Effects of pre-operative enteral immunonutrition for esophageal cancer patients treated with neoadjuvant chemoradiotherapy: protocol for a multicenter randomized controlled trial (point trial, pre-operative immunonutrition therapy).

BACKGROUND: Neoadjuvant chemoradiation followed by esophagectomy has been established as the first-line treatment for locally advanced esophageal cancer. Postoperative enteral nutrition has been widely used to improve perioperative outcomes. However, whether to implement preoperative nutritional intervention during neoadjuvant therapy is yet to be verified by prospective studies. METHODS: POINT trial is a multicenter, open-labeled, randomized controlled trial. A total of 244 patients with surgically resectable esophageal cancer are randomly assigned to nutritional therapy group (arm A) or control group (arm B) with a 2:1 ratio. Both groups receive neoadjuvant chemotherapy with concurrent radiotherapy based on the CROSS regimen followed by minimally invasive esophagectomy. The primary endpoint is the rate of nutrition and immune-related complications after surgery. Secondary endpoints include completion rate of neoadjuvant chemoradiation and related adverse events, rate of pathological complete response, perioperative outcomes, nutritional status, overall survival, progression-free survival and quality of life. DISCUSSION: This trial aims to verify whether immunonutrition during neoadjuvant chemoradiation can reduce the rate of complications and improve perioperative outcomes. Frequent communication and monitoring are essential for a multicenter investigator-initiated trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04513418. The trial was prospectively registered on 14 August 2020, https://www. CLINICALTRIALS: gov/ct2/show/NCT04513418 .

Lanthanide-based metal-organic frameworks solidified by gelatin-methacryloyl hydrogels for improving the accuracy of localization and excision of small pulmonary nodules.

The localization of invisible and impalpable small pulmonary nodules has become an important concern during surgery, since current widely used techniques for localization have a number of limitations, such as invasive features of hookwires and microcoils, and rapid diffusion after injection of indocyanine green (ICG). Lanthanide-based metal-organic frameworks (MOFs) have been proven as potential fluorescent agents because of their prominent luminescent characteristics, including large Stokes shifts, high quantum yields, long decay lifetimes, and undisturbed emissive energies. In addition, lanthanides, such as Eu, can efficiently absorb X-rays for CT imaging. In this study, we synthesized Eu-UiO-67-bpy (UiO = University of Oslo, bpy = 2,2'-bipyridyl) as a fluorescent dye with a gelatin-methacryloyl (GelMA) hydrogel as a liquid carrier. The prepared complex exhibits constant fluorescence emission owing to the luminescent characteristics of Eu and the stable structure of UiO-67-bpy with restricted fluorescence diffusion attributed to the photocured GelMA. Furthermore, the hydrogel provides stiffness to make the injection site tactile and improve the accuracy of localization and excision. Finally, our complex enables fluorescence-CT dual-modal imaging of the localization site.

Graphene oxide suppresses the growth and malignancy of glioblastoma stem cell-like spheroids via epigenetic mechanisms.

BACKGROUND: Glioblastoma stem-like cells (GSCs) are hypothesized to contribute to self-renewal and therapeutic resistance in glioblastoma multiforme (GBM) tumors. Constituting only a small percentage of cancer cells, GSCs possess "stem-like", tumor-initiating properties and display resistance to irradiation and chemotherapy. Thus, novel approaches that can be used to suppress GSCs are urgently needed. A new carbon material-graphene oxide (GO), has been reported to show potential for use in tumor therapy. However, the exact effect of GO on GSCs and the inherent mechanism underlying its action are not clear. In this study, we aimed to investigate the usefulness of GO to inhibit the growth and promote the differentiation of GSCs, so as to suppress the malignancy of GBM. METHODS: In vitro effects of GO on sphere-forming ability, cell proliferation and differentiation were evaluated in U87, U251 GSCs and primary GSCs. The changes in cell cycle and the level of epigenetic modification H3K27me3 were examined. GO was also tested in vivo against U87 GSCs in mouse subcutaneous xenograft models by evaluating tumor growth and histological features. RESULTS: We cultured GSCs to explore the effect of GO and the underlying mechanism of its action. We found, for the first time, that GO triggers the inhibition of cell proliferation and induces apoptotic cell death in GSCs. Moreover, GO could promote the differentiation of GSCs by decreasing the expression of stem cell markers (SOX2 and CD133) and increasing the expression of differentiation-related markers (GFAP and ß-III tubulin). Mechanistically, we found that GO had a striking effect on GSCs by inducing cell cycle arrest and epigenetic regulation. GO decreased H3K27me3 levels, which are regulated by EZH2 and associated with transcriptional silencing, in the promoters of the differentiation-related genes GFAP and ß-III tubulin, thereby enhancing GSC differentiation. In addition, compared with untreated GSCs, GO-treated GSCs that were injected into nude mice exhibited decreased tumor growth in vivo. CONCLUSION: These results suggested that GO could promote differentiation and reduce malignancy in GSCs via an unanticipated epigenetic mechanism, which further demonstrated that GO is a potent anti-GBM agent that could be useful for future clinical applications.

Effects of MIAVS on Early Postoperative ELWI and Respiratory Mechanics.

BACKGROUND: The effects of minimally invasive aortic valve surgery (MIAVS) on the early postoperative extravascular lung water index (ELWI) and respiratory mechanics have rarely been studied. MATERIAL/METHODS: A total of 90 patients were divided into 3 groups: a conventional full sternotomy (CS) group (n=30), an upper ministernotomy (US) group (n=30), and a right anterior thoracotomy (RT) group (n=30). Hemodynamic and respiratory mechanics parameters were recorded at perioperative time points, including before skin incision (T(-1)); at sternum closing (T0); and 4 h (T4), 8 h (T8), 12 h (T12), and 24 h (T24) after the operation. The ventilator support time, ICU length of stay, and postoperative hospitalization time, as well as the thoracic drainage volume and blood transfusion volume, were recorded. RESULTS: The ELWI and pulmonary vascular permeability index (PVPI) increased at T4, and the values were significantly lower in the US group than in the RT group and CS group (P<0.05). At T8, the ELWI and PVPI in the US group and RT group were significantly lower than in the CS group. At T12, there were no significant differences among the 3 groups. In addition, at T4 static lung compliance decreased, plateau airway pressure increased, and airway resistance changed non-significantly. There were no significant differences between the US group and the RT group, but both groups showed better results than the CS group did. CONCLUSIONS: The ELWI and PVPI may transiently increase after aortic valve surgery with cardiopulmonary bypass. Compared with the 12 h required to recover from a conventional sternotomy operation, it may only take 8 h to recover from MIAVS.

An Adjusted Calculation Model of Reduced Heparin Doses in Cardiopulmonary Bypass Surgery in a Chinese Population.

OBJECTIVE: To investigate the safety and efficacy of an adjusted regimen of heparin infusion in cardiopulmonary bypass (CPB) surgery in a Chinese population. DESIGN: Prospective, single-center, observational study. SETTING: University teaching hospital. PARTICIPANTS: Patients having cardiac surgery with CPB were selected for this study using the following criteria: 18 to 75 years of age, undergoing first-time cardiac surgery with conventional median sternotomy, aortic clamping time between 40 and 120 minutes, and preoperative routine blood tests showing normal liver, renal, and coagulation functions. The exclusion criteria include salvage cases, a history of coagulopathy in the family, and long-term use of anticoagulation or antiplatelet drugs. INTERVENTIONS: Sixty patients were divided randomly into a control group (n = 30) receiving a traditional heparin regimen and an experimental group (n = 30) receiving an adjusted regimen. MEASUREMENTS AND MAIN RESULTS: Activated coagulation time (ACT) was monitored at different time points, ACT>480 seconds was set as the safety threshold of CPB. Heparin doses (initial dose, added dose, and total dose), protamine doses (initial dose, added dose, and total dose), CPB time, aortic clamping time, assisted circulation time, sternal closure time, blood transfusion volume, and drainage volume 24 hours after surgery were recorded. There was no significant difference in achieving target ACT after the initial dose of heparin between the 2 groups; CPB time, aortic clamping time, assisted circulation time, postoperative complication rate, and drainage volume between the 2 groups were not significantly different (p>0.05). However, initial and total dosage of heparin, initial and total dosage of protamine, sternal closure time, and intraoperative blood transfusion volume in the experimental group were significantly lower (p< 0.05). CONCLUSIONS: Adjusted regimen of heparin infusion could be used safely and effectively in Chinese CPB patients, which might reduce the initial and total dosage of heparin and protamine as well as sternal closure time and intraoperative blood transfusion volume.

METTL3 achieves lipopolysaccharide-induced myocardial injury via m6A-dependent stabilization of Myh3 mRNA.

Septic cardiomyopathy (SCM) was an important pathological component of severe sepsis and septic shock. N6-methyladenosine (m6A) modification was a common RNA modification in both mRNA and non-coding RNAs and was proved to be involved in sepsis and immune disorders. Therefore, the purpose of this study was to investigate the role and mechanism of METTL3 in lipopolysaccharide-induced myocardial injury. We firstly analyzed the expression changes of various m6A-related regulators in human samples in the GSE79962 data and the Receiver Operating Characteristic curve of significantly changed m6A enzymes, showing that METTL3 had a high diagnostic ability in patients with SCM. Western blotting confirmed the high expression of METTL3 in LPS-treated H9C2 cells, which was consistent with the above results in human samples. In vitro and in vivo, the deficiency of METTL3 could improve the cardiac function, cardiac tissue damage, myocardial cell apoptosis and reactive oxygen species levels in LPS-treated H9C2 cells and LPS-induced sepsis rats, respectively. In addition, we obtained 213 differential genes through transcriptome RNA-seq analysis, and conducted GO enrichment analysis and KEGG pathway analysis through DAVID. We also found that the half-life of Myh3 mRNA was significantly reduced after METTL3 deletion and that Myh3 carried several potential m6A modification sites. In conclusion, we found that downregulation of METTL3 reversed LPS-induced myocardial cell and tissue damage and reduced cardiac function, mainly by increasing Myh3 stability. Our study revealed a key role of METTL3-mediated m6A methylation in septic cardiomyopathy, which may offer a potential mechanism for the therapy of septic cardiomyopathy.

Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions.

Lymph nodes (LNs) are important hubs for metastatic cell arrest and growth, immune modulation, and secondary dissemination to distant sites through a series of mechanisms, and it has been proved that lymph node metastasis (LNM) is an essential prognostic indicator in many different types of cancer. Therefore, it is important for oncologists to understand the mechanisms of tumor cells to metastasize to LNs, as well as how LNM affects the prognosis and therapy of patients with cancer in order to provide patients with accurate disease assessment and effective treatment strategies. In recent years, with the updates in both basic and clinical studies on LNM and the application of advanced medical technologies, much progress has been made in the understanding of the mechanisms of LNM and the strategies for diagnosis and treatment of LNM. In this review, current knowledge of the anatomical and physiological characteristics of LNs, as well as the molecular mechanisms of LNM, are described. The clinical significance of LNM in different anatomical sites is summarized, including the roles of LNM playing in staging, prognostic prediction, and treatment selection for patients with various types of cancers. And the novel exploration and academic disputes of strategies for recognition, diagnosis, and therapeutic interventions of metastatic LNs are also discussed.

Modified Nuss procedure for the treatment of pectus excavatum: Experience of 259 patients.

BACKGROUND: Pectus excavatum is not rare in China. Many treatments for this disease have proved to have many shortcomings. Nuss procedure has been a ground-breaking technology, but it also has some disadvantages. Hence, this study was conducted to review our experience in the use of modified Nuss procedure in our hospital. METHODS: Data from 259 patients suffered from pectus excavatum between August 2020 and August 2021 who were treated with modified Nuss procedure was analyzed retrospectively. RESULT: Age was from 3 to 37 years. The average was 15.54 years. The male was 213 cases and the female was 46 cases. The time patients or their family members found pectus excavatum varied. 10 cases had been repaired previously when patients were admitted in our hospital. The clinical symptoms also varied. Each case had an improvement in Haller index. The average of the postoperative hospitalization was 3.97 days. Most cases were inserted 1 bar. Complication rate was also very low. All patients or their parents or their guardians were satisfied with the appearance of the chest wall after operation. There was no death in the whole observation period. CONCLUSION: From our experience, this modified Nuss procedure have obtained optimistic outcomes with more minimal invasion and low complication rate. This surgical method may be applied to many other hospitals in the future.

Intelligent microneedle patch with prolonged local release of hydrogen and magnesium ions for diabetic wound healing.

Diabetes mellitus, an epidemic with a rapidly increasing number of patients, always leads to delayed wound healing associated with consistent pro-inflammatory M1 polarization, decreased angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Herein, a poly (lactic-co-glycolic acid) (PLGA)-based microneedle patch loaded with magnesium hydride (MgH2) (MN-MgH2) is manufactured for defeating diabetic wounds. The application of microneedle patch contributes to the transdermal delivery and the prolonged release of MgH2 that can generate hydrogen (H2) and magnesium ions (Mg2+) after reaction with body fluids. The released H2 reduces the production of ROS, transforming the pathological microenvironment induced by diabetes mellitus. Meanwhile, the released Mg2+ promotes the polarization of pro-healing M2 macrophages. Consequently, cell proliferation and migration are improved, and angiogenesis and tissue regeneration are enhanced. Such intelligent microneedle patch provides a novel way for accelerating wound healing through steadily preserving and releasing of H2 and Mg2+ locally and sustainably.

Wet-adhesive γ-PGA/ε-PLL hydrogel loaded with EGF for tracheal epithelial injury repair.

Following the global COVID-19 pandemic, the incidence of tracheal epithelial injury is increasing. However, the repair of tracheal epithelial injury remains a challenge due to the slow renewal rate of tracheal epithelial cells (TECs). In traditional nebulized inhalation treatments, drugs are enriched in the lungs or absorbed into the blood, reducing drug concentration at the tracheal injury site. In this study, we prepared an epidermal growth factor (EGF)-loaded gamma-polyglutamic acid (γ-PGA)/epsilon-poly-L-lysine (ε-PLL) (PP) hydrogel (EGF@PP) to promote the repair of tracheal epithelial injury. Epidermal growth factor promotes the proliferation of TECs and enhances vascularization, thereby accelerating injury repair. The PP hydrogel exhibits outstanding wet adhesion, slow drug release, and antibacterial and anti-inflammatory properties, making it suitable for application in the airways and creating an environment conducive to epithelial repair. Here, we established a rabbit model of tracheal injury using a laser to destroy the tracheal epithelium and delivered EGF@PP powder to the injury site under fiberoptic bronchoscopy guidance. Our findings revealed that this was an effective therapeutic strategy for accelerating the repair of tracheal epithelial injury.

TLR4 mediates lung injury and inflammation in intestinal ischemia-reperfusion.

BACKGROUND: Splanchnic ischemia is common in critically ill patients, and it can result in injury not only of the intestine but also in distant organs, particularly in the lung. Local inflammatory changes play a pivotal role in the development of acute lung injury after intestinal ischemia, but the underlying molecular mechanisms are not fully understood. We sought to examine the role of Toll-like receptor 4 (TLR4) in the mouse model of intestinal ischemia-reperfusion (I/R)-induced lung injury and inflammation. MATERIALS AND METHODS: Adult male TLR4 mutant (C3H/HeJ) mice and TLR4 wild-type (WT) (C3H/HeOuJ) mice were subjected to 40 min of intestinal ischemia by clamping the superior mesenteric artery followed by 6 h of reperfusion. Lung histology was assessed and parameters of pulmonary microvascular permeability, inflammatory cytokine expression, and neutrophil infiltration were measured. Activation of mitogen-activated protein kinases (MAPKs) and the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) in the lungs were also detected. RESULTS: After intestinal I/R, lungs from TLR4 mutant mice demonstrated a significantly lower histological injury, a marked reduction of epithelial apoptosis associated with the decreased level of cleaved caspase-3 and the increased ratio of Bcl-xL to Bax proteins, and a large reduction in pulmonary vascular permeability and myeloperoxidase (MPO) activity in comparison with WT mice. TLR4 mutant mice also displayed marked decreases in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) expression. Following intestinal I/R, phosporylation of p38 MAPK and activation of NF-κB and AP-1 were significantly inhibited in lung tissue from TLR4 mutant mice compared with WT controls. CONCLUSIONS: These data suggest that TLR4 plays an important role in the pathogenesis of intestinal I/R-induced acute lung injury and inflammation and that p38 kinase and NF-κB may be involved in TLR4 signaling-mediated lung inflammatory processes during intestinal I/R.

Use of mesoporous polydopamine nanoparticles as a stable drug-release system alleviates inflammation in knee osteoarthritis.

Osteoarthritis drugs are often short-acting; therefore, to enhance their efficacy, long-term, stable-release, drug-delivery systems are urgently needed. Mesoporous polydopamine (MPDA), a natural nanoparticle with excellent biocompatibility and a high loading capacity, synthesized via a self-aggregation-based method, is frequently used in tumor photothermal therapy. Here, we evaluated its efficiency as a sustained and controlled-release drug carrier and investigated its effectiveness in retarding drug clearance. To this end, we used MPDA as a controlled-release vector to design a drug-loaded microsphere system (RCGD423@MPDA) for osteoarthritis treatment, and thereafter, tested the efficacy of the system in a rat model of osteoarthritis. The results indicated that at an intermediate drug-loading dose, MPDA showed high drug retention. Furthermore, the microsphere system maintained controlled drug release for over 28 days. Our in vitro experiments also showed that drug delivery using this microsphere system inhibited apoptosis-related cartilage degeneration, whereas MPDA-only administration did not show obvious cartilage degradation improvement effect. Results from an in vivo osteoarthritis model also confirmed that drug delivery via this microsphere system inhibited cartilage damage and proteoglycan loss more effectively than the non-vectored drug treatment. These findings suggest that MPDA may be effective as a controlled-release carrier for inhibiting the overall progression of osteoarthritis. Moreover, they provide insights into the selection of drug-clearance retarding vectors, highlighting the applicability of MPDA in this regard.

Research progress in seed cells for cartilage tissue engineering.

Cartilage defects trouble millions of patients worldwide and their repair via conventional treatment is difficult. Excitingly, tissue engineering technology provides a promising strategy for efficient cartilage regeneration with structural regeneration and functional reconstruction. Seed cells, as biological prerequisites for cartilage regeneration, determine the quality of regenerated cartilage. The proliferation, differentiation and chondrogenesis of seed cells are greatly affected by their type, origin and generation. Thus, a systematic description of the characteristics of seed cells is necessary. This article reviews in detail the cellular characteristics, research progress, clinical translation challenges and future research directions of seed cells while providing guidelines for selecting appropriate seed cells for cartilage regeneration.

Cartilage defects affect millions of patients worldwide and their repair via conventional treatment is quite difficult. Excitingly, tissue engineering technology provides a promising strategy for efficient cartilage regeneration. The seed cell, as a biological prerequisite for cartilage regeneration, determines the quality of regenerated cartilage. This article reviews in detail the cellular characteristics, research progress, clinical translation challenges and future research directions of various chondrocytes, chondroprogenitor cells and stem cells. Chondrocytes, especially elastic chondrocytes, could complete subcutaneous cartilage regeneration, whereas stem cells are superior for composite defects, allografts and cartilage defects caused by inflammation. In brief, this article provides a guide for selecting appropriate seed cells for cartilage regeneration.

Folic Acid Attenuates Glial Activation in Neonatal Mice and Improves Adult Mood Disorders Through Epigenetic Regulation.

Growing evidence indicates that postnatal immune activation (PIA) can adversely increase the lifetime risk for several neuropsychiatric disorders, including anxiety and depression, which involve the activation of glial cells and early neural developmental events. Several glia-targeted agents are required to protect neonates. Folic acid (FA), a clinical medication used during pregnancy, has been reported to have neuroprotective properties. However, the effects and mechanisms of FA in PIA-induced neonatal encephalitis and mood disorders remain unclear. Here, we investigated the roles of FA in a mouse model of PIA, and found that FA treatment improved depressive- and anxiety-like behaviors in adults, accompanied by a decrease in the number of activated microglia and astrocytes, as well as a reduction in the inflammatory response in the cortex and hippocampus of neonatal mice. Furthermore, we offer new evidence describing the functional differences in FA between microglia and astrocytes. Our data show that epigenetic regulation plays an essential role in FA-treated glial cells following PIA stimulation. In astrocytes, FA promoted the expression of IL-10 by decreasing the level of EZH2-mediated H3K27me3 at its promoter, whereas FA promoted the expression of IL-13 by reducing the promoter binding of H3K9me3 mediated by KDM4A in microglia. Importantly, FA specifically regulated the expression level of BDNF in astrocytes through H3K27me3. Overall, our data supported that FA may be an effective treatment for reducing mood disorders induced by PIA, and we also demonstrated significant functional differences in FA between the two cell types following PIA stimulation.

Repair of Large-Scale Rib Defects Based on Steel-Reinforced Concrete-Designed Biomimetic 3D-Printed Scaffolds with Bone-Mineralized Microenvironments.

Tissue engineering technology provides a promising approach for large-scale bone reconstruction in cases of extensive chest wall defects. However, previous studies did not consider meticulous scaffold design specific to large-scale rib regeneration in terms of three-dimensional (3D) shape, proper porous structures, enough mechanical strength, and osteogenic microenvironments. Thus, there is an urgent need to develop an appropriate bone biomimetic scaffold (BBS) to address this problem. In this study, a BBS with controllable 3D morphology, appropriate mechanical properties, good biocompatibility and biodegradability, porous structure suitable for cell loading, and a biomimetic osteogenic inorganic salt (OIS) microenvironment was successfully prepared by integrating computer-aided design, 3D-printing, cast-molding, and freeze-drying technologies. The addition of the OIS in the scaffold substantially promoted ectopic bone regeneration in vivo, which might be attributed to the activation of osteogenic and angiogenic signaling pathways as well as upregulated expression of osteogenic genes. More importantly, dual long rib defects could be successfully repaired and medullary cavity recanalized by the rib-shaped mature cortical bone, which might be mediated by the activation of osteoclast signaling pathways. Thus, this paper presents a reliable BBS and proposes a new strategy for the repair of large-scale bone defects.

Lumen irregularity dominates the relationship between mechanical stress condition, fibrous-cap thickness, and lumen curvature in carotid atherosclerotic plaque.

High mechanical stress condition over the fibrous cap (FC) has been widely accepted as a contributor to plaque rupture. The relationships between the stress, lumen curvature, and FC thickness have not been explored in detail. In this study, we investigate lumen irregularity-dependent relationships between mechanical stress conditions, local FC thickness (LT(FC)), and lumen curvature (LC(lumen)). Magnetic resonance imaging slices of carotid plaque from 100 patients with delineated atherosclerotic components were used. Two-dimensional structure-only finite element simulations were performed for the mechanical analysis, and maximum principal stress (stress-P1) at all integral nodes along the lumen was obtained. LT(FC) and LC(lumen) were computed using the segmented contour. The lumen irregularity (L-δir) was defined as the difference between the largest and the smallest lumen curvature. The results indicated that the relationship between stress-P1, LT(FC), and LC(lumen) is largely dependent on L-δir. When L-δir ≥ .31 (irregular lumen), stress-P1 strongly correlated with lumen curvature and had a weak/no correlation with local FC thickness, and in 73.4% of magnetic resonance (MR) slices, the critical stress (maximum of stress-P1 over the diseased region) was found at the site where the lumen curvature was large. When L-δir ≤ 0.28 (relatively round lumen), stress-P1 showed a strong correlation with local FC thickness but weak/no correlation with lumen curvature, and in 71.7% of MR slices, the critical stress was located at the site of minimum FC thickness. Using lumen irregularity as a method of identifying vulnerable plaque sites by referring to the lumen shape is a novel and simple method, which can be used for mechanics-based plaque vulnerability assessment.

Melatonin inhibits proliferation and viability and promotes apoptosis in colorectal cancer cells via upregulation of the microRNA-34a/449a cluster.

Colorectal cancer (CRC) has a significant burden on healthcare systems worldwide, and is associated with high morbidity and mortality rates in patients. In 2020, the estimated new cases of colon cancer in the United States are 78,300 in men and 69,650 in women. Thus, developing effective and novel alternative agents and adjuvants with reduced side effects is important to reduce the lethality of the disease and improve the quality of life of patients. Melatonin, a pineal hormone that possesses numerous physiological functions, including anti­inflammatory and antitumor activities, can be found in various tissues, including the gastrointestinal tract. Melatonin exerts anticarcinogenic effects via various mechanisms; however, the identified underlying molecular mechanisms do not explain the full breadth of anti­CRC effects mediated by melatonin. MicroRNAs (miRs) serve critical roles in tumorigenesis, however, whether melatonin can inhibit CRC by regulating miRs is not completely understood. In the present study, the roles and mechanism underlying melatonin in CRC were investigated. The proliferation of human CRC cells was tested by CCK8, EDU and colony formation assay. The apoptosis of cancer cells was detected by flow cytometry and western blotting. A xenograft mouse model was constructed and the proliferation and apoptosis of tumor tissue was detected by Ki­67 and TUNEL staining assay respectively. Reverse transcription­quantitative PCR and western blotting were performed to measure the regulation of miRs on mRNA, and the dual­luciferase report analysis experiment was used to verify the direct target genes of miRs. Compared with the control group, melatonin inhibited viability and proliferation, and induced apoptosis in CRC cells. Additionally, the effect of melatonin in a xenograft mouse model was assessed. Compared with the control group, melatonin significantly enhanced the expression levels of the miR­34a/449a cluster, reduced CRC cell proliferation and viability, and increased CRC cell apoptosis. Finally, the dual­luciferase reporter assay indicated that Bcl­2 and Notch1 were the target mRNAs of the miR­34a/449a cluster. To the best of our knowledge, the present study was the first to suggest that melatonin inhibited proliferation and viability, and promoted apoptosis in CRC cells via upregulating the expression of the miR­34a/449a cluster in vitro and in vivo. Therefore, melatonin may serve as a potential therapeutic for CRC.

Analysis of Safety and Effectiveness of Sodium Alginate/Poly(γ-glutamic acid) Microspheres for Rapid Hemostasis.

Most preventable deaths after trauma are related to hemorrhage and occur early after injury. Timely hemostatic treatment is essential to minimize blood loss and improve survival. Among the various treatment methods, the most economical and effective is to use a hemostatic agent. A powdered hemostatic agent can be used for wounds of any shape or depth with high compactness and excellent accumulation effect. Herein, we chose the natural, hydrophilic polymer poly(γ-glutamic acid) (γ-PGA) to form composite hemostatic microspheres with sodium alginate (SA), which show good biocompatibility, water absorptivity, and viscosity. The morphology and structure of the hemostatic microspheres were determined using Fourier transform infrared spectroscopy and scanning electron microscopy. The overall safety, hemolysis, pyrogenic, and intradermal irritation tests were examined. The relationship between hemostatic pressure and hemostatic time during microsphere use was also measured. The hemostatic effect was analyzed with a liver, spleen, and femoral artery bleeding model. The composite microspheres were well tolerated in vivo and exhibited better hemostatic effects in animal experiments than a microporous polysaccharide powder compound. Research results showed that SA/γ-PGA microspheres are materials with good hemostatic effect, high safety, and great potential in clinical applications.

Anisotropic shock responses of nanoporous Al by molecular dynamics simulations.

Mechanical responses of nanoporous aluminum samples under shock in different crystallographic orientations (<100>, <111>, <110>, <112> and <130>) are investigated by molecular dynamics simulations. The shape evolution of void during collapse is found to have no relationship with the shock orientation. Void collapse rate and dislocation activities at the void surface are found to strongly dependent on the shock orientation. For a relatively weaker shock, void collapses fastest when shocked along the <100> orientation; while for a relatively stronger shock, void collapses fastest in the <110> orientation. The dislocation nucleation position is strongly depended on the impacting crystallographic orientation. A theory based on resolved shear stress is used to explain which slip planes the earliest-appearing dislocations prefer to nucleate on under different shock orientations.

PCGF1 promotes epigenetic activation of stemness markers and colorectal cancer stem cell enrichment.

Colorectal cancer (CRC) stem cells are resistant to cancer therapy and are therefore responsible for tumour progression after conventional therapy fails. However, the molecular mechanisms underlying the maintenance of stemness are poorly understood. In this study, we identified PCGF1 as a crucial epigenetic regulator that sustains the stem cell-like phenotype of CRC. PCGF1 expression was increased in CRC and was significantly correlated with cancer progression and poor prognosis in CRC patients. PCGF1 knockdown inhibited CRC stem cell proliferation and CRC stem cell enrichment. Importantly, PCGF1 silencing impaired tumour growth in vivo. Mechanistically, PCGF1 bound to the promoters of CRC stem cell markers and activated their transcription by increasing the H3K4 histone trimethylation (H3K4me3) marks and decreasing the H3K27 histone trimethylation (H3K27me3) marks on their promoters by increasing expression of the H3K4me3 methyltransferase KMT2A and the H3K27me3 demethylase KDM6A. Our findings suggest that PCGF1 is a potential therapeutic target for CRC treatment.