Pancreatic cancer organotypics: High throughput, preclinical models for pharmacological agent evaluation

Pancreatic cancer carries a terrible prognosis,as the fourth most common cause of cancer death in the Western world.There is clearly a need for new therapies to treat this disease.One of the reasons no effective treatment has been developed in the past decade may in part,be explained by the diverse influences exerted by the tumour microenvironment.The tumour stroma cross-talk in pancreatic cancer can influence chemotherapy delivery and response rate.Thus,appropriate preclinical in vitro models which can bridge simple 2D in vitro cell based assays and complex in vivo models are required to understand the biology of pancreatic cancer.Here we discuss the evolution of 3D organotypic models,which recapitulare the morphological and functional features of pancreatic ductal adenocarcinoma(PDAC).Organotypic cultures are a valid high throughput preclinical in vitro model that maybe a useful tool to help establish new therapies for PDAC.A huge advantage of the organotypic model system is that any component of the model can be easily modulated in a short timeframe.This allows new therapies that can target the cancer,the stromal compartment or both to be tested in a model that mirrors the in vivo situation.A major challenge for the future is to expand the cellular composition of the organotypic model to further develop a system that mimics the PDAC environment more precisely.We discuss how this challenge is being met to increase our understanding of this terrible disease and develop novel therapies that can improve the prognosis for patients.

Preclinical models in ophthalmic oncology-a narrative review

Objective:This review serves as a comprehensive description and summary of currently available preclinical models of three tumors in ophthalmic oncology:conjunctival melanoma(CM),uveal melanoma(UM),and retinoblastoma.Background:Malignant melanomas are the most common tumors of the eye in adults,most often localized in the uvea and conjunctiva.Although the primary tumor can be successfully eliminated in many cases,nearly one in two UMs-and one in three CMs-are fatal to the patient due to metastasis.Effective therapies for metastatic uveal and CMs are unfortunately still not available,so there is an urgent need for new therapeutic strategies to improve prognosis quoad vitam and prolong the survival of melanoma patients.Another widely known tumor of the eye is retinoblastoma,which is the most common pediatric ocular malignancy,occurring in approximately 1 in 15,000-18,000 live births.Overall,it is considered well treatable,with a survival rate of approximately 90%at 3 years,although fatal if untreated.For a long time,enucleation was also considered the treatment of choice,with bilateral cases having one eye irradiated and the eye with the more advanced tumor removed.Since the 1990s,however,systemic chemotherapy has been predominantly used to preserve the quality of life and vision of young patients,although the cellular activity of the retinoblastoma often remains after treatment with chemotherapeutic agents.Prognosis of the disease is immensely depending on the stage and time of diagnosis and is varying between countries due to different developmental status of health care systems.Methods:We review recent advances in the available literature on established preclinical models in CM,UM,and retinoblastoma.In addition,we discuss the advantages and limitations of these models and provide an overview of current alternatives to animal testing in preclinical studies.Conclusions:In the case of all three diseases,further research is needed for improved therapeutic options.Animal models in particular are indispensable for cancer research in order to mimic the extremely complex processes of human carcinogenesis,physiology and progression.Certainly,animal studies do not easily translate to human diseases due to biological differences and limitations.However,they continue to serve as the primary source and link between in vitro testing and clinical studies in patients.In order to minimize animal experiments and possibly even replace them in the future,alternatives such as 3D cell cultures and in silico predictions are useful and insightful additions and require further development.Still,no currently available preclinical model can be fully translated to some of here described diseases.Nevertheless,they all provide essential insights and knowledge that should be of use in the future for better understanding and pursuit of new therapeutic strategies.

Preclinical models of idiosyncratic drug-induced liver injury(iDILI):Moving towards prediction

Idiosyncratic drug-induced liver injury(iDILI) encompasses the unexpected harms that prescription and non-prescription drugs,herbal and dietary supplements can cause to the liver.iDILI remains a major public health problem and a major cause of drug attrition.Given the lack of biomarkers for iDILI prediction,diagnosis and prognosis,searching new models to predict and study mechanisms of iDILI is necessary.One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI.Thus,major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients.However,there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms.Therefore,there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development.Here,the current experimental models and the future directions in iDILI modelling are thoroughly discussed,focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models.We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.

Cardiorenal syndrome： pathophysiological mechanism, preclinical models, novel contributors and potential therapies

Objective To review the current knowledge about the pathophysiological mechanisms,preclinical models,novel contributors and potential therapies of cardiorenal syndrome.Data sources The literature concerning cardioranal syndrome in this review was collected from PubMed published in English up to January 2014.Study selection Original articles and critical reviews related to cardiorenal syndrome were selected and carefully analyzed.Results Cardiorenal syndrome is a condition characterized by kidney and heart failure where failure of one organ worsens the function of the other thus further accelerating the progressive failure of both organs.The pathophysiology of cardiorenal syndrome is not fully understood,but may be caused by a complex combination of neurohormonal system activation,endothelial dysfunction,proteinuria,oxidative stress,uremic toxins and other factors.Managing cardiorenal syndrome is still a major therapeutic challenge in clinical practice because many of the drugs used to control heart failure can worsen renal function,and vice versa.Non-dialyzable uremic toxins,such as indoxyl sulfate,causing detrimental effects on the heart and kidney as well as stimulation of inflammatory responses,may be an effective therapeutic target for cardiorenal syndrome.Conclusions Suitable disease models of cardiorenal syndrome are urgently needed to investigate the pathophysiology and effective therapeutic approaches to the condition.Non-dialyzable protein-bound uremic toxins that may have cardiac and renal effects may provide therapeutic benefit to cardiorenal syndrome patients.

Understanding wound healing in obesity

Obesity has become more prevalent in the global population.It is associated with the development of several diseases including diabetes mellitus,coronary heart disease,and metabolic syndrome.There are a multitude of factors impacted by obesity that may contribute to poor wound healing outcomes.With millions worldwide classified as obese,it is imperative to understand wound healing in these patients.Despite advances in the understanding of wound healing in both healthy and diabetic populations,much is unknown about wound healing in obese patients.This review examines the impact of obesity on wound healing and several animal models that may be used to broaden our understanding in this area.As a growing portion of the population identifies as obese,understanding the underlying mechanisms and how to overcome poor wound healing is of the utmost importance.

Preclinical animal studies in ischemic stroke:Challenges and some solutions

Despite the impressive efficacies demonstrated in preclinical research,hundreds of potentially neuroprotective drugs have failed to provide effective neuroprotec-tion for ischemic stroke in human clinical trials.Lack of a powerful animal model for human ischemic stroke could be a major reason for the failure to develop successful neuroprotective drugs for ischemic stroke.This review recapitulates the available cerebral ischemia animal models,provides an anatomical comparison of the circle of Willis of each species,and describes the functional assessment tests used in these ischemic stroke models.The distinct differences between human ischemic stroke and experimental stroke in available animal models is explored.Innovative animal models more closely resembling human strokes,better techniques in functional out-come assessment and better experimental designs generating clearer and stronger evidence may help realise the development of truly neuroprotective drugs that will benefit human ischemic stroke patients.This may involve use of newer molecules or revisiting earlier studies with new experimental designs.Translation of any resultant successes may then be tested in human clinical trials with greater confidence and optimism.

Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis

The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord （SC）, where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis （mSOD1） and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging （DTI） has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS.

A comprehensive review of animal models for cancer cachexia:Implications for translational research

Cancer cachexia is a multifactorial syndrome characterized by progressive weight loss and a disease process that nutritional support cannot reverse.Although progress has been made in preclinical research,there is still a long way to go in translating research findings into clinical practice.One of the main reasons for this is that existing preclinical models do not fully replicate the conditions seen in clinical patients.Therefore,it is important to understand the characteristics of existing preclinical models of cancer cachexia and pay close attention to the latest developments in preclinical models.The main models of cancer cachexia used in current research are allogeneic and xenograft models,genetically engineered mouse models,chemo-therapy drug-induced models,Chinese medicine spleen deficiency models,zebrafish and Drosophila models,and cellular models.This review aims to revisit and summarize the commonly used animal models of cancer cachexia by evaluating existing preclinical models,to provide tools and support for translational medicine research.

Living biobank-based cancer organoids: prospects and challenges in cancer research

Biobanks bridge the gap between basic and translational research.Traditional cancer biobanks typically contain normal and tumor tissues,and matched blood.However,biospecimens in traditional biobanks are usually nonrenewable.In recent years,increased interest has focused on establishing living biobanks,including organoid biobanks,for the collection and storage of viable and functional tissues for long periods of time.The organoid model is based on a 3D in vitro cell culture system,is highly similar to primary tissues and organs in vivo,and can recapitulate the phenotypic and genetic characteristics of target organs.Publications on cancer organoids have recently increased,and many types of cancer organoids have been used for modeling cancer processes,as well as for drug discovery and screening.On the basis of the current research status,more exploration of cancer organoids through technical advancements is required to improve reproducibility and scalability.Moreover,given the natural characteristics of organoids,greater attention must be paid to ethical considerations.Here,we summarize recent advances in cancer organoid biobanking research,encompassing rectal,gastric,pancreatic,breast,and glioblastoma cancers.Living cancer biobanks that contain cancerous tissues and matched organoids with different genetic backgrounds,subtypes,and individualized characteristics will eventually contribute to the understanding of cancer and ultimately facilitate the development of innovative treatments.

Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative diseases

Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients' daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs.

Revolutionizing preclinical research for pancreatic cancer:the potential of 3D bioprinting technology for personalized therapy

Pancreatic cancer(PC)is a prevalent digestive malignancy worldwide and ranks as the fourth leading cause of cancer-related deaths globally.The incidence and mortality rates have been increasing annually,and due to its insidious onset and high malignancy,most patients are diagnosed at an advanced stage,with a 5-year survival rate of less than 8%(1).PC can be classified into endocrine and exocrine tumors,with over 95% of pancreatic malignant tumors originating from the exocrine portion of the pancreas.

Challenges and opportunities in rare cancer research in China

Cancer is one of the major public health challenges in China.Rare cancers collectively account for a considerable proportion of all malignancies.The lack of awareness of rare cancers among healthcare professionals and the general public,the typically complex and delayed diagnosis,and limited access to clinical trials are key challenges.Recent years have witnessed an increase in funding for research related to rare cancers in China.In this review,we provide a comprehensive overview of rare cancers and summarize the status of research on rare cancers in China and overseas,including the trends of funding and publications.We also highlight the challenges and perspectives regarding rare cancers in China.

Progress and perspective of organoid technology in breast cancer research

Breast cancer,a malignant tumor with a high incidence in women,lacks in vitro research models that can represent the biological functions of breast tumors in vivo.As a new biological tool,the organoid model has unique advantages over traditional methods,such as cell culture and patient-derived xenografts.Combining organoids with other emerging technologies,such as gene engineering and microfluidic chip technology,provides an effective method to compensate for the deficiencies in organoid models of breast cancer in vivo.The emergence of breast cancer organoids has provided new tools and research directions in precision medicine,and drug research.In this review,we summarized the merits and demerits of organoids compared to traditional biological models,explored the latest developments in the combination of new technologies and organoid models,and discussed the construction methods and application prospects of different breast cancer organoid models.

Complications and comorbidities associated with antineoplastic chemotherapy:Rethinking drug design and delivery for anticancer therapy

Despite the considerable advancements in chemotherapy as a cornerstone modality in cancer treatment,the prevalence of complications and pre-existing diseases is on the rise among cancer patients along with prolonged survival and aging population.The relationships between these disorders and cancer are intricate,bearing significant influence on the survival and quality of life of individuals with cancer and presenting challenges for the prognosis and outcomes of malignancies.Herein,we review the prevailing complications and comorbidities that often accompany chemotherapy and summarize the lessons to learn from inadequate research and management of this scenario,with an emphasis on possible strategies for reducing potential complications and alleviating comorbidities,as well as an overview of current preclinical cancer models and practical advice for establishing bio-faithful preclinical models in such complex context.

The current status and reflections on 3D in vitro modeling of liver metastasis in colorectal cancer

Colorectal cancer(CRC)ranks as the third most prevalent cancer worldwide and is identified as the second leading cause of cancer-related fatalities(1).The liver is the most common site for distant metastasis in CRC,with approximately 20%to 25%of newly diagnosed patients experiencing liver metastasis.As the disease progresses,this proportion can increase to as high as 50%(2),making it a primary cause of death in CRC patients.