Animal models are key for confirming causation, for understanding http://nas- bestallcialis.top webcast. a controlled study over the many years that it would take to show an effect. 4 days ago Lisuride Shows Promise as Dravet Syndrome Treatment, Zebrafish Study Suggests It plays a key role in the central nervous system (CNS) and the seizure activity, as measured by the animals' locomotor activity and brain. Thus, this discipline also holds great promise for improving the conservation of wildlife. activities that alter natural habitats is reducing the ability of animals However, none of these words appear in a key paper framing the.
Animal Activity Promise Key Shows
This means that over geologic timescales anything that decreases the size of the ocean phosphate reservoir also decreases oxygen. The study focuses on one such removal process, burial of phosphorus in the organic matter in ocean sediments. The authors hypothesize the following sequence of events: Around million years ago, the evolution of the first burrowing animals significantly increased the extent to which oxygenated waters came into contact with ocean sediments.
Exposure to oxygenated conditions caused the bacteria that inhabit such sediments to store phosphate in their cells something that is observed in modern day experiments. This caused an increase in phosphorus burial in sediments that had been mixed up by burrowing animals. This in turn triggered decreases in marine phosphate concentrations, productivity, organic carbon burial and ultimately oxygen. Because an oxygen decrease was initiated by something requiring oxygen i.
The key argument we make in this paper is that this difference is directly attributable to bioturbation. This means that 1 animals are directly involved in an oxygen-regulating cycle or feedback loop that has previously been overlooked, and 2 we can directly test the idea despite the uncertainties associated with looking so far back in time by looking for a decrease in ocean oxygenation in conjunction with the spread of bioturbation.
My colleague, Dr Tais Dahl from University of Copenhagen, compiled data on ocean metals with oxygen-sensitive burial patterns, which does indeed suggest such an oxygen decrease as bioturbation began — confirming the conclusions of the modelling. It is our hope that wider consideration of this feedback loop and the timing of its onset, will improve our understanding of the extent to which Earth's atmosphere-ocean oxygen reservoir is regulated.
What is new in this study is it attributes the oxygen stabilisation to biology — the presence or absence of animals stirring up the ocean sediments. Earlier this year, researchers from the Nordic Center for Earth Evolution showed that early animals may have needed surprisingly little oxygen to grow, supporting the theory that rising oxygen levels were not crucial for animal life to evolve on Earth. First animals oxygenated the ocean, research suggests. The evolution of the first animals may have oxygenated the earth's oceans — contrary to the traditional view that a rise in oxygen triggered their development.
Scientists investigating one of the greatest riddles of the Earth's past may have discovered a mechanism to help determine how oxygen levels in the atmosphere expanded to allow life to evolve. An international team of scientists, including geochemists from the University of California, Riverside, has uncovered new evidence linking extreme climate change, oxygen rise, and early animal evolution.
Oxygen appeared in the atmosphere up to million years earlier than we previously thought, according to research published today in the journal Nature, raising new questions about the evolution of early life. A new study examining the impact of iron released from continental margin sediments has documented a natural limiting switch that may keep these ocean systems from developing a runaway feedback loop that could lead to unchecked One of science's strongest dogmas is that complex life on Earth could only evolve when oxygen levels in the atmosphere rose to close to modern levels.
But now studies of a small sea sponge fished out of a Danish fjord shows Researchers have designed a machine learning algorithm for drug discovery which has been shown to be twice as efficient as the industry standard, which could accelerate the process of developing new treatments for disease. CMT is not a single disease but a collection of related diseases that result in peripheral neuropathy.
CMT is rare, affecting around 1 in 2, people, and there are likely different loci in the human genome that can cause CMT. As a consequence, each individual form of CMT is extremely rare.
Burgess said that creating animal models for CMT is essential, as vitro models are challenging due to the complexity of this adult-onset degenerative disease. Burgess gave two examples of mouse models for CMT, though he noted that models have also been created in other organisms, including rat, zebrafish, and drosophila.
Burgess discussed models developed for two versions of CMT: Mouse models have been developed that re-create the phenotype and loss of function seen in humans. Burgess noted that these models can recapitulate the phenotype with either a targeted knockout or a spontaneous mutation of the gene, and that because there are no treatments for this disease, predictive validity is not relevant at this point.
This pathogenesis is either related to a dominant negative or a neomorphic activity causing the mutant protein to take on a new pathological function, Burgess said.
Researchers have discovered two alleles that create mice with good face and construct validity for the disease. Based on the success of modeling the GARS mutation in mice, researchers sought to validate the pathogenicity of a de novo mutation that had been identified in a 4-year-old girl who suffered from a severe motor neuropathy and whose whole exome sequencing had identified a base pair deletion in GARS.
Researchers wanted to validate this mutation through mouse modeling and were also hoping to develop a gene therapy approach toward treatment. Researchers found that the patient mutation did cause a dominant axonal neuropathy in the models, while the control mice were normal.
Based on previous studies, researchers knew that transgenic expression of wildtype GARS did not suppress the neuropathy, so they sought to decrease the expression of the mutant form of the protein. Burgess noted that, while the molecular mechanism is still not entirely understood, the treatment the only one available to date appears to work.
He added that the treatment requires testing multiple RNAi sequences for every different allele associated with the disease, and that gene therapy delivered through AAV9 is still somewhat of an experimental delivery system.
Burgess briefly discussed the rigorousness of these preclinical studies. The researchers tried to perform well-powered studies with a sufficient number of mice and used blinded analysis to the extent possible.
They developed multimodal clinically relevant outcome measures including behavioral, electrophysiological, and histological measures. Key biological variables, such as age, were considered, since CMT is a degenerative disease. Finally, the therapy was tested in more than one model with more than one mutation of GARS.
Burgess concluded with a discussion about the importance of the genetic background of mouse models see Figure He noted that every. He said that testing 1, C57 black 6 mice is similar to testing 1 C57 black 6 mouse 1, times, making it difficult to extrapolate findings.
He again emphasized the importance of seeking predictive validity, rather than exact face or construct validity, noting that the precise mutation in the mouse is unlikely to be the same as that in the human, but that a similar mechanistic pathway is the key to translating findings from the animal model into patient therapies.
An idealized mouse model see Figure , said Burgess, would be one in which the patient variant introduced into the mouse resulted in face validity and construct validity, the phenotype was tested on multiple backgrounds, and the model had good predictive validity and could improve patient care.
Jennifer Maier, postdoctoral research associate at the University of California, Los Angeles, introduced workshop participants to a novel species for animal-based research. Monodelphis domestica —otherwise known as the opossum—is a small, pouchless marsupial native to South America. Maier noted that this opossum is a different species than Didelphis virginiana , the opossum common to the United States.
The monodelphis opossum breeds year-round, with litters of up to 13 pups. It is a genetically diverse, U. Department of Agriculture USDA -regulated species that is easy to care for, requiring a standard rat cage with nesting and bedding material, and commercially available opossum chow. However, being a nonsocial species, these animals cannot be group-housed after a certain age. Opossums have some advantages over mice, including a shorter gestation period 14 days versus 21 , slow development, and the fact that there are some human orthologs present in opossums but absent in mice.
The pups are born at a stage that is equivalent to a Compared to mice, opossums take 8 months to reach full maturity and live about 3 years in captivity. The unique biological characteristics of opossums make them a relevant model for studying certain diseases; for example, they have a slower metabolic rate and a lower body temperature than placental mammals.
Maier said that the opossum research community is growing, and that many of the techniques that are used in mice can be adapted to opossums. There are a number of resources available for monodelphis research, including a well-annotated genome, husbandry guides, transcriptome libraries, a well-established embryology guide, and the OpossumBase website, which contains genetic and genomic data for the species.
The research that Maier presented focused on the development and evolution of the limbs. She noted that mammalian limbs have a huge morphological diversity, from the wings of a bat to the pectoral fin of a dolphin to the arm of a human. Research on the limb system is well established, particularly in animals such as the mouse and the chicken, and many of the required genes are known and conserved in the opossum.
Congenital limb malformations are quite common in humans, caused by genetic mutations or environmental triggers. Retinoic acid is a derivative of vitamin A that is contained in some pharmaceuticals, including. Pregnant opossums were treated orally with retinoic acid and the embryos were collected just before birth. All of the animals that were treated with retinoic acid had missing digits oligodactyly , and some sort of craniofacial defect.
Researchers determined that these malformations were associated with disruption of the expression of fibroblast growth factor in the two major limb-signaling centers the apical ectodermal ridge and the zone of polarizing activity. Another area of opossum research involves thalidomide, a well-known teratogen that caused thousands of children to be born with limb, craniofacial, and vascular deformities in the mids. Mice and rats are not susceptible to thalidomide, making it difficult to study in traditional animal models.
Research in which pregnant opossums were injected with thalidomide revealed that the animal is susceptible to the teratogen, with high penetrance of mild deformation and recapitulation of several more severe human thalidomide phenotypes. Opossums exposed to thalidomide gave birth to pups with defects of the heart, blood vessels, limbs, amniotic sac, and craniofacial area. Research is under way for molecular characterization of these phenotypes, said Maier.
In addition to these areas of research on limb formation, monodelphis is also currently being used to study the formation of the mammalian middle ear and intervertebral discs, spinal regeneration, ultraviolet-induced melanoma, and diet-induced hyperlipidemia. Despite the benefits of using monodelphis as a model organism, there are also some drawbacks, Maier said.
One major challenge is the absence of techniques to create knockout or other genetically modified opossums, which complicates functional testing. In conclusion, Maier said that opossums are an excellent model for biomedical and evolutionary questions, and that advances in genetic modification of the species will make the opossum an even more useful species for research.
Keith Mansfield, director of Discovery and Investigative Pathology at Novartis Institutes for Biomedical Research, spoke to workshop participants about using molecular pathology to evaluate animal models for precision disease modeling.
He started with a basic definition of molecular pathology, describing it as focused on the study and diagnosis of disease through the examination of molecules generally DNA, RNA, and protein within organs, tissues, or bodily fluids. Molecular pathology is multidisciplinary in nature, integrating genomics, genetics, proteomics, and. Mansfield said that molecular pathology is used to delineate the molecular basis of morphological or structural changes in tissues and how those changes are related to functional alterations.
Molecular pathology is frequently used in the clinical diagnosis and management of cancer patients and is one of the foundations of precision medicine. One key technique in molecular pathology is molecular localization, the ability to define the spatial distribution of molecules, such as proteins or nucleic acids, in tissue sections. Molecular localization allows the pathologist to understand how alterations in the spatial orientation of these molecules relate to functional deficits in the organism.
Molecular localization can be performed using tools such as immunohistochemistry or in situ hybridization. Immunohistochemistry is a technique that uses antibodies—usually linked to an enzyme or a dye—to test for disease markers in a tissue sample. Mansfield said that immunohistochemistry has advanced enormously over the past decade; automated staining platforms have increased the efficiency and reproducibility of the assay, reducing the length of the process from 12 to hours.
However, he noted that a shortcoming of these assays is the quality of commercial antibodies, and the resulting difficulty in validating an assay before use in the clinic or an experiment. There is no single gold standard to validate an immunohistochemistry assay, said Mansfield.
In his experience, most commercially available antibodies are not specific or sensitive for the target. Traditional immunohistochemistry assays can be used to simultaneously analyze antibodies. However, new platforms—such as image-amassed cytometry, or laser ablation inductively coupled plasma amassed imaging—are highly multiplexed assays, allowing the analysis of up to 20 or 30 markers simultaneously.
Mansfield noted that these technologies are not yet ready for routine use, but they have a lot of potential utility. In situ hybridization allows pathologists to identify specific chromosomes in tissue through the hybridization attachment of probes that have been linked to a dye. Like immunohistochemistry, automated staining platforms have made in situ hybridization more efficient and reproducible.
A new generation of probes has improved sensitivity and specificity, said Mansfield, because they can detect splice variants and single-nucleotide polymorphisms SNPs. Biobanks are a sometimes forgotten but critical resource in molecular pathology, said Mansfield.
Biobanks that contain well-curated collections of normal and diseased human biological samples, in combination with. This side-by-side comparison can determine the comparative relevance as well as the potential limitations of animal models and inform the selection of models that most closely parallel the aspects of the disease under investigation.
Such careful selection of animal models can reduce the number of animals needed to complete an experiment. Mansfield gave an example of the importance of choosing the right animal model: Mansfield noted that, in this case, genetically engineered organoids were better at reproducing the morphology than mouse models. Mansfield stressed that these differences between human and animal models do not mean that animal models are not useful, but that we need to understand how differences in morphology may impact the relevance of the disease in modeling human cancer.
Digital pathology has advanced the field of molecular pathology in significant ways, said Mansfield. In traditional pathology, tissue samples are collected, processed, stained, and delivered to the pathologist who looks at them through a microscope and writes a report.
The slides are archived, but there is little ability to access information contained in the slide or in the report at a later date. In contrast, in digital pathology slides are scanned and stored in a database along with all associated metadata.
This allows pathologists to review slides and data at any time and to analyze morphological diagnoses along with patient metadata in order to discover novel patterns associated with diseases. In addition, digital pathology facilitates whole-slide image analysis, allowing a pathologist to quantitatively measure things such as staining intensities, cell number, cell morphology, and the spatial relationship between cells. Tissue microarrays—in which one slide contains samples from many cases—is another advance in molecular pathology.
Tissue microarrays can hold or more samples on a single slide, and custom arrays can be created that focus on a single species, organ, or disease process. Mansfield noted that the commercially available tissue microarrays are inconsistent in quality, so he finds internal creation of the assays to be beneficial.
The automated platforms for immunohistochemistry and in situ hybridization can be used for these tissue microarrays, and thousands of samples can be analyzed in a matter of hours. Image analysis software can be used to assess and measure the images that are generated with this high-throughput analysis.
Other new technologies in molecular pathology include spatial transcriptomics and genomic expression profiling. Spatial transcriptomics allows the pathologist to profile several thousand genes within a single slide,. Genomic expression profiling can be coupled with morphological interpretation of tissue to assist in elucidating the pathogenesis of disease. Paired samples are routinely taken for genomic profiling and processing for histological analysis, said Mansfield.
The analysis involved in genomic expression profiling is complex because changes in overall gene expression may result from alterations in individual cells as well as from changes in the cellular composition of tissue. Molecular localization studies can be used to confirm expression changes and cellular source. Mansfield concluded that molecular pathology advances our understanding of comparative pathogenesis of human disease in relevant animal models.
He said that molecular pathology is a rapidly advancing field that integrates traditionally anatomical pathology skills with molecular biology and bioinformatic approaches.
Future advances in the field of molecular pathology will build on the use of bioinformatics, particularly highly multiplex localization assays and computational interrogation of digital slide databases.
For these trials, appropriate genetically engineered mouse models GEMMs are identified based on tumor genetics to act as surrogates for the human patient, or patient tumors are engrafted in immunodeficient mice to create patient-derived xenograft PDX models. The mouse models are used to test sensitivity of tumors to treatments, and real-time integration of these data is used to inform patient treatment protocols and improve patient outcome.
Clohessy explained that the genesis of the mouse hospital model came out of an acknowledgment that every patient has a unique disease in terms of its molecular characterization and its progression and response to treatments.
The traditional drug development process does not reflect this, while also suffering from a number of shortcomings. A low response rate does not necessarily mean that the drugs are not useful, said Clohessy, but that perhaps the patient populations are not as well defined as they could be. Clohessy noted that, although there are many promising agents, and much has been invested in the quest to find new cancer drugs, the number of new drugs approved by the U.
In addition, cancer is revealing itself to be a very sophisticated disease capable of modifying itself and developing resistance to treatments. For these reasons—the unique and complex nature of cancer and the inadequate current drug development system—Clohessy said there is a need for improved disease models and a new system of disease classification and drug development.
This ideal new system would provide disease models, including patient surrogates, to account for the complexity of biologic systems and the inherent inter- and intra-patient heterogeneity of human cancers.
The system would link agents to their molecular targets using predictive modeling. Finally, there would be improved clinical trial designs based on predictive biomarker validation strategies, which could be tested and validated with a single trial. By performing pre- and co-clinical trials with GEMMs and PDX models, researchers can determine which patients are more likely to respond to novel therapeutic agents, on the basis of their genetic makeup.
In addition, the progress from bench to bedside for promising new agents, or combinations of already approved drugs, can be streamlined.
The mouse hospital, said Clohessy, is a state-of-the-art animal facility, with personnel who are trained in diseased mouse care, husbandry, and therapeutic treatments, as well as dedicated areas in the vivarium for in vivo imaging, behavioral testing, and surgical procedures. The ultimate goal, said Clohessy, is to have mouse hospitals throughout the country and the world. These hospitals would be credentialed and accredited, and the data from the pre- and co-clinical trials would be centrally deposited.
Clohessy explained that the mouse hospital is currently in the proof-of-concept phase, working in concert with the cancer clinical center and the cancer research institute at Beth Israel Deaconess Medical Center.
Clohessy said that the collaboration between the patient care teams and the researchers is an iterative process that allows patient treatments and patient care to be tailored to improve outcome. Clohessy explained the ideal structure of these co-clinical trials see Figure While the patient is undergo-.
The findings from the initial mouse trials are used to adjust the treatment strategy for the human patient, and at the same time, the initial outcomes of the human patient are used to inform the direction of research in the mouse models. Final outcomes from the mouse trial, along with information about how the human patient has responded to treatments, are used to optimize the treatment of the human patient.
In order to fully realize the potential of mouse co-clinical trials, a number of challenges need to be overcome, said Clohessy. There may be improved ways to utilize the multitude of available cancer models, Clohessy said, and described ongoing research that uses GEMMs to study lung cancer at a single-cell level. Researchers focus on subpopulations of tumor cells to understand how these respond to treat-.
These data from the animal models are used in concert with data from primary human tumors to more fully understand cancer at the cellular level and develop more precise treatments. Using GEMMs in a co-clinical trial approach is lengthy and costly, said Clohessy, as it takes a significant amount of time to develop and breed mouse cohorts that are appropriate models for a single patient. This platform has allowed researchers to isolate prostate cells, grow organoids in vitro, and manipulate their genetic makeup.
These organoids can be placed into genetically homogeneous mice to allow researchers to track the development of disease and study the diversity of human cancers. Leukemia mouse models are used to develop and evaluate novel therapeutic approaches, said Clohessy. A recently developed mouse model allows the study of the dependence of the disease on IDH2 expression. Through a serial transplantation protocol, researchers have developed a number of models with variable sensitivity to the de-induction of the mutation.
These models are compared using metabolomics, genomics, and transcriptomics, and through this comparison, researchers have identified both novel resistance mechanisms and novel vulnerabilities.
Clohessy said that clinical trials for therapeutic approaches based on these findings are in development. These trials offer pets and their owners the chance to receive treatments, while also offering researchers an opportunity to assess new treatments with naturally occurring cancer models and to collect relevant data on toxicity, response, drug dosing, bio-.
In addition, COP has a laboratory that is currently focused on the biology and metabolism of metastasis in osteosarcoma in dogs, and the development of molecular imaging tools to help interrogate laboratory findings and translate them into the clinical trial setting.
Dogs develop cancer in many of the same areas of the body as humans. While dogs and humans are not always a perfect match, there are many types of cancer in dogs that are appropriate models for humans, said LeBlanc. Comparative oncology trials provide an iterative process where studies on dogs can inform studies on humans, and vice versa, with the overall gain in knowledge advancing the understanding of cancer and potential treatments, said LeBlanc see Figure For example, initial studies on dogs with tumors can produce data about potential treatments, including activity, toxicity, pharmacokinetics, and pharmacodynamics.
LeBlanc gave two examples of successful comparative oncology trials. One trial focused on a novel immunocytokine NHS-IL12 , which the manufacturing company was ready to give up on. Dogs receiving the immunocytokine responded favorably. The efficacy data resulted in enough enthusiasm to generate an Investigational New Drug application to the FDA, and eventually phase I clinical trials.
The data also helped in biomarker selection. The second example was a trial to compare three TOPO-1 inhibitors in dogs with lymphoma.
The data from dogs suggested that one of the drugs was more biologically active than the other two, a result that was not obvious from preclinical mouse research. The initiation of a new clinical trial by COP is being done to meet a specific need that is unmet by human drug development and fill a gap, said LeBlanc.
She said that data on drug efficacy may not always be the top priority; trials may focus on target modulation or pharmacodynamic and pharmacokinetic relationships. The FDA views data from comparative oncology trials as important but supplementary; according to LeBlanc, the agency has stated that data from comparative oncology trials will not derail the clinical development of a drug or result in a clinical hold.
Regarding precision medicine, LeBlanc said that the biggest area yet to be addressed is the genetic landscape of canine cancers. Most comparative oncology research to this point has focused on clinical observations, rather than on collecting and analyzing genetic data about potential mutations associated with cancers.
In order to move precision medicine forward, comparative oncology researchers will need analytic tools and expertise to collect genetic information; LeBlanc noted that because they are not bound by privacy rules regarding human data collection, there is an opportunity to build a robust set of data in this area. The goals of these awards are to. The second step of this initiative was a Request for Application RFA for studies investigating the utility of dogs with cancer as models for immunotherapy development.
The short-term goals of this RFA are to establish a network of laboratory scientists and canine clinical trialists to study the anti-tumor effects of immunotherapy agents and novel combinations of immunotherapy and other modalities, and also to establish a coordinating center to implement the clinical protocols and manage data from these trials.
In the long-term, the NCI will use these data to establish the suitability of canine models for studying immunomodulating agents, and to eventually translate the findings to human studies.
LeBlanc concluded that finding success in precision medicine in this area depends on the advancement of our knowledge regarding cancers in dogs. She said, however, that there has been significant progress in recent years in terms of awareness, advocacy, funding, and research, and that comparative oncology presents a great opportunity to learn more and contribute to the care and treatment of both humans and dogs.
There are data from individual patients regarding clinical phenotypes, -omics, socioeconomic factors, environmental exposure, and other factors; there are population-level data on population frequencies, disease correlations, risk statistics, and exposure data; and there are data stemming from model organism research. Despite this plethora of data, most clinical diagnostic pipelines leverage only a tiny fraction of it. Haendel said that the challenge lies not in producing more data but in improving the utilization of data.
One of the problems, said Haendel, is that different communities—including researchers, clinicians, patients, and animal scientists—use different terms to describe signs and symptoms of the same clinical entity. The issue, said Haendel, is that these data are not relatable to one another, and the language barriers between fields become very problematic.
Because of this wide variety in terms, it is quite challenging for researchers to work across multiple research or clinical datasets. Haendel said that there are hundreds, if not thousands, of standards used to describe phenotypic features. The Human Phenotype Ontology project attempts to bridge this phenotypic semantic confusion by using a logic structure to classify phenotypes according to standardized terms. The project uses species-neutral ontologies and homologous concepts, drawing from evidence from the literature, database resources such as OMIM and Orphanet, and other existing clinical and research ontology standards.
The logic model can deduce that palmoplantar hyperkeratosis and ulcerated paws are the same phenotype, based on the underlying phenotypic profile and the terms used to describe the phenotype. This approach makes it possible to integrate data from both clinical and model organism sources. Each source has its own ontology, but the application of species-neutral ontology allows the data to be harmonized. Haendel noted that between—or even within—data sources, the same phenotype is sometimes associated with a different component of the genotype, and that harmonizing these sources creates an opportunity to find novel associations.
Using these data for diagnosis depends on the use of a fuzzy matching algorithm that compares patient genotypic and phenotypic data against similar data from human and model organism sources. The technology also facilitates the matching of patients across the globe through a site called Matchmaker Exchange. By matching undiagnosed patients using both clinical and public data sources, candidate variants can potentially be validated, and patients and providers from around the world can collaborate to find diagnoses.
Burrowing animals may have been key to stabilizing Earth's oxygen
New drug shows promise to treat cocaine addiction The compound targets TAAR 1, which is expressed in key drug is thought to be a 'brake' on dopamine activity, drugs that stimulate One of the ways researchers test the rewarding effects of the drug in animals is called conditioned place preference. Research involving laboratory animals at UCLA leads to many medical The work also holds promise for treating other neurological and the extent to which cardiac electrical activity shortens as heart rate increases is a key. Evolution of the first burrowing animals may have played a major role in and we conclude that animal activity had a decreasing impact on the global oxygen Evolution showed that early animals may have needed surprisingly little oxygen . Continuous MicroCHIPS Glucose Monitoring Shows Promise.