In vivo experiments (e.g., xenografts) allow testing different drug therapies and expanding the collection of biological samples. This kind of experiments in IRCCS institution are based on the model described in Bertotti et al. (2011). Each aliquot implantation defines a biological entity named Biomouse. Since it is possible to implant many tumor aliquots in different sites, the physical animal can host several Biomice. The Biomice can be grouped in Experimental Groups according to the purpose of the research. In this way, the researchers can study tumor growth and treatment response on a subset of animals. The physical animals can assume different status which affect the life cycle of the hosted Biomice. For instance, if the status of an animal is set to dead accidentally, it will not possible to perform measures and explantation activities on all its hosted Biomice. The Xenografts Management Module manages the immune compromised animals and monitors the xenograft life cycle, from their acquisition by the research institute to their death. The main functionalities provided by this module include the following.
The user can register the acquisition of new animals and associate to them different features (e.g., status, strain, age, source). The system promotes the use of barcode readers when animals are equipped with RFid tags, in order to speed up the identification of the animal and the retrieval of related information.
The user should select the target status (e.g., breeding, experimental, dead accidentally, transferred, sacrified). According to the target status additional information are requested. By inserting the animal barcodes, the system check if there are no conflicts in changing the status and insert the corresponding BioEntities (e.g., Biomice) in a list. By clicking on “Finish”, the status of selected animals will be saved.
The user can perform the following actions:
Create a new experimental group: a name and the expected experimental protocol are requested
Load existing/recent groups: by selecting the groups of interest from the listed shown by the system, the user can visualize a description of the group and the set of animals belonging to it
Edit group: the user can rename the group and change the expected protocol
Move animals: after the selection/creation of two groups, the user can move the animals belonging to one group to the other one
There are 4 modes of measuring xenopatients:
Observation. The tumor dimension can be evaluated by means of a categorical measure (i.e., None, Very Small, Small, Medium, Large), optionally associated with the weight of the animal.
Weight. This functionality allows measuring only the weight of the animal
Tumor volume. This functionality allows measuring the tumor mass by means of instruments (e.g., caliper) and optionally tracking the weight of the animal
Tumor volume + weight. It requires weighing the animal and measuring the volume of the implanted tumor mass
In each case, the user can define a number of actions, such as planning treatments, interrupting the treatments in progress, planning the sacrifice of the animal or the explantation without sacrifice. In the former two modes the user can optionally request a review from the Principal Investigator, while in the latter two all actions are always sent to the Principal Investigator for a review.
The system handles the tumor tissue implants into the available recipient mice. The user should select one animal, the site of implantation and the source aliquot. The same animal can be implanted in different sites. Both the animal and the aliquot are retrieved by means of their barcodes (i.e., RFid barcode for the animals, container barcode for the aliquots). The system automatically generates a GenealogyID for the new generated Bioentity. Additional information such as data of the implantation, expected protocol and notes can be edited. When the implantation session is finished (click on “Next step” button), the system ask if the used containers should be emptied. If the containers are emptied all the aliquots stored in these container will be no longer available. In any case, the aliquot quantity used during the implantation is updated Then the system automatically define new experimental groups according to some parameters. The user can redefine these parameters, create new group and/or move the animals among the groups.
The tumor explants marks the end of the xenograft life cycle. The user should select the date of explantation (the current date is automatically selected by the system), the set of tissues that will be explanted, and the animals that have been programmed for this operation. The animals in waste status can be also explanted. By inserting the animal barcode and the implantation site, the system retrieves its associated information. The interface for the collection of biological samples from xenograft explantation is similar to the one of the Biobank collection (see Figure 3). Similarly to the collection procedure of the Biobank, plates or tubes can be loaded or created in the application by means of their barcode. Inserting an aliquot in a given plate position is done by simply clicking on the corresponding cell. By clicking on “Submit” button the explantation session is closed and the aliquots stored in the corresponding containers while the animal status is setted to “explanted”.
A list of experimental groups for which a treatment has been programmed is shown. By selecting the group of interest, the system shows the list of programmed treatments and for each treatment arm, the list the animals selected for the the drug administration. By inserting the barcode of the animal the system check if it is programmed for the programmed treatment and, if there is no error, record the start of treatment.
Using this functionality the user can see the details of the treatment protocols recorded by the system. In particular, the list of steps for each treatment arm can be visualized. Each step defines the used drug, the dosage the administration mode and the number of times in the time unit (e.g., day, hour). Moreover, the user can define a new treatment protocol, for which she should assign an unique name and a description. The protocol will be composed by several arms that can be created and or selected by the existing ones. If the arm is created, some additional information, i.e. the set of steps and their composition should be defined.
Immunocompromised animals that have been implanted with a tumor mass are regularly measured by laboratory technicians to monitor the growth of the tumor and assess the effectiveness of treatments (see Measure paragraph). During this operation, technicians record the observed values and may propose a given course of action for each mouse (e.g., start/stop a treatment, explant). The new measurements and new actions should be reviewed by the supervisor through the “Experiment review” screen (see Figure 1). In the left side of the window (block A) a list of all experimental groups for which new measurements exist is shown. When an experimental group is selected, its measurements and all associated pending actions are shown in the bottom table (block D). To ease the supervisor’s task, any pending action awaiting approval is highlighted, while further information is available in the other tabs (e.g., historical measurement record for each mouse). Moreover, a plot showing the average variation of the tumor mass over time for each treatment arm (block C) provides a useful tool to support the supervisor in the decision-making process. The supervisor may accept the actions proposed by the technician for any measurement, or she may modify or reject them, by means of a set of buttons (block B). She may also add comments, such as explanations or future directions. Once the review is complete, a report is displayed, including all actions (both approved and rejected or modified ones), and sent to both the supervisor and the technician.
This functionality is similar to the New measurements check, but all the experiments in which at least one animal is alive are listed. The user can select the experimental group of interest and perform the same actions available in the New measurements check functionality.
In this screen all the closed experiments, i.e. the experiments in which all the animals have been explanted, are listed. The user can only display the information of the experimental group of interest, see the graphical representation of tumor volume measurements and the history of the data collected for each animal. No further action can be applied on the animals.
Figure 1- Experiment review interface
The system allows to insert new records for the following objects:
Methods of drug administration
Explant scope details
Site of implant
For each record some attributes are required, while other are optional.
The system allows loading by means of a file a batch of data. In particular, the user can load data corresponding to the following actions:
register new animals
make observation of tumor mass
record tumor volume and animal weight
A template with the required field for each operation is provided by the system.