Mouse avatars of human cancers: the temporality of translation in precision oncology.

Patient-derived xenografts (PDXs) are currently promoted as new translational models in precision oncology. PDXs are immunodeficient mice with human tumors that are used as surrogate models to represent specific types of cancer. By accounting for the genetic heterogeneity of cancer tumors, PDXs are hoped to provide more clinically relevant results in preclinical research. Further, in the function of so-called "mouse avatars", PDXs are hoped to allow for patient-specific drug testing in real-time (in parallel to treatment of the corresponding cancer patient). This paper examines the circulation of knowledge and bodily material across the species boundary of human and personalized mouse model, historically as well as in contemporary practices. PDXs raise interesting questions about the relation between animal model and human patient, and about the capacity of hybrid or interspecies models to close existing translational gaps. We highlight that the translational potential of PDXs not only depends on representational matching of model and target, but also on temporal alignment between model development and practical uses. Aside from the importance of ensuring temporal stability of human tumors in a murine body, the mouse avatar concept rests on the possibility of aligning the temporal horizons of the clinic and the lab. We examine strategies to address temporal challenges, including cryopreservation and biobanking, as well as attempts to speed up translation through modification and use of faster developing organisms. We discuss how featured model virtues change with precision oncology, and contend that temporality is a model feature that deserves more philosophical attention.

Human islet xenotransplantation in rodents: A literature review of experimental model trends.

Among the innovations for the treatment of type 1 diabetes, islet transplantation is a less invasive method of treatment, although it is still in development. One of the greatest barriers to this technique is the low number of pancreas donors and the low number of pancreases that are available for transplantation. Rodent models have been chosen in most studies of islet rejection and type 1 diabetes prevention to evaluate the quality and function of isolated human islets and to identify alternative solutions to the problem of islet scarcity. The purpose of this study is to conduct a review of islet xenotransplantation experiments from humans to rodents, to organize and analyze the parameters of these experiments, to describe trends in experimental modeling and to assess the viability of this procedure. In this study, we reviewed recently published research regarding islet xenotransplantation from humans to rodents, and we summarized the findings and organized the relevant data. The included studies were recent reports that involved xenotransplantation using human islets in a rodent model. We excluded the studies that related to isotransplantation, autotransplantation and allotransplantation. A total of 34 studies that related to xenotransplantation were selected for review based on their relevance and current data. Advances in the use of different graft sites may overcome autoimmunity and rejection after transplantation, which may solve the problem of the scarcity of islet donors in patients with type 1 diabetes.

The Resurgence of Xenotransplantation.

There has been an upsurge of interest in xenotransplantation in recent years. This resurgence can attributed to a combination of factors. First, there has been a dramatic improvement in efficacy in several preclinical models, with maximum xenograft survival times increasing to 950 days for islets, 945 days for hearts, and 310 days for kidneys. Second, the rapid development of genome editing technology (particularly the advent of clustered regularly interspaced short palindromic repeats/Cas9) has revolutionized the capacity to generate new donor pigs with multiple protective genetic modifications; what once took many years to achieve can now be performed in months, with much greater precision and scope. Third, the specter of porcine endogenous retrovirus (PERV) has receded significantly. There has been no evidence of PERV transmission in clinical trials and preclinical models, and improved screening methods and new options for the treatment or even elimination of PERV are now available. Balancing these positive developments are several remaining challenges, notably the heavy and often clinically inapplicable immunosuppression required to prevent xenograft rejection. Nonetheless, the potential for xenotransplantation as a solution to the shortage of human organs and tissues for transplantation continues to grow.

Human islet xenotransplantation in rodents: A literature review of experimental model trends

Among the innovations for the treatment of type 1 diabetes, islet transplantation is a less invasive method of treatment, although it is still in development. One of the greatest barriers to this technique is the low number of pancreas donors and the low number of pancreases that are available for transplantation. Rodent models have been chosen in most studies of islet rejection and type 1 diabetes prevention to evaluate the quality and function of isolated human islets and to identify alternative solutions to the problem of islet scarcity. The purpose of this study is to conduct a review of islet xenotransplantation experiments from humans to rodents, to organize and analyze the parameters of these experiments, to describe trends in experimental modeling and to assess the viability of this procedure. In this study, we reviewed recently published research regarding islet xenotransplantation from humans to rodents, and we summarized the findings and organized the relevant data. The included studies were recent reports that involved xenotransplantation using human islets in a rodent model. We excluded the studies that related to isotransplantation, autotransplantation and allotransplantation. A total of 34 studies that related to xenotransplantation were selected for review based on their relevance and current data. Advances in the use of different graft sites may overcome autoimmunity and rejection after transplantation, which may solve the problem of the scarcity of islet donors in patients with type 1 diabetes.

The level of acceptance of spanish medical students of the transplantation of solid organs from animals: a stratified and multicentre study.

INTRODUCTION: Research into the transplantation of solid organs from animals (xenotransplantation) is generating interest and curiosity given that this could be a way of resolving the shortage in transplant organs. However, the fact is that currently xenotransplantation is far from becoming a clinical practice. OBJECTIVE: To analyse the attitude of medical students from Spanish universities towards the donation of organs from animals and to determine the factors affecting their attitudes. TYPE OF STUDY: A sociological, interdisciplinary, observational and multicentre study in Spain. STUDY POPULATION: Students enrolled on the medical degree in Spain (n = 34 000). SAMPLE SIZE: A sample of 9598 students (a confidence level of 99% and precision of ± 1%) stratified by geographical area and academic year. Instrument of measurement: A validated questionnaire of attitude towards organ xenotransplantation (PCID-XenoTx RIOS) which was self-administered and completed anonymously. RESULTS: A completion rate of 95.7% (n = 9275) was obtained. If the results of xenotransplantation were as good as in human donation, 81% (n = 7491) would be in favour, 3% (n = 308) against and 16% (n = 1476) undecided. The following variables affected this attitude: sex (P < 0.001); academic year (P < 0.001); discussion of transplantation with one's family (P < 0.001) and friends (P < 0.001); the opinion of one's partner (P < 0.001); the respondent's attitude towards organ donation (P < 0.001); religion (P < 0.001); and participation in altruistic activities (P < 0.001). The following variables persisted in the multivariate analysis: (1) being a female (OR = 1.794; P < 0.001); (2) academic year (OR = 2.487; P < 0.001); (3) having spoken about the issue with one's family (OR = 1.200; P = 0.019); (4) the favourable opinion of one's partner (OR = 1.526; P = 0.028); (5) an attitude in favour of donation (OR = 2.087; P < 0.001); (6) being an atheist/agnostic, (OR = 2.5; P < 0.001); and (7) a belief that one's religion is in favour of transplantation (OR = 1.317; P = 0.005). CONCLUSIONS: Spanish medical students have a favourable attitude towards xenotransplantation. This willingness and interest could be a decisive platform for the development and strengthening of research, both for centres with a pre-clinical xenotransplantation programme and new healthcare centres.

Level of acceptance of solid organ xenotransplantation among personnel in Spanish, Mexican, and Cuban hospitals.

BACKGROUND: Xenotransplantation is still a long way from becoming a clinical reality. However, in an emergency situation, it could be used as a bridge for replacing vital organs until the arrival of a human organ. To analyze the attitude toward xenotransplantation among hospital personnel from several hospitals in Spain and Latin America. METHODS: A random sample stratified according to the type of hospital and job category (n = 2618) in 10 hospitals in three different countries: Spain (n = 821), Mexico (n = 1595), and Cuba (n = 202). A validated questionnaire (PCID-XenoTx Rios) was self-administered and completed anonymously by the respondents. RESULTS: If the results of xenotransplantation were similar to those achieved using human donor organs, 61% (n = 1591) of the respondents would be in favor, while 9% (n = 234) would be against and 30% (n = 793) would be unsure. The analysis of the variables affecting attitude toward xenotransplantation revealed that attitude varied according to the country of reference and was more favorable among personnel in Cuban hospitals (70% a favor) than in Spanish (57%) and Mexican ones (62%; P = 0.000). However, these differences are mainly determined by job category with the physicians having the most favorable attitude. The ancillary staff, in contrast, had the least favorable attitude (76 vs. 51% respectively; P = 0.000). Of the remaining variables, attitude is significantly related to variables connected to human donation: attitude toward the different kinds of human organ donation (deceased [P < 0.001] and living [P < 0.001]), the possibility of needing a transplant oneself in the future (P < 0.001), and attitude toward donating the organs of a deceased family member (P = 0.004). CONCLUSIONS: A third of healthcare personnel from several hospitals are not in favor of xenotransplantation. It is necessary to provide more information about the matter, especially in hospitals where there is a preclinical xenotransplantation program or where there is access to one, such as in the hospitals in this study.

A study of the attitude of Latin-American residents in Spain toward organ xenotransplantation.

BACKGROUND: It is important to find out what would be the level of acceptance of xenotransplantation in society, especially in populations where there are preclinical trials. The Latin-American population is growing in Spain, given the cultural, religious, and language similarities. OBJECTIVES: (i) to analyze attitude toward xenotransplantation in the population born in Latin America and now residing in Spain; and (ii) to establish the variables that affect this attitude. METHOD: A sample of Latin-American residents in Spain was obtained randomly in 2010 and stratified by the respondent's nationality (n = 1.314). Attitude was evaluated using a validated questionnaire (PCID-XenoTx Rios), which was completed anonymously and self-administered. STATISTICAL ANALYSIS: Student's t-test, the Chi-squared test, Fisher's exact test, and logistic regression analysis. RESULTS: The questionnaire completion rate was 89% (n = 1.165). If it was assumed that xenotransplanted organs functioned as well as human ones, 40% were in favor, 19% against, and 41% undecided. This attitude is related to: age (P = 0.003); sex (P = 0.002); level of education (P < 0.001); descendents (P = 0.003); country of origin (P < 0.001); participation in voluntary prosocial activities (P = 0.006); having spoken about donation and transplantation within the family (P < 0.001); a partner's favorable attitude toward transplantation (P < 0.001); previous experience of donation and/or transplantation (P < 0.001); a belief that one might need a transplant in the future (P < 0.001); and a favorable attitude toward human donation, both deceased as well as living (P < 0.001). In the multivariate analysis, the following variables continue to feature as independent variables: age (older: Odds Ratio = 1.041); sex (male: OR = 1.579); level of education (university: OR = 2.770); descendents (none: OR = 2.386); a partner's attitude toward transplantation (favorable: OR = 2.262); attitude toward deceased organ donation (favorable: OR = 1.587); previous experience of donation and/or transplantation (OR = 1.519); a belief that one might need a transplant in the future (OR = 1.675); and attitude toward related living donation (in favor: OR = 4.405). CONCLUSIONS: Latin Americans who usually reside in Spain have a more negative attitude toward xenotransplantation than the native Spanish population, and their attitude is affected by many psychosocial factors, mainly related to previous attitude toward the different types of human organ donation.

The attitude toward xenocorneal transplantation in wait-listed subjects for corneal transplantation in Korea.

Shortage of donor cornea is a significant problem in Asia, and xenocorneal transplantation is being actively studied to alleviate this problem. However, the attitudes of subjects who await corneal transplants toward xenocorneal transplantation are not known at all. Thus, this study aimed to investigate the attitudes of subjects on the waiting lists for corneal transplants, toward corneal xenotransplantation. A telephone questionnaire survey comprising six items was conducted in 132 subjects among the wait-listed individuals (n = 590) who were awaiting corneal transplantation or had undergone corneal transplantation at Seoul National University Hospital from July, 2003 to August, 2012. Among six inquiries, four questions were used to analyze attitudes toward corneal xenotransplantation. Each question pertained to (1) the acceptance of xenocorneal transplantation, (2) willingness to participate in clinical trials, (3) worries in xenocorneal transplantation, and (4) the concern of self-identity or social life after xenocorneal transplantation. To analyze demographic factors influencing the question, the subjects were arbitrarily divided into two groups: the young (age < 60 yr, n = 58) and the elderly (age ≥ 60 yr, n = 74) or the less-educated (n = 53) and the well-educated with high school diploma, college graduation, or higher education (n = 79). Collected demographic data were analyzed as influencing factors on each question using a chi-square and logistic regression tests. In this study, 42.4% of the subjects (n = 56) expressed favorable views on xenocorneal transplantation using porcine corneas to cure visual loss from corneal blindness. Among those subjects expressing favorable views (n = 56), the willingness to participate in clinical trials, knowing they and their spouses must undergo long-term surveillance, was 62.5% (n = 35). There were 76.5% of subjects (n = 101) expressing worries regarding xenocorneal transplantation, while 28.8% of subjects (n = 38) expressed their concerns about self-identity or social life after xenotransplantation. Younger subjects expressed more worry about xenotransplantation than elderly subjects. The well-educated expressed less concern over self-identity and social life than the less-educated. This survey among subjects who are wait-listed for corneal transplant or who have received a corneal transplant demonstrates that there is an interest in xenocorneal transplantation as an alternate procedure, although there are worries about the procedure that should be further explored in educational campaigns and future studies of the general population.

[Xenotransplantation: recent developments and futur clinical applications]. / Xénotransplantation: nouveaux développements et applications cliniques à l'horizon.

The aim of xenotransplantation is to allow the transplantation of animal organs or cells to humans. This approach would immediately eliminate the human organ shortage that is responsible for a significant mortality of patients on the waiting list for transplantation of organs. The immune differences between pig and human induce an immediate rejection of porcine tissues by humans. This rejection has recently been partially controlled by genetic engineering of pigs, the use of new immunosuppressive drugs and encapsulation of isolated cells. However, due to the risk of transmission of animal infectious agents to humans, the WHO recommends that clinical application of xenotransplantation only takes place if adequate regulations are in place.

Are veterinary students in favor of xenotransplantation? An opinion study in a Spanish university with a xenotransplantation program.

BACKGROUND: The shortage of available transplant organs has made it necessary to search for new alternatives, one of which is xenotransplantation. However, the use of animal organs and the personnel involved in its implementation could face opposition. Our objective was to analyze the attitudes of veterinary degree students in a Spanish university toward xenotransplantation and to determine the factors that affect its acceptance. METHODS: Of the 515 students registered in a veterinary degree course (2007-2008), we surveyed 482 94% of whom completed the questionnaire. Attitudes toward organ xenotransplantation were evaluated using a validated, self-administered questionnaire concerning organ donation, which was completed anonymously. We applied Student's t-tests and chi(2) tests. RESULTS: If xenotransplantation was confirmed as a clinical reality, 91% (n = 436) of those students surveyed would accept a xenotransplanted organ, whereas 9% (n = 46) would not. Furthermore, 95% (n = 457) would accept tissue xenotransplantation and 97% (n = 467) cell xenotransplantation. Attitudes toward xenotransplantation were not affected by the academic year in which a student was studying, even when this was the year in which it was taught as a subject. Attitudes were not associated with any pyschosocial variable or attitude toward deceased organ donation; (P = .779). The students who believed that the demand for organs is not covered had a more favorable attitude toward xenotransplantation than those who think that there is no shortage (91% vs 70%; P = .027). CONCLUSION: Veterinary students had favorable attitudes toward xenotransplantation, assuming that the animal organs functioned as well as human organs. Therefore, these students could play important roles in the future promotion of this technique.

Animales transgénicos: usos y limitaciones en la medicina del siglo XXI / Transgenic animals: uses and limitations in the 21st century medicine

Uno de los avances biotecnológicos más importantes de las últimas décadas fue el desarrollo de los animales transgénicos. En este artículo seanaliza por qué los animales transgénicos son excelentes modelos para estudiar la función y regulación de los genes y para buscar nuevas estrategias terapéuticas para las enfermedades humanas. Se discute su uso como biorreactores para producir productos farmacológicos para el tratamiento de enfermedades y la posibilidad de generar cerdos transgénicos como fuente alternativa a la donación de órganos.(AU)

One of the most important advances in biotechnology during the last decades was the development of transgenic animals. In this article, I discuss why transgenic animals are excellentmodels to analyze gen function and regulation, and to look for new therapeutic strategies for human diseases. Moreover, their use as bioreactors to produce pharmaceutical products for the treatment of human diseases, and the possibility of generating transgenic pigs as analternative source of organ donors for humans is also discussed.(AU)

International human xenotransplantation inventory.

BACKGROUND: Xenotransplantation carries inherent risks of infectious disease transmission to the recipient and even to society at large, and it should only be carried out with strict regulation and oversight. In collaboration with the International Xenotransplantation Association, the University Hospital Geneva, and the World Health Organization, an international inventory has been established (www.humanxenotransplant.org) aiming to collect basic data on all types of currently ongoing or recently performed xenotransplantation procedures in humans. METHODS: We collected information from publications in scientific journals, presentations at international congresses, the internet, and declarations of International Xenotransplantation Association members on xenotransplantation procedures in humans performed during the past 15 years. RESULTS: We identified a total of 29 human applications of xenotransplantation, including 7 that were currently ongoing. Procedures involved transplantation of xenogeneic cells, i.e., islets of Langerhans, kidney cells, chromaffin cells, embryonic stem cells, fetal and adult cells from various organs or extracorporeal perfusion using hepatocytes, liver, spleen, or kidney. The treatments were performed in 12 different countries, 9 of them having no national regulation on xenotransplantation. CONCLUSION: Several clinical applications of cell xenotransplantation are ongoing around the world, often without any clear governmental regulation. This information should be used to inform national health authorities, healthcare staff, and the public, with the objective of encouraging good practices, with internationally harmonized guidelines and regulation of xenotransplantation.

Bias-reduced and separation-proof conditional logistic regression with small or sparse data sets.

Conditional logistic regression is used for the analysis of binary outcomes when subjects are stratified into several subsets, e.g. matched pairs or blocks. Log odds ratio estimates are usually found by maximizing the conditional likelihood. This approach eliminates all strata-specific parameters by conditioning on the number of events within each stratum. However, in the analyses of both an animal experiment and a lung cancer case-control study, conditional maximum likelihood (CML) resulted in infinite odds ratio estimates and monotone likelihood. Estimation can be improved by using Cytel Inc.'s well-known LogXact software, which provides a median unbiased estimate and exact or mid-p confidence intervals. Here, we suggest and outline point and interval estimation based on maximization of a penalized conditional likelihood in the spirit of Firth's (Biometrika 1993; 80:27-38) bias correction method (CFL). We present comparative analyses of both studies, demonstrating some advantages of CFL over competitors. We report on a small-sample simulation study where CFL log odds ratio estimates were almost unbiased, whereas LogXact estimates showed some bias and CML estimates exhibited serious bias. Confidence intervals and tests based on the penalized conditional likelihood had close-to-nominal coverage rates and yielded highest power among all methods compared, respectively. Therefore, we propose CFL as an attractive solution to the stratified analysis of binary data, irrespective of the occurrence of monotone likelihood. A SAS program implementing CFL is available at: http://www.muw.ac.at/msi/biometrie/programs.

Contemporary approaches to cystocele repair: a survey of AUGS members.

INTRODUCTION: To assess practice patterns in the management of cystoceles among American Urogynecologic Society (AUGS) members. STUDY DESIGN: A 22-question survey regarding various cystocele repair techniques was delivered to AUGS members via e-mail. RESULTS: Of 963 members surveyed, there were 315 respondents. For the treatment of primary cystocele, 77% of respondents used midline vaginal plication; 40% used this approach for management of recurrent cystocele. At the time of abdominal sacrocolpopexy, most considered the anterior vaginal graft sufficient to address cystocele. At the time of uterosacral suspension, midline plication was the most common approach to address cystocele. The most commonly used graft material was synthetic mesh (67%). Almost half of respondents used minimally invasive transobturator devices for cystocele repair. CONCLUSION: The wide variety of surgical approaches likely reflects the absence of a clearly defined best practice for cystocele repair, underscoring the need for rigorous surgical trials.

Current regulatory issues in cell and tissue therapy.

Cell-based therapies have grown dramatically in power and scope in recent years. Once limited to blood and BM transplantation, these therapies now encompass tissue repair and regeneration, metabolic support, gene replacement, and immune effector functions, with established and investigational clinical applications in disorders affecting nearly every tissue and organ system. The complexity and novel applications of human cells, tissues, and cellular and tissue-based products (HCT/Ps), however, present potential risks for adverse events. The US Food and Drug Administration, responding to these concerns, has established a tiered, risk-based regulatory structure, in which more rigorous controls and safeguards are required for products thought to pose increased risk. The proposed good tissue practices (GTP) rule and existing good manufacturing practices (GMP) requirements form the principal elements of this regulatory framework. The proposed GTPs are intended to prevent HCT/P contamination with infectious disease agents, and to ensure that these cells and tissues maintain their integrity and function. GMPs focus on production of safe, pure, and potent products, and entail a higher level of process control and product characterization. All HCT/Ps will be required to comply with GTPs. HCT/Ps considered to present greater risks of adverse events, however, will be subject to both GTPs and GMPs, and must obtain premarket approval using the Investigational New Drug (IND) mechanism established for biologics. Although these requirements will present significant challenges for clinician- investigators and laboratories producing HCT/Ps, the regulations fundamentally support good clinical care by increasing safety and control, and enable good science by improving the quality and reliability of data.