Injectable nanocomposite hydrogel with cascade drug release for treatment of uveal melanoma.

Uveal melanoma (UM) is the most common malignant intraocular tumor with the trait of distant metastases. Currently, the standard clinical therapy results in suboptimal outcomes due to ineffective inhibition of tumor metastasis. Thus, developing novel therapeutic modalities for UM remains a critical priority. Herein, we have developed an injectable nanocomposite hydrogel (HA-DOX/LAP gel) through integrating hyaluronic acid-based drug-loaded nanoparticles into an alginate-dopamine gel, delivering the chemotherapeutic drugs, lapatinib and doxorubicin for combinational treatment of UM. HA-DOX/LAP gel is fabricated in situ by a simple injection of the mixed precursor solution into tumor sites and maintains in vivo for more than 21 days. The entrapped drug-loaded nanoparticles can gradually release from HA-DOX/LAP gel, enhancing tumor targeting and penetration, and synchronously releasing lapatinib and doxorubicin into the acidic intracellular environment to synergistically destroy UM cells. In vivo anti-tumor studies conducted in MuM-2B tumor models demonstrated that HA-DOX/LAP gel significantly impedes tumor growth, diminishes postoperative recurrence, and prolongs overall survivals of UM tumor-bearing mice through only single injection. Remarkably, the escaped drug-loaded nanoparticles effectively reduce the risk of tumor metastases. Our findings provide new insights for the development of multifunctional nanocomposite-incorporating combination therapy against UM by targeting tumor recurrence and metastases.

Lapatinib-loaded reductive-responsive hyaluronic acid-cholesterol nanoparticles for inhibiting metastasis of uveal melanoma.

Uveal melanoma (UM) is the most common intraocular primary malignancy in adults with highly metastatic characteristics. Currently, there are no effective therapies to prevent metastasis formation in UM, resulting in a poor prognosis. Herein, we report a novel lapatinib-loaded reductive-responsive nanoparticle platform prepared via the self-assembly of amphiphilic hyaluronic acid-cystamine-cholesteryl hemisuccinate conjugate to suppress the distant metastasis of UM. The platform can maintain a stable nanosphere structure in the physiological environment and effectively deliver the drug to UM tumor sites, enhancing intratumoral drug accumulation and penetration. Upon endocytosis, lapatinib-loaded nanoparticles rapidly disintegrate triggered by intracellular glutathione and release the payload, leading to considerable suppression of MuM-2B cell proliferation, invasion, and migration. Systemic administration of lapatinib-loaded nanoparticles into mice bearing lung metastases of UM resulted in significantly higher metastasis suppression compared to free lapatinib, with histological analyses indicating no detectable toxicity. This nanotherapeutic platform is expected to provide a promising approach for the safe and efficient prevention of metastasis in UM.

A retrospective study utilized MIMIC-IV database to explore the potential association between triglyceride-glucose index and mortality in critically ill patients with sepsis.

Triglyceride-glucose (TyG) index has emerged as a novel biomarker for detecting insulin resistance (IR) and has been proven to be associated with various diseases. However, its correlation with the prognosis of severe sepsis remains unraveled. This retrospective cohort study utilized patient records from the Medical Information Mart for Intensive Care (MIMIC-IV, version 2.2) to examine the outcomes of patients with sepsis. The primary outcomes were hospital mortality and intensive care unit (ICU) mortality. The correlation between the TyG index and outcomes was evaluated through the Kaplan-Meier method, the Log-rank test, and univariate and multivariate Cox regression analyses. Additionally, restricted cubic spline (RCS) regression analysis was employed to delve into the nonlinear relationship between baseline TyG index and outcomes, with trend significance assessed through quartile levels. Subgroup analyses were conducted to evaluate the consistency of the TyG index's prognostic value across various influencing factors. The study included 1,742 patients with sepsis requiring intensive care. The in-hospital mortality rate was 19.75% (344/1,742), and the ICU mortality rate was 14.75% (257/1,742). Cox regression analysis revealed that, in comparison to the first quartile (Q1), patients in the fourth quartile (Q4) had a 63% higher risk of in-hospital mortality (HR 1.63 [95% CI 1.22 to 2.18], P < 0.01) and a 79% higher risk of ICU mortality (HR 1.79 [95% CI 1.28 to 2.51], P < 0.001). Model 3 showed that ICU mortality risks for Q4, Q3, and Q2 were 240%, 75%, and 33% higher, respectively (HR 3.40 [95% CI 2.24 to 5.16], P < 0.001; HR 1.75 [95% CI 1.16 to 2.63], P = 0.007; HR 1.33 [95% CI 1.20 to 1.53], P < 0.001). RCS regression analysis identified a nonlinear association between the TyG index and mortality (overall P < 0.001; P for nonlinearity < 0.001, with an inflection point at 8.9). Subgroup analysis showed that the effect size and direction were consistent across different subgroups, suggesting the stability of the results. This study demonstrates that a higher TyG index is significantly associated with increased in-hospital and ICU mortality risk in critically ill sepsis patients, with evidence of non-linear correlation. Therefore, the TyG index helps identify the mortality prognosis of sepsis patients in the ICU.

The efficacy and safety of autologous epidermal cell suspensions for re-epithelialization of skin lesions: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Successful usage of autologous skin cell suspension (ASCS) has been demonstrated in some clinical trials. However, its efficacy and safety have not been verified. This latest systematic review and meta-analysis aim to examine the effects of autologous epidermal cell suspensions in re-epithelialization of skin lesions. METHODS: Relevant articles were retrieved from PubMed, Embase, Cochrane Database, Web of Science, International Clinical Trials Registry Platform, China National Knowledge Infrastructureris, VIP Database for Chinese Technical Periodicals and Wanfang database. The primary output measure was the healing time, and the secondary outputs were effective rate, size of donor site for treatment, size of study treatment area, operation time, pain scores, repigmentation, complications, scar scale scores and satisfaction scores. Data were pooled and expressed as relative risk (RR), mean difference (MD) and standardized mean difference (SMD) with a 95% confidence interval (CI). RESULTS: Thirty-one studies were included in this systematic review and meta-analysis, with 914 patients who received autologous epidermal cell suspensions (treatment group) and 883 patients who received standard care or placebo (control group). The pooled data from all included studies demonstrated that the treatment group has significantly reduced healing time (SMD = -0.86; 95% CI: -1.59-0.14; p = 0.02, I2 = 95%), size of donar site for treatment (MD = -115.41; 95% CI: -128.74-102.09; p<0.001, I2 = 89%), operation time (MD = 25.35; 95% CI: 23.42-27.29; p<0.001, I2 = 100%), pain scores (SMD = -1.88; 95% CI: -2.86-0.90; p = 0.0002, I2 = 89%) and complications (RR = 0.59; 95% CI: 0.36-0.96; p = 0.03, I2 = 66%), as well as significantly increased effective rate (RR = 1.20; 95% CI: 1.01-1.42; p = 0.04, I2 = 77%). There were no significant differences in the size of study treatment area, repigmentation, scar scale scores and satisfaction scores between the two groups. CONCLUSION: Our meta-analysis showed that autologous epidermal cell suspensions is beneficial for re-epithelialization of skin lesions as they significantly reduce the healing time, size of donar site for treatment, operation time, pain scores and complications, as well as increased effective rate. However, this intervention has minimal impact on size of treatment area, repigmentation, scar scale scores and satisfaction scores.

Prolonged Cadmium Exposure and Osteoclastogenesis: A Mechanistic Mouse and in Vitro Study.

BACKGROUND: Cadmium (Cd) is a highly toxic and widespread environmental oxidative stressor that causes a myriad of health problems, including osteoporosis and bone damage. Although nuclear factor erythroid 2-related factor 2 (NRF2) and its Cap 'n' Collar and basic region Leucine Zipper (CNC-bZIP) family member nuclear factor erythroid 2-related factor 1 (NRF1) coordinate various stress responses by regulating the transcription of a variety of antioxidant and cytoprotective genes, they play distinct roles in bone metabolism and remodeling. However, the precise roles of both transcription factors in bone loss induced by prolonged Cd exposure remain unclear. OBJECTIVES: We aimed to understand the molecular mechanisms underlying Cd-induced bone loss, focusing mainly on the roles of NRF2 and NRF1 in osteoclastogenesis provoked by Cd. METHODS: Male wild-type (WT), global Nrf2-knockout (Nrf2-/-) and myeloid-specific Nrf2 knockout [Nrf2(M)-KO] mice were administered Cd (50 or 100 ppm) via drinking water for 8 or 16 wk, followed by micro-computed tomography, histological analyses, and plasma biochemical testing. Osteoclastogenesis was evaluated using bone marrow-derived osteoclast progenitor cells (BM-OPCs) and RAW 264.7 cells in the presence of Cd (10 or 20 nM) with a combination of genetic and chemical modulations targeting NRF2 and NRF1. RESULTS: Compared with relevant control mice, global Nrf2-/- or Nrf2(M)-KO mice showed exacerbated bone loss and augmented osteoclast activity following exposure to 100 ppm Cd in drinking water for up to 16 wk. In vitro osteoclastogenic analyses suggested that Nrf2-deficient BM-OPCs and RAW 264.7 cells responded more robustly to low levels of Cd (up to 20 nM) with regard to osteoclast differentiation compared with WT cells. Further mechanistic studies supported a compensatory up-regulation of long isoform of NRF1 (L-NRF1) and subsequent induction of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1 (NFATc1) as the key molecular events in the Nrf2 deficiency-worsened and Cd-provoked osteoclastogenesis. L-Nrf1 silenced (via lentiviral means) Nrf2-knockdown (KD) RAW cells exposed to Cd showed dramatically different NFATc1 and subsequent osteoclastogenesis outcomes compared with the cells of Nrf2-KD alone exposed to Cd, suggesting a mitigating effect of the Nrf1 silencing. In addition, suppression of reactive oxygen species by exogenous antioxidants N-acetyl-l-cysteine (2 mM) and mitoquinone mesylate (MitoQ; 0.2µM) mitigated the L-NRF1-associated effects on NFATc1-driven osteoclastogenesis outcomes in Cd-exposed Nrf2-KD cells. CONCLUSIONS: This in vivo and in vitro study supported the authors' hypothesis that Cd exposure caused bone loss, in which NRF2 and L-NRF1 responded to Cd and osteoclastogenic stimuli in a cooperative, but contradictive, manner to coordinate Nfatc1 expression, osteoclastogenesis and thus bone homeostasis. Our study suggests a novel strategy targeting NRF2 and L-NRF1 to prevent and treat the bone toxicity of Cd. https://doi.org/10.1289/EHP13849.

Effects of Virtual Reality on Analgesia in Wound Care and Physical Therapy for Burn Patients: A Systematic Review and Meta-analysis.

OBJECTIVES: This systematic review and meta-analysis aimed to determine the effectiveness of virtual reality (VR) in alleviating pain and improving the experience of burn patients during wound care and physical therapy. DESIGN: A systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, the Cochrane Database, and the Web of Science. REVIEW/ANALYSIS METHODS: We searched four electronic databases for randomized controlled trials (RCTs) published from the earliest available date up to March 1, 2022. The primary outcome was worst pain intensity, while secondary outcomes encompassed pain unpleasantness intensity, time spent thinking about pain, and fun experience intensity. Risk of bias was evaluated using the Cochrane Collaboration's tool. RESULTS: This study included 21 trials. The combined data revealed that the VR group experienced a significant reduction in worst pain intensity, pain unpleasantness intensity, and time spent thinking about pain compared to the control group. Moreover, VR treatment was associated with a significant increase in the fun experience intensity. IMPLICATIONS FOR NURSING: Virtual reality has the potential value of auxiliary analgesia in burn care, and exploring a more perfect scheme of VR-assisted analgesia is worthwhile. CONCLUSIONS: The results of this meta-analysis indicate that VR can effectively reduce worst pain intensity, pain unpleasantness intensity, and time spent thinking about pain during wound care and physical therapy for burn patients. Additionally, it enhances fun experience intensity of the treatment period. Therefore, VR shows promise as a valuable complementary pain management intervention for burn patients.

Causal relationship between the gut microbiome and basal cell carcinoma, melanoma skin cancer, ease of skin tanning: evidence from three two-sample mendelian randomisation studies.

Objectives: The present study used publicly available genome-wide association study (GWAS) summary data to perform three two-sample Mendelian randomization (MR) studies, aiming to examine the causal links between gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. Methods: SNPs associated with exposures to basal cell carcinoma, melanoma skin cancer and ease of skin tanning from the genome-wide association study data of UK Biobank and MRC-IEU (MRC Integrative Epidemiology Unit), and the meta-analysis data from Biobank and MRC-IEU were used as instrumental variables (IVs). The casual estimates were assessed with a two-sample Mendelian randomisation test using the inverse-variance-weighted (IVW) method, Wald ratio, MR-Egger method, maximum likelihood, weighted median, simple mode, and weighted mode. Results: After the application of MR analysis, diffirent effects of multiple groups of gut microbiota was observed for BCC, melanoma skin cancer and ease of skin tanning. The relationships between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning were supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. Conclusion: Our study initially identified potential causal roles between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning, and highlighted the role of gut microbiome in the progression of basal cell carcinoma, melanoma skin cancer, ease of skin tanning.

Efficacy of probiotics or synbiotics in critically ill patients: A systematic review and meta-analysis.

BACKGROUND: This latest systematic review and meta-analysis aim to examine the effects of probiotic and synbiotic supplementation in critically ill patients. METHODS: Relevant articles were retrieved from PubMed, Embase, the Cochrane Database, and the Web of Science. The primary output measure was the incident of ventilator-associated pneumonia, and the secondary outputs were diarrhea, Clostridium diffusion infection (CDI), incident of sepsis, incident of hospital acquired pneumonia, duration of mechanical exploitation, ICU mortality rate, length of ICU stay, in hospital mortality, and length of hospital stay. Data were pooled and expressed as Relative Risk(RR) and Standardized Mean Difference (SMD) with a 95 % confidence interval (CI). RESULTS: 33 studies were included in this systematic review and meta-analysis, with 4065 patients who received probiotics or synbiotics (treatment group) and 3821 patients who received standard care or placebo (control group). The pooled data from all included studies demonstrated that the treatment group has significantly reduced incidence of ventilation-associated pneumonia (VAP) (RR = 0.80; 95 % CI: 0.67-0.96; p = 0.021, I2 = 52.5 %) and sepsis (RR = 0.97; 95 % CI: 0.66-1.42; p = 0.032, I2 = 54.4 %), As well as significantly increased duration of mechanical exploitation (SMD = -0.47; 95 % CI: -0.74-0.20, p = 0.012, I2 = 63.4 %), ICU mobility (RR = 0.95; 95 % CI: 0.71-1.27; p = 0.004, I2 = 62.8 %), length of ICU stay (SMD = -0.29; 95 % CI: -0.58-0.01; p = 0.000, I2 = 82.3 %) and length of hospital stay (SMD = -0.33; 95 % CI: -0.57-0.08, p = 0.000, I2 = 74.2 %) than the control group. There were no significant differences in diarrhea, CDI, incidence of hospital acquired pneumonia, and in hospital mortality between the two groups. CONCLUSION: Our meta-analysis showed that probiotic and synbiotic supplements are beneficial for critically ill patients as they significantly reduce the incidence of ventilator associated pneumonia and sepsis, as well as the duration of mechanical exploitation, length of hospital stay, length of ICU stay, and ICU mortality. However, this intervention has minimal impact on diarrhea, CDI, incidence of hospital acquired pneumonia, and in hospital mortality in critically ill patients.

Development and validation of a nomogram to predict hypothermia in adult burn patients during escharectomy under general anesthesia.

BACKGROUND: It is very common for burn patients to have hypothermia during escharectomy under general anesthesia, which increases the blood transfusion demand of burn patients, and may lead to blood coagulation disorder or even increase the mortality of patients. It is important to predict the occurrence of hypothermia in advance, but we lack a prognostic prediction model. Our study aimed to develop a nomogram to predict the incidence of hypothermia in adult burn patients undergoing escharectomy under general anesthesia to intervention the hazards associated with hypothermia early. METHODS: This retrospective study included 978 adult burn patients who underwent simple escharectomy under general anesthesia during hospitalization between January 2017 and December 2022, they were further divided into a training cohort and a validation cohort. The clinical data were recorded in electronic medical record system and a self-made collection table of intraoperative hypothermia. The preliminary predictive factors for hypothermia which undergoing simple escharectomy under general anesthesia in burn patients were determined using least absolute shrinkage and selection operator (LASSO) at first, then the final predictive factors determined using binary logistic regression analyses and a nomogram to predict the occurrence of hypothermia was established. The index of concordance(C-index), calibration curves, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to evaluate the performance of the model. RESULTS: A total of 211 patients with hypothermia and 767 patients without hypothermia were selected. Least absolute shrinkage and selection operator regression analysis and binary logistic regression results concluded that burn index, urinary volume, blood transfusion volume and irrigation volume were significantly associated with hypothermia in burn patients undergoing escharectomy under general anesthesia. The nomogram based on these four variables had good predictive efficiency for hypothermia in adult burn patients during escharectomy under general anesthesia, the C-index in the training cohort was 0.903, areas under the receiver operating characteristic curves (AUROC) of for the training cohort (95 % CI 0.877-0.920) and 0.875 for the validation cohort (95 % CI 0.852-0.897) indicated satisfactory discriminative ability of the nomogram, and the calibration curves for the training cohort and the validation cohort also fit as well, indicating that the nomogram had good clinical application value. CONCLUSIONS: Hypothermia in burn patients during escharectomy under general anesthesia is associated with burn index, urinary volume, blood transfusion volume and irrigation volume. We successfully developed a practical nomogram to accurately predict hypothermia, which is a practical method helping clinicians rapidly and conveniently diagnose and guide the treatment of hypothermia in burn patients during escharectomy under general anesthesia.

Thermoplastic polyurethane surface coated with polymer brushes for reduced protein and cell attachment.

The objective of this study was to coat negatively charged polymer brushes covalently onto the surface of thermoplastic polyurethane (TPU) using a simple conventional surface free-radical polymerization technique. The coated surfaces were assessed with contact angle, protein adsorption, cell adhesion and bacterial adhesion. Bovine serum albumin (BSA) and bovine fibrinogen (BFG) were used for protein adsorption evaluation. Mouse fibroblasts (NIH-3T3) and Pseudomonas aeruginosa (P. aeruginosa) were used to assess surface adhesion. Results show that the TPU surface modified with the attached polymer brushes exhibited significantly reduced contact angle, protein adsorption, and cell as well as bacterial adhesion, among which the negatively charged polymers showed the extremely low values in all the tests. Its contact angle is 5°, as compared to 70° for original TPU. Its BSA, BFG, 3T3 adhesion and P. aeruginosa adhesion were 93%, 84%, 92%, and 93% lower than original TPU. Furthermore, the TPU surface coated with negatively charged polymer brushes exhibited a hydrogel-like property. The results indicate that placing acrylic acids using a simple surface-initiated free-radical polymerization onto a TPU surface and then converting those to negative charges can be an effective and efficient route for fouling resistant applications.

Nrf2 Mitigates RANKL and M-CSF Induced Osteoclast Differentiation via ROS-Dependent Mechanisms.

Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been shown to be a negative regulator of osteoclast differentiation, but the precise mechanisms have not yet been established. We examined the precise roles of Nrf2 in regulating antioxidants and reactive oxygen species (ROS) levels, especially the cytoplasmic and mitochondrial ROS during osteoclastogenesis in vitro. In the current study, we found that the absence of Nrf2 promotes osteoclast differentiation in bone-marrow-derived macrophages (BMMs) and RAW 264.7 cells. The receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) significantly lowered the levels of Nrf2 and its downstream antioxidant enzymes at mRNA and/or protein levels during osteoclast differentiation in the BMMs of mice and RAW 264.7 mouse leukemic monocytes. Compared to the wild-type cells, Nrf2-deficient cells exhibited heightened sensitivity to both transient RANKL-induced cytoplasmic ROS and prolonged RANKL and M-CSF-induced cytoplasmic and mitochondrial ROS accumulation. Furthermore, exogenous antioxidant agents, including N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and mitoquinone mesylate (MitoQ), exhibited substantial capability to suppress the elevation of ROS levels during osteoclast differentiation induced by Nrf2 deficiency, and they consequently inhibited osteoclast differentiation augmented by the lack of Nrf2. The activation of phosphorylated c-FOS resulting from elevated ROS promoted osteoclast differentiation. The inhibition of c-FOS blocked osteoclast differentiation, which was elevated by Nrf2-deficiency. Taken together, these data reveal that Nrf2 effectively decreased the accumulation of intracellular ROS and the phosphorylation of c-FOS during osteoclastic differentiation by regulating antioxidant enzymes and subsequently inhibited RANKL-induced osteoclast differentiation.

Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats.

Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 is expressed on the cell surface of mature osteoclasts. Anti-Siglec-15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec-15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4-month-old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, -18.7%), trabecular bone volume (-43.1%), trabecular connectivity (-59.7%), and bone stiffness (-76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec-15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Rationally Designed Enzyme-Resistant Peptidic Assemblies for Plasma Membrane Targeting in Cancer Treatment.

Peptides are being increasingly important for subcellular targeted cancer treatment to improve specificity and reverse multidrug resistance. However, there has been yet any report on targeting plasma membrane (PM) through self-assembling peptides. A simple synthetic peptidic molecule (tF4) is developed. It is revealed that tF4 is carboxyl esterase-resistant and self-assembles into vesical nanostructures. Importantly, tF4 assemblies interact with PM through orthogonal hydrogen bonding and hydrophobic interaction to regulate cancer cellular functions. Mechanistically, tF4 assemblies induce stress fiber formation, cytoskeleton reconstruction, and death receptor 4/5 (DR4/5) expression in cancer cells. DR4/5 triggers extrinsic caspase-8 signaling cascade, resulting in cell death. The results provide a new strategy for developing enzyme-resistant and PM-targeting peptidic molecules against cancer.

The role of mechanosensor Piezo1 in bone homeostasis and mechanobiology.

Bones and articular cartilage are important load-bearing tissues. The fluid flow inside the bone cells and cell interaction with the extracellular matrix serve as the mechanical cues for bones and joints. Piezo1 is an ion channel found on the cell surface of many cell types, including osteocytes and chondrocytes. It is activated in response to mechanical stimulation, which subsequently mediates a variety of signaling pathways in osteoblasts, osteocytes, and chondrocytes. Piezo1 activation in osteoblastic cells positively regulates osteogenesis, while its activation in joints mediates cartilage degradation. This review focuses on the most recent research on Piezo1 in bone development and regeneration.

Primary cilia in osteoblasts and osteocytes are required for skeletal development and mechanotransduction.

Primary cilia have been involved in the development and mechanosensation of various tissue types, including bone. In this study, we explored the mechanosensory role of primary cilia in bone growth and adaptation by examining two cilia specific genes, IFT88 and MKS5, required for proper cilia assembly and function. To analyze the role of primary cilia in osteoblasts, Osx1-GFP:Cre mice were bred with IFT88 LoxP/LoxP to generate mice with a conditional knockout of primary cilia in osteoblasts. A significant decrease in body weight was observed in both male (p=0.0048) and female (p=0.0374) conditional knockout (cKO) mice compared to the wild type (WT) controls. The femurs of cKO mice were significantly shorter than that of the WT mice of both male (p=0.0003) and female (p=0.0019) groups. Histological analysis revealed a significant difference in MAR (p=0.0005) and BFR/BS (p<0.0001) between female cKO and WT mice. The BFR/BS of male cKO mice was 58.03% lower compared to WT mice. To further investigate the role of primary cilia in osteocytes, Dmp1-8kb-Cre mice were crossed with MKS5 LoxP/LoxP to generate mice with defective cilia in osteocytes. In vivo axial ulnar loading was performed on 16-week-old mice for 3 consecutive days. The right ulnae were loaded for 120 cycles/day at a frequency of 2Hz with a peak force of 2.9N for female mice and 3.2N for male mice. Load-induced bone formation was measured using histomorphometry. The relative values of MS/BS, MAR and BFR/BS (loaded ulnae minus nonloaded ulnae) in male MKS5 cKO mice were decreased by 24.88%, 46.27% and 48.24%, respectively, compared to the controls. In the female groups, the rMS/BS was 52.5% lower, the rMAR was 27.58% lower, and the rBFR/BS was 41.54% lower in MKS5 cKO mice than the WT group. Histological analysis indicated that MKS5 cKO mice showed significantly decreased response to mechanical loading compared to the controls. Taken together, these data highlight a critical role of primary cilia in bone development and mechanotransduction, suggesting that the presence of primary cilia in osteoblasts play an important role in skeletal development, and primary cilia in osteocytes mediate mechanically induced bone formation.

Effect of transverse wrist crease perforator flap on repairing soft tissue defect of fingers and its influence on hand function.

OBJECTIVE: To investigate the effect of transverse wrist crease perforator flap repair on sensory nerve function, survival of flap, hand function, hand appearance and satisfaction rate in patients with soft tissue defect of fingers. METHODS: This retrospective study was performed in 30 patients admitted to the Hand and Foot Microsurgery Department of our hospital between January 2018 and December 2020. These patients were divided into to the control group and the experimental group (15 patients for each group) according to the operative methods. Patients in the control group underwent abdominal flap repair, while patients in the experimental group received transverse wrist crease perforator flap repair. Intraoperative parameters, sensory nerve function, function of finger reconstruction, survival rate of skin flap, degree of scar contracture and flap bloatedness, DASH score, two-point discrimination and satisfaction rate were compared between the two groups. RESULTS: Compared with the control group, the operative time in the experiment group was obviously decreased (P<0.05). There was no difference in amount of bleeding between the two groups. The proportion of sensory nerve function grade S3+ and S4 in the experimental group was significantly increased in contrast to the control group (P<0.05). The total excellent and good rate in function of finger reconstruction in the experiment group was significantly higher than that in the control group, while no difference was found in the survival rate of skin flap and scar contracture between the two groups. Compared with the control group, DASH score, two-point discrimination distance, and degree of flap bloatedness in the experiment group were significantly reduced and the patients' satisfaction rate in the experiment group was remarkably increased (all P<0.05). CONCLUSION: Transverse wrist crease perforator flap repair plays a critical role in reducing operative time, improving sensory nerve function and recovery of hand function, and alleviating flap bloatedness. It is an optimal treatment for soft tissues defect of fingers.

GE11 peptide-decorated acidity-responsive micelles for improved drug delivery and enhanced combination therapy of metastatic breast cancer.

Nanotechnology-mediated drug delivery systems suffer from insufficient retention in tumor tissues and unreliable drug release at specific target sites. Herein, we developed an epidermal growth factor receptor-targeted multifunctional micellar nanoplatform (GE11-DOX+CEL-M) by encapsulating celecoxib into polymeric micelles based on the conjugate of GE11-poly(ethylene glycol)-b-poly(trimethylene carbonate) with doxorubicin to suppress tumor growth and metastasis. The polymeric micelles maintained stable nanostructures under physiological conditions but quickly disintegrated in a weakly acidic environment, which is conducive to controlled drug release. Importantly, GE11-DOX+CEL-M micelles effectively delivered the drug combination to tumor sites and enhanced tumor cell uptake through GE11-mediated active tumor targeting. Subsequently, GE11-DOX+CEL-M micelles dissociated in response to intracellular slightly acidic microenvironmental stimuli, resulting in rapid release of celecoxib and doxorubicin to synergistically inhibit the proliferation and migration of tumor cells. Systemic administration of GE11-DOX+CEL-M micelles into mice bearing subcutaneous 4T1 tumor models resulted in higher tumor growth suppression and decreased lung metastasis of tumor cells compared with micelles without GE11 decoration or delivering only doxorubicin. Furthermore, the micelles effectively reduced the systemic toxicity of the chemotherapy drugs. This nanotherapeutic system provides a promising strategy for safe and effective cancer therapy.

Hydrolytically Degradable PEG-Based Inverse Electron Demand Diels-Alder Click Hydrogels.

Hydrogels cross-linked by inverse electron demand Diels-Alder (iEDDA) click chemistry are increasingly used in biomedical applications. With a few exceptions in naturally derived and chemically modified macromers, iEDDA click hydrogels exhibit long-term hydrolytic stability, and no synthetic iEDDA click hydrogels can undergo accelerated and tunable hydrolytic degradation. We have previously reported a novel method for synthesizing norbornene (NB)-functionalized multiarm poly(ethylene glycol) (PEG), where carbic anhydride (CA) was used to replace 5-norbornene-2-carboxylic acid. The new PEGNBCA-based thiol-norbornene hydrogels exhibited unexpected fast yet highly tunable hydrolytic degradation. In this contribution, we leveraged the new PEGNBCA macromer for forming iEDDA click hydrogels with [methyl]tetrazine ([m]Tz)-modified macromers, leading to the first group of synthetic iEDDA click hydrogels with highly tunable hydrolytic degradation kinetics. We further exploited Tz and mTz dual conjugation to achieve tunable hydrolytic degradation with an in vitro degradation time ranging from 2 weeks to 3 months. Finally, we demonstrated the excellent in vitro cytocompatibility and in vivo biocompatibility of the new injectable PEGNBCA-based iEDDA click cross-linked hydrogels.

Characterization and assessment of lung and bone marrow derived endothelial cells and their bone regenerative potential.

Angiogenesis is important for successful fracture repair. Aging negatively affects the number and activity of endothelial cells (ECs) and subsequently leads to impaired bone healing. We previously showed that implantation of lung-derived endothelial cells (LECs) improved fracture healing in rats. In this study, we characterized and compared neonatal lung and bone marrow-derived endothelial cells (neonatal LECs and neonatal BMECs) and further asses3sed if implantation of neonatal BMECs could enhance bone healing in both young and aged mice. We assessed neonatal EC tube formation, proliferation, and wound migration ability in vitro in ECs isolated from the bone marrow and lungs of neonatal mice. The in vitro studies demonstrated that both neonatal LECs and neonatal BMECs exhibited EC traits. To test the function of neonatal ECs in vivo, we created a femoral fracture in young and aged mice and implanted a collagen sponge to deliver neonatal BMECs at the fracture site. In the mouse fracture model, endochondral ossification was delayed in aged control mice compared to young controls. Neonatal BMECs significantly improved endochondral bone formation only in aged mice. These data suggest BMECs have potential to enhance aged bone healing. Compared to LECs, BMECs are more feasible for translational cell therapy and clinical applications in bone repair. Future studies are needed to examine the fate and function of BMECs implanted into the fracture sites.