Gut complement induced by the microbiota combats pathogens and spares commensals.

Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein, we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization and is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as an innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.

Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3-5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.

Dysregulated Lung Commensal Bacteria Drive Interleukin-17B Production to Promote Pulmonary Fibrosis through Their Outer Membrane Vesicles.

Idiopathic pulmonary fibrosis (IPF) is a severe form of lung fibrosis with a high mortality rate. However, the etiology of IPF remains unknown. Here, we report that alterations in lung microbiota critically promote pulmonary fibrosis pathogenesis. We found that lung microbiota was dysregulated, and the dysregulated microbiota in turn induced production of interleukin-17B (IL-17B) during bleomycin-induced mouse lung fibrosis. Either lung-microbiota depletion or IL-17B deficiency ameliorated the disease progression. IL-17B cooperated with tumor necrosis factor-α to induce expression of neutrophil-recruiting genes and T helper 17 (Th17)-cell-promoting genes. Three pulmonary commensal microbes, which belong to the genera Bacteroides and Prevotella, were identified to promote fibrotic pathogenesis through IL-17R signaling. We further defined that the outer membrane vesicles (OMVs) that were derived from the identified commensal microbes induced IL-17B production through Toll-like receptor-Myd88 adaptor signaling. Together our data demonstrate that specific pulmonary symbiotic commensals can promote lung fibrosis by regulating a profibrotic inflammatory cytokine network.

Expression Landscape and Functional Roles of HOXA4 and HOXA5 in Lung Adenocarcinoma.

BACKGROUND: The role of HOXA family genes in the occurrence and progression of a variety of human cancers has been scatteredly reported. However, there is no systematic study on the differential expression, prognostic significance and potential molecular mechanism of HOXA4 and HOXA5 in LUAD. METHODS: In-house immunohistochemistry (IHC), multi-center microarrays, RT-qPCR and RNA-seq data were incorporated for comprehensively evaluating the expression and prognostic value of HOXA4 and HOXA5 in LUAD. The mechanism of HOXA4 and HOXA5 in the formation and development of LUAD was analyzed from multiple aspects of immune correlations, upstream transcriptional regulation, functional states of single cells and co-expressed gene network. The functional roles of HOXA4 and HOXA5 in LUAD were validated by in vitro experiments. RESULTS: As a result, in 3201 LUAD samples and 2494 non-cancer lung samples, HOXA4 and HOXA5 were significantly downexpressed (P < 0.05). The aberrant expression of HOXA5 was significantly correlated with the clinical progression of LUAD (P < 0.05). HOXA5 showed remarkable prognostic value for LUAD patients (P < 0.05). The expression of HOXA4 and HOXA5 in LUAD were negatively correlated with tumor purity and positively correlated with the infiltration of various immune cells such as B cells, T cells and macrophages. HOXA4 and HOXA5 overexpression had notable inhibitory effect on the proliferation, migration and invasion of LUAD cells. CONCLUSIONS: In conclusion, the identified downexpressed HOXA4 and HOXA5 had significant distinguishing ability for LUAD samples and affected the cellular functions of LUAD cells. The low expression of HOXA5 indicated worse overall survival of LUAD patients. Therefore, the two HOXA family genes especially HOXA5 may serve as potential biomarkers for LUAD.

Special Considerations in Chinese Face-Lift Procedure: Insights From a 15-Year Experience of 1026 Cases.

BACKGROUND: There is extensive literature on different face-lift techniques; however, few articles published in the English language address the particularities of the face-lift for Chinese patients. Because of differences in facial anatomy, facial aging, and patient expectations, facial rejuvenation procedures for Chinese patients can be quite different from those of White patients. METHODS: The study includes 1026 consecutive primary face-lift cases performed by the senior author (D.Y.) from 2006 to 2019. Of these, 1010 patients were female and 16 were male. The average age of the patient at the time of primary face-lift was 40.5 years. The face-lift procedures included midface lift in 108 cases, midface and lower-face lift in 882 cases, and midface and lower-face lift with brow lift in 36 cases. All patients received superficial musculoaponeurotic system (SMAS) treatment, in the form of lateral SMASectomy in 607 cases, high-SMAS technique in 84 cases, modified high-SMAS short-scar technique in 108 cases, minimal access cranial suspension technique in 38 cases, and modified minimal access cranial suspension technique in 189 cases. Photographs of patients were analyzed to assess persistent features of facial aging. Complications such as hematoma, skin slough, infection, and nerve injury were also reviewed. RESULTS: Most patients obtained consistently good results with minimal risk and complications. All surgical techniques discussed were safe and reproducible, providing various options for surgeons. CONCLUSIONS: Special attention should be taken when planning a facial rejuvenation procedure for Chinese patients. Anatomic variations dictate a greater emphasis on the management of tissue ptosis, particularly regarding lateral brow descent and malar fat pad descent. In our practice, various face-lift techniques can produce excellent results. Surgeons must adopt a technique that serves patients well and is, ideally, safe, consistent, easily reproducible, and applicable to various anatomic problems. In addition, every surgery is customized to the patient's anatomy and concerns. Therefore, the surgeon must adopt individualized technique according to the needs and desires of each patient.

The impact of lung microbiota dysbiosis on inflammation.

Host-microbiota interaction plays fundamental roles in the homeostasis of mucosal immunity. Dysbiosis of intestinal microbiota has been demonstrated to participate in various immune responses and many multifactorial diseases. Study of intestinal microbiota has moved beyond the consequences of dysbiosis to the causal microbiota associated with diseases. However, studies of pulmonary microbiota and its dysbiosis are still in their infancy. Improvement of culture-dependent and -independent techniques has facilitated our understanding of lung microbiota that not only exists in healthy lung tissue but also exerts great impact on immune responses under both physiological and pathological conditions. In this review, we summarize recent progresses of lung microbiota dysbiosis and its impact on the local immune system that determines the balance of tolerance and inflammation. We discuss the causal roles of pulmonary dysbiosis under disease settings, and propose that the interaction between lung microbiota and host is critical for establishing the immune homeostasis in lung.

ADSCs inhibit photoaging- and photocarcinogenesis-related inflammatory responses and extracellular matrix degradation.

BACKGROUND: Skin is a dynamic organ that maintains homeostasis and provides protection against environmental stimuli and pathogens. However, constant solar ultraviolet (UV) radiation can induce photoaging and photocarcinogenesis, thus reducing skin barrier function by altering skin at the cellular and structural levels. Adipose-derived stem cells (ADSCs) ameliorate signs of skin photoaging, but their antiphotoaging mechanism remains elusive. In this study, we explored the mechanism by which ADSCs improve skin photoaging. METHODS: Female C57BL/6J mice were used as experimental subjects and were randomly divided into three groups. We used Western blot analysis, Real time-polymerase chain reaction, and immunofluorescence to analyze the expression of photoaging- and photocarcinogenesis-related inflammasomes, extracellular matrix components, and related factors. RESULTS: The results showed that ADSCs reduced the UVB irradiation-mediated increase in MMP2, MMP13, phospho-NF-κB p65, Nlrp3, and VCAM-1 mRNA expression. The TGF-ß2 expression trend was opposite that of the above genes. ADSCs ameliorated the downregulation of α6 integrin, CD34, and collagen I by UVB irradiation. Simultaneously, ADSCs reduced the overexpression of COX2 and TNF-α induced by UVB irradiation. CONCLUSION: These results demonstrated that ADSCs could restore skin barrier function at the cellular and structural levels, enhance hair follicle stem cell (HFSCs) activity by regulating TGF-ß2 and inhibit photoaging- and photocarcinogenesis-related inflammatory responses and extracellular matrix degradation.

Lateral Superficial Muscular Aponeurotic System Stacking/Superficial Muscular Aponeurotic Systemectomy With Orbicularis-Malar Fat Repositioning: A Procedure Tailored for Female Asian Patients.

BACKGROUND: Important differences in facial anatomy and how faces age must be considered when performing facelifts in Asian populations. Few facelift methods are specifically designed for Asian patients. OBJECTIVE: This study evaluated the efficacy of lateral superficial muscular aponeurotic system (SMAS)-stacking/SMAS-ectomy with orbicularis-malar fat repositioning. MATERIALS AND METHODS: Between February 2013 and December 2016, 62 women underwent the evaluated technique and completed the follow-up (15 months, ranging from 3 to 38.5 months). Three blinded, independent observers graded wrinkles, laxity, nasolabial fold depth, malar prominence, and tear trough deformity using quantitative comprehensive grading scales. FACE-Q scale items were assessed, and complications were recorded. RESULTS: The mean postoperative scores for wrinkles, laxity, nasolabial fold depth, malar prominence, and tear trough deformity decreased from 2.64, 2.62, 2.01, 2.06, and 2.40 to 1.48, 1.34, 0.93, 1.21, and 1.27, respectively. The preoperative and postoperative scores differed significantly for all parameters (p < .05). The FACE-Q results showed that the patients were highly satisfied with their appearance, quality of life, adverse effects, and care. CONCLUSION: The authors' technique allows midfacial and periorbital rejuvenation and offers dual benefits by correcting individual facial asymmetries and reshaping the jowls and neck contour in Asian patients.

Early-life undernutrition reprograms CD4+ T-cell glycolysis and epigenetics to facilitate asthma.

BACKGROUND: Exposure to early-life undernutrition is closely related to higher risks of adverse immunologic outcomes in adulthood. Although it has been suggested that asthma has its origins in early life, its underlying mechanisms remain largely unknown. OBJECTIVE: We characterized the effects of early-life undernutrition on T lymphocytes, which play a pivotal role in immune diseases, and we investigated whether this contributes to susceptibility to asthma in adulthood. METHODS: Pregnant mice were fed a protein restriction diet (PRD) to establish an early-life undernutrition model. Naive CD4+ T cells (CD4+CD62LhiCD44-) from offspring were used throughout the study. TH2 differentiation was examined by using fluorescence-activated cell sorting and ELISA under TH2-polarized conditions in vitro and through ovalbumin-induced experimental asthma in vivo. T-cell metabolism was measured with a Seahorse XF96 Analyzer. DNA methylation levels were measured by using bisulfite sequencing. RESULTS: PRD CD4+ T cells displayed increased activation and proliferation and were prone to differentiate into TH2 cells both in vitro and in vivo, leading to susceptibility to experimental asthma. Mechanistically, early-life undernutrition upregulated mechanistic target of rapamycin 1-dependent glycolysis and induced conserved noncoding DNA sequence 1 DNA hypomethylation in the TH2 cytokine locus of CD4+ T cells. Glycolysis blockades undermined increased TH2 skewing and alleviated experimental asthma in PRD mice. CONCLUSION: Early-life undernutrition induced mechanistic target of rapamycin 1-dependent glycolysis upregulation and TH2 cytokine locus hypomethylation in CD4+ T cells, resulting in increased T-cell activation, proliferation, and TH2 skewing and further susceptibility to experimental asthma.

Facial Resurfacing With Prefabricated Induced Expanded Skin Flap.

Massive facial damages extremely affect the facial appearance and function. In existing publications, the surgical flap transfer was still prior to other methods in repairing the facial injury. Among them, the prefabricated induced expanded skin flap seems more effective based on the facial specific features and damage range. In this study, a literature research was carried out in the database of PubMed. A total of 85 patients were included and all of them underwent the method of prefabricated expanded flap to reconstruct the massive facial defects. The prefabricated induced expanded skin flaps harvested from the neck and chest area have prominent advantage in resetting massive facial deformities. All the flaps survived demonstrated an excellent texture and color match with the facial defects areas. However, the unsolved problems are still existed in these flaps and further research is necessary to obtain a satisfactory outcome for both patients and surgeons.

Protective Mechanism of Adipose-Derived Stem Cells in Remodelling of the Skin Stem Cell Niche During Photoaging.

BACKGROUND/AIMS: Skin photoaging is primarily caused by the functional attrition of skin stem cells. The skin stem cell niche plays an important role in maintaining stem cell survival and behaviour. In our study, we hypothesized that UVB irradiation induces skin photoaging by changing skin stem cell niches and that transferred adipose-derived stem cells (ADSCs) can remodel the niches by affecting the BMP signalling pathway and transdifferentiating into skin stem cells. METHODS: Sixty-four C57BL/6J mice were divided into the following groups: a control group, the UVB group and the UVB+ADSCs group. Western blot assays, immunofluorescence analysis and real-time PCR were used to measure differences in the expression of niche components among the three groups. Furthermore, we tested whether transplanted ADSCs express skin stem cell markers, such as p63, α6-integrin and CD34. RESULTS: The expression levels of Bmp4, its downstream factors Smad1 and MAPK1 and a regulatory factor of the niche, i.e., NFATc1, were lower in the UVB group than were those in the control group (P< 0.05) but higher in the UVB+ADSCs group than were those in the UVB group (P< 0.05). Compared with Bmp4, Nanog (a downstream factor of Bmp4), and MMP13 (a regulatory factor of the niche), ICAM-1 (a proinflammatory gene), p63 (a basal transcription factor), ß1-integrin, Mtnr1a and Tyr (melanogenesis-related factors) showed the opposite expression trends (P< 0.05). Bmp2 and Collagen IV levels did not significantly change among the three groups (P> 0.05). Skin stem cell markers, such as p63, α6-integrin and CD34, were coexpressed in the ADSCs, which suggested the ADSCs may transdifferentiate into skin stem cells. CONCLUSION: We found that UVB irradiation results in typical photoaging signs by altering skin stem cell niches and that Bmp4 was a key factor in BMP signalling in hair follicles. ADSCs reversed these typical photoaging signs by remodelling skin stem cell niches through BMP4 pathway modulation and transdifferentiation into skin stem cells.

The Individualized Facelift Technique in Improving Facial Asymmetry for Asian Patients.

PURPOSE: Among multiple influential factors affecting facial symmetry, the role of soft tissue is often overlooked. Skin and skeletal differences between Asian and Caucasian people also require the adaptation of current techniques for Asian patients. This article aimed to explore the ability of individual facelift techniques to improve facial symmetry and reset youthful eye in Asian people, while a new method, called the grid method, was tried to evaluate the improvement in facial symmetry. METHODS: The authors conducted a review of 58 consecutive facelifts, which were all performed by a single surgeon between April 2009 and December 2016 following institutional review board approval. Among them, 21 patients underwent lower eyelid blepharoplasty. The original frontal photograph of each patient was evaluated by the grid method. Five independent plastic surgeons reviewed the facial asymmetry of the images before and after the operations using a visual analog scale to analyze the facial asymmetry of the patients. RESULTS: In the preoperative group evaluated by the grid, the mean facial asymmetry score was 4.11, while in the postoperative group, the mean score was 1.07, which was significantly lower than the mean score before the operation (p < 0.001). The change in mean scores illustrated that the technique was effective in improving facial symmetry in Asian people. A total of 8 patients experienced hematomas and recovered well without obvious sequelae. CONCLUSIONS: The individual facelift technique was effective for improving facial symmetry and reshaping youthful eye in Asian people.

miR-203a controls keratinocyte proliferation and differentiation via targeting the stemness-associated factor ΔNp63 and establishing a regulatory circuit with SNAI2.

Keratinocyte differentiation plays a pivotal role in the function of epidermal barrier and can be triggered by extracellular calcium in vitro and in vivo, but the precise mechanism still need to be further investigated. On the other hand, it is known that microRNAs control multiple biological events including cellular proliferation and differentiation. The present study demonstrated that miR-203a expression was upregulated in calcium-induced HaCaT Cells in a dose-dependent manner, whereas the stemness-associated factors SNAI2 and ΔNp63 were downregulated. Furthermore, SNAI2 and ΔNp63 were identified as the targets of miR-203a by computational prediction and luciferase reporter assays. The protein levels of SNAI2 and ΔNp63 were suppressed by ectopic expression of miR-203a. Functionally, silencing of miR-203a or overexpression of SNAI2 and ΔNp63 attenuated cell cycle arrest induced by calcium without any changes in cellular apoptosis. Additionally, ectopic expression of SNAI2 inhibited miR-203a in calcium-induced HaCaT cells, by binding to the promoter region of miR-203a. In conclusion, our findings demonstrate that miR-203a plays an essential role in keratinocyte proliferation and differentiation caused by extracellular calcium by targeting the SNAI2 and ΔNp63 genes. Furthermore, SNAI2 was found to suppress the transcription of miR-203a. Our data highlights a coherent cross-talk between two transcription factors (SNAI2 and ΔNp63) and miR-203a in keratinocyte differentiation and epidermal development.

MicroRNA-488-3p sensitizes malignant melanoma cells to cisplatin by targeting PRKDC.

Deregulation of microRNAs (miRNAs) has been implicated in drug resistance in various types of cancers, including malignant melanoma (MM). MiR-488-3p has been reported as a tumor suppressor in several cancers. However, the exact expression patterns of miR-488-3p and the precise molecular mechanisms underlying its role in MM remain largely unknown and require further investigation. In this study, we demonstrated that miR-488-3p is significantly downregulated in MM clinical specimens and cell lines. Ectopic expression of miR-488-3p resulted in markedly increased drug sensitivity of MM cells in vitro and in vivo. The DNA-activated, catalytic polypeptide (PRKDC), which encodes DNA-dependent protein kinase catalytic subunit (DNA-PKcs), was identified as a direct target of miR-488-3p using luciferase reporter assays, qRT-PCR, and western blotting analyses. PRKDC knockdown by small interfering RNA (siRNA) alone promoted sensitivity of MM cells to cisplatin (DDP) while overexpression of PRKDC partially rescued the miR-488-3p-mediated acceleration of sensitivity to DDP in MM cells. Taken together, our results indicate that miR-488-3p serves as a drug resistance sensitizer in MM, supporting its potential as a promising therapeutic candidate.

Effect of cytochrome P450 2C19*17 allelic variant on cardiovascular and cerebrovascular outcomes in clopidogrel-treated patients: A systematic review and meta-analysis.

BACKGROUND: We aimed to evaluate the associations of gain-of-function allele of CYP2C19*17 and risk of clinical events in clopidogrel-treated patients with cardiovascular and cerebrovascular diseases (CCVDs). MATERIALS AND METHODS: Literature search was conducted in PubMed, EMBASE, and Cochrane Library. Odds ratio (OR) combined with 95% confidence interval (CI) was the pooled statistics. Subgroup analysis was performed by disease type, bleeding events, and race. RESULTS: Thirteen eligible studies involving 14,239 patients with CYP2C19*17 carriers or noncarriers were included in the meta-analysis. CYP2C19*17 was significantly related to decreased risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with coronary artery disease (CAD) (OR = 0.76, 95% CI: 0.60-0.98, P = 0.03), however, irrelevant with stent thrombosis in neither CAD nor ischemic heart disease patients. CYP2C19*17 was also significantly linked to decreased risk of high platelet reactivity (HPR) in CCVD patients (OR = 0.61, 95% CI: 0.43-0.88, P = 0.008). Meanwhile, CYP2C19*17 was significantly associated with bleeding risk in CCVD patients (OR = 1.89, 95% CI: 1.09-3.25, P = 0.02) but not related to major bleeding risk (OR = 1.35, 95% CI: 0.87-2.08, P = 0.18). Several outcomes in Caucasian subgroup were reverse to the overall results, such as bleeding events and HPR, which lacked significance. CONCLUSION: CYP2C19*17 had a significant effect on the reduced risks of MACCE and HPR as well as increased bleeding risk, but not on the risks of stent thrombosis and major bleeding in clopidogrel-treated CCVD patients. Outcomes might be different in different races.

Thyrotropin-releasing hormone and its analogs accelerate wound healing.

BACKGROUND: Thyrotropin-releasing hormone (TRH) is a classical hormone that controls thyroid hormone production in the anterior pituitary gland. However, recent evidence suggested that TRH is expressed in nonhypothalamic tissues such as epidermal keratinocytes and dermal fibroblasts, but its function is not clear. This study aimed to investigate the effects of TRH and its analogs on wound healing and explore the underlying mechanisms. MATERIALS AND METHODS: A stented excisional wound model was established, and the wound healing among vehicle control, TRH, and TRH analog taltirelin treatment groups was evaluated by macroscopic and histologic analyses. Primary fibroblasts were isolated from rat dermis and treated with vehicle control, TRH or taltirelin, cell migration, and proliferation were examined by scratch migration assay, MTT, and 5-ethynyl-2'- deoxyuridine (EdU) assay. The expression of α-Smooth muscle actin in fibroblasts was detected by Western blot and immunocytochemical analysis. RESULTS: TRH or taltirelin-treated wounds exhibited accelerated wound healing with enhanced granulation tissue formation and increased re-epithelialization and tissue formation. Furthermore, TRH or taltirelin promoted the migration and proliferation of fibroblasts and induced the expression of α-Smooth muscle actin in fibroblasts. CONCLUSIONS: TRH is important in upregulating the phenotypes of dermal fibroblasts and plays a role in accelerating wound healing.

What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years.

BACKGROUND: Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on LCBM, problems have emerged, such as confusing research structures. AIM: To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation, clinical treatment, and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research. METHODS: We used tools, including R, VOSviewer and CiteSpace software, to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection. We also performed enrichment and protein-protein interaction analyses of gene expression datasets from LCBM cases worldwide. RESULTS: Research on LCBM has received extensive attention from scholars worldwide over the last 20 years. Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions. The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis. The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence. CONCLUSION: Novel therapies for LCBM face animal testing and drug resistance issues. Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.

A systematic review of p53 as a biomarker of survival in patients with osteosarcoma.

Osteosarcoma is the most common malignant bone tumor, and the prognosis of patients with osteosarcoma is still unsatisfactory with low survival rates. There are many studies assessing the prognostic role of upregulated p53 in patients presenting osteosarcoma, and there is no consistent finding. To summarize the existing evidence about whether the presence of upregulated p53 was a biomarker of survival in patients with osteosarcoma, we performed a systematic review and meta-analysis of relevant publications. We assessed the effect of upregulated p53 on the 3-year overall survival and the 3-year disease-free survival by calculating the pooled odds ratio (OR) with corresponding 95% confidence interval (95%CI). Fifteen studies with a total of 609 patients with osteosarcoma were finally included into the systematic review and meta-analysis. Compared with osteosarcoma patients with low or undetectable p53, patients with upregulated p53 were obviously associated with decreased 3-year overall survival (OR = 0.29, 95 %CI 0.19-0.43, P < 0.001). In addition, patients with upregulated p53 were obviously associated with decreased 3-year disease-free survival (OR = 0.06, 95 %CI 0.02-0.23, P < 0.001). The results from the systematic review and meta-analysis highlight that p53 is an effective biomarker of survival in patients with osteosarcoma. In addition, more studies with a large sample size are needed to identify the effect of p53 expression in osteosarcoma patients.

Hypoxia preconditioning enhances the viability of ADSCs to increase the survival rate of ischemic skin flaps in rats.

UNLABELLED: Use of a skin flap has been a common technique in reconstructive surgery for more than five decades. However, partial necrosis of its distal end is still a serious postoperative complication. Many theories about this problem have been proposed, including deficient blood supply, which is the most accepted theory. In this study we demonstrated that hypoxic preconditioning enhanced the viability of adipose-derived stem cells (ADSCs) in vivo and improved their ability to increase the survival rate of ischemic skin flaps in rats. Seven days after flap elevation, the flap survival rate in the hypoxic preconditioned ADSC group was higher than that in the control group. Moreover, histological examination showed that more ADSCs survived in flaps treated by hypoxic preconditioning. Vascular density in the hypoxic preconditioned ADSC group was 30-90 % greater than that in the control group. In addition, the expressions of vascular endothelial growth factor and hypoxia inducible factor-1α (HIF-1α) were higher in the hypoxic preconditioned ADSC group than in the control group (p < 0.05). This enhancive phenomenon reached its highest level at the precondition times of 3 and 7 days in the hypoxic preconditioned ADSC group. We conclude that hypoxia preconditioning effectively enhances the viability of ADSCs to increase the survival rate of ischemic skin flaps. Furthermore, 3 days is the optimal preconditioning time point. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .