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The WHO International Programme on Chemical Safety (IPCS) framework for analyzing the relevance of a cancer mode of action (MoA) for humans (IPCS cancer-HRF) is an application to assess human relevance of tumorigenic hazards found through rodent bioassays. The chloroacetanilide herbicides, butachlor and alachlor, induced enterochromaffin-like (ECL) cell tumors in rat stomachs, at the highest doses. This study analyzed the human relevance of this tumor by applying the IPCS cancer-HRF using published data. In a postulated MoA, early key events (KEs) included decreased mucosal thickness in the fundic region, due to reduced parietal cells. The following KEs included increased pH of gastric acid and hypergastrinemia, leading to enhanced cell proliferation and hyperplasia, and resulting in the outcome of an ECL cell tumor. The data showed consistencies in dose-response and temporal concordance with the KEs and specificity in the tumor response, providing strengthened evidence of the KEs. While the early KE was not the same, similar MoAs have already been established for omeprazole and ciprofloxacin. The integrated data indicated that the postulated MoAs were biologically plausible. Alternative MoAs were excluded.. Based on sufficient evidence, an MoA was established in rats. When addressing chemically inducible MoAs of human relevance, KEs of hypergastrinemia and trophic ECL cell hyperplasia were judged to not be qualitatively and quantitatively plausible in humans. The MoA in rats is unlikely to be present in humans; however, the potential effects on parietal cells cannot be excluded. Thus, the IPCS cancer-HRF is very useful for assessing human relevance.

Type 1 diabetes mellitus occurs when beta cell mass is reduced to less than 20% of the normal level due to immune system destruction of beta cell resulting in an inability to secrete enough insulin. The prevalence of diabetes is expanding according to the American Diabetes Association and the World Health Organization (WHO), foretold to exceed 350 million by 2030. The current treatment does not cure many of the serious complications associated with the disease such as neuropathy, nephropathy, dyslipidemia, retinopathy and cardiovascular disease. Whole pancreas or isolated pancreatic islet transplantation as an alternative therapy can prevent or reduce some of the complications of diabetes. However, the shortage of matched organ or islets cells donor and alloimmune responses limit this therapeutic strategy. Recently, several reports have raised extremely promising results to use different sources of stem cells to differentiate insulin-producing cells and focus on the expansion of these alternative sources. Stem cells, due to their potential for multiple differentiation and self-renewal can differentiate into all cell types, including insulin-producing cells (IPCs). Generation of new beta cells can be achieved from various stem cell sources, including embryonic stem cells (ESCs), adult stem cells, such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs). Thus, this chapter discusses on the assistance of cellular reprogramming of various stem cells as candidates for the generation of IPCs using transcription factors/miRNA, cytokines/small molecules and tissue engineering.

Following the discovery of Asian citrus psyllid (ACP) in 1998 and Huanglongbing (HLB) in 2005, this destructive disease associated with the phloem-limited bacterium Candidatus Liberibacter asiaticus (CLas) now affects most mature citrus trees in Florida. Despite the endemic presence of ACP and HLB, Florida citrus growers continue to plant new trees. The young trees are more vulnerable to both ACP infestation and CLas infection; therefore, protection from the vector psyllid by exclusion or other control methods is of paramount importance. Individual protective covers (IPCs), bags made from fine mesh netting, are a vector exclusion tool, which could prevent psyllids from transmitting CLas to young trees during the early years of growth. The use of IPCs is an environmentally friendly pest management strategy, contrary to the frequent use of insecticides to control ACPs. In this study, we investigated the efficacy of IPCs to protect trees from ACP and CLas infection in a citrus grove in southwest Florida during the first two years after planting. IPCs were compared against insecticide applications to control ACPs and tree health and growth were assessed. We found that IPCs effectively excluded psyllids, prevented CLas infection, altered microclimatic conditions in the tree canopy, and positively influenced most of the horticultural traits measured. However, IPCs promoted the incidence of other “diseases” such as greasy spot and sooty mold and of scale insects but reduced occurrence of citrus canker and citrus leaf miner. This suggests that use of IPCs may be an effective approach to protect young trees from ACP and HLB, but integrated pest management approaches will be needed for other pests during IPC use and after removal to maintain overall health of citrus trees.

Species-specific lung tumors in the mouse are induced by a number of chemicals. The underlying cause appears to be a high metabolic activity of mouse lung, due to relatively high abundance of Clara cells in mice compared with humans and the mouse-specific cytochrome P450 isoform 2f2 in the Clara cells. The chemicals are activated to reactive intermediates, leading to local cytotoxicity or mitogenicity resulting in increased cell proliferation and tumors. Rats have lower metabolic activity than mice (already below the threshold needed to cause lung tumors upon lifetime exposure) and activity in humans is lower than in rats. The carcinogenic risk for human lung is low for this mode of action (MOA). Fluensulfone has shown an increased incidence of lung adenomas in mice, but not in rats, at high doses. Fluensulfone is not genotoxic. MOA studies were conducted investigating key events of the postulated MOA. Fluensulfone is extensively metabolized by mouse lung microsomes, whereas no metabolic activity is seen with human lung microsomes. Cyp 2f2 is a major contributor in fluensulfone's metabolism and Cyp 2e1 is not involved. Furthermore, administration of fluensulfone to mice led to an early increase in Clara cell proliferation. The International Programme on Chemical Safety (IPCS) MOA and human relevance framework was used to evaluate the collective data on fluensulfone. We concluded that fluensulfone leads to species-specific mouse lung tumors and that these tumors are likely not relevant to human hazard or risk.

Bone marrow-derived mesenchymal stem cells (BMSCs) have the ability to differentiate into insulin-producing cells (IPCs). Bio-scaffolds derived from decellularized organs can act as a carrier for seed cells and may have broad applications in regenerative medicine. This study investigated the effect of native pancreatic stroma obtained from decellularized pancreas on the proliferation, migration and differentiation of BMSCs into IPCs, and explored the potential underlying molecular mechanism. The decellularized pancreas bio-scaffold was obtained by perfusion with Triton X-100/ammonium hydroxide, followed by digestion with a mixture of pepsin and hydrochloric acid to prepare the stroma solution. Islet-like cells were differentiated from BMSCs by a three-step induction method. The differences on the cytological behavior with or without stroma were evaluated by morphological observation, insulin release assay, qRT-PCR assay and western blot analysis. Our results showed that, stroma derived from decellularized pancreas could promote the proliferation and migration of BMSCs. Furthermore, the formation of IPCs could also be promoted, which possessed similar morphology to endogenous islets. During the induced differentiation process, the presence of stroma significantly increased the expression of insulin 1, insulin 2 and Pdx-1, as well as insulin release. This was accompanied by an increase in the phosphorylation of Akt and ERK in third stage cell clusters, which was prevented by the addition of the inhibitors PD98059 and LY294002, respectively. In summary, decellularized pancreatic stroma could promote the proliferation, migration and differentiation of BMSCs into IPCs, and this involved the activation of Akt and ERK signal pathways.

Since the publication of the International Programme on Chemical Safety (IPCS) Harmonized Scheme for Mutagenicity Testing, there have been a number of publications addressing test strategies for mutagenicity. Safety assessments of substances with regard to genotoxicity are generally based on a combination of tests to assess effects on three major end points of genetic damage associated with human disease: gene mutation, clastogenicity and aneuploidy. It is now clear from the results of international collaborative studies and the large databases that are currently available for the assays evaluated that no single assay can detect all genotoxic substances. The World Health Organization therefore decided to update the IPCS Harmonized Scheme for Mutagenicity Testing as part of the IPCS project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. The approach presented in this paper focuses on the identification of mutagens and genotoxic carcinogens. Selection of appropriate in vitro and in vivo tests as well as a strategy for germ cell testing are described.

Transplantation of functional insulin-producing cells (IPCs) provides a novel mode for insulin replacement, but is often accompanied by many undesirable side effects. Our previous studies suggested that IPCs could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells. To obtain a better method through which to acquire more similar IPCs, we compared the difference between IPCs of the GLP-1 group and IPCs of the non-GLP-1 group in the morphological features in cellular level and physiological function. The levels of insulin secretion were measured by ELISA. The insulin and glucagon-like peptide-1 (GLP-1) mRNA gene expression was determined by real-time quantitative PCR. The morphological features were detected by atomic force microscopy (AFM) and laser confocal scanning microscopy (LCSM). Intracellular Ca(2+) levels and Glucagon-like peptide-1 receptor (GLP-1R) levels were determined by flow cytometer (FCM). We found that IPCs of the GLP-1 group had bigger membrane particle size and average roughness (Ra ) than IPCs of the non-GLP-1 group but still smaller than normal human pancreatic beta cells. The physiology function of IPCs of the GLP-1 group were much closer to normal human pancreatic beta cells than IPCs of the non-GLP-1 group. GLP-1 could improve the similarity of IPCs from human adipose tissue-derived mesenchymal stem cells and pancreatic beta cells in cellular ultrastructure and function.

Thiazopyr increases the incidence of male rat thyroid follicular-cell tumors; however, it is not carcinogenic in mice. Thiazopyr is not genotoxic. Thiazopyr exerts its carcinogenic effect on the rat thyroid gland secondary to enhanced metabolism of thyroxin leading to hormone imbalance. The relevance of these rat tumors to human health was assessed by using the 2006 IPCS Human Relevance Framework. The postulated rodent tumor mode of action was tested against the Bradford Hill criteria and was found to satisfy the conditions of dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity that fits with a well-established mode of action for thyroid follicular-cell tumors. Although the postulated mode of action could theoretically operate in humans, marked quantitative differences in the inherent susceptibility for neoplasia to thyroid hormone imbalance in rats allows for the conclusion that thiazopyr does not pose a carcinogenic hazard to humans.

An international workshop was held in 2006 to evaluate experimental techniques for hazard identification and hazard characterization of sensitizing agents in terms of their ability to produce data, including dose-response information, to inform risk assessment. Human testing to identify skin sensitizers is discouraged for ethical reasons. Animal-free alternatives, such as quantitative structure-activity relationships and in vitro testing approaches, have not been sufficiently developed for such application. Guinea pig tests do not generally include dose-response assessment and are therefore not designed for the assessment of potency, defined as the relative ability of a chemical to induce sensitization in a previously naive individual. In contrast, the mouse local lymph node assay does include dose-response assessment and is appropriate for this purpose. Epidemiological evidence can be used only under certain circumstances for the evaluation of the sensitizing potency of chemicals, as it reflects degree of exposure as well as intrinsic potency. Nevertheless, human diagnostic patch test data and quantitative elicitation data have provided very important information in reducing allergic contact dermatitis risk and sensitization in the general population. It is therefore recommended that clinical data, particularly dose-response data derived from sensitized patients, be included in risk assessment.

Globally, very few college or university chemistry courses incorporate toxicology although public perception of chemicals and the chemical industry as threats to health and the environment has had an adverse effect on chemistry and on the use of its products. The International Union for Pure and Applied Chemistry (IUPAC) through its Commission on Toxicology recognized this and, with the support of the Committee on the Teaching of Chemistry has used the IUPAC web site to promote distance learning in toxicology for chemists. After preparation of a thoroughly refereed consensus Glossary of Terms for Chemists of Terms Used in Toxicology, a textbook Fundamental Toxicology for Chemists and a set of educational modules entitled Essential Toxicology were compiled and put through the normal thorough review procedure of IUPAC before being approved by the organization. There is now an additional Glossary of Terms Used in Toxicokinetics. The modules are freely downloadable in Adobe PDF format and are designed to be used both by educators and by students. Educators are asked to select whatever is appropriate to their students and to use the material as they wish, adding content specifically relevant to their circumstances. For self-study, the web modules have self-assessment questions and model answers. Currently the original Glossary for Chemists of Terms Used in Toxicology is being revised and it is expected that this will lead to further developments. The currently available components of the IUPAC programme may be accessed through the IUPAC website at the Subcommittee on Toxicology and Risk Assessment page: http://www.iupac.org/divisions/VII/VII.C.2/index.html.

The study of inherited cardiac disorders is hampered by the lack of suitable in vitro human cardiac disease models and relevant functional assays. A potential solution to this cell-sourcing challenge may be the recently described human induced pluripotent stem cell (hiPSC) technology. Pioneering studies were successful in establishing patient-specific, hiPSC-derived cardiomyocyte models of the most common inherited cardiac arrhythmogenic disorders, such as the different long QT syndrome subtypes (types 1, 2, 3, 8), overlap syndrome LQTS3/Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT) types 1 and 2, and arrhythmogenic right ventricular cardiomyopathy (ARVC). These studies initially demonstrated the ability of the generated hiPSC models to recapitulate the disease processes in the culture dish. More recently, such studies were also able to provide new mechanistic insights into the disease processes, as well as to derive a unique drug-screening platform to test existing and novel therapeutic treatment options in an environment resembling the human physiological milieu. Moreover, initial evidence suggests that such models can help to optimize drug treatment in a personalized manner in the future. Nevertheless, several hurdles still exist for using hiPSC-based models for the aforementioned tasks, such as the hiPSC-derived cardiomyocytes' relatively immature phenotype, and also the resulting cell heterogeneity. Extensive research work is ongoing to address these challenges, as well as to add new opportunities for the field by utilizing recent advances in gene editing technologies. Here, we discuss the significant findings that hiPSC-based models have provided for each of the inherited cardiac arrhythmia syndromes so far, and the current challenges that this technique is facing.

The use of different sources of stem cells including embryonic and mesenchymal stem cells is a novel therapy for diabetic’s patients. However the efficiency of differentiation is not enough to complete treatment. An important point in the induction of stem cells into IPCs in vitro is the role of the pancreatic niche (which includes the stromal and epithelial niche). It can physically contact to adjacent cells and influence stem cell behavior via close range signaling. In this respect, we hypnotized that Pancreatic Stromal Cell (PSC) as a fundamental factor of the stromal niche may have an effective role in the generation IPCs (i.e, the efficiency of differentiation and function of newlyformed β-cells) in vitro. Therefore in this study, MSCs derived from umbilical cord (UC-MSCs) vain and bone marrow (BM-MSCs) was selected to differentiate into IPCs in co-culture with rat PSCs. Our results have demonstrated that only BM-MSCs were able to differentiate into IPCs. Cells in Islet-like clusters with (out) co-cultured with rat pancreatic stromal cells, produced insulin and C-peptide and released them to culture medium at the end of the induction protocol; however they did not respond to glucose challenges very well. The presence of rat pancreatic stromal cells, up-regulated the expressions of insulin, Glut2, and Nkx2.2 were at the mRNA level in IPCs. These results suggested that rat PSCs possibly affect MSCs differentiation into IPCs by increasing the number of immature β-cells.

Two groups of scientists have just announced what is being described as a leap forward in human stem cell research.1–3 Both have found ways of producing what are being called “induced pluripotent cells” (iPCs), stem cells that they hope will demonstrate the same key properties of regeneration and unrestricted differentiation that human embryonic stem cells (hESCs) possess, but which are derived from skin cells not from embryos. In simple terms, these scientists have succeeded in reprogramming skin cells to behave like hESCs. Stem cell research has been hailed as one of the most important and exciting areas of science, because it is believed that these types of cells will not only play an important part in regenerative medicine, but also yield valuable scientific information. These latest developments in cell reprogramming represent a milestone for stem cell science. No longer does the paradigm of irreversible cell specialisation hold true; instead, almost any type of cell might have the potential to become any other. The advent of techniques for producing these iPCs has also been hailed as an ethical breakthrough. Up until now, the production of hESCs has required a process (unacceptable to some) which involves the destruction of embryos. Many of these embryos are available as by-products of IVF; but in addition, the process of somatic cell nuclear transfer (therapeutic cloning) to produce cloned embryonic stem cells requires a supply of human oocytes, which must currently be harvested from female donors at no insignificant cost. In a nutshell, iPCs seem to enable us to produce “embryo-free” human pluripotent stem cells, and in a “gender-neutral” way—that is, without the need for human oocytes. The response from the scientific community, ethical commentators and the public has, however, reflected an inherent confusion over the ethical significance of this research. The anti-embryo …

The purpose of these guidelines is to provide concise guidance on the planning, performing and interpretation of studies to monitor groups or individuals exposed to genotoxic agents. Most human carcinogens are genotoxic but not all genotoxic agents have been shown to be carcinogenic in humans. Although the main interest in these studies is due to the association of genotoxicity with carcinogenicity, there is also an inherent interest in monitoring human genotoxicity independently of cancer as an endpoint. The most often studied genotoxicity endpoints have been selected for inclusion in this document and they are structural and numerical chromosomal aberrations assessed using cytogenetic methods (classical chromosomal aberration analysis (CA), fluorescence in situ hybridisation (FISH), micronuclei (MN)); DNA damage (adducts, strand breaks, crosslinking, alkali-labile sites) assessed using bio-chemical/electrophoretic assays or sister chromatid exchanges (SCE); protein adducts; and hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations. The document does not consider germ cells or gene mutation assays other than HPRT or markers of oxidative stress, which have been applied on a more limited scale.

Introduction Indwelling pleural catheters (IPCs) are an alternative method for controlling recurrent, symptomatic malignant pleural effusions, currently reserved for cases of known trapped lung, or after an initial unsuccessful talc pleurodesis. 1 A 2.8% pleural infection rate has been observed in patients with an IPC 2 leading to the concern that this risk of infection may increase further with systemic chemotherapy. Objectives Determine whether systemic chemotherapy increased the number of IPC related pleural infections. Whether the risk was related to the interval between chemotherapy and IPC insertion. Methods A detailed retrospective review was performed of the first 100 patients treated with an IPC from February 2011 to December 2013 at Queen Alexandra Hospital, Portsmouth. Results 11 of the 100 IPC insertions developed pleural infection (11%), four of whom had received chemotherapy (see table). Overall 15 patients received chemotherapy after IPC insertion with an interval varying from 0 days (same day) to 43 days, with a median of 9 days. The 2 × 2 table compared the proportion of patients developing pleural infection with and without chemotherapy. Further analyses assessed the interval from chemotherapy to IPC insertion and whether it influenced the numbers of pleural infections, using cut-off points at 7, 14, 21 and 28 days. There was no significant difference at any of these time-points (p=NS). Conclusions The pleural infection rate with an IPC was slightly higher than previous published series. There was however no significant increase in pleural infection in those receiving chemotherapy, although these analyses did not account for variability in tumour type, tumour stage, performance, co-morbidity and leucopenia at time of insertion. While the analyses were not significant, this needs to be retested in larger or combined registries of patients treated with IPCs for pleural malignancy. References Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ. BTS Pleural Disease Guideline Group. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65 Van Meter ME, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med . 2011;26(1):70–76

The inefficiency of generating induced pluripotent somatic cells (iPS) engendered two contending models, namely the Stochastic model and Elite model. Although the former is more favorable to explain the inherent inefficiencies, it may be fallible to extrapolate the same working model to reprogramming of cancer cells. Indeed, tumor cells are known to be inherently heterogeneous with respect to distinctive characteristics thus providing a suitable platform to test whether the reprogramming process of cancer cells is biased. Here, we report our observations that all randomly picked induced pluripotent cancer cells (iPCs) established previously do not possess mutations known in the parental population. This unanticipated observation is most parsimoniously explained by the Elite model, whereby putative early tumor progenies were selected during induction to pluripotency.

The International Programme on Chemical Safety sponsored a collaborative study to evaluate the utility of neurobehavioral test methods for identifying neurotoxic chemicals. The protocol consisted of a functional observational battery and automated assessment of motor activity. The study involved four laboratories in the United States and four in Europe, each of which evaluated the dose- and time-related effects of seven prototypic chemicals following both single and 4-week repeated exposures. The protocol was designed to assess the general utility and reliability of neurobehavioral screening procedures in a diversity of testing situations. The results of chemical testing indicated that all participating laboratories generally could detect and characterize the effects of known neurotoxicants, despite some differences on specific endpoints. These data provide important information regarding the reliability and sensitivity of neurobehavioral screening methods over a range of laboratory conditions. The purpose of this workshop was to describe the background and study design of the collaborative effort, present the data (including comparison of results across laboratories), and discuss issues regarding the conduct and interpretation of these behavioral tests, as well as future directions for neurotoxicity screening.

The IPCS Human Relevance Framework was evaluated for a DNA-reactive (genotoxic) carcinogen, 4-aminobiphenyl, based on a wealth of data in animals and humans. The mode of action involves metabolic activation by N-hydroxylation, followed by N-esterification leading to the formation of a reactive electrophile, which binds covalently to DNA, principally to deoxyguanosine, leading to an increased rate of DNA mutations and ultimately to the development of cancer. In humans and dogs, the urinary bladder urothelium is the target organ, whereas in mice it is the bladder and liver; in other species, other tissues can be involved. Differences in organ specificity are thought to be due to differences in metabolic activation versus inactivation. Based on qualitative and quantitative considerations, the mode of action is possible in humans. Other biological processes, such as toxicity and regenerative proliferation, can significantly influence the dose response of 4-aminobiphenyl-induced tumors. Based on the IPCS Human Relevance Framework, 4-aminobiphenyl would be predicted to be a carcinogen in humans, and this is corroborated by extensive epidemiologic evidence. The IPCA Human Relevance Framework is useful in evaluating DNA-reactive carcinogens.

The International Programme on Chemical Safety (IPCS) sponsored a collaborative study to examine the intra- and inter-laboratory variation associated with the preparation and bioassay of complex chemical mixtures. The mixtures selected were National Institute of Standards and Technology (NIST) Standard Reference Materials (SRMs). 20 laboratories worldwide participated in the collaborative trial. The participating laboratories extracted the organic portion of two particulate samples — an air-particulate sample and a diesel-particulate sample - and bioassayed the extracts. The laboratories simultaneously bioassayed a NIST-prepared extract of coal tar and two control compounds (benzo[ a ]pyrene, and 1-nitropyrene). The bioassay method used was the Salmonella/mammalian microsome plate-incorporation test using strains TA98 and TA100. Study design also allowed for a comparison of sonication and Soxhlet extraction techniques. The mean extractable masses for the air particles and diesel particles were approximately 5% and 1.75%, respectively. The particulate samples were mutagenic in both strains with and without activation in all 20 laboratories. For TA100 the with and without activation slope values for the air particulate were 162 and 137 revertants per mg particles, respectively. For TA98 the respective diesel slope values were 268 and 269. The mutagenicity slope values for the diesel particles ranged from 3090 (TA98, + S9) to 6697 (TA100, + S9) revertants per mg particles. The coal tar solution was negative for both strains when exogenous activation was not used but was mutagenic in both strains with exogenous activation. The benzo[ a ]pyrene and 1-nitropyrene were used as positive controls and gave results consistent with the literature. This paper provides a complete summary of the data collected during the collaborative study. Companion papers provide further analysis and interpretation of the results.

Formaldehyde and glutaraldehyde cause toxicity to the nasal epithelium of rats and mice upon inhalation. In addition, formaldehyde above certain concentrations induces dose-related increases in nasal tumors in rats and mice, but glutaraldehyde does not. Using the 2006 IPCS human framework for the analysis of cancer mode of action (MOA), an MOA for formaldehyde was formulated and its relevance was tested against the properties of the noncarcinogenic glutaraldehyde. These compounds produce similar patterns of response in histopathology and in genotoxicity tests (although formaldehyde has been much more extensively tested studied). The MOA is based on the induction of sustained cytotoxicity and reparative cell proliferation induced by formaldehyde at concentrations that also induce nasal tumors upon long-term exposure. Data on dose dependency and temporal relationships of key events are consistent with this MOA. While a genotoxic MOA can never be ruled out for a compound that is clearly genotoxic, at least in vitro, the nongenotoxic properties fundamental to the proposed MOA can explain the neoplastic response in the nose and may be more informative than genotoxicity in risk assessment. It is not yet fully explained why glutaraldehyde remains noncarcinogenic upon inhalation, but its greater inherent toxicity may be a key factor. The dual aldehyde functions in glutaraldehyde are likely to produce damage resulting in fewer kinetic possibilities (particularly for proteins involved in differentiation control) and lower potential for repair (nucleic acids) than would be the case for formaldehyde. While there have been few studies of possible glutaraldehyde-associated cancer, the evidence that formaldehyde is a human carcinogen is strong for nasopharyngeal cancers, although less so for sinonasal cancers. This apparent discrepancy could be due in part to the classification of human nasal tumors with tumors of the sinuses, which would receive much less exposure to inhaled formaldehyde. Evaluation of the human relevance of the proposed MOA of formaldehyde in rodents is restricted by human data limitations, although the key events are plausible. It is clear that the human relevance of the formaldehyde MOA in rodents cannot be excluded on either kinetic or dynamic grounds.

The framework developed by the International Programme on Chemical Safety (IPCS) for assessing the mode of action of tumour induction of chemicals in experimental animals has been illustrated with d-limonene, sodium saccharin, di(2-ethylhexyl)phthalate (DEHP) and sulfamethazine as examples. d-Limonene causes renal tumours only in male rats through a response associated with alpha(2u)-globulin. Sodium saccharin induces urinary bladder tumours only in male rats through formation of a urinary precipitate causing erosion of the bladder surface and extensive regenerative hyperplasia. DEHP causes liver tumours in rats and mice through activation of the receptor PPAR alpha leading to peroxisome proliferation and hepatocellular proliferation. Sulfamethazine induces thyroid follicular cell tumours in rats and mice through a mechanism involving altered thyroid hormone homeostasis.

Antidotes may play an important role in the treatment of poisoning. For many physicians and toxicologists an antidote is an antidote. According to the IPCS definition, an antidote is a therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic. Given this wide definition, the efficacy of an antidote may vary considerably depending on which toxic action(s) is/are being counteracted and on the level of counteracting power: An almost 100% efficacy is seen using specific antagonists, such as naloxone in opiate poisoning or flumazenil in benzodiazepine poisoning, e.g. resulting in complete reversal of opiate toxicity unless complications, such as anoxic brain damage, have developed. At the other end of the efficacy scale, we may place chelating agents for heavy metal poisoning and diazepam for organophosphorus insecticide poisoning. Therefore, in the IPCS/EC evaluation series of antidotes, some chelating agents are considered only to be an adjunct to supportive care which is the cornerstone of treatment. When teaching clinical toxicology or recommending the use of antidotes in poisoned patients, the expected efficacy level of the antidote in question should be stressed. This may be particularly important in severe poisonings when the antidote may only be considered as an adjunct to supportive care, e.g. deferoxamine in acute iron poisoning. Unless this is stressed, the unexperienced physician may rely too much on the antidote and may not pay sufficient attention to the supportive care. In this presentation, the varying efficacy levels of antidotes are discussed as based on the presently ongoing IPCS/EC evaluation programme on antidotes.

A flow chart is presented as a recommended sequence of tests to predict the carcinogenic hazard, and to predict and quantify the mutagenic hazard to germ cells of chemicals to humans. Ten associated principles of testing for these endpoints are also suggested. These recommendations are the result of a meeting convened under the auspices of the International Programme on Chemical Safety (IPCS), as part of their project on 'Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals'. The meeting was held at Carshalton, Surrey, from 13-17 February 1995.

Three complex mixtures (air particles, diesel particles and a coal tar fraction) and two pure compounds (benzo[a]pyrene and 1-nitropyrene) were tested in both the pre-incubation and the plate incorporation assay employing Salmonella typhimurium TA98 and TA100. Each experiment was conducted independently 2 or 4 times in duplicate in the presence and absence of metabolic activation. The mutagenic activities were calculated by least squares linear regression from the slope of the linear portion of each dose-response curve. Although slightly higher mutagenic activity was observed in the pre-incubation assay for the two pure compounds and with the plate incorporation assay for the diesel particulate sample, the overall data from both assays gave similar values and good correlations in TA100 and TA98. The results indicate that the pre-incubation assay could be used for these samples instead of the plate incorporation assay.

Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted. Graphical Abstract Bone marrow MSCs are isolated from the long bone of SD rats. Then they are expanded and through directed differentiation insulin-producing cells are formed. The differentiated cells are loaded onto a collagen scaffold. If one-stage transplantation is planned, a drug delivery system must be incorporated to ensure immediate oxygenation, promote vascularization and provide some growth factors. Some mechanisms involved in the immunomodulatory function of MSCs. These are implemented either by cell to cell contact or by the release of soluble factors. Collectively, these pathways results in an increase in T-regulatory cells.

Background The regulatory mechanism of insulin-producing cells (IPCs) differentiation from induced pluripotent stem cells (iPSCs) in vitro is very important in the phylogenetics of pancreatic islets, the molecular pathogenesis of diabetes, and the acquisition of high-quality pancreatic β-cells derived from stem cells for cell therapy. Methods miPSCs were induced for IPCs differentiation. miRNA microarray assays were performed by using total RNA from our iPCs-derived IPCs containing undifferentiated iPSCs and iPSCs-derived IPCSs at day 4, day 14, and day 21 during step 3 to screen the differentially expressed miRNAs (DEmiRNAs) related to IPCs differentiation, and putative target genes of DEmiRNAs were predicted by bioinformatics analysis. miR-690 was selected for further research, and MPCs were transfected by miR-690-agomir to confirm whether it was involved in the regulation of IPCs differentiation in iPSCs. Quantitative Real-Time PCR (qRT-PCR), Western blotting, and immunostaining assays were performed to examine the pancreatic function of IPCs at mRNA and protein level respectively. Flow cytometry and ELISA were performed to detect differentiation efficiency and insulin content and secretion from iPSCs-derived IPCs in response to stimulation at different concentration of glucose. The targeting of the 3′-untranslated region of Sox9 by miR-690 was examined by luciferase assay. Results We found that miR-690 was expressed dynamically during IPCs differentiation according to the miRNA array results and that overexpression of miR-690 significantly impaired the maturation and insulinogenesis of IPCs derived from iPSCs both in vitro and in vivo. Bioinformatic prediction and mechanistic analysis revealed that miR-690 plays a pivotal role during the differentiation of IPCs by directly targeting the transcription factor sex-determining region Y (SRY)-box9. Furthermore, downstream experiments indicated that miR-690 is likely to act as an inactivated regulator of the Wnt signaling pathway in this process. Conclusions We discovered a previously unknown interaction between miR-690 and sox9 but also revealed a new regulatory signaling pathway of the miR-690/Sox9 axis during iPSCs-induced IPCs differentiation. Electronic supplementary material The online version of this article (10.1186/s13287-019-1154-8) contains supplementary material, which is available to authorized users.

Background Current approach for diabetes treatment remained several adverse events varied from gastrointestinal to life-threatening symptoms. Regenerative therapy regarding Edmonton protocol has been facing serious limitations involving protocol efficiency and safety. This led to the study for alternative insulin-producing cell (IPC) resource and transplantation platform. In this study, evaluation of encapsulated human dental pulp-derived stem cell (hDPSC)-derived IPCs by alginate (ALG) and pluronic F127-coated alginate (ALGPA) was performed. Results The results showed that ALG and ALGPA preserved hDPSC viability and allowed glucose and insulin diffusion in and out. ALG and ALGPA-encapsulated hDPSC-derived IPCs maintained viability for at least 336 h and sustained pancreatic endoderm marker (NGN3), pancreatic islet markers (NKX6.1, MAF-A, ISL-1, GLUT-2 and INSULIN), and intracellular pro-insulin and insulin expressions for at least 14 days. Functional analysis revealed a glucose-responsive C-peptide secretion of ALG- and ALGPA-encapsulated hDPSC-derived IPCs at 14 days post-encapsulation. Conclusion ALG and ALGPA encapsulations efficiently preserved the viability and functionality of hDPSC-derived IPCs in vitro and could be the potential transplantation platform for further clinical application.

Long noncoding RNAs (lncRNAs) have been extensively explored over the past decade, including mice and humans. However, their impact on the transdifferentiation of canine bone marrow mesenchymal stem cells (cBMSCs) into insulin-producing cells (IPCs) is largely unknown. In this study, we used a three-step induction procedure to induce cBMSCs into IPCs, and samples (two biological replicates each) were obtained after each step, the samples consisted of &ldquo, BMSCs&rdquo, (B), &ldquo, stage 1&rdquo, (S1), &ldquo, stage 2&rdquo, (S2), &ldquo, stage 3&rdquo, (S3), and &ldquo, islets&rdquo, (I). After sequencing, 15,091 lncRNAs were identified, and we screened 110, 41, 23, and 686 differentially expressed lncRNAs (padjusted &lt, 0.05) in B vs. S1, S1 vs. S2, S2 vs. S3, and I vs. S3 pairwise comparisons, respectively. In lncRNA target prediction, there were 166,623 colocalized targets and 2,976,362 correlated targets. Gene Ontology (GO) analysis showed that binding represented the main molecular functions of both the cis- and trans-modes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the insulin signaling pathway, Rap1 signaling pathway, tight junctions, MAPK signaling pathway, and cell cycle were enriched for these relative genes. The expression of lncRNAs was verified using qRT-PCR. This study provides a lncRNA catalog for future research concerning the mechanism of the transdifferentiation of cBMSCs into IPCs.

Two IUDs (Copper T 220 C and Alza T IPCS 52) were comparatively studied by randomized insertions in 200 Thai women who attended the Family Planning Clinic at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University. Point estimates of the pregnancy rate and rate of removal for bleeding and pain at 18 months were lower for the copper device than for the Alza T IPCS 52, but neither these nor any other pertinent event rates reached statistical significance. Study of the Alza device was halted before the completion of 2 years because reports from other centres indicated an unacceptable pregnancy rate beyond 2 years.

Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders., Graphical Abstract ga1

Indwelling Pleural Catheters (IPC) are increasingly being used for management of recurrent pleural effusions (RPEs). Use of IPC for management of both malignant and non-malignant recurrent pleural effusions has been associated with complications such as dysfunctional or nonfunctioning IPCs. Alteplase, a tissue plasminogen activator (tPA) is often used to restore flow of non-draining IPC in symptomatic patients. We present a case of a sixty-eight-year old patient with life-threatening pleural hemorrhage following intrapleural catheter instillation of tPA that was managed successfully by thoracotomy. Our case describe the importance of individualizing the fibrinolytic dose, frequency and the indwelling time in high risk patients. We have reviewed the current literature and recommendations for use of fibrinolytic therapy for IPC in high risk patients on anticoagulation.

Friedreich's ataxia (FRDA) is a rare neurodegenerative disorder which is caused by triplet repeat expansion (GAA) in the first intron of FXN gene. In this present study, we generated induced pluripotent stem cells (iPSC) lines from fibroblasts of three unrelated FRDA patients using integration-free episomal vectors. All iPSC lines express the pluripotency markers such as OCT4 and SSEA4, display normal karyotypes and can differentiate into all three germ layers via in vivo teratoma formation assay., NA