The pharmaceutical industry has been desperately searching for efficient drug discovery methods. Organ-on-a-Chip, a cutting-edge technology that can emulate the physiological environment and ...functionality of human organs on a chip for disease modeling and drug testing, shows great potential for revolutionizing the drug development pipeline. However, successful translation of this novel engineering platform into routine pharmacological and medical scenarios remains to be realized. In this review, we discuss how the Organ-on-a-Chip technology can have critical roles in different preclinical stages of drug development and highlight the current challenges in translation and commercialization of this technology for the pharmacological and medical end-users. Moreover, this review sheds light on the future developmental trends and need for a next-generation Organ-on-a-Chip platform to bridge the gap between animal studies and clinical trials for the pharmaceutical industry.
Organ-on-a-Chip is a promising interdisciplinary technique emulating in vivo physiology and pathology for in vitro disease modeling, drug screening, and precision medicine.The Organ-on-a-Chip technology can be organically incorporated into the drug development pipeline from early drug discovery to preclinical screening, testing, and translation of new drugs, which bridges the gap between animal studies and clinical trials involving human subjects.The future development of personalized Organ-on-a-Chip and continuous integration of novel engineering tools (e.g., automation handling, 3D printing. and in situ multisensors) and biological concepts (e.g., patient-specific induced pluripotent stem cells and organoids) into Organ-on-a-Chip platform will unprecedentedly promote its biomedical applications.
Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor ...microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
Evidence associating diet with the incidence of renal cell carcinoma (RCC) is inconclusive. We aimed to summarize evidence associating dietary factors with RCC incidence and assess the strength and ...validity of this evidence.
We conducted an umbrella review of systematic reviews or meta-analyses (SRoMAs) that assessed the association between diet and RCC incidence. Through April 2021, PubMed, Web of Science, Embase, The Cochrane Library, Scopus, and WCRF were searched. Two independent reviewers selected studies, extracted data, and appraised the quality of SRoMAs. According to credibility assessment criteria, evidence can be divided into five categories: convincing (class I), highly suggestive (class II), suggestive (class III), weak (class IV), and nonsignificant (class V).
Twenty-nine meta-analyses were obtained after screening. After excluding 7 overlapping meta-analyses, 22 meta-analyses including 502 individual studies and 64 summary hazard ratios for RCC incidence were included: dietary patterns or dietary quality indices (n = 6), foods (n = 13), beverages (n = 4), alcohol (n = 7), macronutrients (n =15), and micronutrients (n =19). No meta-analyses had high methodological quality. Five meta-analyses exhibited small study effects; one meta-analysis showed evidence of excess significance bias. No dietary factors showed convincing or highly suggestive evidence of association with RCC in the overall analysis. Two protective factors had suggestive evidence (vegetables (0.74, 95% confidence interval 0.63 to 0.86) and vitamin C (0.77, 0.66 to 0.90)) in overall analysis. One protective factor had convincing evidence (moderate drinking (0.77, 0.70 to 0.84)) in Europe and North America and one protective factor had highly suggestive evidence (cruciferous vegetables (0.78, 0.70 to 0.86)) in North America.
Although many meta-analyses have assessed associations between dietary factors and RCC, no high-quality evidence exists (classes I and II) in the overall analysis. Increased intake of vegetables and vitamin C is negatively associated with RCC risk. Moderate drinking might be beneficial for Europeans and North Americans, and cruciferous vegetables might be beneficial to North Americans, but the results should be interpreted with caution. More researches are needed in the future.
PROSPERO CRD42021246619.
Introduction
Lymphatic vessels (LVs) maintain fluid homeostasis by draining excess interstitial fluid, which is accomplished by two distinct LVs: initial LVs and collecting LVs. The interstitial ...fluid is first drained into the initial LVs through permeable “button-like” lymphatic endothelial cell (LEC) junctions. Next, the drained fluid (“lymph”) transports to lymph nodes through the collecting LVs with less permeable “zipper-like” junctions that minimize loss of lymph. Despite the significance of LEC junctions in lymphatic drainage and transport, it remains unclear how luminal or interstitial flow affects LEC junctions in vascular endothelial growth factors A and C (VEGF-A and VEGF-C) conditions. Moreover, it remains unclear how these flow and growth factor conditions impact lymphatic sprouting.
Methods
We developed a 3D human lymphatic vessel-on-chip that can generate four different flow conditions (no flow, luminal flow, interstitial flow, both luminal and interstitial flow) to allow an engineered, rudimentary LV to experience those flows and respond to them in VEGF-A/C.
Results
We examined LEC junction discontinuities, lymphatic sprouting, LEC junction thicknesses, and cell contractility-dependent vessel diameters in the four different flow conditions in VEGF-A/C. We discovered that interstitial flow in VEGF-C generates discontinuous LEC junctions that may be similar to the button-like junctions with no lymphatic sprouting. However, interstitial flow or both luminal and interstitial flow stimulated lymphatic sprouting in VEGF-A, maintaining zipper-like LEC junctions. LEC junction thickness and cell contractility-dependent vessel diameters were not changed by those conditions.
Conclusions
In this study, we provide an engineered lymphatic vessel platform that can generate four different flow regimes and reveal the roles of interstitial flow and VEGF-A/C for lymphatic sprouting and discontinuous junction formation.
From November 2014 to March 2015, 46 patients with forearm hematoma were treated by routine nursing approach including pressuring the hematoma with bandage for 8 hours and relieving once per hour ...without replacing artery compression hemostasis device. 51 patients from April to October 2015 were treated by improved nursing approach which is applied to shorten the binding strength and dressing time, to raise the limb and compress with magnesium sulfate. To evaluate clinical effect of two groups by swelling subsided time. 3 hours arm circumference and the incidence of radial artery occlusion before leaving hospital.
A simple sequence repeat (SSR) marker was used to assess the genetic diversity and population structure of an endangered relic species
Emmenopterys henryi
Oliv., endemic to China. A total of 124 ...samples from six populations were analyzed using eight pairs of SSR primers. Total 114 alleles were detected with an average of 14.3 alleles per locus. The presence of null alleles can result in low genetic diversity parameters (H
e
and allelic richness) for all loci and mostly likely caused the deviation from Hardy–Weinberg equilibrium (HWE). The Polymorphism information content (PIC) values were higher which indicates that selection of SSR markers were suitable choice for assessing the genetic diversity in
E. henryi
. Our results revealed that the natural populations of
E. henryi
have a high degree of genetic diversity. Genetic diversity amongst the six
E. henryi
populations in decreasing order were: GJY > LS > DWS > WYS > HS > JGS. Further, genetic structure and the Neighbor-Joining (NJ) cluster analysis indicated that there were cross-mixing among the 124 samples. Four populations (i.e., HS, DWS, JGS and WYS) were clustered in one group, whereas LS and GJY population were clustered separately as two groups. A Principal Component Analysis (PCA) also showed a similar clustering trend. The results of
F
st
(0.085) and AMOVA indicated that the genetic variation resided within the populations and existence of frequent gene exchanges among populations. Based on these results, populations with abundant genetic variation and rare alleles should be conserved in situ and ex situ. Furthermore, seeds from the different populations with high levels of genetic diversity could be collected and propagated in order to capture the maximum available genetic diversity. The present study on genetic diversity of
E.henryi
could be helpful in expanding the understanding on species survival and also for developing an effective long term conservation strategy.
Rubus corchorifolius (Shanmei or mountain berry, 2n = 14) is widely distributed in China, and its fruits possess high nutritional and medicinal values. Here, we reported a high-quality ...chromosome-scale genome assembly of Shanmei, with contig size of 215.69 Mb and 26,696 genes. Genome comparison among Rosaceae species showed that Shanmei and Fupenzi (Rubus chingii Hu) were most closely related, followed by blackberry (Rubus occidentalis), and that environmental adaptation-related genes were expanded in the Shanmei genome. Further resequencing of 101 samples of Shanmei collected from four regions in the provinces of Yunnan, Hunan, Jiangxi, and Sichuan in China revealed that among these samples, the Hunan population of Shanmei possessed the highest diversity and represented the more ancestral population. Moreover, the Yunnan population underwent strong selection based on the nucleotide diversity, linkage disequilibrium, and historical effective population size analyses. Furthermore, genes from candidate genomic regions that showed strong divergence were significantly enriched in the flavonoid biosynthesis and plant hormone signal transduction pathways, indicating the genetic basis of adaptation of Shanmei to the local environment. The high-quality assembled genome and the variome dataset of Shanmei provide valuable resources for breeding applications and for elucidating the genome evolution and ecological adaptation of Rubus species.
Mounds constructed by plateau zokors, which is widely distributed in alpine meadows significantly modified plant community structure. However, the variations of plant community structure under the ...disturbance of plateau zokor-made mound are less concerned. Therefore, we investigated the responses of plant community on zokor-made mound of different years (1 a and 3–4 a), and compared with undisturbed sites (no mound) in an alpine meadow in the eastern Qinghai-Tibetan Plateau (QTP), China. Species richness, coverage and Simpson diversity index were all significantly reduced by the presence of zokor-made mound, but plant heights were significantly increased, particularly in grasses and sedges. Several perennial forage species showed an increased importance value and niche breadth, including
Koeleria macrantha, Elymus nutans
and
Poa pratensis
. The effect of zokor-made mound on niche overlap showed that more intense interspecific competition produced a greater utilization of environmental resources. And this interspecific niche overlap was strengthened as succession progressed. The bare mound created by zokor burrowing activities provided a colonizing opportunity for non-dominant forage species, resulting in abundant plant species and plant diversity during the succession period. We concluded that presence of zokor-made mound was conducive to regeneration and vitality of plant community in alpine meadows, thus improving their resilience to anthropogenic stress.
Cancer immunotherapy focuses on the use of patients’ adaptive immune systems to combat cancer. In the past decade, FDA has approved many immunotherapy products for cancer patients who suffer from ...primary tumors, tumor relapse, and metastases. However, these immunotherapies still show resistance in many patients and often lead to inconsistent responses in patients due to variations in tumor genetic mutations and tumor immune microenvironment. Microfluidics‐based organ‐on‐a‐chip technologies or microphysiological systems have opened new ways that can provide relatively fast screening for personalized immunotherapy and help researchers and clinicians understand tumor‐immune interactions in a patient‐specific manner. They also have the potential to overcome the limitations of traditional drug screening and testing, given the models provide a more realistic 3D microenvironment with better controllability, reproducibility, and physiological relevance. This review focuses on the cutting‐edge microphysiological organ‐on‐a‐chip devices developed in recent years for studying cancer immunity and testing cancer immunotherapeutic agents, as well as some of the largest challenges of translating this technology to clinical applications in immunotherapy and personalized medicine.
This review focuses on the cutting‐edge microphysiological systems developed in recent years for studying cancer‐immune interaction and testing cancer immunotherapies such as adoptive cell therapy and immune checkpoint blockade. Some of the largest challenges and potential ways of translating this technology to clinical applications are then discussed for personalized and precision medicine.
Microphysiological Systems for Cancer Immunotherapy
The cover image depicts immune cells combating tumor cells at a microscopic level in a microphysiological system. The system possesses biophysical ...and biochemical sensors that can detect the cytokines and chemokines released by the cells and can be used to test and screen effective immunotherapies against cancer. More details can be found in article number 2300077 by Yansong Peng and Esak Lee.
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