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Hasenberg, Tobias, Severin Mühleder, Andrea Dotzler, Sophie Bauer, Krystyna Labuda, Wolfgang Holnthoner, Heinz Redl, Roland Lauster, and Uwe Marx. "Emulating human microcapillaries in a multi-organ-chip platform." Journal of Biotechnology 216 (December 2015): 1–10. http://dx.doi.org/10.1016/j.jbiotec.2015.09.038.
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Vivas, Aisen, Albert van den Berg, Robert Passier, Mathieu Odijk, and Andries D. van der Meer. "Fluidic circuit board with modular sensor and valves enables stand-alone, tubeless microfluidic flow control in organs-on-chips." Lab on a Chip 22, no. 6 (2022): 1231–43. http://dx.doi.org/10.1039/d1lc00999k.
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Translational Organ-on-Chip Platform (TOP) is a multi-institutional effort to develop an open platform for automated organ-on-chip culture that actively facilitates the integration of components from various developers.
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Satoh, T., S. Sugiura, K. Shin, R. Onuki-Nagasaki, S. Ishida, K. Kikuchi, M. Kakiki, and T. Kanamori. "A multi-throughput multi-organ-on-a-chip system on a plate formatted pneumatic pressure-driven medium circulation platform." Lab on a Chip 18, no. 1 (2018): 115–25. http://dx.doi.org/10.1039/c7lc00952f.
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Ong, Louis Jun Ye, Terry Ching, Lor Huai Chong, Seep Arora, Huan Li, Michinao Hashimoto, Ramanuj DasGupta, Po Ki Yuen, and Yi-Chin Toh. "Self-aligning Tetris-Like (TILE) modular microfluidic platform for mimicking multi-organ interactions." Lab on a Chip 19, no. 13 (2019): 2178–91. http://dx.doi.org/10.1039/c9lc00160c.
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An, Fan, Yueyang Qu, Xianming Liu, Runtao Zhong, and Yong Luo. "Organ-on-a-Chip: New Platform for Biological Analysis." Analytical Chemistry Insights 10 (January 2015): ACI.S28905. http://dx.doi.org/10.4137/aci.s28905.
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Direct detection and analysis of biomolecules and cells in physiological microenvironment is urgently needed for fast evaluation of biology and pharmacy. The past several years have witnessed remarkable development opportunities in vitro organs and tissues models with multiple functions based on microfluidic devices, termed as “organ-on-a-chip”. Briefly speaking, it is a promising technology in rebuilding physiological functions of tissues and organs, featuring mammalian cell co-culture and artificial microenvironment created by microchannel networks. In this review, we summarized the advances in studies of heart-, vessel-, liver-, neuron-, kidney- and Multi-organs-on-a-chip, and discussed some noteworthy potential on-chip detection schemes.
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Coppeta, J. R., M. J. Mescher, B. C. Isenberg, A. J. Spencer, E. S. Kim, A. R. Lever, T. J. Mulhern, R. Prantil-Baun, J. C. Comolli, and J. T. Borenstein. "A portable and reconfigurable multi-organ platform for drug development with onboard microfluidic flow control." Lab on a Chip 17, no. 1 (2017): 134–44. http://dx.doi.org/10.1039/c6lc01236a.
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Baker, Matthew, James Munro Cameron, Alexandra Sala, Georgios Antoniou, Holly Butler, Paul Brennan, Justin Conn, et al. "Multicancer early detection with a spectroscopic liquid biopsy platform." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3034. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3034.
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3034 Background: A rapid, low-cost, sensitive, multi-cancer early detection (MCED) test would be transformational in the diagnostics field. Earlier cancer detection and instigation of treatment can increase survival rates. An effective test must accurately identify the small proportion of patients with typically non-specific symptoms who actually have cancer. Such symptoms don’t easily segregate by organ system, necessitating a multi-cancer approach. Methods: In this large-scale study ( n = 2094 patients) we applied the Dxcover Cancer Liquid Biopsy to differentiate cancer against non-cancer, as well as organ specific tests to identify cancers of the brain, breast, colorectal, kidney, lung, ovary, pancreas, and prostate. The test uses Fourier transform infrared spectroscopy to analyze all macromolecules in a minute volume of patient serum, and machine learning to build a classifier of the resultant spectral profiles for calling the likelihood of cancer. Results: For the overall cancer classification, our model achieved 90% sensitivity with 61% specificity when tuned for sensitivity, with detection rates of 93% for stage I, 84% for stage II, 92% for stage III and 95% for stage IV. We also tuned for maximum sensitivity or specificity, whilst the other statistic was fixed above a minimum value of 45%. This resulted in 94% sensitivity with 47% specificity, and 94% specificity with 48% sensitivity, respectively. For organ specific cancer classifiers area under the curve values were calculated for all cancers: brain (0.90), breast (0.74), colorectal (0.91), kidney (0.91), lung (0.90), ovarian (0.85), pancreatic (0.81) and prostate (0.85). Conclusions: Cancer treatment is often more effective when given earlier and this low-cost strategy can facilitate the requisite earlier diagnosis. With further development, the Dxcover MCED test could have a significant impact on early detection of cancer, which is vital in the quest for improved survival and quality of life.
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Baker, Matthew, James Munro Cameron, Alexandra Sala, Georgios Antoniou, Holly Butler, Paul Brennan, Justin Conn, et al. "Multicancer early detection with a spectroscopic liquid biopsy platform." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 3034. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3034.
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3034 Background: A rapid, low-cost, sensitive, multi-cancer early detection (MCED) test would be transformational in the diagnostics field. Earlier cancer detection and instigation of treatment can increase survival rates. An effective test must accurately identify the small proportion of patients with typically non-specific symptoms who actually have cancer. Such symptoms don’t easily segregate by organ system, necessitating a multi-cancer approach. Methods: In this large-scale study ( n = 2094 patients) we applied the Dxcover Cancer Liquid Biopsy to differentiate cancer against non-cancer, as well as organ specific tests to identify cancers of the brain, breast, colorectal, kidney, lung, ovary, pancreas, and prostate. The test uses Fourier transform infrared spectroscopy to analyze all macromolecules in a minute volume of patient serum, and machine learning to build a classifier of the resultant spectral profiles for calling the likelihood of cancer. Results: For the overall cancer classification, our model achieved 90% sensitivity with 61% specificity when tuned for sensitivity, with detection rates of 93% for stage I, 84% for stage II, 92% for stage III and 95% for stage IV. We also tuned for maximum sensitivity or specificity, whilst the other statistic was fixed above a minimum value of 45%. This resulted in 94% sensitivity with 47% specificity, and 94% specificity with 48% sensitivity, respectively. For organ specific cancer classifiers area under the curve values were calculated for all cancers: brain (0.90), breast (0.74), colorectal (0.91), kidney (0.91), lung (0.90), ovarian (0.85), pancreatic (0.81) and prostate (0.85). Conclusions: Cancer treatment is often more effective when given earlier and this low-cost strategy can facilitate the requisite earlier diagnosis. With further development, the Dxcover MCED test could have a significant impact on early detection of cancer, which is vital in the quest for improved survival and quality of life.
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Giampetruzzi, Lucia, Amilcare Barca, Flavio Casino, Simonetta Capone, Tiziano Verri, Pietro Siciliano, and Luca Francioso. "Multi-Sensors Integration in a Human Gut-On-Chip Platform." Proceedings 2, no. 13 (November 13, 2018): 1022. http://dx.doi.org/10.3390/proceedings2131022.
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In the conventional culture systems in vitro, the challenging organoid approach have recently been overcome by the development of microfluidic Organ Chip models of human intestine. The potential future applications of Intestine-on-Chips in disease modelling, drug development and personalized medicine are leading research to identify and investigate limitations of modern chip-based systems and to focus the attention on the gut epithelium and its specific barrier function playing a significant role in many human disorders and diseases. In this paper, we propose and discuss the importance to implement a multi-parameter analysis on an engineered platform for developing an Epithelial Gut On Chip model.
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Chramiec, A., E. Öztürk, M. Wang, K. Ronaldson-Bouchard, D. N. Tavakol, K. Yeager, M. Summers, D. Teles, and G. Vunjak-Novakovic. "296P Recapitulation of organ-specific breast cancer metastasis using an engineered multi-tissue platform." Annals of Oncology 32 (September 2021): S493—S494. http://dx.doi.org/10.1016/j.annonc.2021.08.579.
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Dornhof, Johannes, Jochen Kieninger, Harshini Muralidharan, Jochen Maurer, Gerald A. Urban, and Andreas Weltin. "Microfluidic organ-on-chip system for multi-analyte monitoring of metabolites in 3D cell cultures." Lab on a Chip 22, no. 2 (2022): 225–39. http://dx.doi.org/10.1039/d1lc00689d.
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An organ-on-chip platform equipped with microsensors for long-term microfluidic cultivation and metabolic monitoring (O2, Glu, Lac) of 3D tumour organoid cultures grown from patient-derived single cancer stem cells.
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Yen, Daniel P., Yuta Ando, and Keyue Shen. "A cost-effective micromilling platform for rapid prototyping of microdevices." TECHNOLOGY 04, no. 04 (December 2016): 234–39. http://dx.doi.org/10.1142/s2339547816200041.
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Micromilling has great potential in producing microdevices for lab-on-a-chip and organ-on-a-chip applications, but has remained under-utilized due to the high machinery costs and limited accessibility. In this paper, we assessed the machining capabilities of a low-cost 3-D mill in polycarbonate material, which were showcased by the production of microfluidic devices. The study demonstrates that this particular mill is well suited for the fabrication of multi-scale microdevices with feature sizes from micrometers to centimeters.
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Wang, Ying I., Carlota Oleaga, Christopher J. Long, Mandy B. Esch, Christopher W. McAleer, Paula G. Miller, James J. Hickman, and Michael L. Shuler. "Self-contained, low-cost Body-on-a-Chip systems for drug development." Experimental Biology and Medicine 242, no. 17 (February 17, 2017): 1701–13. http://dx.doi.org/10.1177/1535370217694101.
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Integrated multi-organ microphysiological systems are an evolving tool for preclinical evaluation of the potential toxicity and efficacy of drug candidates. Such systems, also known as Body-on-a-Chip devices, have a great potential to increase the successful conversion of drug candidates entering clinical trials into approved drugs. Systems, to be attractive for commercial adoption, need to be inexpensive, easy to operate, and give reproducible results. Further, the ability to measure functional responses, such as electrical activity, force generation, and barrier integrity of organ surrogates, enhances the ability to monitor response to drugs. The ability to operate a system for significant periods of time (up to 28 d) will provide potential to estimate chronic as well as acute responses of the human body. Here we review progress towards a self-contained low-cost microphysiological system with functional measurements of physiological responses. Impact statement Multi-organ microphysiological systems are promising devices to improve the drug development process. The development of a pumpless system represents the ability to build multi-organ systems that are of low cost, high reliability, and self-contained. These features, coupled with the ability to measure electrical and mechanical response in addition to chemical or metabolic changes, provides an attractive system for incorporation into the drug development process. This will be the most complete review of the pumpless platform with recirculation yet written.
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Shanti, Aya, Bisan Samara, Amal Abdullah, Nicholas Hallfors, Dino Accoto, Jiranuwat Sapudom, Aseel Alatoom, Jeremy Teo, Serena Danti, and Cesare Stefanini. "Multi-Compartment 3D-Cultured Organ-on-a-Chip: Towards a Biomimetic Lymph Node for Drug Development." Pharmaceutics 12, no. 5 (May 19, 2020): 464. http://dx.doi.org/10.3390/pharmaceutics12050464.
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The interaction of immune cells with drugs and/or with other cell types should be mechanistically investigated in order to reduce attrition of new drug development. However, they are currently only limited technologies that address this need. In our work, we developed initial but significant building blocks that enable such immune-drug studies. We developed a novel microfluidic platform replicating the Lymph Node (LN) microenvironment called LN-on-a-chip, starting from design all the way to microfabrication, characterization and validation in terms of architectural features, fluidics, cytocompatibility, and usability. To prove the biomimetics of this microenvironment, we inserted different immune cell types in a microfluidic device, which showed an in-vivo-like spatial distribution. We demonstrated that the developed LN-on-a-chip incorporates key features of the native human LN, namely, (i) similarity in extracellular matrix composition, morphology, porosity, stiffness, and permeability, (ii) compartmentalization of immune cells within distinct structural domains, (iii) replication of the lymphatic fluid flow pattern, (iv) viability of encapsulated cells in collagen over the typical timeframe of immunotoxicity experiments, and (v) interaction among different cell types across chamber boundaries. Further studies with this platform may assess the immune cell function as a step forward to disclose the effects of pharmaceutics to downstream immunology in more physiologically relevant microenvironments.
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Sun, Qiyue, Jianghua Pei, Qinyu Li, Kai Niu, and Xiaolin Wang. "Reusable Standardized Universal Interface Module (RSUIM) for Generic Organ-on-a-Chip Applications." Micromachines 10, no. 12 (December 5, 2019): 849. http://dx.doi.org/10.3390/mi10120849.
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The modular-based multi-organ-on-a-chip enables more stable and flexible configuration to better mimic the complex biological phenomena for versatile biomedical applications. However, the existing magnetic-based interconnection modes are mainly realized by directly embedding and/or fixing magnets into the modular microfluidic devices for single use only, which will inevitably increase the complexity and cost during the manufacturing process. Here, we present a novel design of a reusable standardized universal interface module (RSUIM), which is highly suitable for generic organ-on-chip applications and their integration into multi-organ systems. Both pasting-based and clamping-based interconnection modes are developed in a plug-and-play manner without fluidic leakage. Furthermore, due to the flexibility of the modular design, it is simple to integrate multiple assembled modular devices through parallel configuration into a high throughput platform. To test its effectiveness, experiments on the construction of both the microvascular network and vascularized tumor model are performed by using the integration of the generic vascularized organ-on-a-chip module and pasting-based RSUIM, and their quantitative analysis results on the reproducibility and anti-cancer drug screening validation are further performed. We believe that this RSUIM design will become a standard and critical accessory for a broad range of organ-on-a-chip applications and is easy for commercialization with low cost.
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Horland, Reyk, Eva-Maria Materne, Ilka Wagner, Katharina Schimek, Tobias Hasenberg, Alexandra Lorenz, Annika Jaenicke, et al. "The Multi-Organ-Chip (MOC) – A universal microfluidic platform for long-term tissue maintenance and substance testing." Toxicology Letters 229 (September 2014): S139. http://dx.doi.org/10.1016/j.toxlet.2014.06.490.
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Rajan, Shiny Amala Priya, Julio Aleman, MeiMei Wan, Nima Pourhabibi Zarandi, Goodwell Nzou, Sean Murphy, Colin E. Bishop, et al. "Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform." Acta Biomaterialia 106 (April 2020): 124–35. http://dx.doi.org/10.1016/j.actbio.2020.02.015.
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Di Tocco, Joshua, Daniela Lo Presti, Carlo Massaroni, Stefano Cinti, Sara Cimini, Laura De Gara, and Emiliano Schena. "Plant-Wear: A Multi-Sensor Plant Wearable Platform for Growth and Microclimate Monitoring." Sensors 23, no. 1 (January 3, 2023): 549. http://dx.doi.org/10.3390/s23010549.
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Wearable devices are widely spreading in various scenarios for monitoring different parameters related to human and recently plant health. In the context of precision agriculture, wearables have proven to be a valuable alternative to traditional measurement methods for quantitatively monitoring plant development. This study proposed a multi-sensor wearable platform for monitoring the growth of plant organs (i.e., stem and fruit) and microclimate (i.e., environmental temperature—T and relative humidity—RH). The platform consists of a custom flexible strain sensor for monitoring growth when mounted on a plant and a commercial sensing unit for monitoring T and RH values of the plant surrounding. A different shape was conferred to the strain sensor according to the plant organs to be engineered. A dumbbell shape was chosen for the stem while a ring shape for the fruit. A metrological characterization was carried out to investigate the strain sensitivity of the proposed flexible sensors and then preliminary tests were performed in both indoor and outdoor scenarios to assess the platform performance. The promising results suggest that the proposed system can be considered one of the first attempts to design wearable and portable systems tailored to the specific plant organ with the potential to be used for future applications in the coming era of digital farms and precision agriculture.
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Soragni, Camilla, Gwenaëlle Rabussier, Leon J. de Windt, Sebastian J. Trietsch, Henriëtte L. Lanz, and Chee P. Ng. "High throughput assay to quantify oxidative stress in organ-on-a-chip placenta models in a multi-chip platform." Placenta 112 (September 2021): e26. http://dx.doi.org/10.1016/j.placenta.2021.07.087.
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Baert, Y., I. Ruetschle, W. Cools, A. Oehme, A. Lorenz, U. Marx, E. Goossens, and I. Maschmeyer. "A multi-organ-chip co-culture of liver and testis equivalents: a first step toward a systemic male reprotoxicity model." Human Reproduction 35, no. 5 (May 1, 2020): 1029–44. http://dx.doi.org/10.1093/humrep/deaa057.
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Abstract STUDY QUESTION Is it possible to co-culture and functionally link human liver and testis equivalents in the combined medium circuit of a multi-organ chip? SUMMARY ANSWER Multi-organ-chip co-cultures of human liver and testis equivalents were maintained at a steady-state for at least 1 week and the co-cultures reproduced specific natural and drug-induced liver–testis systemic interactions. WHAT IS KNOWN ALREADY Current benchtop reprotoxicity models typically do not include hepatic metabolism and interactions of the liver–testis axis. However, these are important to study the biotransformation of substances. STUDY DESIGN, SIZE, DURATION Testicular organoids derived from primary adult testicular cells and liver spheroids consisting of cultured HepaRG cells and hepatic stellate cells were loaded into separate culture compartments of each multi-organ-chip circuit for co-culture in liver spheroid-specific medium, testicular organoid-specific medium or a combined medium over a week. Additional multi-organ-chips (single) and well plates (static) were loaded only with testicular organoids or liver spheroids for comparison. Subsequently, the selected type of medium was supplemented with cyclophosphamide, an alkylating anti-neoplastic prodrug that has demonstrated germ cell toxicity after its bioactivation in the liver, and added to chip-based co-cultures to replicate a human liver–testis systemic interaction in vitro. Single chip-based testicular organoids were used as a control. Experiments were performed with three biological replicates unless otherwise stated. PARTICIPANTS/MATERIALS, SETTING, METHODS The metabolic activity was determined as glucose consumption and lactate production. The cell viability was measured as lactate dehydrogenase activity in the medium. Additionally, immunohistochemical and real-time quantitative PCR end-point analyses were performed for apoptosis, proliferation and cell-specific phenotypical and functional markers. The functionality of Sertoli and Leydig cells in testicular spheroids was specifically evaluated by measuring daily inhibin B and testosterone release, respectively. MAIN RESULTS AND THE ROLE OF CHANCE Co-culture in multi-organ chips with liver spheroid-specific medium better supported the metabolic activity of the cultured tissues compared to other media tested. The liver spheroids did not show significantly different behaviour during co-culture compared to that in single culture on multi-organ-chips. The testicular organoids also developed accordingly and produced higher inhibin B but lower testosterone levels than the static culture in plates with testicular organoid-specific medium. By comparison, testosterone secretion by testicular organoids cultured individually on multi-organ-chips reached a similar level as the static culture at Day 7. This suggests that the liver spheroids have metabolised the steroids in the co-cultures, a naturally occurring phenomenon. The addition of cyclophosphamide led to upregulation of specific cytochromes in liver spheroids and loss of germ cells in testicular organoids in the multi-organ-chip co-cultures but not in single-testis culture. LARGE-SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION The number of biological replicates included in this study was relatively small due to the limited availability of individual donor testes and the labour-intensive nature of multi-organ-chip co-cultures. Moreover, testicular organoids and liver spheroids are miniaturised organ equivalents that capture key features, but are still simplified versions of the native tissues. Also, it should be noted that only the prodrug cyclophosphamide was administered. The final concentration of the active metabolite was not measured. WIDER IMPLICATIONS OF THE FINDINGS This co-culture model responds to the request of setting up a specific tool that enables the testing of candidate reprotoxic substances with the possibility of human biotransformation. It further allows the inclusion of other human tissue equivalents for chemical risk assessment on the systemic level. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by research grants from the Scientific Research Foundation Flanders (FWO), Universitair Ziekenhuis Brussel (scientific fund Willy Gepts) and the Vrije Universiteit Brussel. Y.B. is a postdoctoral fellow of the FWO. U.M. is founder, shareholder and CEO of TissUse GmbH, Berlin, Germany, a company commercializing the Multi-Organ-Chip platform systems used in the study. The other authors have no conflict of interest to declare.
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Yazdanbakhsh, Nima, and Joachim Fisahn. "High throughput phenotyping of root growth dynamics, lateral root formation, root architecture and root hair development enabled by PlaRoM." Functional Plant Biology 36, no. 11 (2009): 938. http://dx.doi.org/10.1071/fp09167.
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Plant organ phenotyping by non-invasive video imaging techniques provides a powerful tool to assess physiological traits and biomass production. We describe here a range of applications of a recently developed plant root monitoring platform (PlaRoM). PlaRoM consists of an imaging platform and a root extension profiling software application. This platform has been developed for multi parallel recordings of root growth phenotypes of up to 50 individual seedlings over several days, with high spatial and temporal resolution. PlaRoM can investigate root extension profiles of different genotypes in various growth conditions (e.g. light protocol, temperature, growth media). In particular, we present primary root growth kinetics that was collected over several days. Furthermore, addition of 0.01% sucrose to the growth medium provided sufficient carbohydrates to maintain reduced growth rates in extended nights. Further analysis of records obtained from the imaging platform revealed that lateral root development exhibits similar growth kinetics to the primary root, but that root hairs develop in a faster rate. The compatibility of PlaRoM with currently accessible software packages for studying root architecture will be discussed. We are aiming for a global application of our collected root images to analytical tools provided in remote locations.
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Tang, Xuming, Dongxiang Xue, Tuo Zhang, Benjamin E. Nilsson-Payant, Lucia Carrau, Xiaohua Duan, Miriam Gordillo, et al. "A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection." Nature Cell Biology 25, no. 3 (March 2023): 381–89. http://dx.doi.org/10.1038/s41556-023-01095-y.
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AbstractCOVID-19 is a systemic disease involving multiple organs. We previously established a platform to derive organoids and cells from human pluripotent stem cells to model SARS-CoV-2 infection and perform drug screens1,2. This provided insight into cellular tropism and the host response, yet the molecular mechanisms regulating SARS-CoV-2 infection remain poorly defined. Here we systematically examined changes in transcript profiles caused by SARS-CoV-2 infection at different multiplicities of infection for lung airway organoids, lung alveolar organoids and cardiomyocytes, and identified several genes that are generally implicated in controlling SARS-CoV-2 infection, including CIART, the circadian-associated repressor of transcription. Lung airway organoids, lung alveolar organoids and cardiomyocytes derived from isogenic CIART−/− human pluripotent stem cells were significantly resistant to SARS-CoV-2 infection, independently of viral entry. Single-cell RNA-sequencing analysis further validated the decreased levels of SARS-CoV-2 infection in ciliated-like cells of lung airway organoids. CUT&RUN, ATAC-seq and RNA-sequencing analyses showed that CIART controls SARS-CoV-2 infection at least in part through the regulation of NR4A1, a gene also identified from the multi-organoid analysis. Finally, transcriptional profiling and pharmacological inhibition led to the discovery that the Retinoid X Receptor pathway regulates SARS-CoV-2 infection downstream of CIART and NR4A1. The multi-organoid platform identified the role of circadian-clock regulation in SARS-CoV-2 infection, which provides potential therapeutic targets for protection against COVID-19 across organ systems.
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Rivest, François, Victor de Gautard, Vytautas Navikas, Saska Brajkovic, and Bastian Nicolai. "Abstract 5642: Validation of a novel multiplex immuno-fluorescence panel for the spatial analysis of the tumor microenvironment." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5642. http://dx.doi.org/10.1158/1538-7445.am2023-5642.
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Abstract IHC counterparts. Subsequently, the panel was transferred on a multi-organ TMA including several tumoral and non-tumoral specimens, showing robust performance across multiple tissue types. The protocol was optimized to achieve high staining quality for all 13 markers in terms of signal specificity Investigation of the tumor microenvironment (TME) by multiplex immunofluorescence (mIF) has accelerated the understanding of the spatial immune context in tumors. mIF has proven to be a powerful technique for the identification of new potential biomarkers and therapeutical targets. Despite increased application of mIF assays to characterize the TME, state-of-the art protocols remain technically challenging. Manual execution and use of dedicated reagents render them lengthy and costly. Moreover, their reproducibility is often questioned together with their transferability between different tissue types. Here, we show the development and validation of an Immuno-Oncology (IO) Core Panel of 13 clinically relevant biomarkers to enable spatial analysis of the immune TME on the COMET™ platform across various tissue types. Formalin-fixed paraffin-embedded human tissue sections from tonsil and a 24-cores multi-organ tissue microarray (TMA) were stained using the IO Core Panel from Lunaphore on the COMET™ platform by fully automated sequential immunofluorescence (seqIF™), which consists of cycles of staining, imaging, and elution. The panel allows for simultaneous detection of CD3, CD4, CD8, CD45, FoxP3, PD1, PD-L1, CD11c, CD20, CD56, CD68, aSMA and Ki-67 by indirect immunofluorescence using unlabeled primary antibodies and Alexa Fluor™ Plus secondary antibodies. The 13-plex IO Core panel was initially developed and validated on tonsil as positive control tissue. To compare immunofluorescent (IF) and immunohistochemistry (IHC) staining patterns, the sections retrieved from COMET™ after seqIF™, were stained by a histology facility with standard IHC established for routine pathological diagnosis. All markers demonstrate accurate detection with specific IF staining, comparably to gold-standard, sensitivity, ratio to background and dynamic range. The repeatability and reproducibility of the automated IO Core Panel on the COMET™ platform was verified by day-to-day tests on one platform and tests among multiple platforms, respectively. Our study demonstrated the robustness of the validated IO Core Panel across multiple tissue types with highly specific and reproducible results. The marker detection with standard indirect immunofluorescence on the COMET™ instrument allows for future, rapid expansion and customization of the panel including additional primary antibodies towards the need of the individual underlying scientific question. Citation Format: François Rivest, Victor de Gautard, Vytautas Navikas, Saska Brajkovic, Bastian Nicolai. Validation of a novel multiplex immuno-fluorescence panel for the spatial analysis of the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5642.
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Khassawneh, Basheer, Chengsong Zhu, Briana Barkes, Brian Vestal, Sarah Shrock, May Gillespie, Karin Pacheco, et al. "Autoantibody profile in sarcoidosis, analysis from the GRADS sarcoidosis cohort." PLOS ONE 17, no. 10 (October 20, 2022): e0274381. http://dx.doi.org/10.1371/journal.pone.0274381.
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Background Sarcoidosis, a multi-systemic granulomatous disease, is a predominantly T-cell disease but evidence for a role for humoral immunity in disease pathogenesis is growing. Utilizing samples from the Genomic Research in Alpha-1 anti-trypsin Deficiency and Sarcoidosis (GRADS) study, we examined the prevalence of autoantibodies in sarcoidosis patients with pulmonary-only and extra-pulmonary organ involvement compared to normal controls. Study design and methods We analyzed serum samples from sarcoidosis patients who participated in the GRADS study utilizing an autoantigen microarray platform for both IgM and IgG antibodies. The cohort included sarcoidosis patients with pulmonary-only disease (POS, n = 106), sarcoidosis patients with extra-pulmonary disease (EPS, n = 120) and a normal control cohort (NC, n = 101). Organ involvement was assessed following a standardized format across all GRADS participating centers. Results Sarcoidosis patients overall had increased levels of IgM and IgG autoantibodies compared to normal controls. In addition, several autoantibodies were elevated in the POS and EPS cohorts compared to the NC cohort. Differences in autoantibody levels were also noted between the POS and the EPS cohorts. When comparing organ involvement with sarcoidosis, bone, spleen and ear, nose and throat involvement had higher IgM expression than other organs. Conclusion Sarcoidosis patients have elevated IgM and IgG autoantibody levels compared to normal controls. In addition, individuals with pulmonary as well as additional organ involvement had higher IgM expression. Further research is needed focusing on specific organ-autoantibody pairs and role of autoantibodies in disease pathogenesis.
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Cameron, Tiffany C., Avineet Randhawa, Samantha M. Grist, Tanya Bennet, Jessica Hua, Luis G. Alde, Tara M. Caffrey, Cheryl L. Wellington, and Karen C. Cheung. "PDMS Organ-On-Chip Design and Fabrication: Strategies for Improving Fluidic Integration and Chip Robustness of Rapidly Prototyped Microfluidic In Vitro Models." Micromachines 13, no. 10 (September 22, 2022): 1573. http://dx.doi.org/10.3390/mi13101573.
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The PDMS-based microfluidic organ-on-chip platform represents an exciting paradigm that has enjoyed a rapid rise in popularity and adoption. A particularly promising element of this platform is its amenability to rapid manufacturing strategies, which can enable quick adaptations through iterative prototyping. These strategies, however, come with challenges; fluid flow, for example, a core principle of organs-on-chip and the physiology they aim to model, necessitates robust, leak-free channels for potentially long (multi-week) culture durations. In this report, we describe microfluidic chip fabrication methods and strategies that are aimed at overcoming these difficulties; we employ a subset of these strategies to a blood–brain-barrier-on-chip, with others applied to a small-airway-on-chip. Design approaches are detailed with considerations presented for readers. Results pertaining to fabrication parameters we aimed to improve (e.g., the thickness uniformity of molded PDMS), as well as illustrative results pertaining to the establishment of cell cultures using these methods will also be presented.
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Kim, Gyeong-Ji, Kwon-Jai Lee, Jeong-Woo Choi, and Jeung Hee An. "Drug Evaluation Based on a Multi-Channel Cell Chip with a Horizontal Co-Culture." International Journal of Molecular Sciences 22, no. 13 (June 29, 2021): 6997. http://dx.doi.org/10.3390/ijms22136997.
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We developed a multi-channel cell chip containing a three-dimensional (3D) scaffold for horizontal co-culture and drug toxicity screening in multi-organ culture (human glioblastoma, cervical cancer, normal liver cells, and normal lung cells). The polydimethylsiloxane (PDMS) multi-channel cell chip (PMCCC) was based on fused deposition modeling (FDM) technology. The architecture of the PMCCC was an open-type cell chip and did not require a pump or syringe. We investigated cell proliferation and cytotoxicity by conducting 3-(4,5-dimethylthiazol-2-yl)-2,5-dphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays and analysis of oleanolic acid (OA)-treated multi-channel cell chips. The results of the MTT and LDH assays showed that OA treatment in the multi-channel cell chip of four cell lines enhanced chemoresistance of cells compared with that in the 2D culture. Furthermore, we demonstrated the feasibility of the application of our multi-channel cell chip in various analysis methods through Annexin V-fluorescein isothiocyanate/propidium iodide staining, which is not used for conventional cell chips. Taken together, the results demonstrated that the PMCCC may be used as a new 3D platform because it enables simultaneous drug screening in multiple cells by single point injection and allows analysis of various biological processes.
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Abu-Dawas, Sadeq, Hawra Alawami, Mohammed Zourob, and Qasem Ramadan. "Design and Fabrication of Low-Cost Microfluidic Chips and Microfluidic Routing System for Reconfigurable Multi-(Organ-on-a-Chip) Assembly." Micromachines 12, no. 12 (December 11, 2021): 1542. http://dx.doi.org/10.3390/mi12121542.
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A low-cost, versatile, and reconfigurable fluidic routing system and chip assembly have been fabricated and tested. The platform and its accessories were fabricated in-house without the need for costly and specialized equipment nor specific expertise. An agarose-based artificial membrane was integrated into the chips and employed to test the chip-to-chip communication in various configurations. Various chip assemblies were constructed and tested which demonstrate the versatile utility of the fluidic routing system that enables the custom design of the chip-to-chip communication and the possibility of fitting a variety of (organ-on-a-chip)-based biological models with multicell architectures. The reconfigurable chip assembly would enable selective linking/isolating the desired chip/compartment, hence allowing the study of the contribution of specific cell/tissue within the in vitro models.
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Fedi, Arianna, Chiara Vitale, Marco Fato, and Silvia Scaglione. "A Human Ovarian Tumor & Liver Organ-on-Chip for Simultaneous and More Predictive Toxo-Efficacy Assays." Bioengineering 10, no. 2 (February 18, 2023): 270. http://dx.doi.org/10.3390/bioengineering10020270.
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In oncology, the poor success rate of clinical trials is becoming increasingly evident due to the weak predictability of preclinical assays, which either do not recapitulate the complexity of human tissues (i.e., in vitro tests) or reveal species-specific outcomes (i.e., animal testing). Therefore, the development of novel approaches is fundamental for better evaluating novel anti-cancer treatments. Here, a multicompartmental organ-on-chip (OOC) platform was adopted to fluidically connect 3D ovarian cancer tissues to hepatic cellular models and resemble the systemic cisplatin administration for contemporarily investigating drug efficacy and hepatotoxic effects in a physiological context. Computational fluid dynamics was performed to impose capillary-like blood flows and predict cisplatin diffusion. After a cisplatin concentration screening using 2D/3D tissue models, cytotoxicity assays were conducted in the multicompartmental OOC and compared with static co-cultures and dynamic single-organ models. A linear decay of SKOV-3 ovarian cancer and HepG2 liver cell viability was observed with increasing cisplatin concentration. Furthermore, 3D ovarian cancer models showed higher drug resistance than the 2D model in static conditions. Most importantly, when compared to clinical therapy, the experimental approach combining 3D culture, fluid-dynamic conditions, and multi-organ connection displayed the most predictive toxicity and efficacy results, demonstrating that OOC-based approaches are reliable 3Rs alternatives in preclinic.
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Pinezich, Meghan, and Gordana Vunjak-Novakovic. "Bioengineering approaches to organ preservation ex vivo." Experimental Biology and Medicine 244, no. 8 (March 19, 2019): 630–45. http://dx.doi.org/10.1177/1535370219834498.
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The advent of successful solid organ transplantation is undoubtedly among the most significant medical achievements of the 20th century. Despite advances in the field of transplantation since its inception over 50 years ago, our approach to donor organ preservation outside of the body remains unchanged. Recently, attempts have been made to replace static cold storage with more sophisticated ex vivo machine perfusion. Rather than cooling the organ on ice to slow metabolic processes, machine perfusion aims to support normal metabolic function in a near-physiologic environment and to provide a platform on which the organ can be evaluated, preserved, and recovered. Ex vivo machine perfusion devices have demonstrated early success with respect to transplant outcomes in heart, lung, and liver, with perfusion times limited to several hours. The continued development of more advanced perfusion systems is likely to extend the duration of ex vivo organ support to days or even weeks, and enable recovery of initially unsuitable donor organs. In this review, we discuss recent clinical and pre-clinical studies, state-of-the-art organ preservation technologies, existing limitations, and a perspective on future developments. Impact statement Over the past several decades, ex vivo perfusion has emerged as a promising technology for the assessment, preservation, and recovery of donor organs. Many exciting pre-clinical findings have now been translated to clinical use, and successful transplantation following ex vivo perfusion has been achieved for heart, lung, and liver. While machine perfusion provides distinct advantages over traditional cold preservation, many challenges remain, including that of long-term (multi-day) ex vivo support. Here, we provide an overview of the current status of ex vivo machine perfusion in the pre-clinical and clinical setting and share our perspective on the future direction of the field.
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Järvinen, Tero A. H., and Toini Pemmari. "Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine." Nanomaterials 10, no. 2 (January 28, 2020): 226. http://dx.doi.org/10.3390/nano10020226.
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Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic blood vessels in the regenerating tissues have a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an appealing opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives to a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine.
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Tunesi, Marta, Luca Izzo, Ilaria Raimondi, Diego Albani, and Carmen Giordano. "A miniaturized hydrogel-based in vitro model for dynamic culturing of human cells overexpressing beta-amyloid precursor protein." Journal of Tissue Engineering 11 (January 2020): 204173142094563. http://dx.doi.org/10.1177/2041731420945633.
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Recent findings have highlighted an interconnection between intestinal microbiota and the brain, referred to as microbiota–gut–brain axis, and suggested that alterations in microbiota composition might affect brain functioning, also in Alzheimer’s disease. To investigate microbiota–gut–brain axis biochemical pathways, in this work we developed an innovative device to be used as modular unit in an engineered multi-organ-on-a-chip platform recapitulating in vitro the main players of the microbiota–gut–brain axis, and an innovative three-dimensional model of brain cells based on collagen/hyaluronic acid or collagen/poly(ethylene glycol) semi-interpenetrating polymer networks and β-amyloid precursor protein-Swedish mutant-expressing H4 cells, to simulate the pathological scenario of Alzheimer’s disease. We set up the culturing conditions, assessed cell response, scaled down the three-dimensional models to be hosted in the organ-on-a-chip device, and cultured them both in static and in dynamic conditions. The results suggest that the device and three-dimensional models are exploitable for advanced engineered models representing brain features also in Alzheimer’s disease scenario.
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Díaz Lantada, Andrés, Wilhelm Pfleging, Heino Besser, Markus Guttmann, Markus Wissmann, Klaus Plewa, Peter Smyrek, Volker Piotter, and Josefa García-Ruíz. "Research on the Methods for the Mass Production of Multi-Scale Organs-On-Chips." Polymers 10, no. 11 (November 7, 2018): 1238. http://dx.doi.org/10.3390/polym10111238.
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The success of labs- and organs-on-chips as transformative technologies in the biomedical arena relies on our capacity of solving some current challenges related to their design, modeling, manufacturability, and usability. Among present needs for the industrial scalability and impact promotion of these bio-devices, their sustainable mass production constitutes a breakthrough for reaching the desired level of repeatability in systematic testing procedures based on labs- and organs-on-chips. The use of adequate biomaterials for cell-culture processes and the achievement of the multi-scale features required, for in vitro modeling the physiological interactions among cells, tissues, and organoids, which prove to be demanding requirements in terms of production. This study presents an innovative synergistic combination of technologies, including: laser stereolithography, laser material processing on micro-scale, electroforming, and micro-injection molding, which enables the rapid creation of multi-scale mold cavities for the industrial production of labs- and organs-on-chips using thermoplastics apt for in vitro testing. The procedure is validated by the design, rapid prototyping, mass production, and preliminary testing with human mesenchymal stem cells of a conceptual multi-organ-on-chip platform, which is conceived for future studies linked to modeling cell-to-cell communication, understanding cell-material interactions, and studying metastatic processes.
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Noorani, Behnam, Aditya Bhalerao, Snehal Raut, Ehsan Nozohouri, Ulrich Bickel, and Luca Cucullo. "A Quasi-Physiological Microfluidic Blood-Brain Barrier Model for Brain Permeability Studies." Pharmaceutics 13, no. 9 (September 15, 2021): 1474. http://dx.doi.org/10.3390/pharmaceutics13091474.
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Microfluidics-based organ-on-a-chip technology allows for developing a new class of in-vitro blood-brain barrier (BBB) models that recapitulate many hemodynamic and architectural features of the brain microvasculature not attainable with conventional two-dimensional platforms. Herein, we describe and validate a novel microfluidic BBB model that closely mimics the one in situ. Induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) were juxtaposed with primary human pericytes and astrocytes in a co-culture to enable BBB-specific characteristics, such as low paracellular permeability, efflux activity, and osmotic responses. The permeability coefficients of [13C12] sucrose and [13C6] mannitol were assessed using a highly sensitive LC-MS/MS procedure. The resulting BBB displayed continuous tight-junction patterns, low permeability to mannitol and sucrose, and quasi-physiological responses to hyperosmolar opening and p-glycoprotein inhibitor treatment, as demonstrated by decreased BBB integrity and increased permeability of rhodamine 123, respectively. Astrocytes and pericytes on the abluminal side of the vascular channel provided the environmental cues necessary to form a tight barrier and extend the model’s long-term viability for time-course studies. In conclusion, our novel multi-culture microfluidic platform showcased the ability to replicate a quasi-physiological brain microvascular, thus enabling the development of a highly predictive and translationally relevant BBB model.
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Ando, Yayoi, Tatsunori Shimoi, Kuniko Sunami, Natsuko Tsuda Okita, Mikio Mori, Taro Shibata, Kenichi Nakamura, and Noboru Yamamoto. "Progress report of a cross-organ and biomarker-based platform study: BELIEVE trial NCCH1901." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): TPS1611. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.tps1611.
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TPS1611 Background: Cancer Genomic Medicine (CGM) has been developing and more patients have received the comprehensive genomic profiling (GCP) test under national healthcare system in Japan. However, the number of patients who could receive the genomically matched therapy based on the results of CGP tests was limited. To improve the drug accessibility, we initiated a cross-organ, biomarker-based clinical trial (NCCH1901, the BELIEVE trial). It was a platform trial and could be considered as the Japanese counterpart to the National Cancer Institute's Molecular Analysis for Therapy Choice (NCI-MATCH) study in the United States. Methods: It was a multi-institutional joint research nationwide led by NCCH with a master’s protocol. Several drug cohorts were pre-established, allowing patients to participate in molecularly targeted treatments recommended as a result of CGP test. All drugs were provided for free from the pharmaceutical companies. The objective of this trial was to administer off-label drugs for the respective genomic abnormalities and collect efficacy and safety data for patients of the drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. This trial has been conducted under both of the Japanese Clinical Trial Act and the patient-proposed healthcare services which enable patients to receive unapproved, off-label drugs partially covered by National Health Insurance. The protocol and the informed consent forms were approved by the National Cancer Center Hospital (NCCH) certified review board and the Ministry of Health, Labour and Welfare (MHLW). The trial was registered in the Japan Registry of Clinical Trials (jRCTs031190104). As of January 31, 2023, we have 20 drug cohorts and the planned number of enrollments for each cohort was 50 with the target lesions and 30 without the target lesions. There were more than 500 patients so far. The most common cancer was brain tumours, followed by carcinoma of endocrine organs and the colorectal cancer. BRAF mutation and ERBB2 amplification were the frequent genomic abnormalities registered in this trial. Five drug cohorts have already finished recruiting and 2 drug cohorts assessed their efficacies. We are still continuing to discuss several pharmaceutical companies to increase the drugs cohorts in this platform. This trial is now recruiting the patients and is contributing significantly to increase the treatment opportunity for the cancer patients. Clinical trial information: jRCTs031190104 .
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Pizarroso, Nuria, Pablo Fuciños, Catarina Gonçalves, Lorenzo Pastrana, and Isabel Amado. "A Review on the Role of Food-Derived Bioactive Molecules and the Microbiota–Gut–Brain Axis in Satiety Regulation." Nutrients 13, no. 2 (February 16, 2021): 632. http://dx.doi.org/10.3390/nu13020632.
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Obesity is a chronic disease resulting from an imbalance between energy intake and expenditure. The growing relevance of this metabolic disease lies in its association with other comorbidities. Obesity is a multifaceted disease where intestinal hormones such as cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY), produced by enteroendocrine cells (EECs), have a pivotal role as signaling systems. Receptors for these hormones have been identified in the gut and different brain regions, highlighting the interconnection between gut and brain in satiation mechanisms. The intestinal microbiota (IM), directly interacting with EECs, can be modulated by the diet by providing specific nutrients that induce environmental changes in the gut ecosystem. Therefore, macronutrients may trigger the microbiota–gut–brain axis (MGBA) through mechanisms including specific nutrient-sensing receptors in EECs, inducing the secretion of specific hormones that lead to decreased appetite or increased energy expenditure. Designing drugs/functional foods based in bioactive compounds exploiting these nutrient-sensing mechanisms may offer an alternative treatment for obesity and/or associated metabolic diseases. Organ-on-a-chip technology represents a suitable approach to model multi-organ communication that can provide a robust platform for studying the potential of these compounds as modulators of the MGBA.
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Tiwari, Shivani, Varsha Sharma, Mubarak Mujawar, Yogendra Kumar Mishra, Ajeet Kaushik, and Anujit Ghosal. "Biosensors for Epilepsy Management: State-of-Art and Future Aspects." Sensors 19, no. 7 (March 28, 2019): 1525. http://dx.doi.org/10.3390/s19071525.
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Epilepsy is a serious neurological disorder which affects every aspect of patients’ life, including added socio-economic burden. Unfortunately, only a few suppressive medicines are available, and a complete cure for the disease has not been found yet. Excluding the effectiveness of available therapies, the timely detection and monitoring of epilepsy are of utmost priority for early remediation and prevention. Inability to detect underlying epileptic signatures at early stage causes serious damage to the central nervous system (CNS) and irreversible detrimental variations in the organ system. Therefore, development of a multi-task solving novel smart biosensing systems is urgently required. The present review highlights advancements in state-of-art biosensing technology investigated for epilepsy diseases diagnostics and progression monitoring or both together. State of art epilepsy biosensors are composed of nano-enabled smart sensing platform integrated with micro/electronics and display. These diagnostics systems provide bio-information needed to understand disease progression and therapy optimization timely. The associated challenges related to the development of an efficient epilepsy biosensor and vision considering future prospects are also discussed in this report. This review will serve as a guide platform to scholars for understanding and planning of future research aiming to develop a smart bio-sensing system to detect and monitor epilepsy for point-of-care (PoC) applications.
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Hemke, Robert, Kai Yang, Jad Husseini, Miriam A. Bredella, and F. Joseph Simeone. "Organ dose and total effective dose of whole-body CT in multiple myeloma patients." Skeletal Radiology 49, no. 4 (October 15, 2019): 549–54. http://dx.doi.org/10.1007/s00256-019-03292-z.
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Abstract Objective To evaluate organ dose and total effective dose of whole-body low-dose CT (WBLDCT) performed on different CT-scanner models in patients with multiple myeloma (MM) and to compare it to the effective dose of radiographic skeletal survey and representative diagnostic CTs. Material and methods We retrospectively analyzed data from 228 patients (47.4% females, mean age 67.9 ± 10.4 years, mean weight 81.8 ± 22.4 kg) who underwent WBLDCT for the work-up or surveillance of MM. Patients were scanned using one of six multi-detector CT-scanners. Organ doses and total effective doses per scan were calculated using a commercially available dose-management platform (Radimetrics, Bayer Healthcare, Leverkusen, Germany). The median effective dose was compared to radiographic skeletal survey and representative diagnostic CTs. Results The mean effective dose of our WBLDCT-protocol was 4.82 mSv. A significantly higher effective dose was observed in females compared to males (4.95 vs. 4.70 mSv, P = 0.002). Mean organ dose ranged from 3.72 mSv (esophagus) to 13.09 mSv (skeleton). Mean effective dose varied amongst different CT-scanners (range 4.34–8.37 mSv). The median effective dose of WBLDCT was more than twice the dose of a skeletal survey (4.82 vs. 2.04 mSv), 23% higher than a diagnostic contrast-enhanced chest CT (3.9 mSv), 46% lower than a diagnostic contrast-enhanced abdomen/pelvis CT (9.0 mSv), and 45% lower than a lumbar spine CT (8.7 mSv). Conclusions WBLDCT in MM has a higher effective dose than a radiographic skeletal survey, but a lower effective dose than diagnostic CTs of lumbar spine, abdomen and pelvis. This underlines the broad applicability of WBLDCT in the management of MM patients.
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Singh, Pragya, Daniel Montemayor, Annapurna Pamreddy, Viktor Drel, HongPing Ye, Anthony Franzone, Yanyi Zang, et al. "332 Role of Kynurenine/Tryptophan Ratio in Kidney-Lung crosstalk in two porcine trauma-induced multi-organ injury models." Journal of Clinical and Translational Science 7, s1 (April 2023): 99. http://dx.doi.org/10.1017/cts.2023.379.
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OBJECTIVES/GOALS: Multiple Organ Failure, often precipitated by Acute Lung Injury, is a life-threatening condition that causes death in military and civilian life. Furthermore, Acute Kidney Injury is very common, increasing morbidity and mortality rates. Therefore, understanding the molecular difference between survivors and non-survivors is urgently needed. METHODS/STUDY POPULATION: A 24-hour unilateral pulmonary contusion porcine model (pneumonectomy) of trauma-induced Multiple Organ Failure (MOF) model (n=17) and separate 48-hour polytrauma injury of bilateral pulmonary contusion, traumatic brain injury, and hemorrhage (polytrauma) MOF model (n=26) was developed at Dr. Batchinsky's AREVA laboratory. Serum was assayed at baseline and 3h or 6h post-trauma for amino acid metabolites using the Zip-Chip platform for mass spectrometry. The IDO1 enzyme activity assay kit (ab235936) was used to measure IDO1 enzyme activity in the tissue. Mass Spectrometry Imaging (MSI) was employed to frozen kidney tissues. Tissues were sectioned to 10- micron thickness. For MSI, the DAN matrix was utilized, and MALDI-MSI images were processed and obtained from METASPACE and SCILS software. RESULTS/ANTICIPATED RESULTS: In the pneumonectomy model, 10 survived, 7 died, and in the polytrauma group, 13 survived, and 13 died. In the pneumonectomy model, there was a significant increase in the serum kynurenine/tryptophan (KYN/TRP) ratio in the non-survivors 3h post-injury. A similar pattern was found in the validation group, which showed a significant increase in the KYN/TRP ratio at 6h post-trauma in non-survivors from the polytrauma model. There was a significant increase in IDO1 enzyme activity in non-survivor kidney tissues and a downregulation of tryptophan (TRP) metabolite in the kidney section in the non-survivor group post-trauma. DISCUSSION/SIGNIFICANCE: An increase in the KYN/TRP ratio post-trauma identified the pigs that suffered early mortality. A decrease in TRP metabolite and an increase in IDO1 enzyme activity in the kidney could contribute to an increase in KYN in the non-survivors. As a result, focusing on therapeutics targeting the KYN/TRP to reduce the incidence and severity of MOF is warranted.
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Maibohm, Christian, Alberto Saldana-Lopez, Oscar F. Silvestre, and Jana B. Nieder. "3D Polymer Structures for the Identification of Optimal Dimensions for Cellular Growth for 3D Lung Alveolar Models." Engineering Proceedings 4, no. 1 (April 16, 2021): 33. http://dx.doi.org/10.3390/micromachines2021-09596.
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Organ-on-chips and scaffolds for tissue engineering are vital assay tools for pre-clinical testing and prediction of human response to drugs and toxins, while providing an ethically sound alternative to animal testing and a low-cost alternative to expensive clinical studies. An important success criterion for these models is the ability to have structural parameters for optimized performance. In this study we show how the two-photon polymerization fabrication method can be used to create 3D test platforms made for analyzing optimal scaffold parameters for cell growth. We design and fabricate a 3D grid structure, designed as a set of wall structures with niches of various dimensions for probing the optimal niche for cell attachment. The 3D grid structures are fabricated from bio-compatible polymer SZ2080 and subsequently seeded with A549 lung epithelia cells. The seeded structures are incubated and imaged with multi-color spectral confocal microscopy at several time points, to determine the volume of cell material present in the different niches of the grid structure. Spectral imaging with linear unmixing is used to separate the auto-fluorescence contribution from the scaffold from the fluorescence of the cells and use it to determine the volume of cell material present in the different sections of the grid structure. The variation in structural parameters influences the incubated A549 cells’ distribution and morphology. In future, this kind of differentiated 3D growth platform could be applied for optimized culture growth, cell differentiation and advanced cell therapies.
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Forshaw, Denise, Emma C. Wall, Gordon Prescott, Hakim-Moulay Dehbi, Angela Green, Emily Attree, Lyth Hismeh, et al. "STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol." PLOS ONE 18, no. 2 (February 15, 2023): e0272472. http://dx.doi.org/10.1371/journal.pone.0272472.
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Introduction Long COVID (LC), the persistent symptoms ≥12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace. Methods and analysis This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an integrated care pathway (Coverscan™, a multi-organ MRI, and Living with COVID Recovery™, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that integrated care pathway interventions are delivered as “standard of care” in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6–10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The trial also includes an economic evaluation which will be described separately. Ethics and dissemination The protocol was reviewed by South Central—Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan™ has UK certification (UKCA 752965). All participants will provide written consent to take part in the trial. The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations. Trial registration number ISRCTN10665760.
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Low, Lucie A., and Danilo A. Tagle. "Organs-on-chips: Progress, challenges, and future directions." Experimental Biology and Medicine 242, no. 16 (March 26, 2017): 1573–78. http://dx.doi.org/10.1177/1535370217700523.
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The National Institutes of Health Microphysiological Systems (MPS) program, led by the National Center for Advancing Translational Sciences, is part of a joint effort on MPS development with the Defense Advanced Research Projects Agency and with regulatory guidance from FDA, is now in its final year of funding. The program has produced many tangible outcomes in tissue chip development in terms of stem cell differentiation, microfluidic engineering, platform development, and single and multi-organ systems—and continues to help facilitate the acceptance and use of tissue chips by the wider community. As the first iteration of the program draws to a close, this Commentary will highlight some of the goals met, and lay out some of the challenges uncovered that will remain to be addressed as the field progresses. The future of the program will also be outlined. Impact statement This work is important to the field as it outlines the progress and challenges faced by the NIH Microphysiological Systems program to date, and the future of the program. This is useful information for the field to be aware of, both for current program stakeholders and future awardees and partners.
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Ramadan, Qasem, Sajay Bhuvanendran Nair Gourikutty, and Qingxin Zhang. "OOCHIP: Compartmentalized Microfluidic Perfusion System with Porous Barriers for Enhanced Cell–Cell Crosstalk in Organ-on-a-Chip." Micromachines 11, no. 6 (May 31, 2020): 565. http://dx.doi.org/10.3390/mi11060565.
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Improved in vitro models of human organs for predicting drug efficacy, interactions, and disease modelling are crucially needed to minimize the use of animal models, which inevitably display significant differences from the human disease state and metabolism. Inside the body, cells are organized either in direct contact or in close proximity to other cell types in a tightly controlled architecture that regulates tissue function. To emulate this cellular interface in vitro, an advanced cell culture system is required. In this paper, we describe a set of compartmentalized silicon-based microfluidic chips that enable co-culturing several types of cells in close proximity with enhanced cell–cell interaction. In vivo-like fluid flow into and/or from each compartment, as well as between adjacent compartments, is maintained by micro-engineered porous barriers. This porous structure provides a tool for mimicking the paracrine exchange between cells in the human body. As a demonstrating example, the microfluidic system was tested by culturing human adipose tissue that is infiltrated with immune cells to study the role if the interplay between the two cells in the context of type 2 diabetes. However, the system provides a platform technology for mimicking the structure and function of single- and multi-organ models, which could significantly narrow the gap between in vivo and in vitro conditions.
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Phan-Everson, Tien, Zachary Lewis, Giang Ong, Yan Liang, Emily Brown, Liuliu Pan, Aster Wardhani, et al. "Abstract 4617: A complete pipeline for high-plex spatial proteomic profiling and analysis on the cosmxtm spatial molecular imager and atomtm spatial informatics platform." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4617. http://dx.doi.org/10.1158/1538-7445.am2023-4617.
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Abstract Detecting and analyzing large numbers of proteins using whole-slide imaging is critical for a comprehensive picture of immune response to cancer. Many existing approaches for high-plex proteomics face issues around simplicity, speed, scalability, and big data analysis. Here, we present an integrated workflow from sample preparation through downstream analysis that addresses many key concerns around high plex proteomics. The CosMx Spatial Molecular Imager (SMI) and AtoMx Spatial Informatics Platform (SIP) comprise of a turnkey, end-to-end workflow that efficiently handles highly multiplex protein analysis at plex sizes exceeding 110 targets. We demonstrate an extension of our commercially available 64-plex human immuno-oncology panel to higher numbers of targets and show how the cloud computing-enabled AtoMx SIP allows flexible construction of analytic pipelines for cell typing and spatial analyses. The CosMx protein assay uses antibodies conjugated with oligonucleotides, which are detected using universal, multi-analyte CosMx readout reagents. The CosMx Human Immuno-oncology panel was optimized to comprehensively profile lymphoid and stromal lineages within the tumor microenvironment as well as markers of cancer signaling and progression. Each CosMx SMI antibody was validated on multi-organ FFPE tissue microarrays covering prevalent solid tumor types with matched controls, and 52 human FFPE cell lines, including overexpression lines for key targets such as GITR, CD278, PD-L1, and PD-1. CosMx SMI uses a deep learning algorithm to segment whole cells and a semi-supervised algorithm to classify cell types. The AtoMx SIP provides full analysis support, including a whole-slide image viewer, and methods for performing built-in or fully customizable analyses for cell typing, ligand-receptor analysis, neighborhood analysis and spatial differential expression. Within the cancer sample profiled, we performed in-depth single-cell proteomic profiling across different cell populations. We detected TLS, characterized TLS maturation, and identified immune interactions with the tumor microenvironment. The CosMx SMI assay profiled the composition and spatial organization of infiltrating immune cells within and around the tumor microenvironment. We found that markers of T cell activation and exhaustion varied across the tumor landscape. CosMx SMI is a high-plex spatial multi-omics platform that enables detection of more than 110 proteins at subcellular resolution in real-world FFPE tissues. The extensibility of the CosMx protein assay to large numbers of protein targets and our flexible, scalable bioinformatic platform provides a straightforward and robust solution for comprehensive immune phenotyping with full spatial context. FOR RESEARCH USE ONLY. Not for use in diagnostic procedures. Citation Format: Tien Phan-Everson, Zachary Lewis, Giang Ong, Yan Liang, Emily Brown, Liuliu Pan, Aster Wardhani, Mithra Korukonda, Carl Brown, Dwayne Dunaway, Edward Zhao, Dan McGuire, Sangsoon Woo, Alyssa Rosenbloom, Brian Filanoski, Rhonda Meredith, Kan Chantranuvatana, Brian Birditt, Hye Son Yi, Erin Piazza, Jason Reeves, John Lyssand, Vik Devgan, Michael Rhodes, Gary Geiss, Joseph Beechem. A complete pipeline for high-plex spatial proteomic profiling and analysis on the cosmxtm spatial molecular imager and atomtm spatial informatics platform. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4617.
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Rafii, Shahin, Jason M. Butler, Ginsberg Michael, Jennifer L. Gori, Hans-Peter Kiem, and Scandura Jospeh. "Vascular Niche-Derived Angiocrine Factors Specify and Maintain Hematopoietic Stem Cells." Blood 126, no. 23 (December 3, 2015): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v126.23.sci-25.sci-25.
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Abstract Organ-specific endothelial cells (ECs) are both conduits for delivery of nutrients and also establish an instructive vascular niche. The vascular niche produces paracrine factors, (i.e., angiocrine factors), that balance self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) (1,2). Activation of Akt-mTOR pathway in sinusoidal ECs (SECs) stimulates physiological expression of angiocrine factors, including Kit-ligand, Notch-ligands, Wnts, FGFs, BMPs and TGFb, that expand long-term repopulating HSPCs. Activation of MAPkinase in ECs upregulates expression of GM-CSF, M-CSF, IL6, IL7, SDF-1 and G-CSF (..others) to accelerate HSPC multi-lineage differentiation. We developed an ex vivo vascular niche in which HSPC/EC co-cultures are maintained and expanded in serum-free conditions. This vascular niche platform produces physiologic levels of angiocrine factors that balance expansion/differentiation of human cord blood, mobilized peripheral blood, and steady state bone marrow HSPCs that maintain their ability to reconstitute hematopoiesis in vivo. In contrast to our vascular platform, co-culture with bone marrow-derived mesenchymal does not support long-term expansion of HSPCs. In collaboration with Drs. Kiem and Gori at Hutchinson Cancer Center, we have shown that ECs expand repopulating nonhuman primate marrow-derived HSPCs. Transplantation of the vascular-niche expanded gene-modified HSPCs reconstituted long-term multi-lineage hematopoiesis in autologous transplantation setting in nonhuman primates. Importantly, intravenous co-infusion of the vascular niche with HSPCs did not cause infusional toxicity. Vascular niche-expanded HSPCs supported robust hematopoietic recovery underscoring the essential function of vascular niche-signals in hematopoietic reconstitution without provoking fibrosis (3). The ECs also supplies key signals that induce emergence of HSPCs from hemogenic ECs. To prove this point, we transduced adult human or mouse ECs with Runx1/Spi1/Gfi1/FosB transcription factors along with vascular niche-induction allowing for conversion of these ECs into stable and long-term engraftable HSPCs, including functional immune cells (4). Importantly, transition through a pluripotent state results in poorly engraftable hematopoietic cells that are unstable and upon exposure to pathophysiological stressors differentiate aberrantly into other cell-types. Remarkably, signals from vascular niche support specification of repopulating multipotent-HSPCs from both human and nonhuman primate pluripotent stem cells (5). In summary, we developed and characterized a vascular niche platform that provides physiologically relevant levels of key angiocrine factors that stimulate safe clinical-scale expansion of authentic adult, cord blood, and primitive HSPCs under GMP-grade culture conditions. We are currently translating the vascular niche platform to the clinical setting, to evaluate the potential of co-transplantation of HSPCs with vascular niche cells to reconstruct injured EC niches thereby accelerating short- and long-term hematopoietic recovery. This first-in-man clinical application will set the stage for repopulation with true hematopoietic stem cells, thereby enabling use of a vascular niche for treatment of a wide range of acquired, inherited, and malignant hematopoietic diseases. 1. Butler JM …… Rafii S. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell, 3:251-64, 2010. 2. Nolan D........Rafii S. Molecular and cellular signatures of tissue-specific vascular heterogeneity in organ maintenance and regeneration. Developmental Cell, 26(2):204-19, 2013. 3. Ding BS …..Rafii S. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.Nature 505(7481):97-102, 2014. 4. Sandler VM, Lis R ...... Butler JM, Scandura JM, Rafii S. Reprogramming of Human Endothelium Into Engraftable Hematopoietic Progenitors by Vascular Niche Induction.Nature, 511(7509):312-8, 2014. 5. Gori J., Butler JM, .....Rafii S, Kiem HP. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells. Journal of Clinical Investigation, 125(3): 1243-54, 2015. Disclosures Rafii: Angiocrine Bioscience: Consultancy, Equity Ownership.
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Hameed, Shihab A., Alaa Haddad, Mohamed Hadi habaebi, and Ali Nirabi. "Dermatological diagnosis by mobile application." Bulletin of Electrical Engineering and Informatics 8, no. 3 (September 1, 2019): 847–54. http://dx.doi.org/10.11591/eei.v8i3.1502.
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Health care mobile application delivers the right information at the right time and place to benefit patient’s clinicians and managers to make correct and accurate decisions in health care fields, safer care and less waste, errors, delays and duplicated errors.Lots of people have knowledge a skin illness at some point of their life, For the reason that skin is the body's major organ and it is quite exposed, significantly increasing its hazard of starting to be diseased or ruined.This paper aims to detect skin disease by mobile app using android platform providing valid trustworthy and useful dermatological information on over 4 skin diseases such as acne, psoriasis content for each skin condition, skin rush and Melanoma. It will include name, image, description, symptoms, treatment and prevention with support multi languages English and Bahasa and Mandarin. the application has the ability to take and send video as well as normal and magnified photos to your dermatologist as an email attachment with comments on safe secure network, this app also has a built in protected privacy features to access to your photo and video dermatologists. The mobile application help in diagnose and treat their patients without an office visit teledermatology is recognized by all major insurance companies doctor.
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Yang, Jiwon, Jing Jiao, Kyle Draheim, Danying Cai, Michael A. Brehm, Leonard D. Shultz, Dale L. Greiner, Mingshan Cheng, and James G. Keck. "Abstract 2049: A novel, rapid, sensitive, and reproducible in vivo platform to assess efficacy and toxicity of bispecific antibodies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2049. http://dx.doi.org/10.1158/1538-7445.am2022-2049.
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Abstract A bispecific T-cell engager (BiTE) enhances the antitumor capabilities of T-cells by directing them to recognize a tumor-specific antigen. Several BiTEs are currently in clinical trials, and there is one FDA-approved BiTE for cancer therapy at the moment. However, one of the biggest challenges BiTE is currently facing is cytokine release syndrome (CRS). While most patients have mild flu-like symptoms, some patients experience a severe inflammatory syndrome, which could ultimately cause multi-system organ failure and death. Thus, the key is to accurately predict the risk-benefit ratio of each individual before starting the treatment. Unfortunately, there is no reliable in vitro or in vivo model to predict the toxicity and efficacy of BiTE at the moment. Additionally, one of the most challenging factors for pre-clinical evaluation of BiTEs for toxicity and efficacy is the inherent differences among patients’ immune systems. Here, we developed an in vivo PBMC-humanized mouse model that can evaluate both toxicity and efficacy of BiTE and other immune-oncology therapeutics in each individual mouse. The platform was validated using an anti-CD28 superagonist (TGN1412), which none of the pre-clinical in vitro assays and in vivo studies, including non-human primates, executed before clinical trials were able to predict the observed clinical toxicities. This model uses luciferase-tagged human B-cell lymphoma Raji tumor cells to allow the measurement of tumor burden and response to treatment, along with toxicity simultaneously. In addition, we showed that this platform can determine individual PBMC donor differences, and potential adverse drug combinations and drug dose-response with efficacy and safety on individual PBMC donors. The model we developed can potentially be used as a predictive and reproducible platform to identify patient, cancer, and therapy combinations at risk for developing CRS. This model will also help to optimize the therapeutic drug dose range to improve the safety profile of BiTE and other immune-oncology drugs. We believe this platform will greatly benefit not only the scientific community but potentially cancer patients as well. Citation Format: Jiwon Yang, Jing Jiao, Kyle Draheim, Danying Cai, Michael A. Brehm, Leonard D. Shultz, Dale L. Greiner, Mingshan Cheng, James G. Keck. A novel, rapid, sensitive, and reproducible in vivo platform to assess efficacy and toxicity of bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2049.
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Drilon, Alexander E., Haiying Liu, Felice Wu, David Chen, Timothy Richard Wilson, Brian P. Simmons, and Fabrice Barlesi. "Tumor-agnostic precision immuno-oncology and somatic targeting rationale for you (TAPISTRY): A novel platform umbrella trial." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS3154. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps3154.
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TPS3154 Background: Actionable genomic alterations are found in many solid tumors in pediatric and adult populations. Identifying such alterations can match patients (pts) to genome-driven therapies. Although TRK and immune checkpoint inhibitor therapies have tumor-agnostic approval for NTRK-rearranged and tumor mutational burden (TMB)-high cancers, respectively, similar approvals remain an unmet need for other genome-driven cancers, limiting pt access to potentially active therapies. Platform master protocol studies leveraging comprehensive next-generation sequencing (NGS) are a pragmatic means of evaluating multiple genome-driven therapies in rare biomarker-selected populations. Contemporary study designs include adult and pediatric pts to expand care across age groups. Methods: TAPISTRY (NCT04589845) is a phase 2, global, open-label, multi-cohort study evaluating the efficacy and safety of targeted therapy or immunotherapy, as single agents or in combination, in pts with unresectable, locally advanced/metastatic solid tumors. Eligible pts have tumors that harbor genomic alterations or are TMB-high by NGS (Foundation Medicine or CLIA/equivalent-certified laboratory). General inclusion criteria: PD on prior treatment/no available acceptable treatment; measurable disease (by RECIST v1.1, RANO, INRC), adequate ECOG/equivalent PS and end organ function. Pts will be assigned to treatment according to eligibility criteria for biomarker-defined cohorts (Table). Pediatric pts may be enrolled if age-appropriate formulations/dosages are established. Samples will be taken for central NGS biomarker testing at baseline (tissue/blood), tumor assessments (blood) and at response/PD (optional tissue/blood). Tumor assessments (CT, MRI, PET) will be completed at baseline then every 6–8 weeks, depending on cohort. Primary endpoint: confirmed ORR by independent review committee (IRC; RECIST v1.1). Key secondary endpoints: ORR (by investigator [INV], per RECIST/INRC); DoR, CBR, PFS, time to CNS PD (by IRC and INV, per RECIST/INRC); intracranial efficacy (Cohorts A–D; per RANO [primary brain tumors]/RECIST [baseline CNS mets]); OS; patient-reported outcomes; safety; pharmacokinetics and immunogenicity (Cohorts D and F). Treatment will continue until PD, loss of clinical benefit, unacceptable toxicity, discontinuation or death. Target enrollment is 650 pts at 100+ sites based on screening 40,000+ pts; 3 pts enrolled as of 9 Feb 2021. Clinical trial information: NCT04589845. [Table: see text]
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Russo, Angela, Brian P. Cain, Tia Jackson-Bey, Alfredo Lopez Carrero, Jane Miglo, Shannon MacLaughlan, Brett C. Isenberg, Jonathan Coppeta, and Joanna E. Burdette. "Increased Local Testosterone Levels Alter Human Fallopian Tube mRNA Profile and Signaling." Cancers 15, no. 7 (March 30, 2023): 2062. http://dx.doi.org/10.3390/cancers15072062.
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Fallopian tube epithelium (FTE) plays a critical role in reproduction and can be the site where High Grade Serous Ovarian Carcinoma (HGSOC) originates. Tumorigenic oviductal cells, which are the murine equivalent of human fallopian tube secretory epithelial cells (FTSEC), enhance testosterone secretion by the ovary when co-cultured with the ovary, suggesting that testosterone is part of the signaling axis between the ovary and FTSEC. Furthermore, testosterone promotes proliferation of oviductal cells. Oral contraceptives, tubal ligation, and salpingectomy, which are all protective against developing ovarian cancer, also decrease circulating levels of androgen. In the current study, we investigated the effect of increased testosterone on FTE and found that testosterone upregulates wingless-type MMTV integration family, member 4 (WNT4) and induces migration and invasion of immortalized human fallopian tube cells. We profiled primary human fallopian tissues grown in the microfluidic system SOLO-microfluidic platform –(MFP) by RNA sequencing and found that p53 and its downstream target genes, such as paired box gene 2 (PAX2), cyclin-dependent kinase inhibitor 1A (CDK1A or p21), and cluster of differentiation 82 (CD82 or KAI1) were downregulated in response to testosterone treatment. A microfluidic platform, the PREDICT-Multi Organ System (PREDICT-MOS) was engineered to support insert technology that allowed for the study of cancer cell migration and invasion through Matrigel. Using this system, we found that testosterone enhanced FTE migration and invasion, which was reversed by the androgen receptor (AR) antagonist, bicalutamide. Testosterone also enhanced FTSEC adhesion to the ovarian stroma using murine ovaries. Overall, these results indicate that primary human fallopian tube tissue and immortalized FTSEC respond to testosterone to shift expression of genes that regulate invasion, while leveraging a new strategy to study migration in the presence of dynamic fluid flow.
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Brandon Brown, Bandar E Almansouri, Diane E Heck, and Hong Duck Kim. "Surveillance utilizes multi-omics in cardiovascular disease: Diet and its potentiality in Preventive index." GSC Biological and Pharmaceutical Sciences 17, no. 3 (December 30, 2021): 001–9. http://dx.doi.org/10.30574/gscbps.2021.17.3.0323.
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Cardiovascular Disease (CVD) is characterized by multidimensional risks including drug, diet, lifestyle, stress, and metabolomics diseases which cause mortality and morbidity depending on age and status of chronic diseases. However, emerging evidence indicated it is preventable health complications that depend on risk management along with lifestyle change, and personalized medication that include alternative measures like Diet use following molecular diagnostic and imaging analysis. CVD is mainly attributed to the narrowing of blood vessels through atherosclerotic lesions and/or thrombosis. Hypertension, obesity, and hyperlipidemia are major risk factors for the development of CVD and treating these diseases is essential in slowing down progression of CVD. Inflammation appears to play a pivotal role in CVD and can be measured through a simple blood assay (CRP). Multi-omics approaches have been essential in the development of treatments for CVD, in the prevention of CVD, and in the diagnosis of CVD. There are many outcomes available to help with diagnosing CVD and omics platforms have helped scientists and clinician develop these diagnostic tools. Radiomics has played a key part in the diagnosis of CVD as being able to view the diseased heart is essential in determining CVD progression and the treatment options suitable for that secondary disease related. Nutrigenomics is emerging as the future of medicine such as utilizing treatment strategy innovation instead of medications, but it is still in its infancy. Nutrigenomics will open the doors to different therapeutic drug targets and allow us the ability to be more specific in our treatment options. There are only a few gene-diet interactions documented that increase a person’s chances of developing CVD. Curating an individual diet and treatment plan based on somebody’s genetic disposition or skewed immune responses following personalized diagnosis will be essential in the survival of these severe CVD patients. Key issues referring to risk surveillance and prevention is a distant approach which reflects several factors: for example, what type of tools can be used to conduct diagnosis, molecular diagnostic tools detect what type of biomarkers are present prior to prescribing the personalized diet and to ensure diagnostic accuracy. Recently, increasing findings emphasize dual aspects of diet such as immune enhancers and modulators in which gut microbiota has been proven to play a major factor in development of CVD. The future direction of omics studies will foster the ability to test the impact of gut microbiome of a patient with CVD following diet driven organ protection as well as prescribe essential components of the diet that can be adjusted with proper probiotic medication. Proper diet adjustments can correct the organ dysfunction that occurred due to interaction between molecular mismatch and cellular damage following stress-mediated damage or chronic disease. Further micro-scale assays and molecular diagnostic techniques following nutrigenomics application to the patient could be beneficial to allow patient’ care shift from physician driven and clinic based to self-management with knowledge based at home treatment programs that work by envisioning molecular reprogramming and rejuvenation of damaged organ. These at home treatments can be utilized with development of radiological data with innovation of software. The aim of the short review is to visualize the current role of nutrigenomics and diet formulation for integrative care (e.g., diagnosis, prevention, and treatment of CVD) which would take advantage of earlier prevention synchronized with current medical tests, imaging techniques. Health economy like management can reduce medical cost with disease prevention disease and could modulate the following: enhance knowledge-based interaction between body and diet, discuss cognitive enhancement how sensing with molecular behavior under image-management platform, monitor drug surveillance of current treatment options in CVD and the pitfalls of current omics application and data transformation needs for patient care in the future.
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Singh, Veerpal, Ayman Saad, Jeanne Palmer, Jasleen K. Randhawa, and Parameswaran N. Hari. "Response to Bortezomib Based Induction Therapy in Newly Diagnosed Light Chain (AL) Amyloidosis." Blood 114, no. 22 (November 20, 2009): 1867. http://dx.doi.org/10.1182/blood.v114.22.1867.1867.
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Abstract Abstract 1867 Poster Board I-892 Bortezomib has been shown to have significant activity in the suppression of light chain production and induction of responses in patients with relapsed refractory AL Amyloidosis. We analyzed the outcomes of 16 (9 male) newly diagnosed biopsy proven AL Amyloidosis patients treated with Bortezomib based regimens at our institution. All patients received initial therapy with Bortezomib and dexamethasone (dex). Patients with a Karnofsky performance score ( KPS) >70 received Bortezomib at starting doses of 1.3 mg/m2 along with dexamethasone 40 mg on days 1,4,8, 11 ( with a 10 day rest period). Patients with a lower KPS received Bortezomib/Dex on a weekly schedule as tolerated. Dose adjustments were made based on side effects such as neuropathy, hypotension, GI disturbances or electrolyte imbalances. Patients tolerating Bortezomib/dex with improvement in KPS had cyclophosphamide (4) or lenalidomide (1) added to their initial therapy. Patients: Median age was 64 years (39–88). Nine had kappa light chain involvement. Organ involvement was renal (73%), cardiac (63%), hepatic (25%), tongue or soft tissue (20%), GI (30%). Median KPS was 70 (50 –100). Ten of the 16 patients were treated as in-patients due to multi-organ dysfunction. Five patients required hemodialysis within a month of diagnosis. Cardiac involvement was stage 3 (Mayo risk group) in 25%. Three patients were unevaluable: 2 dying before 2 cycles and 1 discontinued therapy (Grade 3 liver dysfunction). Median follow up was 5 months (range 2–33 mo). Results: Evaluable (receiving at least 2 cycles) patients have all had a free light chain response. The overall hematological response rate was 100% with 55% partial remission (PR) and 45% complete remission (CR). Median cycles to achievement of a light chain response was 2 (range 1–4). Four patients underwent autologous stem cell transplantation with no mortality. Five (40%) of the responders have had an organ response (3 renal, 1 macroglossia, 1 cardiac) with only patients alive for >5 months having any evidence of organ response. Five (40%) of the evaluable patients have died with progressive cardiac involvement (2), relapsed disease (2) or renal failure (1) with refusal of dialysis. In patients receiving at least one dose of bortezomib, non-hematologic toxicity (>grade 2) included -neuropathy (20%), hypotension (20%), severe diarrhea (12%), sepsis (12%), paralytic ileus (6%), liver dysfunction (6%), sudden death (6%). Conclusions: Bortezomib in combination with dexamethasone has a high response rate in newly diagnosed AL amyloidosis. This regimen was well tolerated in a cohort of severe, multisystem amyloidosis patients with low treatment related mortality. Light chain responses were fast whereas organ responses were not seen prior to 5 months of therapy. The regimen also served as a platform for further intensification with the addition of lenalidomide, cyclophosphamide or autologous transplant in responders. Disclosures: Off Label Use: Bortezomib for the therapy of amyloidosis. Hari:Millenium: Honoraria, Research Funding.