Publications by authors named "Xu Cao"

455 Publications

Graphene Oxide Loaded on TiO-Nanotube-Modified Ti Regulates the Behavior of Human Gingival Fibroblasts.

Int J Mol Sci 2022 Aug 5;23(15). Epub 2022 Aug 5.

Laboratory of Biomaterials and Biomechanics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China.

Surface topography, protein adsorption, and the loading of coating materials can affect soft tissue sealing. Graphene oxide (GO) is a promising candidate for improving material surface functionalization to facilitate soft tissue integration between cells and biomaterials. In this study, TiO nanotubes (TNTs) were prepared by the anodization of Ti, and TNT-graphene oxide composites (TNT-GO) were prepared by subsequent electroplating. The aim of this study was to investigate the effect of TNTs and TNT-GO surface modifications on the behavior of human gingival fibroblasts (HGFs). Commercially pure Ti and TNTs were used as the control group, and the TNT-GO surface was used as the experimental group. Scanning electron microscopy, X-ray photoelectron spectroscopy, and X-ray diffraction were used to perform sample characterization. Cell adhesion, cell proliferation, cell immunofluorescence staining, a wound-healing assay, real-time reverse-transcriptase polymerase chain reaction (RT-PCR), and Western blotting showed that the proliferation, adhesion, migration, and adhesion-related relative gene expression of HGFs on TNT-GO were significantly enhanced compared to the control groups, which may be mediated by the activation of integrin β1 and the MAPK-Erk1/2 pathway. Our findings suggest that the biological reactivity of HGFs can be enhanced by the TNT-GO surface, thereby improving the soft tissue sealing ability.
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http://dx.doi.org/10.3390/ijms23158723DOI Listing
August 2022

Knockout of Leads to Autism-like Behaviors and Developmental Delay in Zebrafish.

Int J Mol Sci 2022 Jul 29;23(15). Epub 2022 Jul 29.

Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

mutations have been associated with autism spectrum disorder (ASD) and other related neurodevelopmental disorders (NDDs) such as intellectual disability (ID) in several cohorts. has been implicated in brain development, as it is required for ciliogenesis in and is required for dendritic arborization in mice. However, a causative relationship between the disruption of Katnal2 function and behavioral defects has not been established. Here, we generated a null allele in zebrafish using CRISPR/Cas9-mediated genome editing and carried out morphological and behavioral characterizations. We observed that embryos displayed delayed embryonic development especially during the convergence and extension (CE) movement. The hatched larvae showed reduced brain size and body length. In the behavioral tests, the zebrafish exhibited reduced locomotor activity both in larvae and adults; increased nocturnal waking activity in larvae; and enhanced anxiety-like behavior, impaired social interaction, and reduced social cohesion in adults. These findings indicate an important role for in development and behavior, providing an in vivo model to study the mechanisms underlying the ASD related to mutations.
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http://dx.doi.org/10.3390/ijms23158389DOI Listing
July 2022

Senescent preosteoclast secretome promotes metabolic syndrome associated osteoarthritis through cyclooxygenase 2.

Elife 2022 Jul 26;11. Epub 2022 Jul 26.

Department of Orthopaedic Surgery, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, United States.

Background: Metabolic syndrome-associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA.

Methods: Analysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using preosteoclast culture system.

Results: Humans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal antiinflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA.

Conclusions: Our findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential.

Funding: This work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to MW, R01AR079620 to SD, and P01AG066603 to XC.
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http://dx.doi.org/10.7554/eLife.79773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365389PMC
July 2022

Lamprey immunity protein enables early detection and recurrence monitoring for bladder cancer through recognizing Neu5Gc-modified uromodulin glycoprotein in urine.

Biochim Biophys Acta Mol Basis Dis 2022 Jul 16;1868(12):166493. Epub 2022 Jul 16.

College of Life Science, Liaoning Normal University, Dalian, Liaoning, China. Electronic address:

The clinical management of bladder cancer (BCa) is hindered by the lack of reliable biomarkers. We aimed to investigate the potential of lamprey immunity protein (LIP), a lectin that specifically binds to multi-antennary sialylated N-glycolylneuraminic acid (Neu5Gc) structures on UMOD glycoproteins in the urine of BCa patients. Primary BCa patients had higher levels of LIP-bound Neu5Gc in urine than healthy participants and patients receiving postoperative treatment did. In addition, lectin chip assay and mass spectrometry were used to analyze the glycan chain structure, which can recognize the UMOD glycoprotein decorated with multi-antennary sialylated Neu5Gc structures. Furthermore, compared with urine samples from healthy patients (N = 2821, T/C = 0.12 ± 0.09) or benign patients (N = 360, T/C = 0.11 ± 0.08), the range of the urine T/C ratio detected using LIP test paper was 1.97 ± 0.32 in patients with bladder cancer (N = 518) with significant difference (P < 0.0001). Our results indicate that LIP may be a tool for early BCa identification, diagnosis, and monitoring. Neu5Gc-modified UMOD glycoproteins in urine and Neu5Gc-modified N-glycochains and sialyltransferases may function as potential markers in clinical trials.
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http://dx.doi.org/10.1016/j.bbadis.2022.166493DOI Listing
July 2022

Medial meniscus tears are most prevalent in type I ACL tears, while type I ACL tears only account for 8% of all ACL tears.

Knee Surg Sports Traumatol Arthrosc 2022 Jul 17. Epub 2022 Jul 17.

Department of Orthopaedic Surgery, Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China.

Purpose: This study aimed to assess the distribution of different anterior cruciate ligament (ACL) tear locations in different magnetic resonance imaging (MRI) planes, and to explore the relationships of ACL tear types with both meniscus injuries and bone bruising.

Methods: A retrospective study was performed in patients under 60 years old who underwent MRI scans in the sagittal and coronal oblique planes of the knee for ACL tears between 2014 and 2020. Patients with reports of chronic tears, partial tears, or prior surgeries were excluded. Tear locations were classified into five types, and the meniscus tear measurement variables included the presence of ramp, root, bucket-handle, and other types of tears. All injuries were confirmed by arthroscopy. Meanwhile, the presence and location of bone bruising were analysed and scored with the Whole-Organ Magnetic Resonance Imaging Score (WORMS) bone bruising subscale.

Results: A total of 291 patients were included. The prevalence rates of type I and type III injuries were 23/291 (7.9%) and 145/291 (49.8%) in the sagittal plane and 22/291 (7.6%) and 179/291 (61.5%) in the oblique coronal plane, respectively. The prevalence of medial meniscus tears with ACL tears was 126/291 (43.3%), while that of lateral meniscus tears with ACL tears was 77/291 (26.5%). The highest prevalence of medial meniscus injury with ACL tears was 15/22 (68.2%) for type I injuries. Bone bruises were located on the lateral femoral center in 125 patients (46%) and on the lateral tibia posterior in 132 patients (48%); the common areas of bone bruising were slightly correlated with type III ACL tears but not correlated with type I ACL tears.

Conclusion: The plane in which an MRI scan is performed affects the classification of ACL tears. The tear type is associated with the prevalence of medial meniscus injuries, and medial meniscus tears are most prevalent in type I ACL tears.

Level Of Evidence: IV.
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http://dx.doi.org/10.1007/s00167-022-07068-2DOI Listing
July 2022

Proper animal experimental designs for preclinical research of biomaterials for intervertebral disc regeneration.

Biomater Transl 2021 28;2(2):91-142. Epub 2021 Jun 28.

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.

Low back pain is a vital musculoskeletal disease that impairs life quality, leads to disability and imposes heavy economic burden on the society, while it is greatly attributed to intervertebral disc degeneration (IDD). However, the existing treatments, such as medicines, chiropractic adjustments and surgery, cannot achieve ideal disc regeneration. Therefore, advanced bioactive therapies are implemented, including stem cells delivery, bioreagents administration, and implantation of biomaterials etc. Among these researches, few reported unsatisfying regenerative outcomes. However, these advanced therapies have barely achieved successful clinical translation. The main reason for the inconsistency between satisfying preclinical results and poor clinical translation may largely rely on the animal models that cannot actually simulate the human disc degeneration. The inappropriate animal model also leads to difficulties in comparing the efficacies among biomaterials in different reaches. Therefore, animal models that better simulate the clinical charateristics of human IDD should be acknowledged. In addition, in vivo regenerative outcomes should be carefully evaluated to obtain robust results. Nevertheless, many researches neglect certain critical characteristics, such as adhesive properties for biomaterials blocking annulus fibrosus defects and hyperalgesia that is closely related to the clinical manifestations, e.g., low back pain. Herein, in this review, we summarized the animal models established for IDD, and highlighted the proper models and parameters that may result in acknowledged IDD models. Then, we discussed the existing biomaterials for disc regeneration and the characteristics that should be considered for regenerating different parts of discs. Finally, well-established assays and parameters for in vivo disc regeneration are explored.
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http://dx.doi.org/10.12336/biomatertransl.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255780PMC
June 2021

Direct evidence of drought stress memory in mulberry from a physiological perspective: Antioxidative, osmotic and phytohormonal regulations.

Plant Physiol Biochem 2022 Sep 6;186:76-87. Epub 2022 Jul 6.

Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, 212018, China; Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang, Jiangsu, 212018, China. Electronic address:

Drought stress commonly happens more than once during the life cycle of perennial trees. Stress memory endows better capacity to cope with repeated stresses for plants, while the underlying mechanisms are not fully elucidated. In this study, 2-month-old saplings of two mulberry cultivars (Husang32 and 7307 of Morus multicaulis) with or without an early soil water deficit were subjected to subsequent drought for 9 days. The shoot height growth, biomass production, stable carbon isotope discrimination, phytohormones, reactive oxygen species (ROS), osmotic substances and antioxidant enzymes were analyzed after the first and the second drought, respectively. Drought priming saplings sustained comparable or slightly higher biomass accumulation under the second drought than those non-priming. They also exhibited decreased levels of soluble sugars, free proline and soluble proteins, lower accumulation of malonaldehyde (MDA) and superoxide anion (O), reduced activities of superoxide dismutase (SOD) and peroxidase (POD) compared to non-priming plants. Moreover, cultivar Husang32 exhibited elevated abscisic acid (ABA) and jasmonic acid (JA) where 7307 displayed opposite changes. PCA suggests that MDA, HO, free proline, SOD and POD in roots, and ROS, soluble sugars and glutamate reductase in leaves are dominant factors influenced by stress memory. ABA and JA in leaves also play important roles in exerting drought imprints. Collectively, stress memory can confer mulberry resistance to recurrent drought via combined regulations of antioxidative protection, osmotic adjustment and phytohormonal responses.
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http://dx.doi.org/10.1016/j.plaphy.2022.07.001DOI Listing
September 2022

Vascular defects associated with hereditary hemorrhagic telangiectasia revealed in patient-derived isogenic iPSCs in 3D vessels on chip.

Stem Cell Reports 2022 07 30;17(7):1536-1545. Epub 2022 Jun 30.

Department of Anatomy and Embryology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands; Department of Anatomy and Embryology and Human iPSC Hotel, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. Electronic address:

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by weak blood vessels. HHT1 is caused by mutations in the ENDOGLIN (ENG) gene. Here, we generated induced pluripotent stem cells (hiPSCs) from a patient with rare mosaic HHT1 with tissues containing both mutant (ENG) and normal cells, enabling derivation of isogenic diseased and healthy hiPSCs, respectively. We showed reduced ENG expression in HHT1 endothelial cells (HHT1-hiPSC-ECs), reflecting haploinsufficiency. HHT1-hiPSC-ECs and the healthy isogenic control behaved similarly in two-dimensional (2D) culture, forming functionally indistinguishable vascular networks. However, when grown in 3D organ-on-chip devices under microfluidic flow, lumenized vessels formed in which defective vascular organization was evident: interaction between inner ECs and surrounding pericytes was decreased, and there was evidence for vascular leakage. Organs on chip thus revealed features of HHT in hiPSC-derived blood vessels that were not evident in conventional 2D assays.
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http://dx.doi.org/10.1016/j.stemcr.2022.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287680PMC
July 2022

Role of Thigh Muscle Changes in Knee Osteoarthritis Outcomes: Osteoarthritis Initiative Data.

Radiology 2022 Jun 21:212771. Epub 2022 Jun 21.

From the Division of Musculoskeletal Radiology, Russell H. Morgan Department of Radiology and Radiological Science (B.M., S.D.), Russell H. Morgan Department of Radiology and Radiological Science (J.E.), and Department of Orthopedic Surgery (B.Z., M.W., X.C.), Johns Hopkins University School of Medicine, 601 N Caroline St, JHOC 3142, Baltimore, MD 21287; Tehran University of Medical Sciences, School of Medicine, Tehran, Iran (M.D., K.M.); Sharif University of Technology, Tehran, Iran (N.N.); Department of Radiology, Boston University School of Medicine, Boston, Mass (F.W.R., A.G.); and Department of Radiology, University of Erlangen-Nuremberg, Erlangen, Germany (F.W.R.).

Background Longitudinal data on the association of quantitative thigh muscle MRI markers with knee osteoarthritis (KOA) outcomes are scarce. These associations are of clinical importance, with potential use for thigh muscle-directed disease-modifying interventions. Purpose To measure KOA-associated longitudinal changes in MRI-derived muscle cross-sectional area (CSA) and adipose tissue and their association with downstream symptom worsening and knee replacement (KR). Materials and Methods In a secondary analysis of the Osteoarthritis Initiative multicenter prospective cohort (February 2004 through October 2015), knees of participants with available good-quality thigh MRI scans at baseline and at least one follow-up visit were included and classified as with and without KOA according to baseline radiographic Kellgren-Lawrence grade of 2 or higher and matched for confounders with use of propensity score matching. An automated deep learning model for thigh MRI two-dimensional segmentation was developed and tested. Markers of muscle CSA and intramuscular adipose tissue (intra-MAT) were measured at baseline and 2nd- and 4th-year follow-up (period 1) and compared between knees with and without KOA by using linear mixed-effect regression models. Furthermore, in knees with KOA, the association of period 1 changes in muscle markers with risk of KR (Cox proportional hazards) and symptom worsening (mixed-effect models) during the 4th to 9th year (period 2) was evaluated. Results This study included 4634 matched thighs (2317 with and 2317 without KOA) of 2344 participants (mean age, 62 years ± 9 [SD]; 1292 women). Compared with those without, knees with KOA had a decrease in quadriceps CSA (mean difference, -8.21 mm/year; = .004) and an increase in quadriceps intra-MAT (1.98 mm/year; = .007). Decreased CSA and increased intra-MAT of quadriceps during period 1 was predictive of downstream (period 2) KOA symptom worsening (Western Ontario and McMaster Universities Osteoarthritis Index total score: odds ratio, 0.24 [negative association] [ < .001] and 1.38 [ = .012], respectively). Quadriceps CSA changes were negatively associated with higher future KR risk (hazard ratio, 0.70; < .001). Conclusion Knee osteoarthritis was associated with longitudinal MRI-derived decreased quadriceps cross-sectional area and increased intramuscular adipose tissue. These potentially modifiable risk factors were predictive of downstream symptom worsening and knee replacement. Clinical trial registration no. NCT00080171 © RSNA, 2022
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http://dx.doi.org/10.1148/radiol.212771DOI Listing
June 2022

The effect of implants loaded with stem cells from human exfoliated deciduous teeth on early osseointegration in a canine model.

BMC Oral Health 2022 06 17;22(1):238. Epub 2022 Jun 17.

Laboratory of Biomaterials and Biomechanics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

Background: This in vivo experimental study investigated the effect of stem cells from human exfoliated deciduous teeth (SHEDs) on early osteogenesis around implants.

Methods: In four healthy adult male Beagle dogs, the left mandibular received implants and SHED as the experimental group, and the right mandibular received implants and phosphate-buffered saline as the control group. The Beagle dogs were randomly divided into groups A and B, which were sacrificed at 2 and 4 weeks after implantation. Micro-computed tomography and histological analysis were used to investigate the effect of SHED-loading on the early osseointegration around the implants.

Results: The total bone-to-implant contact (BIC%) and interthread bone improved significantly. The analysis of the bone volume fraction and trabecular thickness showed that the bone trabecula around the implants in the SHEDs group was thicker and denser than that in the control group, suggesting a better osseointegration.

Conclusions: The application of implants pre-adhered with SHEDs improved and accelerated early osseointegration around the implant, resulting in thicker and denser trabecular bone.
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http://dx.doi.org/10.1186/s12903-022-02264-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206344PMC
June 2022

Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced T differentiation via up-regulating Nr4a2.

Sci Adv 2022 06 15;8(24):eabn7662. Epub 2022 Jun 15.

Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.

Steroid nuclear receptor coactivator 2 (SRC2) is a member of a family of transcription coactivators. While SRC1 inhibits the differentiation of regulatory T cells (T) critical for establishing immune tolerance, we show here that SRC2 stimulates T differentiation. SRC2 is dispensable for the development of thymic T, whereas naive CD4 T cells from mice deficient of SRC2 specific in T () display defective T differentiation. Furthermore, the aged mice spontaneously develop autoimmune phenotypes including enlarged spleen and lung inflammation infiltrated with IFNγ-producing CD4 T cells. mice also develop severer experimental autoimmune encephalomyelitis (EAE) due to reduced T. Mechanically, SRC2 recruited by NFAT1 binds to the promoter and activates the expression of , which then stimulates Foxp3 expression to promote T differentiation. Members of SRC family coactivators thus play distinct roles in T differentiation and are potential drug targets for controlling immune tolerance.
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http://dx.doi.org/10.1126/sciadv.abn7662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200286PMC
June 2022

Comprehensive analysis of the MYB transcription factor gene family in Morus alba.

BMC Plant Biol 2022 Jun 8;22(1):281. Epub 2022 Jun 8.

Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, 212018, Jiangsu, China.

Background: The V-myb myeloblastosis viral oncogene homolog (MYB) family of proteins is large, containing functionally diverse transcription factors. However, MYBs in Morus are still poorly annotated and a comprehensive functional analysis of these transcription factors is lacking.

Results: In the present study, a genome-wide identification of MYBs in Morus alba was performed. In total 166 MaMYBs were identified, including 103 R2R3-MYBs and four 3R-MaMYBs. Comprehensive analyses, including the phylogenetic analysis with putative functional annotation, motif and structure analysis, gene structure organization, promoter analysis, chromosomal localization, and syntenic relationships of R2R3-MaMYBs and 3R-MaMYBs, provided primary characterization for these MaMYBs. R2R3-MaMYBs covered the subgroups reported for R2R3-MYBs in Arabidopsis and Populus, and had two Morus-specific subgroups, indicating the high retention of MYBs in Morus. Motif analysis revealed high conservative residues at the start and end of each helix and residues consisting of the third helix in R2 and R3 repeats. Thirteen intron/exon patterns (a-m) were summarized, and the intron/exon pattern of two introns with phase numbers of 0 and 2 was the prevalent pattern for R2R3-MaMYBs. Various cis-elements in promoter regions were identified, and were mainly related to light response, development, phytohormone response, and abiotic and biotic stress response and secondary metabolite production. Expression patterns of R2R3-MaMYBs in different organs showed that MaMYBs involved in secondary cell wall components and stress responsiveness were preferentially expressed in roots or stems. R2R3-MaMYBs involved in flavonoid biosynthesis and anthocyanin accumulation were identified and characterized based on functional annotation and correlation of their expression levels with anthocyanin contents.

Conclusion: Based on a comprehensive analysis, this work provided functional annotation for R2R3-MYBs and an informative reference for further functional dissection of MYBs in Morus.
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http://dx.doi.org/10.1186/s12870-022-03626-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175366PMC
June 2022

Acoustic Fabrication of Living Cardiomyocyte-based Hybrid Biorobots.

ACS Nano 2022 Jun 7. Epub 2022 Jun 7.

Bio-Acoutic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine Stanford University, Palo Alto, California 94304-5427, United States.

Organized assemblies of cells have demonstrated promise as bioinspired actuators and devices; still, the fabrication of such "biorobots" has predominantly relied on passive assembly methods that reduce design capabilities. To address this, we have developed a strategy for the rapid formation of functional biorobots composed of live cardiomyocytes. We employ tunable acoustic fields to facilitate the efficient aggregation of millions of cells into high-density macroscopic architectures with directed cell orientation and enhanced cell-cell interaction. These biorobots can perform actuation functions both through naturally occurring contraction-relaxation cycles and through external control with chemical and electrical stimuli. We demonstrate that these biorobots can be used to achieve controlled actuation of a soft skeleton and pumping of microparticles. The biocompatible acoustic assembly strategy described here should prove generally useful for cellular manipulation in the context of tissue engineering, soft robotics, and other applications.
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http://dx.doi.org/10.1021/acsnano.2c01908DOI Listing
June 2022

Mechanisms of bone pain: Progress in research from bench to bedside.

Bone Res 2022 Jun 6;10(1):44. Epub 2022 Jun 6.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.

The field of research on pain originating from various bone diseases is expanding rapidly, with new mechanisms and targets asserting both peripheral and central sites of action. The scope of research is broadening from bone biology to neuroscience, neuroendocrinology, and immunology. In particular, the roles of primary sensory neurons and non-neuronal cells in the peripheral tissues as important targets for bone pain treatment are under extensive investigation in both pre-clinical and clinical settings. An understanding of the peripheral mechanisms underlying pain conditions associated with various bone diseases will aid in the appropriate application and development of optimal strategies for not only managing bone pain symptoms but also improving bone repairing and remodeling, which potentially cures the underlying etiology for long-term functional recovery. In this review, we focus on advances in important preclinical studies of significant bone pain conditions in the past 5 years that indicated new peripheral neuronal and non-neuronal mechanisms, novel targets for potential clinical interventions, and future directions of research.
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http://dx.doi.org/10.1038/s41413-022-00217-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170780PMC
June 2022

Targeting tumor-associated macrophages for cancer immunotherapy.

Int Rev Cell Mol Biol 2022 27;368:61-108. Epub 2022 Apr 27.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States. Electronic address:

Tumor-associated macrophages (TAMs) are one of the most abundant immune components in the tumor microenvironment and play a plethora of roles in regulating tumorigenesis. Therefore, the therapeutic targeting of TAMs has emerged as a new paradigm for immunotherapy of cancer. Herein, the review summarizes the origin, polarization, and function of TAMs in the progression of malignant diseases. The understanding of such knowledge leads to several distinct therapeutic strategies to manipulate TAMs to battle cancer, which include those to reduce TAM abundance, such as depleting TAMs or inhibiting their recruitment and differentiation, and those to harness or boost the anti-tumor activities of TAMs such as blocking phagocytosis checkpoints, inducing antibody-dependent cellular phagocytosis, and reprogramming TAM polarization. In addition, modulation of TAMs may reshape the tumor microenvironment and therefore synergize with other cancer therapeutics. Therefore, the rational combination of TAM-targeting therapeutics with conventional therapies including radiotherapy, chemotherapy, and other immunotherapies is also reviewed. Overall, targeting TAMs presents itself as a promising strategy to add to the growing repertoire of treatment approaches in the fight against cancer, and it is hopeful that these approaches currently being pioneered will serve to vastly improve patient outcomes and quality of life.
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http://dx.doi.org/10.1016/bs.ircmb.2022.02.002DOI Listing
April 2022

Impacts of anthropogenic groundwater recharge (AGR) on nitrate dynamics in a phreatic aquifer revealed by hydrochemical and isotopic technologies.

Sci Total Environ 2022 Sep 23;839:156187. Epub 2022 May 23.

Ministry of Education Key Laboratory of Groundwater Circulation and Environmental Evolution, China University of Geosciences (Beijing), Beijing 100083, China. Electronic address:

Although anthropogenic groundwater recharge (AGR) can either elevate or decline the concentration of nitrate in the phreatic aquifer with high hydraulic conductivity, the long-term impact of AGR on nitrate dynamics in the phreatic aquifer and its reason is seldom disclosed. In this study, the hydrogen and oxygen stable isotopes (δH-HO and δO-HO) combined with mixing stable isotope analysis in R (MixSIAR) were used to group the study area into the dominant area of AGR by surface water (AGRSW) and the dominant area of natural groundwater recharged by precipitation (NGRP). Hydrochemical parameters and multiple stable isotopes, including δH-HO, δO-HO, δN-NO, δO-NO, and δC-DIC, were applied to explore the impacts of AGR on the concentration, biogeochemical processes, and main sources of nitrate. The results showed that AGR by surface water with low nitrate content can reduce nitrate pollution in groundwater. The characteristic of δO-NO value revealed that nitrification was the primary biogeochemical process of nitrogen in groundwater. AGR may enhance nitrification as indicated by the δO-NO value closer to the nitrification theoretical line. Dual nitrate stable isotopes and MixSIAR revealed that chemical fertilizer (CF), soil nitrogen (SN), and surface water (SW) contributed 10.88%, 49.92%, and 27.64% to nitrate in AGRSW groundwater, respectively, which was significantly different from their contributions to NGRP groundwater (p < 0.05). Notably, AGR significantly increased the contribution of SW but decreased the contribution of CF and SN in groundwater. This study provided a basis and guidance for groundwater quality assessment and pollution control in the phreatic aquifer with high hydraulic conductivity.
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http://dx.doi.org/10.1016/j.scitotenv.2022.156187DOI Listing
September 2022

Lamprey immunity protein enables detection for bladder cancer through recognizing N-hydroxyacetylneuraminic acid (Neu5Gc)-modified as a diagnostic marker and exploration of its production mechanism.

Biochem Biophys Res Commun 2022 07 10;614:153-160. Epub 2022 May 10.

College of Life Science, Liaoning Normal University, Dalian, China; Lamprey Research Center, Liaoning Normal University, Dalian, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, China. Electronic address:

Previous studies have demonstrated that Neu5Gc is highly expressed in breast, ovarian, prostate, colon and lung cancers, but not in normal human cells. The presence of Neu5Gc is important for prognosis and is associated with aggressiveness, metastasis, and tumor grade. However, increased Neu5Gc in bladder cancer remains unclear. LIP from lamprey binds the carbohydrate receptor of N-glycolylneuraminic acid (Neu5Gc). The combination of Neu5Gc and LIP suggested that it might be used as a diagnostic tool for the detection of Neu5Gc tumor antigen. Here, the classical animal model of bladder cancer was successfully induced by MNU bladder perfusion. The ELISA results showed that the expression level of Neu5Gc in the urine of normal rats was 94.96 ± 21.01ng/mg, and that of bladder cancer rats was 158.28 ± 34.86 ng/mg. In addition, the results of SNA and LIP immunohistochemistry demonstrated the high expression of Neu5Gc in bladder cancer. After the addition of Neu5Gc to BIU-87 and SV-HUC-1 cells, transcriptomic sequencing and real-time quantitative PCR analysis demonstrated that the gene expression of Neu5Gc synthesis pathway was significantly increased. These data suggest that LIP provides a new tool for the detection of biological samples, especially urine from patients with bladder cancer or suspected cancer, and that revealing the mechanism of abnormal glycosylation can provide theoretical basis for clinical studies.
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http://dx.doi.org/10.1016/j.bbrc.2022.04.121DOI Listing
July 2022

Self-training Strategy based on Finite Element Method for Adaptive Bioluminescence Tomography Reconstruction.

IEEE Trans Med Imaging 2022 Apr 18;PP. Epub 2022 Apr 18.

Bioluminescence tomography (BLT) is a promising pre-clinical imaging technique for a wide variety of biomedical applications, which can non-invasively reveal functional activities inside living animal bodies through the detection of visible or near-infrared light produced by bioluminescent reactions. Recently, reconstruction approaches based on deep learning have shown great potential in optical tomography modalities. However, these reports only generate data with stationary patterns of constant target number, shape, and size. The neural networks trained by these data sets are difficult to reconstruct the patterns outside the data sets. This will tremendously restrict the applications of deep learning in optical tomography reconstruction. To address this problem, a self-training strategy is proposed for BLT reconstruction in this paper. The proposed strategy can fast generate large-scale BLT data sets with random target numbers, shapes, and sizes through an algorithm named random seed growth algorithm and the neural network is automatically self-trained. In addition, the proposed strategy uses the neural network to build a map between photon densities on surface and inside the imaged object rather than an end-to-end neural network that directly infers the distribution of sources from the photon density on surface. The map of photon density is further converted into the distribution of sources through the multiplication with stiffness matrix. Simulation, phantom, and mouse studies are carried out. Results show the availability of the proposed self-training strategy.
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http://dx.doi.org/10.1109/TMI.2022.3167809DOI Listing
April 2022

DNA aptamer-based dual-responsive nanoplatform for targeted MRI and combination therapy for cancer.

RSC Adv 2022 Jan 31;12(7):3871-3882. Epub 2022 Jan 31.

School of Medical Imaging, Xuzhou Medical University Xuzhou 221004 P. R. China

Accurate drug delivery is a common topic, and it has always been an aim that scientists strive to achieve. To address this need, multifunctional and stimulus-sensitive nanoplatforms have attracted significant attention. Here we fabricated a glutathione (GSH) and adenosine-5'-triphosphate (ATP) dual-sensitive nanoplatform for controlled drug release and activatable MRI of tumors based on DNA aptamer and manganese dioxide (MnO) nanosheets. Cleverly utilizing the DNA tunability, AS1411 aptamer which binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, was designed with ATP aptamer and its cDNA to load the anticancer drug, doxorubicin (Dox). The formed DNA-Dox complex was delivered to the tumor region with the help of MnO nanosheets and AS1411 aptamer. Then, the on-demand drug release in tumor cells was realized with the co-effect of the ATP aptamer and GSH reduction. It was found that without the structure of the MnO nanosheets being broken by GSH, Dox almost could not be released even in the presence of ATP. Similarly, without ATP, Dox was still maintained in the duplex even with GSH. Further combining the MRI ability and chemodynamic therapy of the produced Mn, an improved effect of the inhibition of tumor growth and imaging was achieved. Our designed DNA aptamer-based dual-responsive nanoplatform can realize the targeted drug delivery and MRI of breast tumor cells both and .
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http://dx.doi.org/10.1039/d1ra08373bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8981167PMC
January 2022

Increased signal intensity, not volume variation of infrapatellar fat pad in knee osteoarthritis: A cross-sectional study based on high-resolution magnetic resonance imaging.

J Orthop Surg (Hong Kong) 2022 Jan-Apr;30(1):10225536221092215

Department of Orthopaedic Surgery, 504354Third Xiangya Hospital of Central South University, Changsha, China.

Background: Infrapatellar fat pad (IPFP) is regarded as an essential knee tissue involved in osteoarthritis (OA) for its potential structural-related or metabolism-related function. This cross-sectional study aims to identify which part is more related to OA.

Methods: Patients with knee OA ( = 53) and healthy controls ( = 54) were prospectively recruited. Based on high-resolution magnetic resonance imaging with a slice thickness of only 0.35 mm, IPFP structural-related parameters (volume and maximal area), metabolism-related parameter (signal), degeneration indicators, and patellar maltracking indicators (patellar translation, patellofemoral angle, and Insall-Salvati ratio) were measured. IPFP volume (maximal area, and signal) was compared between healthy controls and OA patients. The level of significance for all comparisons was set as .05.

Results: OA patients had higher IPFP signal (672.9 ± 136.9 vs 567.3 ± 63.6, = .009), but no significant difference in IPFP volume or maximal area compared with healthy controls. In healthy controls, IPFP signal was positively associated with age ( = 1.481; 95% CI: 0.286-2.676; .018); IPFP maximal area was positively related to Insall-Salvati ratio ( = 0.001; 95% CI: 0.0003-0.0017; .039), but not associated with patellar translation and patellofemoral angle. In OA patients, IPFP signal was positively associated with cartilage loss ( = 0.005; 95% CI: 0.003-0.007; .013); no correlation between knee pain and IPFP volume or maximal area was observed.

Conclusions: The metabolism-related function of IPFP, which can be reflected by the IPFP signal, might play a more critical role in OA progression than its structural function.
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http://dx.doi.org/10.1177/10225536221092215DOI Listing
April 2022

Editorial: Optical Molecular Imaging in Cancer Research.

Front Oncol 2022 28;12:870583. Epub 2022 Mar 28.

Thayer School of Engineering, Dartmouth College, Hanover, NH, United States.

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http://dx.doi.org/10.3389/fonc.2022.870583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995548PMC
March 2022

Differentiating solitary brain metastases from glioblastoma by radiomics features derived from MRI and 18F-FDG-PET and the combined application of multiple models.

Sci Rep 2022 04 6;12(1):5722. Epub 2022 Apr 6.

Department of Radiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.

This study aimed to explore the ability of radiomics derived from both MRI and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) images to differentiate glioblastoma (GBM) from solitary brain metastases (SBM) and to investigate the combined application of multiple models. The imaging data of 100 patients with brain tumours (50 GBMs and 50 SBMs) were retrospectively analysed. Three model sets were built on MRI, 18F-FDG-PET, and MRI combined with 18F-FDG-PET using five feature selection methods and five classification algorithms. The model set with the highest average AUC value was selected, in which some models were selected and divided into Groups A, B, and C. Individual and joint voting predictions were performed in each group for the entire data. The model set based on MRI combined with 18F-FDG-PET had the highest average AUC compared with isolated MRI or 18F-FDG-PET. Joint voting prediction showed better performance than the individual prediction when all models reached an agreement. In conclusion, radiomics derived from MRI and 18F-FDG-PET could help differentiate GBM from SBM preoperatively. The combined application of multiple models can provide greater benefits.
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http://dx.doi.org/10.1038/s41598-022-09803-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986767PMC
April 2022

Two-stage deep learning network-based few-view image reconstruction for parallel-beam projection tomography.

Quant Imaging Med Surg 2022 Apr;12(4):2535-2551

Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, China.

Background: Projection tomography (PT) is a very important and valuable method for fast volumetric imaging with isotropic spatial resolution. Sparse-view or limited-angle reconstruction-based PT can greatly reduce data acquisition time, lower radiation doses, and simplify sample fixation modes. However, few techniques can currently achieve image reconstruction based on few-view projection data, which is especially important for PT in living organisms.

Methods: A 2-stage deep learning network (TSDLN)-based framework was proposed for parallel-beam PT reconstructions using few-view projections. The framework is composed of a reconstruction network (R-net) and a correction network (C-net). The R-net is a generative adversarial network (GAN) used to complete image information with direct back-projection (BP) of a sparse signal, bringing the reconstructed image close to reconstruction results obtained from fully projected data. The C-net is a U-net array that denoises the compensation result to obtain a high-quality reconstructed image.

Results: The accuracy and feasibility of the proposed TSDLN-based framework in few-view projection-based reconstruction were first evaluated with simulations, using images from the DeepLesion public dataset. The framework exhibited better reconstruction performance than traditional analytic reconstruction algorithms and iterative algorithms, especially in cases using sparse-view projection images. For example, with as few as two projections, the TSDLN-based framework reconstructed high-quality images very close to the original image, with structural similarities greater than 0.8. By using previously acquired optical PT (OPT) data in the TSDLN-based framework trained on computed tomography (CT) data, we further exemplified the migration capabilities of the TSDLN-based framework. The results showed that when the number of projections was reduced to 5, the contours and distribution information of the samples in question could still be seen in the reconstructed images.

Conclusions: The simulations and experimental results showed that the TSDLN-based framework has strong reconstruction abilities using few-view projection images, and has great potential in the application of PT.
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http://dx.doi.org/10.21037/qims-21-778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923870PMC
April 2022

Conventional MRI-derived subchondral trabecular biomarkers and their association with knee cartilage volume loss as early as 1 year: a longitudinal analysis from Osteoarthritis Initiative.

Skeletal Radiol 2022 Apr 2. Epub 2022 Apr 2.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 601 N Caroline St, JHOC 4240, Baltimore, MD, 21287, USA.

Objective: To study associations between MRI-derived subchondral trabecular biomarkers obtained from conventional MRI sequences and knee cartilage loss over 12 and 24 months, using the FNIH osteoarthritis (OA) biomarkers consortium.

Materials And Methods: Data of the 600 subjects in the FNIH OA biomarkers consortium (a nested case-control study within Osteoarthritis Initiative [OAI]) were extracted from the online database. Baseline knee MRI (intermediate-weighted (IW) sequences) were evaluated to determine conventional MRI-derived trabecular thickness (cTbTh) and bone-to-total ratio (cBV/TV). The measurements for medial and lateral volumes of cartilages using baseline, 12-, and 24-month knee MRI were extracted from the OAI database, and cartilage volume loss over 12 and 24 months of follow-up were determined using Relative Change Index. The association between conventional MRI-based subchondral trabecular biomarkers and cartilage volume loss were studied using logistic regression models, adjusted for relevant confounders including age, sex, body mass index (BMI), vitamin D use, Kellgren Lawrence grade (KLG), and tibiofemoral alignment.

Results: Higher medial cTbTh and cBV/TV at baseline were associated with increased odds of medial tibial cartilage volume loss over 12 months (ORs: 1.01 [1.00-1.02] and 1.24 [1.10-1.39] per 1-SD change) and 24 months (ORs: 1.01 [1.00-1.02] and 1.22 [1.08-1.37], per 1-SD change). No significant association was observed between medial subchondral trabecular biomarkers and lateral tibial or femoral (medial or lateral) cartilage volume loss over the first and second follow-up years.

Conclusions: Conventional MRI-derived subchondral trabecular biomarkers (higher medial cTbTh and cBV/TV) may be associated with increased medial tibial cartilage volume loss as early as 1 year.
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http://dx.doi.org/10.1007/s00256-022-04042-4DOI Listing
April 2022

Coassembly of Warm Temperature-Sensitive Transient Receptor Potential Vanilloid (TRPV) 3 and TRPV4 Channel Complexes with Distinct Functional Properties.

Mol Pharmacol 2022 06 31;101(6):390-399. Epub 2022 Mar 31.

Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (F.H., C.N., K.W.); Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing, China (X.C.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (K.W.)

Heteromeric assembly of temperature-sensitive transient receptor potential (TRP) ion channels has been suggested to underlie the molecular basis of fine-tuning of temperature detection and chemical sensation. However, whether warm temperature-sensitive TRP vanilloid (TRPV) 3 and TRPV4 channels robustly expressed in the skin can form heteromeric assembly remains largely unknown. In this study, we show that TRPV3 and TRPV4 channels can coassemble into functional heterotetrameric channels with distinct properties. Confocal imaging reveals a colocalization and association of TRPV3 and TRPV4 proteins in cell membrane. Coimmunoprecipitation analysis demonstrates a strong protein-protein interaction between TRPV3 and TRPV4 subunits from heterogeneously expressed cells or mouse skin tissues through their C termini but not in TRPV3 knockout tissues. Coexpression of TRPV3 and TRPV4 channels yields a heterotetrameric channel complexes characterized by an intermediate single-channel conductance, distinct activation threshold, and pharmacology. Taken together, our findings demonstrate a heterotetrameric assembly of TRPV3 and TRPV4 channels, which may help explain the role of temperature-sensitive TRPV channels in fine-tuning of environmental detection and sensation in the skin. SIGNIFICANCE STATEMENT: The coassembly of transient receptor potential vanilloid (TRPV) 3 and TRPV4 channel complexes increases the functional diversity within the channel subfamily, which may serve as a molecular basis for fine-tuning of environmental detection and temperature sensation in mammals.
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http://dx.doi.org/10.1124/molpharm.121.000370DOI Listing
June 2022

Dynamic evolution of small signalling peptide compensation in plant stem cell control.

Nat Plants 2022 04 28;8(4):346-355. Epub 2022 Mar 28.

School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.

Gene duplications are a hallmark of plant genome evolution and a foundation for genetic interactions that shape phenotypic diversity. Compensation is a major form of paralogue interaction but how compensation relationships change as allelic variation accumulates is unknown. Here we leveraged genomics and genome editing across the Solanaceae family to capture the evolution of compensating paralogues. Mutations in the stem cell regulator CLV3 cause floral organs to overproliferate in many plants. In tomato, this phenotype is partially suppressed by transcriptional upregulation of a closely related paralogue. Tobacco lost this paralogue, resulting in no compensation and extreme clv3 phenotypes. Strikingly, the paralogues of petunia and groundcherry nearly completely suppress clv3, indicating a potent ancestral state of compensation. Cross-species transgenic complementation analyses show that this potent compensation partially degenerated in tomato due to a single amino acid change in the paralogue and cis-regulatory variation that limits its transcriptional upregulation. Our findings show how genetic interactions are remodelled following duplications and suggest that dynamic paralogue evolution is widespread over short time scales and impacts phenotypic variation from natural and engineered mutations.
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http://dx.doi.org/10.1038/s41477-022-01118-wDOI Listing
April 2022

An osteoarthritis subtype characterized by synovial lipid metabolism disorder and fibroblast-like synoviocyte dysfunction.

J Orthop Translat 2022 Mar 12;33:142-152. Epub 2022 Mar 12.

Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, China.

Background: The heterogeneity of osteoarthritis (OA) significantly limits the effectiveness of pharmacological treatments in an unselected patient population. In this context, the identification of OA subtypes is meaningful for the development of therapies that target specific types of OA pathogenesis.

Methods: Expression array profiles of 70 OA and 36 control synovial samples were extracted from the GEO database. Unsupervised consensus clustering was performed based on the most variable genes to identify OA subclusters. Next, Joint samples from OA patients were obtained. We divided the OA patient into two subpopulations according to synovial ADCY7 levels. Synovium and cartilage samples from different OA subpopulations were evaluated. In addition, we established a high-fat diet (HFD)-induced rat OA model. We evaluated OA progression, lipid metabolism, synovitis and fibroblast-like synoviocytes (FLS) function in this HFD-induced OA model.

Results: 70 OA patients were categorized into three distinct subclusters. We noted that one subcluster was characterized by synovial lipid metabolism disorder GO terms. We further identified the most noticeable KEGG pathway "Regulation of lipolysis in adipocytes" in this subcluster as well as the most significantly differentially expressed gene, ADCY7. We found that the ADCY7 high expressing group (32.6%) exhibited features of synovial inflammatory lipolysis epithelial-mesenchymal transition (EMT) tendency, as well as faster join space narrowing. The HFD induced OA-like degeneration in rat joints. We observed similar synovial inflammatory lipolysis and EMT in FLS, characterized by higher proliferative and invasive activity and elevated proinflammatory and procatabolic properties. ADCY7 was highly expressed in the synovium of the HFD-OA model rats and the inhibition of ADCY7 effectively attenuated these HFD-induced degenerative changes as well as synovial inflammatory lipolysis and FLS dysfunction. In HFD-FLSs, ADCY7 promoted the phosphorylation of PKA as well as its downstream lipid droplet-associated protein PLIN1 and hormone-sensitive lipase (HSL). The inhibition of PKA largely alleviated ADCY7-mediated HFD-FLS dysfunction.

Conclusions: We described a synovial EMT and lipid metabolism disorder in the pathogenesis of OA. This novel mechanism may represent a currently undefined OA subtype. ADCY7 is a potential molecular marker of this pathomechanism.

The Translational Potential Of This Article: Utilizing synovial samples from OA patients, we identified a subpopulation with high ADCY7 expression. This may represent a currently undefined OA subtype and explain the clinical phenomenon of more severe synovial inflammation in obese OA patients. In addition, we established an HFD-induced OA rat model and found an upregulation of ADCY7 in the synovium. We confirmed that the inhibition of ADCY7 could effectively attenuate HFD-induced degenerative changes as well as the inflammatory lipolysis and FLS dysfunction observed in the rat model. This suggests that ADCY7 and its downstream pathways are potential pharmacological targets for treating this lipid-metabolism-disorder-related OA mechanism.
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http://dx.doi.org/10.1016/j.jot.2022.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919236PMC
March 2022

Uncovering the Pharmacological Mechanisms of Gexia-Zhuyu Formula (GXZY) in Treating Liver Cirrhosis by an Integrative Pharmacology Strategy.

Front Pharmacol 2022 7;13:793888. Epub 2022 Mar 7.

Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.

Liver cirrhosis (LC) is a fibrotic lesion of liver tissue caused by the repeated progression of chronic hepatitis. The traditional Chinese medicine Gexia-Zhuyu formula (GXZY) has a therapeutic effect on LC. However, its pharmacological mechanisms on LC remain elucidated. Here, we used the network pharmacology approach to explore the action mechanisms of GXZY on LC. The compounds of GXZY were from the traditional Chinese medicine systems pharmacology (TCMSP) database, and their potential targets were from SwissTargetPrediction and STITCH databases. The disease targets of LC came from GeneCards, DisGeNET, NCBI gene, and OMIM databases. Then we constructed the protein-protein interaction (PPI) network to obtain the key target genes. And the gene ontology (GO), pathway enrichment, and expression analysis of the key genes were also performed. Subsequently, the potential action mechanisms of GXZY on LC predicted by the network pharmacology analyses were experimentally validated in LC rats and LX2 cells. A total of 150 components in GXZY were obtained, among which 111 were chosen as key compounds. The PPI network included 525 targets, and the key targets were obtained by network topological parameters analysis, whereas the predicted key genes of GXZY on LC were AR, JUN, MYC, CASP3, MMP9, GAPDH, and RELA. Furthermore, these key genes were related to pathways in cancer, hepatitis B, TNF signaling pathway, and MAPK signaling pathway. The and experiments validated that GXZY inhibited the process of LC mainly via the regulation of cells proliferation and migration through reducing the expression of MMP9. In conclusion, through the combination of network pharmacology and experimental verification, this study offered more insight molecular mechanisms of GXZY on LC.
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http://dx.doi.org/10.3389/fphar.2022.793888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940433PMC
March 2022

Individual pulse monitoring and dose control system for pre-clinical implementation of FLASH-RT.

Phys Med Biol 2022 04 15;67(9). Epub 2022 Apr 15.

Thayer School of Engineering, Dartmouth College, Hanover NH 03755, United States of America.

Existing ultra-high dose rate (UHDR) electron sources lack dose rate independent dosimeters and a calibrated dose control system for accurate delivery. In this study, we aim to develop a custom single-pulse dose monitoring and a real-time dose-based control system for a FLASH enabled clinical linear accelerator (Linac).A commercially available point scintillator detector was coupled to a gated integrating amplifier and a real-time controller for dose monitoring and feedback control loop. The controller was programmed to integrate dose for each radiation pulse and stop the radiation beam when the prescribed dose was delivered. Additionally, the scintillator was mounted in a solid water phantom and placed underneath mice skin fordose monitoring. The scintillator was characterized in terms of its radiation stability, mean dose-rate (Ḋm), and dose per pulse () dependence.Theexhibited a consistent ramp-up period across ∼4-5 pulse. The plastic scintillator was shown to be linear withḊm(40-380 Gy s) and(0.3-1.3 Gy Pulse) to within +/- 3%. However, the plastic scintillator was subject to significant radiation damage (16%/kGy) for the initial 1 kGy and would need to be calibrated frequently. Pulse-counting control was accurately implemented with one-to-one correspondence between the intended and the actual delivered pulses. The dose-based control was sufficient to gate on any pulse of the Linac.dosimetry monitoring with a 1 cm circular cut-out revealed that during the ramp-up period, the averagewas ∼0.045 ± 0.004 Gy Pulse, whereas after the ramp-up it stabilized at 0.65 ± 0.01 Gy Pulse.The tools presented in this study can be used to determine the beam parameter space pertinent to the FLASH effect. Additionally, this study is the first instance of real-time dose-based control for a modified Linac at ultra-high dose rates, which provides insight into the tool required for future clinical translation of FLASH-RT.
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http://dx.doi.org/10.1088/1361-6560/ac5f6fDOI Listing
April 2022

Promoting antibody-dependent cellular phagocytosis for effective macrophage-based cancer immunotherapy.

Sci Adv 2022 03 18;8(11):eabl9171. Epub 2022 Mar 18.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

Macrophages are essential in eliciting antibody-dependent cellular phagocytosis (ADCP) of cancer cells. However, a satisfactory anticancer efficacy of ADCP is contingent on early antibody administration, and resistance develops along with cancer progression. Here, we investigate the mechanisms underlying ADCP and demonstrate an effective combinatorial strategy to potentiate its efficacy. We identified paclitaxel as a universal adjuvant that efficiently potentiated ADCP by a variety of anticancer antibodies in multiple cancers. Rather than eliciting cytotoxicity on cancer cells, paclitaxel polarized macrophages toward a state with enhanced phagocytic ability. Paclitaxel-treated macrophages down-regulated cell surface CSF1R whose expression was negatively correlated with patient survival in multiple malignancies. The suppression of CSF1R in macrophages enhanced ADCP of cancer cells, suggesting a role of CSF1R in regulating macrophage phagocytic ability. Together, these findings define a potent strategy for using conventional anticancer drugs to stimulate macrophage phagocytosis and promote the therapeutic efficacy of clinical anticancer antibodies.
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http://dx.doi.org/10.1126/sciadv.abl9171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932662PMC
March 2022
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