cultivable state is quite likely; therefore, sensitive and specif ic molecular techniques might reveal the etiological role of bacterial infection in gallbladder carcinogenesis. If bacteria are found to be causing cancers, then eradication of such infections might help in reducing the incidence of some cancers.

Human papillomavirus does not have a causal role in colorectal carcinogenesis

AIM: To investigate the presence of human papillomavirus(HPV) DNA along with the integration,the quantification and the expression of the HPV16 in colorectal cancers.METHODS: A prospective series of colorectal tumors were genotyped for HPV DNA.The clinical and pathological variables of the HPV-positive tumors were compared to those of HPV-negative samples.The integration status of HPV16 was evaluated by calculating E2/E6 ng ratios.HPV16-positive tumors were also evaluated for(1) E2,E4,E5,E6 and E7 viral gene ng quantification;(2) relative quantification compared to W12 cells; and(3) viral E2,E4,E5,E6 and E7 mR NA transcripts by real-time polymerase chain reaction.RESULTS: HPV infection was detected in 16.9% of all tumors examined,and HPV16 was the most frequent type detected(63.6% of positive tissues).Notably,the clinical and pathological features of HPV-positive colorectal cancers were not significantly different than those of HPV-negative cancers(χ2 and t-test for all clinical and pathological features of HPV-positive vs HPV-negative colorectal cancers: p ns).HPV16 DNA was present exclusively in episomal form,and the HPV16 E2,E4,E5,E6 and E7 genes were detected in tracenanogram quantities.Furthermore,the HPV16 genes ranged from 10-3 to 10-9 compared to W12 cells at an episomal stage.Although the extractions were validated by housekeeping gene expression,all the HPV16 positive tissues were transcriptionally inactive for the E2,E4,E5,E6 and E7 mR NAs.CONCLUSION: Based on our results,HPV is unlikely involved in colorectal carcinogenesis.

Chemopreventive effect of oltipraz on AFB_1-induced hepatocarcinogenesis in tree shrew model

INTRODUCTIONHepatocellular carcinoma (HCC) is one of themajor cancers in the world with a mortality of morethan 250 000 cases yearly.More than 137 000 casesof HCC were diagnosed each year in China,whichacount approximately for more than 40 percent ofthe total number in the world.HCC has become thesecond major cause of death for cancer in

Maternal and Fetal Exposure to Four Carcinogenic Environmental Metals

Objective To examine maternal and fetal exposure levels to four carcinogenic metals, arsenic （As）, cadmium （Cd）, nickel （Ni）, and beryllium （Be）, and to investigate their environmental influences. Methods Metal concentrations in maternal and umbilical cord blood were measured by inductively coupled plasma-mass spectrometry （ICP-MS）. Environmental factors that might play a role in exposure were analyzed using Mann Whitney nonparametric U-tests and multiple linear regression. Results The concentrations of As, Cd, and Ni in umbilical cord blood （5.41, 0.87, and 139.54 gg/L） were significantly lower than those in maternal blood （6.91, 1.93, and 165.93 p.g/L）. There were significant positive correlations between the maternal and cord concentrations of each carcinogen. Our results showed that： （i） exposures to potentially harmful occupational factors during pregnancy were associated with high levels of maternal As, Cd, and Ni; （ii） living close to major transportation routes （〈500 m） or exposure to second-hand smoke during pregnancy increased the maternal Cd levels and （iii） living close to industrial chimneys induced high maternal Ni levels. Multiple linear regression analysis showed that these environmental factors remained significant in models of the influences of these four carcinogens. Conclusion Both mothers and fetuses had been exposed to As, Cd, Ni, and Be. The increased levels of these carcinogens in pregnant women were associated with some detrimental environmental factors, such as occupational exposure, contact with second-hand smoke and living close to major transportation routes or industrial chimneys.

Opisthorchis viverrini:The carcinogenic human liver fluke

Opisthorchiasis caused by Opisthorchis viverrini remains a major public health problem in many parts of Southeast Asia, including Thailand, Lao PDR, Vietnam and Cambodia. The infection is associated with a number of hepatobiliary diseases, including cholangitis, obstructive jaundice, hepatomegaly, cholecystitis and cholelithiasis. Multi-factorial etiology of cholangiocarcinoma, mechanical damage, parasite secretions, and immunopathology may enhance cholangiocarcinogenesis. Moreover, both experimental and epidemiological evidences strongly implicate liver fluke infection as the major risk factor in cholangiocarcinoma, cancer of the bile ducts. The liver fluke infection is induced by eating raw or uncooked fish products that is the tradition and popular in the northeastern and northern region, particularly in rural areas, of Thailand. The health education programs to prevent and control opisthorchiasis are still required in the high-risk areas.

Toxicity and Carcinogenicity of Ozone in Combination with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and Dibutyl Phthalate in B6C3F1 Mice for 16 and 32 Weeks

Objective To evaluate the toxic and carcinogenic potential of ozone alone or in combination with 4-（N-methyl-N-nitrosamino）-1-（3-pyridyl）-1-butanone （NNK） and/or dibutyl phthalate （DBP）. Methods Male and female B6C3F1 mice were exposed, through inhalation, intravenous administration and diet, to 0.5 ppm of ozone, 1.0 mg/kg of NNK and 5000 ppm of DBP, individually and in combination for 16 and 32 weeks. Results No treatment-related death was seen, but significant differences in body and organ weights between control and treated mice were observed during the study. No incidence of lung tumor incidence was recorded in mice exposed to either ozone alone or combined treatment. Oviductal carcinomas were observed in female mice exposed to ozone or DBP alone for 16 weeks and ozone in combination with NNK and DBP for 32 weeks. Conclusion Although ozone alone and in conjunction with NNK and/or DBP does not induce lung cancer under our experimental conditions, they induce oviductal carcinomas in B6C3F1 mice.

Relationship between Structures and Carcinogenicities of Heterocyclic Amines

Semi-empirical molecular orbital calculations were performed on heterocyclic aromatic amines(HCAs). The relationship between the structures and the carcinogenicities can be rationally elucidated by the models based on the metabolism of HCAs and the Di-region theory. The degree of easiness for the formation of Di-region electrophilic centers determines the carcinogenic activity. There is a good linear relationship between the observed carcinogenicities and the PM3 calculated parameters, with r=0.973 and F=29.8>F ** 0.01 .

Carcinogenic potential of duodenal reflux juice from patients with long-standing postgastrectomy

AIM: To determine whether study on the carcinogenic potential of reflux juice from patients with remote gastrectomy could clarify the inherent relationship between duodenal reflux and gastric stump cancer. METHODS: A total of 37 reflux juice samples (13 Billroth I, 24 Billroth II) were employed in the present study. A two-stage transformation assay using BALB/c 3T3 cells was carried out to test the initiating or promoting activity of these samples. RESULTS: Two of 18 (11.1%) reflux samples exerted initiating activities, whereas 9/19 (47.4%) samples enhanced the MNNG-initiating cell transformation, suggesting the duodenal reflux juice might more frequently possess the tumor-promoter activity (P = 0.029). In addition, there was no difference in initiating activities of the samples irrespective of surgical procedures (P = 0.488), while Billroth II samples exhibited stronger tumor-promoter activity than Billroth I samples (P = 0.027). Furthermore, the promoter activities were well correlated with the histological changes of the stomas (r(s) = 0.625, P = 0.004), but neither their cytotoxicities nor initiating activities had this correlation (Probabilities were 0.523 and 0.085, respectively). CONCLUSION: The duodenal reflux juice from patients with remote postgastrectomy did have carcinogenic potential, and suggested that tumor-promoting activity should principally account for the high incidence of gastric cancer in gastrectomy patients. In contrast, it is difficult to explain the high stump-cancer incidence with the N-nitroso compounds theory-a popular theory for the intact stomach carcinogenesis, and it seemed to be justified to focus chemo-prevention of this cancer on the tumor-promoting potential of reflux juice.

Anti-carcinogenic properties of curcumin on colorectal cancer

Curcumin has been used in traditional Indian medicine for many centuries for its anti-inflammatory and anticarcinogenic properties.There has been some promising research concerning curcumin as a safe therapeutic agent for many cancers,colorectal cancer being among them.This has been shown through research in cell cultures,animal models,and humans.At this time,it appears that curcumin’s anti-carcinogenic properties are most likely due to its effects on multiple molecular targets,such as nuclear factorκ-light-chain-enhancer of activated B cells(NF-κB)and activator protein 1(AP-1).NF-κB and AP-1 are both major transcription factors that regulate inflammation and thus affect cell proliferation,differentiation and even apoptosis.Curcumin has also been shown to affect a variety of other key players involved in carcinogenesis,such as cyclooxygenase-2,matrix metallopeptidases 2 and 9 and tumor necrosis factorαinduced vascular cell adhesion molecule,just to name a few.Although many molecular targets are involved,curcumin has been well tolerated in many studies:doses up to 8 g a day have been confirmed to be safe for humans.In this brief review,we will examine the current studies and literature and touch upon many molecular pathways affected by curcumin,and demonstrate the exciting possibility of curcumin as a chemopreventive agent for colorectal cancer.

MUTAGENICITY AND CARCINOGENICITY OF FISH SAUCE FROM A COUNTY WITH THE HIGH RISK FOR GASTRIC CANCER IN CHINA

The mutagenicity and carcinogenicity of fish sauce (FS) sample from Changle County, a high gastric cancer mortality (113.20/105) area, were investigated with the biologic short-term tests and laboratory animal experiment. The results showed that the extract of FS was markedly direct mutagenic toward S. typhimurium TA100, induced high sister chromatid exchanges (SCE) and micronucleus (MN) in V79 cells after nitrosation with sodium nitrite. But the non-nitrosated FS did not. The nitrosated fish sauce (NFS) also induced SOS in E. coli PQ37 and alkylation of calfthymus DNA. The potency of NFS to induce unscheduled DNA synthesis (UDS) in human normal gastric mucosal cells was increased about fivefold compared with FS. When the NFS extract was given to newborn rats by gavage, dys-plasia and adenocaroinoma were induced in the glandular stomach in the 4th and 16th experimental week, respectively. N-nitrosamides were also found in NFS, which may account for the mutagenicity and carcinogenicity of NFS. It is indicated that FS, a traditional daily eaten seasoning, may contribute to the causes of the high gastric cancer mortality for the local residents.

Interactions of chemical carcinogens and genetic variation in hepatocellular carcinoma

In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B 1 (AFB 1 ) epoxide reacts with guanine in DNA and can lead to genetic changes. In HCC, the tumor suppressor gene p53 codon 249 mutation is associated with AFB 1 exposure and mutations in the K -ras oncogene are related to vinyl chloride exposure. Numerous genetic alterations accumulate during the process of hepatocarcinogenesis. Chemical carcinogen DNA-adduct formation is the basis for these genetic changes and also a molecular marker which reflects exposure level and biological effects. Metabolism of chemical carcinogens, including their activation and detoxification, also plays a key role in chemical hepatocarcinogenesis. Cytochrome p450 enzymes, N -acetyltransferases and glutathione S -transferases are involved in activating and detoxifying chemical carcinogens. These enzymes are polymorphic and genetic variation influences biological response to chemical carcinogens. This genetic variation has been postulated to influence the variability in risk for HCC observed both within and across populations. Ongoing studies seek to fully understand the mechanisms by which genetic variation in response to chemical carcinogens impacts on HCC risk.

Tobacco-specific Carcinogen 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-butanone(NNK) Activating ERK1/2 MAP Kinases and Stimulating Proliferation of Human Mammary Epithelial Cells

Cigarette smoking is correlated with the development of various cancers. 4- （Methylnitresoamino） -1- （3-pyridyl） - 1-butanone（NNK） is one of the major tobacco-specific carcinogens in the cigarette smoke, which increases the risk of breast cancer. In the present study, it was demonstrated that NNK rapidly activated ERK1 and ERK2 MAP kinases in human normal mammary epithelial cells. It was found that there are two different routes for the activation of ERK1/2 with NNK. One is from nicotinic receptor nAchR to MEK1/2, and the other is from tyrosine kinase containing receptor to MEK1/2. The tobacco-specific carcinogen NNK shows a strong proliferative effect on normal human mammary epithelial cells and cancer mammary epithelial cells.

Studies on the Mutagenicity and Teratogenicity of Kuianchun and Its Potential Carcinogenicity Prediction

Kuianchun is a newly synthesized antibacterial and growth-promoting drug. This paper selected a battery of three short-term tests, including Ames test, micronucleus test and sperm abnormality test, to detect the mutagenicity of Kuianchun. The carcinogenicity prediction and battery selection method (CPBS method) was used to determine the probability of carcinogenicity of Kuianchun based upon the results of short-term tests mentioned above. In addition, traditional teratogenic test was selected to study teratogenicity of Kuianchun. In Ames test, Kuianchun showed mutagenic for Salmonella typhimurium strains TA98 and TA100 in the absence and presence of microsomal metabolic activation system (S9-mix). However, the mutagenicity was reduced by the addition of S9-mix. In micronucleus test, Kuianchun was administered intra-peritoneally to male mouse 30 hours and 6 hours before they were killed respectively. The result indicated that there was no significant difference on the number of micronucleated polychromatic erythrocytes (PCEs) in the mouse bone marrow induced by Kuianchun compared with the negative contrast (50% DMSO) (P>0.05). In sperm abnormality test, Kuianchun was administered through a gastric incubation to male mouse as a suspension in 2% Tween-80. The dosage levels were 450, 750, 1000 and 1500mg/kg per day for 5 days. The result indicated that the percentage of abnormal sperms induced by Kuianchun was not significant compared with the negative contrast (P > 0.05). In traditional teratogenic test, Kuianchun was given orally to pregnant mouse at 1730, 1/20 and 1/15 LD50 during 6 - 15days of pregnancy period (the LD50 = 9000mg/kg). No toxicity was found either on mother and embryo in mouse, and teratogenic effects were also not observed at all tested dosages.The probability of carcinogenicity of Kuianchun is 23.8%(6 = 0.238). The result demonstrated that Kuianchun is a non-carcinogen.

Levels of Genotoxic and Carcinogenic Ingredients in Plant Food Supplements and Associated Risk Assessment

The present study describes the selection, analysis and risk assessment of genotoxic and carcinogenic ingredients of botanicals and botanical preparations which can be found in food and plant food supplements (PFS). First an inventory was made of botanical ingredients that are of possible concern for human health because of their genotoxic and/or carcinogenic properties. In total, 30 botanical ingredients were selected and subsequently judged for their actual genotoxic and/or carcinogenic potential. Among the 30 compounds considered, 18 compounds were judged to be both genotoxic and carcinogenic. Interestingly, the majority of these compounds belong to the group of alkenylbenzenes or unsaturated pyrrolizidine alkaloids. Subsequently, based on available carcinogenicity data and estimated daily human exposure that was determined focusing on the intake from PFS, the Margin of Exposure (MOE) was calculated for the alkenylbenzenes estragole, methyleugenol, safrole and β-asarone. Calculating the MOEs for intake estimates of these alkenylbenzenes from PFS resulted in MOE values that were generally lower than 10,000 and often lower than 100. In some cases the MOE was even below 10 meaning that the estimated daily intake is in the range of dose levels causing malignant tumors in experimental animals. This result indicates that the use of PFS containing the genotoxic carcinogens estragole, methyleugenol, safrole or β-asarone might raise a potential concern for human health and would be of high priority for risk management.

Pairwise comparisons in the analysis of carcinogenicity data

Analysis of carcinogenicity data generally involves a trend test across all dose groups and a pairwise comparison of the high dose group with the control. The most commonly used test for a positive trend is the Cochran-Armitage test. This test is asymptotically normal. For the pairwise comparison of the high dose group with the control group, we propose two modifications: the first modification is to apply the test on the data from high dose and control groups after dropping the data from the low and the medium dose groups;the second modification is to adjust the test conditional on data from all dose groups. We compare the power performance of these two modifications for the pairwise comparisons.

A SEQUENTIAL TESTING PROGRAM FOR PREDICTING AND IDENTIFICATING CARCINOGENS AND ITS APPLICATION

In this paper our studies about the sequential testing program for predicting and identificating carcinogens, sequential discriminant method and cost- effectiveness analysis are summarized. The analysis of our database of carcinogeniclty and genotoxicity of chemicals demonstrates the uncertainty . of short- term tests ( STTs ) to predict carcinogens and the results of most routine STTs are statistically dependent. We recommend the sequential testing program combining STTs and carclnogenicity assay, the optimal STT batteries, the rules of the sequential discrimination and the preferal choices of STTs tor specific chemical class. For illustrative pmposes the carclnogenicity prediction of several sample chamicals is presented. The results of cost-effectiveness analysis suggest that this program has vast social-economic effectiveness.