Translational bioengineering strategies for peripheral nerve regeneration:opportunities,challenges,and novel concepts

Peripheral nerve injuries remain a challenging problem in need of better treatment strategies.Despite best efforts at surgical reconstruction and postoperative rehabilitation,patients are often left with persistent,debilitating motor and sensory deficits.There are currently no therapeutic strategies proven to enhance the regenerative process in humans.A clinical need exists for the development of technologies to promote nerve regeneration and improve functional outcomes.Recent advances in the fields of tissue engineering and nanotechnology have enabled biomaterial scaffolds to modulate the host response to tissue repair through tailored mechanical,chemical,and conductive cues.New bioengineered approaches have enabled targeted,sustained delivery of protein therapeutics with the capacity to unlock the clinical potential of a myriad of neurotrophic growth factors that have demonstrated promise in enhancing regenerative outcomes.As such,further exploration of combinatory strategies leveraging these technological advances may offer a pathway towards clinically translatable solutions to advance the care of patients with peripheral nerve injuries.This review first presents the various emerging bioengineering strategies that can be applied for the management of nerve gap injuries.We cover the rationale and limitations for their use as an alternative to autografts,focusing on the approaches to increase the number of regenerating axons crossing the repair site,and facilitating their growth towards the distal stump.We also discuss the emerging growth factor-based therapeutic strategies designed to improve functional outcomes in a multimodal fashion,by accelerating axonal growth,improving the distal regenerative environment,and preventing end-organs atrophy.

Translational research and innovation in modern transplant practice:Paradigms from Greece and around the world

The continuous clinical and technological advances,together with the social,health and economic challenges that the global population faces,have created an environment where the evolution of the field of transplantation is essentially necessary.The goal of this special issue is to provide a picture of the current status of transplantation in Greece as well as in many other countries in Europe and around the world.Authors from Greece and several other countries provide us with valuable insight into their respective areas of transplant expertise,with a main focus on the field of translational research and innovation.The papers that are part of this Special Issue“Translational Research and Innovation and the current status of Transplantation in Greece”have presented innovative and meaningful approaches in modern transplant research and practice.They provide us with a clear overview of the current landscape in transplantation,including liver transplantation in the context of a major pandemic,the evolution of living donor kidney transplantation or the evolution of the effect of hepatitis C virus infection in transplantation,while at the same time explore more recent challenges,such as the issue of frailty in the transplant candidate and the changes brought by newer treatments,such as immunotherapy,in transplant oncology.Additionally,they offer us a glimpse of the effect that technological innovations,such as virtual reality,can have on transplantation,both in terms of clinical and educational aspects.Just as critical is the fact that this Special Issue emphasizes the multidisciplinary,collaborative efforts currently taking place that link transplant research and innovation with other cutting-edge disciplines such as bioengineering,advanced information technology and artificial intelligence.In this Special Issue,in addition to the clinical and research evolution of the field of transplantation,we are witnessing the importance of interdisciplinary collaboration in medicine.

The 8th National Gastric Cancer Academic Conference: focus on specification, translational research, and plan

The 8th National Gastric Cancer Academic Conference, organized by Gastric Cancer Association of Chinese Anti- cancer Association and co-hosted by Beijing Cancer Hospital, Chinese Journal of Cancer Research （CJCR）, Translational Gastrointestinal Cancer （TGC）, Chinese Journal of Gastrointestinal Surgery, and Chinese Journal of Practical Surgery, was held at Beijing International Convention Center from June 15 to 16, 2013. Prof. Dr. Jiafu Ji, MD, FACS, the president of Gastric Cancer Committee, Chinese Anti-Cancer Association （CACA） and Editor-in-Chief of TGC, was the chairman of the conference （Figure 1）. Prof. Dr. Yan Sun, MD, academician of Chinese Academy of Engineering （CAE）, was the honorary chairman of the

Novel translational strategies in colorectal cancer research

Defining translational research is still a complex task. In oncology, translational research implies using our basic knowledge learnt from in vitro and in vivo experiments to directly improve diagnostic tools and therapeutic approaches in cancer patients. Moreover, the better understanding of human cancer and its use to design more reliable tumor models and more accurate experimental systems also has to be considered a good example of translational research. The identification and characterization of new molecular markers and the discovery of novel targeted therapies are two main goals in colorectal cancer translational research. However, the straightforward translation of basic research findings, specifically into colorectal cancer treatment and vice versa is still underway. In the present paper, a summarized view of some of the new available approaches on colorectal cancer translational research is provided. Pros and cons are discussed for every approach exposed.

Patient-centered developments in colon-and rectal cancer with a multidisciplinary international team:From translational research to national guidelines

Rarely,scientific developments centered around the patient as a whole arepublished.Our multidisciplinary group,headed by gastrointestinal surgeons,applied this research philosophy considering the most important aspects of thediseases“colon-and rectal cancer”in the long-term developments.Good expertcooperation/knowledge at the Comprehensive Cancer Center Ulm(CCCU)wereapplied in several phase III trials for multimodal treatments of primary tumors(MMT)and metastatic diseases(involving nearly 2000 patients and 64 centers),fortreatment individualization of MMT and of metastatic disease,for psychooncology/quality of life involving the patients’wishes,and for disease prevention.Most of the targets initially were heavily rejected/discussed in thescientific communities,but now have become standards in treatments andnational guidelines or are topics in modern translational research protocolsinvolving molecular biology for e.g.,“patient centered individualized treatment”.In this context we also describe the paths we had to tread in order to realize ournew goals,which at the end were highly beneficial for the patients from manypoints of view.This description is also important for students and youngresearchers who,with an actual view on our recent developments,might want toknow how medical progress was achieved.

CONFERENCE At-A-Glance SOCIETY FOR ACUPUNCTURE RESEARCH“Translational Research in Acupuncture:Bridging Science,Practice and Community” Chapel Hill,NC,March 19-21,2010

THURSDAY,March 18 Pre-Conference Workshops"lntroduction to current issues in acupunclure research""ConsideratiOns for developing COllaboration research between AOM COlleges and conventionaI medicalinstitutions"

Translational research in early neuroscience careers of high school students

Essentially, the knowledge of science alone offers little utility. With-out the ability to investigate, apply and communicate, science serves no purpose. That is not to undermine the importance of scientific knowledge, but there currently exists a major flaw in our high school educational system that inhibits meaningful learning experiences for most students. Application of science in local high schools is largely directed at improving performance on multiple-choice exams. Standardized tests taken by high school students are slowly progressing,

A “Stem Cells in Cancer” special issue in Translational Cancer Research

Somatic stem cells （SSCs）, being essential in maintaining homeostasis of normal tissue, replenish dying cells and regenerate damaged tissues for organism. On the other hand, with the self-renewed ability, SSCs are ideal cellular targets to be acquired in multiple mutations transforming SSCs to cancer stem cells （CSCs） which cause malignancies and even recurrence after cancer treatment if CSCs fail to be eradicated （1）.

A comprehensive review of 3D cancer models for drug screening and translational research

The 3D cancer models fill the discovery gap of 2D cancer models and play an important role in cancer research.In addition to cancer cells,a range of other factors include the stroma,density and composition of extracellular matrix,cancer-associated immune cells(e.g.,cancer-associated fibroblasts cancer cell-stroma interactions and subsequent interactions,and a number of other factors(e.g.,tumor vasculature and tumor-like microenvironment in vivo)has been widely ignored in the 2D concept of culture.Despite this knowledge,the continued use of monolayer cell culture methods has led to the failure of a series of clinical trials.This review discusses the immense importance of tumor microenvironment(TME)recapitulation in cancer research,prioritizing the individual roles of TME elements in cancer histopathology.The TME provided by the 3D model fulfills the requirements of in vivo spatiotemporal arrangement,components,and is helpful in analyzing various different aspects of drug sensitivity in preclinical and clinical trials,some of which are discussed here.Furthermore,it discusses models for the co-assembly of different TME elements in vitro and focuses on their synergistic function and responsiveness as tumors.Furthermore,this review broadly describes of a handful of recently developed 3D models whose main focus is limited to drug development and their screening and/or the impact of this approach in preclinical and translational research.

Status of precision medicine approaches to traumatic brain injury

Traumatic brain injury(TBI)is a serious condition in which trauma to the head causes damage to the brain,leading to a disruption in brain function.This is a significant health issue worldwide,with around 69 million people suffering from TBI each year.Immediately following the trauma,damage occurs in the acute phase of injury that leads to the primary outcomes of the TBI.In the hours-to-days that follow,secondary damage can also occur,leading to chronic outcomes.TBIs can range in severity from mild to severe,and can be complicated by the fact that some individuals sustain multiple TBIs,a risk factor for worse long-term outcomes.Although our knowledge about the pathophysiology of TBI has increased in recent years,unfortunately this has not been translated into effective clinical therapies.The U.S.Food and Drug Administration has yet to approve any drugs for the treatment of TBI;current clinical treatment guidelines merely offer supportive care.Outcomes between individuals greatly vary,which makes the treatment for TBI so challenging.A blow of similar force can have only mild,primary outcomes in one individual and yet cause severe,chronic outcomes in another.One of the reasons that have been proposed for this differential response to TBI is the underlying genetic differences across the population.Due to this,many researchers have begun to investigate the possibility of using precision medicine techniques to address TBI treatment.In this review,we will discuss the research detailing the identification of genetic risk factors for worse outcomes after TBI,and the work investigating personalized treatments for these higher-risk individuals.We highlight the need for further research into the identification of higher-risk individuals and the development of personalized therapies for TBI.

Global progress against cancer—challenges and opportunities

The last ten years have seen remarkable progress in cancer research. However, despite significant breakthroughs in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Cancer＇s complexity compounded with financial, policy and regulatory roadblocks has slowed the rate of progress being made against cancer. In this paper, we review a few of the most recent breakthroughs that are fueling medical advances and bringing new hope for patients affected by this devastating disease. We also address the challenges facing us and the opportunities to accelerate future progress against cancer. The efforts of the American Association for Cancer Research （AACK） to address the cancer burden already extend beyond the borders of the United States of America. The AACR is committed to increasing its efforts to stem the tide of cancer worldwide by promoting innovative programs, strategies, and initiatives for cancer researchers and all those engaged in cancer-related biomedical sciences around the world.

Gastric cancer molecular classification based on immunohistochemistry and in situ hybridization:Analysis in western patients after curative-intent surgery

BACKGROUND Gastric cancer(GC)is a highly heterogeneous disease,and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subgroups.However,the costs and technical complexity of molecular methodologies remains an obstacle to its adoption,and their clinical significance by other approaches needs further evidence.AIM To evaluate the clinicopathological characteristics and long-term survival of GC based on the subgroups of molecular classification by immunohistochemistry(IHC)and in situ hybridization(ISH).METHODS We retrospectively evaluated all patients who underwent D2-gastrectomy between 2009 and 2016 in a Western cohort of GC patients treated with curative intent.Microsatellite instability(MSI)status,E-cadherin,and p53 expression were analyzed by IHC,and Epstein-Barr virus(EBV)by ISH.Tissue microarrays were constructed for analysis.Clinicopathological characteristics and survival of GC were evaluated according to subtypes defined by The Cancer Genome Atlas(TCGA)Research Network Group and Asian Cancer Research Group(ACRG)classification systems.RESULTS A total of 287 GC patients were included.Based on IHC and ISH analysis,five profiles were defined as follows:E-cadherin aberrant(9.1%),MSI(20.9%),p53 aberrant(36.6%),EBV positivity(10.5%),and p53 normal(31%),which corresponded to tumors that showed no alteration in another profile.A flowchart according to the TCGA and ACRG classifications were used to define the subtypes,where clinical and pathological characteristics associated with GC subtypes were evidenced.Proximal location(P<0.001),total gastrectomy(P=0.001),and intense inflammatory infiltrate(P<0.001)were characteristics related to EBV subtype.MSI subtype was predominantly associated with advanced age(P=0.017)and the presence of comorbidities(P=0.011).While Laurén diffuse type(P<0.001)and advanced stage(P=0.029)were related to genomically stable(GS)subtype.GS tumors and microsatellite stable/epithelial to mesenchymal transition phenotype subtype had worse disease-free survival(DFS)and overall survival(OS)than other subtypes.Conversely,MSI subtype of GC had better survival in both classifications.Type of gastrectomy,pT and the TCGA subtypes were independent factors associated to DFS and OS.CONCLUSION The IHC/ISH analysis was able to distinguish immunophenotypic groups of GC with distinct characteristics and prognosis,resembling the subtypes of the molecular classifications.Accordingly,this method of classification may represent a viable option for use in a clinical setting.

Animal modeling in bone research—Should we follow the White Rabbit?

Animal models are live subjects applied to translational research.They provide insights into human diseases and enhance biomedical knowledge.Livestock development has favored the pace of human social development over millennia.Today's society is more aware of animal welfare than past generations.The general public has marked objections to animal research and many species are falling into disuse.The search for an ideal methodology to replace animal use is on,but animal modeling still holds great importance to human health.Bone research,in particular,has unmet requirements that in vitro technologies cannot fully address.Standardizing novel models remains necessary and rabbits are gaining in popularity as potential bone models.Our aim here is to provide a broad overview of animal modeling and its ethical implications,followed by a narrower focus on bone research and the role rabbits are playing in the current scenario.

Deleterious effects of whole-body vibration on the spine:A review of in vivo,ex vivo,and in vitro models

Occupational exposure to whole-body vibration is associated with the develop-ment of musculoskeletal,neurological,and other ailments.Low back pain and other spine disorders are prevalent among those exposed to whole-body vibration in occupational and military settings.Although standards for limiting exposure to whole-body vibration have been in place for decades,there is a lack of understanding of whole-body vibration-associated risks among safety and healthcare profession-als.Consequently,disorders associated with whole-body vibration exposure remain prevalent in the workforce and military.The relationship between whole-body vibra-tion and low back pain in humans has been established largely through cohort stud-ies,for which vibration inputs that lead to symptoms are rarely,if ever,quantified.This gap in knowledge highlights the need for the development of relevant in vivo,ex vivo,and in vitro models to study such pathologies.The parameters of vibrational stimuli(eg,frequency and direction)play critical roles in such pathologies,but the specific cause-and-effect relationships between whole-body vibration and spinal pa-thologies remain mostly unknown.This paper provides a summary of whole-body vibration parameters;reviews in vivo,ex vivo,and in vitro models for spinal patholo-gies resulting from whole-body vibration;and offers suggestions to address the gaps in translating injury biomechanics data to inform clinical practice.

Magnetic Resonance Imaging Studies of Neurodegenerative Disease:From Methods to Translational Research

Neurodegenerative diseases(NDs)have become a significant threat to an aging human society.Numerous studies have been conducted in the past decades to clarify their pathologic mechanisms and search for reliable biomarkers.Magnetic resonance imaging(MRI)is a powerful tool for investigating structural and functional brain alterations in NDs.With the advantages of being non-invasive and non-radioactive,it has been frequently used in both animal research and large-scale clinical investigations.MRI may serve as a bridge connecting micro-and macro-level analysis and promoting bench-to-bed translational research.Nevertheless,due to the abundance and complexity of MRI techniques,exploiting their potential is not always straightforward.This review aims to briefly introduce research progress in clinical imaging studies and discuss possible strategies for applying MRI in translational ND research.

Non-human primate pluripotent stem cells for the preclinical testing of regenerative therapies

Non-human primates play a key role in the preclinical validation of pluripotent stem cell-based cell replacement therapies.Pluripotent stem cells used as advanced therapy medical products boost the possibility to regenerate tissues and organs affected by degenerative diseases.Therefore,the methods to derive human induced pluripotent stem cell and embryonic stem cell lines following clinical standards have quickly developed in the last 15 years.For the preclinical validation of cell replacement therapies in non-human primates,it is necessary to generate non-human primate pluripotent stem cell with a homologous quality to their human counterparts.However,pluripotent stem cell technologies have developed at a slower pace in non-human primates in comparison with human cell systems.In recent years,however,relevant progress has also been made with non-human primate pluripotent stem cells.This review provides a systematic overview of the progress and remaining challenges for the generation of non-human primate induced pluripotent stem cells/embryonic stem cells for the preclinical testing and validation of cell replacement therapies.We focus on the critical domains of(1)reprogramming and embryonic stem cell line derivation,(2)cell line maintenance and characterization and,(3)application of non-human primate pluripotent stem cells in the context of selected preclinical studies to treat cardiovascular and neurodegenerative disorders performed in non-human primates.

Biobanking in the digital pathology era

Digital Pathology is becoming more and more important to achieve the goal of precision medicine.Advances in whole-slide imaging,software integration,and the accessibility of storage solutions have changed the pathologists’clinical practice,not only in terms of laboratory workflow but also for diagnosis and biomarkers analysis.In parallel with the pathology setting advancement,translational medicine is approaching the unprecedented opportunities unrevealed by artificial intelligence(AI).Indeed,the increased usage of biobanks’datasets in research provided new challenges for AI applications,such as advanced algorithms,and computer-aided techniques.In this scenario,machine learning-based approaches are being propose in order to improve biobanks from biospecimens collection repositories to computational datasets.To date,evidence on how to implement digital biobanks in translational medicine is still lacking.This viewpoint article summarizes the currently available literature that supports the biobanks’role in the digital pathology era,and to provide possible practical applications of digital biobanks.

A Critique of Eye-Tracking Approach in Translation Process Research

With the rapid growth of eye-tracking studies in translation process research, concomitant methodologicalproblems have become increasingly prominent. This paper starts with the discussion of the controversial “eye-mindassumption”, and then focuses on various threats to experimental validity in research design and problems witheye-tracking data filtering and analysis. It is hoped that this discussion would be beneficial to those who are now orwill be engaged in eye-tracking based translation studies.

From Farming to Engineering： The Microbiota and Allergic Diseases

The steady increase of lgE-dependent allergic diseases after the Second World War is a unique phenomenon in the history of humankind. Numerous cross-sectional studies, comprehensive longitudinal cohort studies of children living in various types of environment, and mechanistic experimental studies have pointed to the disappearance of ＂protective factors＂ related to major changes in lifestyle and environment. A common unifying concept is that of the immunoregulatory role of the gut microbiota. This review focuses on the protection against allergic disorders that is provided by the farming environment and by exposure to microbial diversity. It also questions whether and how microbial bioengineering will be able in the future to restore an interplay that was beneficial to the proper immunological development of children in the past and that was irreversibly disrupted by changes in lifestyle. The protective ＂farming environment＂ includes independent and additional influences： contact with animals, stay in barns/stables, and consumption of unprocessed milk and milk products, by mothers during pregnancy and by children in early life. More than the overall quanti- ty of microbes, the biodiversity of the farm microbial environment appears to be crucial for this protection, as does the biodiversity of the gut microbiota that it may provide. Use of conventional probiotics, especially various species or strains of Lactobacillus and Bifidobacterium, has not fulfilled the expectations of allergists and pediatricians to prevent allergy. Among the specific organisms present in cowsheds that could be used for prevention, Acinetobacter （A.） lwoffii F78, Lactococcus （ L.） lactis G121, and Staphylococcus （S.） sciuri W620 seem to be the most promising, based on experimental studies in mouse models of allergic respiratory diseases. However, the development of a new generation of probiotics based on very productive research on the farming environment faces several obstacles that cannot be overcome without a close collaboration between microbiologists, immunologists, and bioengineers, as well as pediatricians, allergists, specialists of clinical trials, and ethical committees.

The Role of Cooking for Hospital Food Service in Cancer Care-Units: Nutrition Is a Supportive Care While Cooking Appears to Be a Prescription

Cancer cachexia and treatment-induced side effects can contribute to deterioration in nutritional status in patients declining the quality of life and survival rates. Culinary practices may provide new strategies to minimize the symptoms. NEODIA (learning to live with a cancer on a day-to-day basis) is an observational program whose objective is to better understand the occurrence of treatment-related side effects as well as culinary and dietary habits in cancer patients followed in the Cancer Unit of the Beauvais City Hospital, France. First study step in 2010 has investigated culinary solutions to improve the quality of life of the patient at home. The present part tries in particular to answer the question if the culinary advising is transposable to the offer of restoration proposed by institutions of care in oncology. We first conducted an investigation on the determinants of quality of life in patients currently treated in a hospital service involving 41 people. In a second step, we are collecting information on the food supply itself, using advising of some patient’s specially prepared to test meals as a translational research expertise. The results of our survey show that patient’s remarks constitute real guidelines to adapt the practices in culinary production and healthy catering management. Based on these results, the consistency of frozen prepared meals has been analyzed regarding their potential to regulate the under nutrition-inducing treatment-related side effects. Conducted by the patient’s panel of the translational research group the study highlights the benefits of agro-food products and margins of progress.