Converting Treatment Plans From Helical Tomotherapy to L-Shape Linac: Clinical Workflow and Dosimetric Evaluation.

This work evaluated a commercial fallback planning workflow designed to provide cross-platform treatment planning and delivery. A total of 27 helical tomotherapy intensity-modulated radiotherapy plans covering 4 anatomical sites were selected, including 7 brain, 5 unilateral head and neck, 5 bilateral head and neck, 5 pelvis, and 5 prostate cases. All helical tomotherapy plans were converted to 7-field/9-field intensity-modulated radiotherapy and volumetric-modulated radiotherapy plans through fallback dose-mimicking algorithm using a 6-MV beam model. The planning target volume (PTV) coverage ( D1, D99, and homogeneity index) and organs at risk dose constraints were evaluated and compared. Overall, all 3 techniques resulted in relatively inferior target dose coverage compared to helical tomotherapy plans, with higher homogeneity index and maximum dose. The organs at risk dose ratio of fallback to helical tomotherapy plans covered a wide spectrum, from 0.87 to 1.11 on average for all sites, with fallback plans being superior for brain, pelvis, and prostate sites. The quality of fallback plans depends on the delivery technique, field numbers, and angles, as well as user selection of structures for organs at risk. In actual clinical scenario, fallback plans would typically be needed for 1 to 5 fractions of a treatment course in the event of machine breakdown. Our results suggested that <1% dose variance can be introduced in target coverage and/or organs at risk from fallback plans. The presented clinical workflow showed that the fallback plan generation typically takes 10 to 20 minutes per case. Fallback planning provides an expeditious and effective strategy for transferring patients cross platforms, and minimizing the untold risk of a patient missing treatment(s)

Characteristic gene expression in the liver monocyte-macrophage-DC system is associated with the progression of fibrosis in NASH

BackgroundThe monocyte-macrophage-dendritic cell (DC) (MMD) system exerts crucial functions that may modulate fibrogenesis in nonalcoholic steatohepatitis (NASH). In this study, we explored the cell characteristics, distribution and developmental trajectory of the liver MMD system in NASH mice with fibrosis and clarified characteristic genes of the MMD system involved in liver fibrosis progression in NASH mice and patients.MethodsSingle cells in liver tissue samples from NASH and normal mice were quantified using single-cell RNA sequencing (scRNA-seq) analysis. Differentially expressed genes (DEGs) in the MMD system by pseudotime analysis were validated by tyramide signal amplification (TSA)-immunohistochemical staining (IHC) and analyzed by second harmonic generation (SHG)/two-photon excitation fluorescence (TPEF).ResultsCompared with control mice, there were increased numbers of monocytes, Kupffer cells, and DCs in two NASH mouse models. From the transcriptional profiles of these single cells, we identified 8 monocyte subsets (Mono1-Mono8) with different molecular and functional properties. Furthermore, the pseudotime analysis showed that Mono5 and Mono6 were at the beginning of the trajectory path, whereas Mono2, Mono4, Kupffer cells and DCs were at a terminal state. Genes related to liver collagen production were at the late stage of this trajectory path. DEGs analysis revealed that the genes Fmnl1 and Myh9 in the MMD system were gradually upregulated during the trajectory. By TSA-IHC, the Fmnl1 and Myh9 expression levels were increased and associated with collagen production and fibrosis stage in NASH mice and patients.ConclusionsOur transcriptome data provide a novel landscape of the MMD system that is involved in advanced NASH disease status. Fmnl1 and Myh9 expression in the MMD system was associated with the progression of NASH fibrosis

Plasma-activated tight and uniform grown of metal-organic frame-work on carbon cloth for stable Li metal anode

The significant expansion in volume and the formation of dendrites on lithium metal anodes lead to poor electrochemical reversi-bility. In this study, ZnO, N-dually doped carbon (p-ZNCC) was synthesized using oxygen plasma assistance and zeolitic imidazo-late framework-8 (ZIF-8). The use of plasma ensures tight and uniform growth of ZIF-8 particles on carbon fiber, promoting the formation of lithiophilic pyrrolic N after sintering. This enables uniform lithium deposition and rapid lithium-ion diffusion during the operation. The resulting lithium electrode with the p-ZNCC host (p-ZNCC-Li) exhibits stable lithium stripping/plating for up to 3000 h and a voltage hysteresis of 36 mV when cycled at 10 mA cm-2-10 mAh cm-2. Electrochemical impedance spectroscopy (EIS) reveals low charge transfer resistance and a high diffusion coefficient for p-ZNCC-Li. Moreover, the LNMO||p-ZNCC-Li cell demonstrates improved capacity retention at 1 C after 250 cycles. This study introduces a novel approach to growing metal-organic frameworks (MOFs) with dual lithiophilic spots on carbon cloth, promising advancements in lithium metal anode design

Development and fabrication of co-axially electrospun biomimetic periosteum with a decellularized periosteal ECM shell/PCL core structure to promote the repair of critical-sized bone defects

Periosteum is crucial to the initial healing of bone defects because it provides a stable periosteum-specific microenvironment and abundant osteogenic cells towards bone repair. However, the usage of autologous periosteum is restricted for limited availability. Xenogeneic decellularized periosteum (DP) preserves periosteum-specific cues but the hardly-controlled physicochemical properties render it inconvenient to use widely. Our study aimed to fabricate a tissue-engineered periosteum (TEP) with a continuous periosteum-specifically bioactive surface and tailored physicochemical properties by co-axial electrospinning of poly(ε-caprolactone) (PCL)/periosteal decellularized extracellular matrix (dECM) to promote bone defects healing. Before use, DP was confirmed for effective removal of residual DNA and well preservation of biological components, e.g., collagen and glycosaminoglycans. After optimization of fabrication processes, PCL/dECM co-axially electrospun membrane (PEC) bore an exquisite core-shell structure, which was effectively equipped with composite advantages of dECM and PCL. Notably, PEC stood out in terms of tensile strength and long-term durability within a physiological environment compared to that of the dECM uniaxial electrospun membrane (ECM). Besides, PEC exhibited remarkably better cell proliferation, migration, bio-mineralization, and osteogenic properties as compared to that of the electrospun PCL membrane. Moreover, PEC-TEP could significantly enhance the recovery of critical-sized bone defects in rats than that of PCL-TEP. To the best of our knowledge, biomimetic PEC-TEP was fabricated and used for the first time to repair bone defects. This novel strategy is promising to fabricate a dECM-based advanced membrane for tissue engineering

Development and fabrication of co-axially electrospun biomimetic periosteum with a decellularized periosteal ECM shell/PCL core structure to promote the repair of critical-sized bone defects

Periosteum is crucial to the initial healing of bone defects because it provides a stable periosteum-specific microenvironment and abundant osteogenic cells towards bone repair. However, the usage of autologous periosteum is restricted for limited availability. Xenogeneic decellularized periosteum (DP) preserves periosteum-specific cues but the hardly-controlled physicochemical properties render it inconvenient to use widely. Our study aimed to fabricate a tissue-engineered periosteum (TEP) with a continuous periosteum-specifically bioactive surface and tailored physicochemical properties by co-axial electrospinning of poly(ε-caprolactone) (PCL)/periosteal decellularized extracellular matrix (dECM) to promote bone defects healing. Before use, DP was confirmed for effective removal of residual DNA and well preservation of biological components, e.g., collagen and glycosaminoglycans. After optimization of fabrication processes, PCL/dECM co-axially electrospun membrane (PEC) bore an exquisite core-shell structure, which was effectively equipped with composite advantages of dECM and PCL. Notably, PEC stood out in terms of tensile strength and long-term durability within a physiological environment compared to that of the dECM uniaxial electrospun membrane (ECM). Besides, PEC exhibited remarkably better cell proliferation, migration, bio-mineralization, and osteogenic properties as compared to that of the electrospun PCL membrane. Moreover, PEC-TEP could significantly enhance the recovery of critical-sized bone defects in rats than that of PCL-TEP. To the best of our knowledge, biomimetic PEC-TEP was fabricated and used for the first time to repair bone defects. This novel strategy is promising to fabricate a dECM-based advanced membrane for tissue engineering

Targeting FBXO22 enhances radiosensitivity in non-small cell lung cancer by inhibiting the FOXM1/Rad51 axis

Abstract Radioresistance is a major constraint on the efficacy of lung cancer radiotherapy, but its mechanism has not been fully elucidated. Here, we found that FBXO22 was aberrantly highly expressed in lung cancer and that FBXO22 knockdown increased the radiosensitivity of lung cancer cells. Mechanistically, FBXO22 promoted Rad51 gene transcription by increasing the level of FOXM1 at the Rad51 promoter, thereby inducing the formation of lung cancer radioresistance. Furthermore, we found that deguelin, a potential inhibitor of FBXO22, enhanced radiosensitivity in an FBXO22/Rad51-dependent manner and was safely tolerated in vivo. Collectively, our results illustrate that FBXO22 induces lung cancer radioresistance by activating the FOXM1/Rad51 axis and provide preclinical evidence for the clinical translation of this critical target

Enzymatically Bioactive Nucleus Pulposus Matrix Hydrogel Microspheres for Exogenous Stem Cells Therapy and Endogenous Repair Strategy to Achieve Disc Regeneration

Abstract Exogenous stem cell therapy and endogenous repair has shown great potential in intervertebral disc regeneration. However, limited nutrients and accumulation of lactate largely impair the survival and regenerative capacity of implanted stem cells and endogenous nucleus pulposus cells (NPCs). Herein, an injectable hydrogel microsphere (LMGDNPs) have been developed by immersing lactate oxidase (LOX)‐manganese dioxide (MnO2) nanozyme (LM) into glucose‐enriched decellularized nucleus pulposus hydrogel microspheres (GDNPs) through a microfluidic system. LMGDNPs showed a delayed release profile of LOX and satisfactory enzymatic capacity in consuming lactate. Mesenchymal stem cells (MSCs) plated on LMGDNPs exhibited better cell viability than cells on GelMA and decellularized nucleus pulposus microspheres (DNP) and showed a obviously increased NPCs phenotype. LMGDNPs prevented MSCs and NPCs death and promoted extracellular matrix synthesis by exhausting lactate. It is determined that LMGDNPs promoted NPCs autophagy by activating transforming growth factor β2 overlapping transcript 1 (TGFB2‐OT1), relying on the nanozyme. MSCs‐loaded LMGDNPs largely preserved disc hydration and alleviated matrix degradation in vivo. Summarily, LMGDNPs promoted cell survival and matrix regeneration by providing a nutrient supply, exhausting lactate, and activating autophagy via TGFB2‐OT1 and its downstream pathway and may serve as an ideal delivery system for exogenous stem cell therapy and endogenous repair

Enrichment of short mutant cell-free DNA fragments enhanced detection of pancreatic cancerResearch in context

Background: Analysis of cell-free DNA (cfDNA) is promising for broad applications in clinical settings, but with significant bias towards late-stage cancers. Although recent studies have discussed the diverse and degraded nature of cfDNA molecules, little is known about its impact on the practice of cfDNA analysis. Methods: We developed single-strand library preparation and hybrid-capture-based cfDNA sequencing (SLHC-seq) to analysis degraded cfDNA fragments. Next we used SLHC-seq to perform cfDNA profiling in 112 pancreatic cancer patients, and the results were compared with 13 previous reports. Extensive analysis was performed in terms of cfDNA fragments to explore the reasons for higher detection rate of KRAS mutations in the circulation of pancreatic cancers. Findings: By applying the new approach, we achieved higher efficiency in analysis of mutations than previously reported using other detection assays. 791 cancer-specific mutations were detected in plasma of 88% patients with KRAS hotspots detected in 70% of all patients. Only 8 mutations were detected in 28 healthy controls without any known oncogenic or truncating alleles. cfDNA profiling by SLHC-seq was largely consistent with results of tissue-based sequencing. SLHC-seq rescued short or damaged cfDNA fragments along to increase the sensitivity and accuracy of circulating-tumour DNA detection. Interpretation: We found that the small mutant fragments are prevalent in early-stage patients, which provides strong evidence for fragment size-based detection of pancreatic cancer. The new pipeline enhanced our understanding of cfDNA biology and provide new insights for liquid biopsy. Keywords: Pancreatic cancer, Cell-free DNA, Fragmentation, Tissue biopsy, Diagnosis and prognosi

Decellularized Disc Hydrogels for hBMSCs tissue-specific differentiation and tissue regeneration

Tissue specificity, a key factor in the decellularized tissue matrix (DTM), has shown bioactive functionalities in tuning cell fate—e.g., the differentiation of mesenchymal stem cells. Notably, cell fate is also determined by the living microenvironment, including material composition and spatial characteristics. Herein, two neighboring tissues within intervertebral discs, the nucleus pulposus (NP) and annulus fibrosus (AF), were carefully processed into DTM hydrogels (abbreviated DNP-G and DAF-G, respectively) to determine the tissue-specific effects on stem cell fate, such as specific components and different culturing methods, as well as in vivo regeneration. Distinct differences in their protein compositions were identified by proteomic analysis. Interestingly, the fate of human bone marrow mesenchymal stem cells (hBMSCs) also responds to both culturing methods and composition. Generally, hBMSCs cultured with DNP-G (3D) differentiated into NP-like cells, while hBMSCs cultured with DAF-G (2D) underwent AF-like differentiation, indicating a close correlation with the native microenvironments of NP and AF cells, respectively. Furthermore, we found that the integrin-mediated RhoA/LATS/YAP1 signaling pathway was activated in DAF-G (2D)-induced AF-specific differentiation. Additionally, the activation of YAP1 determined the tendency of NP- or AF-specific differentiation and played opposite regulatory effects. Finally, DNP-G and DAF-G specifically promoted tissue regeneration in NP degeneration and AF defect rat models, respectively. In conclusion, DNP-G and DAF-G can specifically determine the fate of stem cells through the integrin-mediated RhoA/LATS/YAP1 signaling pathway, and this tissue specificity is both compositional and spatial, supporting the utilization of tissue-specific DTM in advanced treatments of intervertebral disc degeneration