The causal effect of reproductive factors on pelvic floor dysfunction: a Mendelian randomization study.

BACKGROUND: Pelvic floor dysfunction (PFD) is an extremely widespread urogynecologic disorder, the prevalence of which increases with aging. PFD has severely affected women's quality of life and has been called a social cancer. While previous studies have identified risk factors such as vaginal delivery and obesity for PFD, other reproductive factors, including age at menarche (AAMA), have been largely overlooked. Therefore, we used a Mendelian randomization (MR) study for the first time to investigate the potential causal relationship between reproductive factors and PFD. METHODS: We obtained summary statistics from genome-wide association studies (GWAS) for female genital prolapse (FGP), stress urinary incontinence (SUI), and five reproductive factors. Two-sample Mendelian randomization analysis (TSMR) was performed to explore the causal associations between these factors. The causal effects of reproductive factors on FGP and SUI were primarily estimated using the standard inverse variance weighting (IVW) method, with additional complementary and sensitivity analyses conducted using multiple approaches. A multivariate Mendelian randomization (MVMR) study was also conducted to adjust for pleiotropic effects and possible sources of selection bias and to identify independent exposure factors. RESULTS: Our findings revealed that advanced age at first sexual intercourse (AFS) and age at first birth (AFB) exhibited negative causal effects on both FGP and SUI. AAMA showed negative causal effects solely on FGP, while age at last live birth (ALB) and age at menopause (AAMO) did not demonstrate any causal effect on either FGP or SUI. And the MVMR results showed that AFB and AFS had independent negative causal effects on FGP and SUI, respectively. CONCLUSIONS: This study, for the first time, investigates the causal relationship between reproductive factors and PFD. The results suggested a causal relationship between some reproductive factors, such as AFB and AFS, and PFD, but there were significant differences between FGPand SUI. Therefore, future studies should explore the underlying mechanisms and develop preventive measures for reproductive factors to reduce the disease burden of PFD.

The causal effect of educational attainment on stress urinary incontinence: a two-sample mendelian randomization study.

BACKGROUND: Stress urinary incontinence (SUI) is characterized by involuntary urine leakage in response to increased abdominal pressure, such as coughing, laughing, or sneezing. It significantly affects women's quality of life and imposes a substantial disease burden. While pregnancy and childbirth have been previously identified as risk factors for SUI, educational attainment may also play a role. Therefore, this paper investigates the causal relationship between educational attainment and SUI using two-sample Mendelian randomization (TSMR) analysis, years of schooling (YOS), and college or university degree (CUD) as proxies. METHODS: Summary statistics of YOS, CUD, and SUI were obtained from genome-wide association studies (GWAS), and TSMR analysis was applied to explore potential causal relationships between them. Causal effects were mainly estimated using the standard inverse variance weighting (IVW) method, and complementary and sensitivity analyses were also performed using multiple methods. RESULTS: The results indicate that both YOS (OR = 0.994, 95% CI: 0.992-0.996; P = 7.764E-10) and CUD (OR = 0.987, 95% CI: 0.983-0.991; P = 1.217E-09) may have a negative causal effect on SUI. CONCLUSIONS: Improving educational attainment may go some way towards reducing the risk of SUI. Therefore, it is important to increase efforts to improve the imbalance in educational development and safeguard women's health.

A Survey of Primary Care Practices on Their Use of the Intensive Behavioral Therapy for Obese Medicare Patients.

OBJECTIVE: To fill the gap in knowledge on systematic differences between primary care practices (PCP) that do or do not provide intensive behavioral therapy (IBT) for obese Medicare patients. METHODS: A mixed modality survey (paper and online) of primary care practices obtained from a random sample of Medicare databases and a convenience sample of practice-based research network practices. KEY RESULTS: A total of 287 practices responded to the survey, including 140 (7.4% response rate) from the random sample and 147 (response rate not estimable) from the convenience sample. We found differences between the IBT-using and non-using practices in practice ownership, patient populations, and participation in Accountable Care Organizations. The non-IBT-using practices, though not billing for IBT, did offer some other assistance with obesity for their patients. Among those who had billed for IBT, but stopped billing, the most commonly cited reason was billing difficulties. Many providers experienced denied claims due to billing complexities. CONCLUSIONS: Although the Centers for Medicare and Medicaid Services established payment codes for PCPs to deliver IBT for obesity in 2011, very few providers submitted fee-for-service claims for these services after almost 10 years. A survey completed by both a random and convenience sample of practices using and not using IBT for obesity payment codes revealed that billing for these services was problematic, and many providers that began using the codes discontinued using them over the past 7 years.

Bone-targeted erythrocyte-cancer hybrid membrane-camouflaged nanoparticles for enhancing photothermal and hypoxia-activated chemotherapy of bone invasion by OSCC.

BACKGROUND: Jaw bones are the most common organs to be invaded by oral malignancies, such as oral squamous cell carcinoma (OSCC), because of their special anatomical relationship. Various serious complications, such as pathological fractures and bone pain can significantly decrease the quality of life or even survival outcomes for a patient. Although chemotherapy is a promising strategy for bone invasion treatment, its clinical applications are limited by the lack of tumor-specific targeting and poor permeability in bone tissue. Therefore, it is necessary to develop a smart bone and cancer dual targeting drug delivery platform. RESULTS: We designed a dual targeting nano-biomimetic drug delivery vehicle Asp8[H40-TPZ/IR780@(RBC-H)] that has excellent bone and cancer targeting as well as immune escape abilities to treat malignancies in jaw bones. These nanoparticles were camouflaged with a head and neck squamous cell carcinoma WSU-HN6 cell (H) and red blood cell (RBC) hybrid membrane, which were modified by an oligopeptide of eight aspartate acid (Asp8). The spherical morphology and typical core-shell structure of biomimetic nanoparticles were observed by transmission electron microscopy. These nanoparticles exhibited the same surface proteins as those of WSU-HN6 and RBC. Flow cytometry and confocal microscopy showed a greater uptake of the biomimetic nanoparticles when compared to bare H40-PEG nanoparticles. Biodistribution of the nanoparticles in vivo revealed that they were mainly localized in the area of bone invasion by WSU-HN6 cells. Moreover, the Asp8[H40-TPZ/IR780@(RBC-H)] nanoparticles exhibited effective cancer growth inhibition properties when compared to other TPZ or IR780 formulations. CONCLUSIONS: Asp8[H40-TPZ/IR780@(RBC-H)] has bone targeting, tumor-homing and immune escape abilities, therefore, it is an efficient multi-targeting drug delivery platform for achieving precise anti-cancer therapy during bone invasion.

Cross-linked γ-cyclodextrin metal-organic framework-a new stationary phase for the separations of benzene series and polycyclic aromatic hydrocarbons.

The cross-linked γ-cyclodextrin metal-organic framework (CL-CD-MOF) was synthesized by crosslinking γ-cyclodextrin metal-organic framework (γ-CD-MOF) with diphenyl carbonate to separate benzene series and polycyclic aromatic hydrocarbons (PAHs). The separation ability of the CL-CD-MOF packed column was assessed in both reverse-phase (RP-) and normal-phase (NP-) modes. The retention mechanisms of these compounds were discussed and confirmed by combining molecular simulations in detail. It was found that baseline separation could be obtained in RP-HPLC mode and it was superior to commercial C18 column in separating xylene isomers. The interaction between CL-CD-MOF and analytes, such as dipole-dipole interaction, π-electron transfer interaction, hydrophobic interaction, and van der Waals force, may dominate the chromatographic separation, and CL-CD-MOF column had a certain shape recognition ability. In addition, the composition of the mobile phase also had a crucial effect. Moreover, the column demonstrated satisfactory stability and repeatability (the relative standard deviations of retention time, peak height, peak area, and half peak width for six replicate separations of the tested analytes were within the ranges 0.17-1.1%, 0.96-1.9%, 0.23-1.7%, and 0.32-1.9%, respectively) and there was no significant change in the separation efficiency for at least 3 years of use. Thermodynamic characteristics indicated that the process of separations on the CL-CD-MOF column was both negative enthalpy change (ΔH) and entropy change (ΔS) controlled. The excellent performance made CL-CD-MOF a promising HPLC stationary phase material for separation and determination of benzene series and PAHs.

Predicted and actual outcome of anterior intrusion with Invisalign assessed with cone-beam computed tomography.

INTRODUCTION: The purpose of this study was to compare predicted anterior teeth intrusion measurements with the actual clinical intrusion measurements using cone-beam computed tomography. Understanding the precision of the software in anticipating changes may help practitioners predict the need for overcorrection. METHODS: Twenty-two patients, with a mean age of 23.74 years, who underwent Invisalign (Align Technology, Santa Clara, Calif) clear aligners treatment for both arches only after having completed treatment with an initial series of aligners were included in this study. The pretreatment and posttreatment cone-beam computed tomography scans after the initial series were acquired by a single orthodontist practitioner. ClinCheck measurements were recorded with Align Technology. The long axis of the anterior tooth intrusion movement was measured in 142 teeth. A comparison between the predicted and actual measurements of anterior intrusion of the teeth was performed, and the intraclass correlation coefficients showed an almost perfect agreement in the linear measurements. RESULTS: A statistically notable difference between the predicted and actual measurements of anterior intrusion. The predicted intrusion movement of the maxillary canines (P = 0.001), maxillary lateral incisors (P <0.0001), and maxillary central incisors (P <0.0001) significantly differed from the actual values. Similarly, the intrusion movement in the mandibular teeth seemed to be inaccurate, with significant differences in the mandibular canines (P <0.0001) and mandibular lateral and central incisors (P <0.0001). CONCLUSIONS: The mean precision of true anterior intrusion with Invisalign clear aligners was 51.19%, and the mean amount of correction was 48.81%. The use of other supplementary methods of anterior teeth intrusion may be helpful to reduce the rate of midcourse corrections and refinements.

The expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in the compression area during orthodontic relapse.

OBJECTIVE: This study investigated the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in the compression area during orthodontic relapse in rat molars. MATERIALS AND METHODS: Thirty Wistar rats (6 weeks old) underwent orthodontic tooth movement (OTM) of the left first maxillary molar for 21 days, followed by removal of the force device. The contralateral maxillary molar served as a control with no mechanical force stimuli. Animals were sacrificed at 0, 1, 3, 7, and 14 days of relapse after force withdrawal. Tooth relapse and alveolar bone parameters were measured using microcomputed tomography (micro-CT). Maxilla sections were obtained for haematoxylin and eosin (HE), immunohistochemical staining [EMMPRIN, nuclear factor kappa B ligand (RANKL) and vascular endothelial growth factor (VEGF)] and tartrate-resistant acid phosphatase (TRAP). Correlation analyses were then performed. RESULTS: After force removal, nearly 79.88% of the total relapse occurred within the initial 3 days. The number of osteoclasts clearly increased while the alveolar bone density decreased on the pressure side on Day 3 of relapse. Moreover, the EMMPRIN expression level significantly increased on Day 1, peaked up on Day 3 and decreased on Days 7 and 14. Statistically, a strong positive correlation was found between EMMRPIN expression and the osteoclast number and RANKL and VEGF expression. CONCLUSION: EMMPRIN was highly expressed on the pressure side during the orthodontic tooth relapse, which could be involved in osteoclastogenesis and alveolar bone resorption in association with RANKL and VEGF expression.

Genetic diversity is a predictor of mortality in humans.

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease. RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%. CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

A clinical study evaluating the combination of LISA and SNIPPV for the treatment of respiratory distress syndrome in preterm infants.

To compare the therapeutic effect of less invasive surfactant administration (LISA) followed by synchronized nasal intermittent positive pressure ventilation (SNIPPV) and traditional intubate-Surfactant-Extubate (InSurE) strategy for the treatment of neonatal respiratory distress syndrome (NRDS). A single-center, non-randomized and single- blinded study Tertiary neonatal intensive care unit 89 infants enrolled were preterm with gestational age < 366/7 weeks and clinically diagnosed with neonatal RDS (NRDS) Interventions: 32 infants were assigned to the LISA + SNIPPV group and 57 infants to the InSurE + nCPAP group. No statistically significant differences were noted in the baseline characteristics of the enrolled infants. A lower proportion of infants developed BPD in the LISA + SNIPPV group compared to the InSurE + CPAP group [10 (31.25%) vs. 21 (36.84%), P > 0.05]; however, there was no statistically significant difference. The number needed to treat (NNT) with LISA + SNIPPV to prevent BPD development is 18. The mortality rate was not significant between our study arms [1 (3.13%) vs 2 (3.51%), P > 0.05]. There were no statistically significant differences in the durations (days) of MV [(12.18 ± 13.89) vs. (11.35 ± 11.61), P > 0.05], oxygen therapy [(35.03 ± 19.13) vs. (39.75 ± 17.91), P > 0.05] and re-intubation rates [(0.19 ± 0.40) vs. (0.21 ± 0.45), P > 0.05] between the two study groups. In terms of complications, the incidence of patent ductus arteriosus (PDA) [24 (75.00%) vs. 27 (47.37%), P < 0.05] was higher and a lower rate of disturbed liver function [1 (3.23%) vs. 19 (33.33%), P < 0.05] were observed in the LISA + SNIPPV group. Acid-base imbalances were reportedly significantly higher in the InSurE group (P < 0.05). No significant differences in other complications were noted. In the interventional group, FiO2 requirements were significantly lower up until the 3rd week of treatment [FiO2 at day 0, (30.75 ± 4.78) vs. (34.66 ± 9.83), P < 0.05; FiO2 at day 21, (25.32 ± 3.74) vs. (29.11 ± 8.17), P < 0.05], as was RSS on days 2 [(0.77 ± 0.38) vs. (1.94 ± 0.75), P < 0.05] and 3 [(0.66 ± 0.33) vs. (1.89 ± 0.82), P < 0.05] after treatment. Additionally, infants in the standard group had a significantly prolonged hospital stay (days) [(45.97 ± 16.93) vs. (54.40 ± 16.26), P < 0.05]. The combination of LISA and SNIPPV for NRDS can potentially lower the rate of BPD, FiO2 demand and shorten the length of hospitalization.

Enzyme-Empowered "Two Birds with One Stone" Strategy for Amplifying Tumor Apoptosis and Metabolic Clearance.

Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel "two birds with one stone" technique for amplifying enzyme-mediated tumor apoptosis and enzyme-promoted metabolic clearance is proposed and achieved using GOx-functionalized rhenium nanoclusters-doped polypyrrole (Re@ReP-G). Re@ReP-G reduces ATP production while increasing H2O2 concentrations in the tumor microenvironment through GOx-induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti-apoptotic Bcl-2 proteins, the upregulation of pro-apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser-induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, H2O2 catalyzes the conversion of rhenium nanoclusters in Re@ReP-G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP-G-based "two birds with one stone" therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms.

Immunomodulatory properties of mesenchymal stromal/stem cells: The link with metabolism.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) are the most promising stem cells for the treatment of multiple inflammatory and immune diseases due to their easy acquisition and potent immuno-regulatory capacities. These immune functions mainly depend on the MSC secretion of soluble factors. Recent studies have shown that the metabolism of MSCs plays critical roles in immunomodulation, which not only provides energy and building blocks for macromolecule synthesis but is also involved in the signaling pathway regulation. AIM OF REVIEW: A thorough understanding of metabolic regulation in MSC immunomodulatory properties can provide new sights to the enhancement of MSC-based therapy. KEY SCIENTIFIC CONCEPTS OF REVIEW: MSC immune regulation can be affected by cellular metabolism (glucose, adenosine triphosphate, lipid and amino acid metabolism), which further mediates MSC therapy efficiency in inflammatory and immune diseases. The enhancement of glycolysis of MSCs, such as signaling molecule activation, inflammatory cytokines priming, or environmental control can promote MSC immune functions and therapeutic potential. Besides glucose metabolism, inflammatory stimuli also alter the lipid molecular profile of MSCs, but the direct link with immunomodulatory properties remains to be further explored. Arginine metabolism, glutamine-glutamate metabolism and tryptophan-kynurenine via indoleamine 2,3-dioxygenase (IDO) metabolism all contribute to the immune regulation of MSCs. In addition to the metabolism dictating the MSC immune functions, MSCs also influence the metabolism of immune cells and thus determine their behaviors. However, more direct evidence of the metabolism in MSC immune abilities as well as the underlying mechanism requires to be uncovered.

Ground glass opacity resection extent assessment trial (GREAT): A study protocol of multi-institutional, prospective, open-label, randomized phase III trial of minimally invasive segmentectomy versus lobectomy for ground glass opacity (GGO)-containing early-stage invasive lung adenocarcinoma.

Background: With widely use of computed tomography (CT) screening, an increasing number of early-stage lung cancers appearing as ground glass opacity (GGO) have been detected. Therefore, attempts have been made to investigate the feasibility of segmentectomy instead of lobectomy for those patients with GGO. However, the two recently released phase III trials failed to distinguish between GGO-containing lesions from pure solid nodules in the inclusion criteria, and the surgical methods did not distinguish between minimally invasive surgery and open thoracotomy. In addition, total lesion size≤ 2cm was taken as the inclusion criterion, instead of the solid part size recommended in the eighth edition of Union for International Cancer Control/International Association for the Study of Lung Cancer/American Joint Committee on Cancer (UICC/IASLC/AJCC) staging system. Hence, this present trial aims to figure out whether minimally invasive segmentectomy shows superiority in perioperative outcomes and non-inferiority in oncological prognosis over minimally invasive lobectomy among patients with GGO-containing clinical stage T1a-T1b lung invasive adenocarcinoma (IADC). Methods/design: Sample sizes are 1024 patients, who will be randomized into minimally invasive segmentectomy and lobectomy groups . Patients will be collected from 19 hospitals in China. Patients with peripheral mixed ground glass opacity (mGGO) with 0.5cm

Bibliometric analysis of studies on stress urinary incontinence surgery.

Background: Stress urinary incontinence (SUI) is characterized by the involuntary leakage of urine during activities that increase abdominal pressure. In recent years, a considerable number of studies on SUI surgery have been published. However, there has been a lack of systematic quantification and comprehensive summarization of these studies. Bibliometrics is a discipline that utilizes measurement methods to quantify scientific literature. Thus, this study utilized publications from the Web of Science (WOS) as a data source and conducted a comprehensive analysis and visualization of studies related to SUI surgery in recent years using bibliometric techniques. Methods: We conducted a search and retrieved information on 988 studies related to SUI surgery in the WOS Core Collection. The data covered ten years from September 7, 2013, to September 7, 2023. We employed VOSviewer software, CiteSpace software, and Bibliometrix for analysis and visualization. Results: Over the ten years, the number of publications exhibited a fluctuating trend, initially decreasing and then increasing. The United States emerged as the leading contributor in terms of both publication volume and quality. The University of Alabama Birmingham ranked as the institution with the highest number of publications, while the International Urogynecology Journal featured the most publications among journals. Conclusions: This paper presents a bibliometric analysis of publications related to SUI surgery from 2013 to 2023. The aim is to offer researchers a concise overview of the field and inspire future research directions.

Global burden and trends of ectopic pregnancy: An observational trend study from 1990 to 2019.

BACKGROUND: Ectopic pregnancy (EP) is one of the leading causes of death in women in early pregnancy, and the mortality of EP have gradually decreased over time in developed countries such as the United Kingdom and the United States. However, epidemiological information on EP has been lacking in recent years, so we analyzed EP data over a thirty-year period from 1990-2019 with the help of Global Burden of Disease study (GBD) data to fill this gap. METHODS: According to the EP data in GBD for the three decades from 1990 to 2019, we used estimated annual percentage changes (EAPC) to assess the trend of age-standardized incidence rate (ASIR), age-standardized death rate (ASDR) and age-standardized disability adjusted life years (AS-DALYs) trends in EP and to explore the correlation between socio-demographic index (SDI) stratification, age stratification and EP. RESULTS: Global ASIR, ASDR, AS-DALYs for EP in 2019 are 170.33/100,000 persons (95% UI: 133.18 to 218.49), 0.16/100,000 persons (95% UI, 0.14 to 0.19) and 9.69/100,000 persons (95% UI, 8.27 to 11.31), respectively. At the overall level, ASDR is significantly negatively correlated with SDI values (R = -0.699, p < 0.001). Besides that, ASDR and AS-DALYs have basically the same pattern. In addition, iron deficiency is one of the risk factors for EP. CONCLUSIONS: In the past three decades, the morbidity, mortality and disease burden of EP have gradually decreased. It is noteworthy that some economically disadvantaged areas are still experiencing an increase in all indicators, therefore, it is more important to strengthen the protection of women from ethnic minorities and low-income groups.

Microneedle systems: cell, exosome, and nucleic acid based strategies.

Cells, exosomes, and nucleic acids play crucial roles in biomedical engineering, holding substantial clinical potential. However, their utility is often hindered by various drawbacks, including cellular immunogenicity, and instability of exosomes and nucleic acids. In recent years, microneedle (MN) technology has revolutionized drug delivery by offering minimal invasiveness and remarkable versatility. MN has emerged as an ideal platform for the extraction, storage, and delivery of these biological components. This review presents a comprehensive overview of the historical progression and recent advances in the field of MN. Specifically, it highlights the current applications of cell-, exosome-, and nucleic acid-based MN systems, while presenting prevailing research challenges. Additionally, the review provides insights into the prospects of MN in this area, aiming to provide new ideas for researchers and facilitate the clinical translation of MN technology.

Humoral immune response after Ad26.COV2.S vaccination in patients with multiple sclerosis treated with natalizumab.

The immunomodulatory effects of disease-modifying therapies for multiple sclerosis might affect the immune response to vaccines for severe acute respiratory syndrome coronavirus 2. We analyzed the severe acute respiratory syndrome coronavirus 2-specific antibody response and lymphocyte profile before and after Ad26.COV2.S (Johnson & Johnson) vaccination in natalizumab-treated patients with multiple sclerosis. There was a 72-fold increase in mean anti-severe acute respiratory syndrome coronavirus 2 spike immunoglobulin G levels 4 weeks after vaccination and a 137-fold increase after 6 months. Other immune signals were within normal ranges. Natalizumab-treated patients with multiple sclerosis had a robust immune response to Ad26.COV2.S vaccine, and other immune signals were not significantly affected.

The mechanisms and functions of TGF-ß1 in tendon healing.

Tendon injury accounts for 30% of musculoskeletal diseases and often leads to disability, pain, healthcare cost, and lost productivity. Following injury to tendon, tendon healing proceeds via three overlapping healing processes. However, due to the structural defects of the tendon itself, the tendon healing process is characterized by the formation of excessive fibrotic scar tissue, and injured tendons rarely return to native tendons, which can easily contribute to tendon reinjury. Moreover, the resulting fibrous scar is considered to be a precipitating factor for subsequent degenerative tendinopathy. Despite this, therapies are almost limited because underlying molecular mechanisms during tendon healing are still unknown. Transforming Growth Factor-ß1 (TGF-ß1) is known as one of most potent profibrogenic factors during tendon healing process. However, blockage TGF-ß1 fails to effectively enhance tendon healing. A detailed understanding of real abilities of TGF-ß1 involved in tendon healing can bring promising perspectives for therapeutic value that improve the tendon healing process. Thus, in this review, we describe recent efforts to identify and characterize the roles and mechanisms of TGF-ß1 involved at each stage of the tendon healing and highlight potential roles of TGF-ß1 leading to the fibrotic response to tendon injury.

From fetal tendon regeneration to adult therapeutic modalities: TGF-ß3 in scarless healing.

Tendon injuries are common disorders that can significantly impact people's lives. Unfortunately, the limited regenerative ability of tendons results in tissue healing in a scar-mediated manner. The current therapeutic strategies fail to fully recover the functions of the injured tendons, and as such, the conception of 'scarless healing' has gained prominent attention in the field of regenerative medicine. Interestingly, injured fetal tendons possess the capability to heal through regeneration, which builds an ideal blueprint for adult tendon regeneration. Studies have shown that fetal biochemical cues have the potential to improve adult tendon healing. Here we review the biological factors that contribute to fetal tendon regeneration and how manipulation of these biochemical cues in the adult tendon healing process could achieve regeneration.

We reviewed the biological factors that contribute to fetal tendon regeneration and how manipulation of these biochemical cues in the adult tendon healing process could achieve regeneration. The results showed that inflammation and TGF-ß level are the main elements involved in fetal tendon regeneration. Experimental manipulation of these biochemical cues in the adult tendon healing process demonstrated that although the blockade of TGF-ß1, TGF-ß2 and inflammation reduced scar tissue in adult tendon healing, this inhibition also destroyed the mechanical properties of the tendons. An effective alternative is regulating the specific downstream profibrotic effectors of both TGF-ß1 and inflammation, which is preferable to those that completely inhibit these factors. Finally, TGF-ß3 is a master regulator allowing a shift from adult scar healing to scarless healing, and the administration of TGF-ß3 is a viable strategy to promote adult regenerative healing. In terms of mechanisms, TGF-ß3 can activate Smad7 and inhibit the JNK/c-Jun signaling pathway to promote tendon regenerative healing.