Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

Injectable and Microporous Microgel-Fiber Granular Hydrogel Loaded with Bioglass and siRNA for Promoting Diabetic Wound Healing.

Injectable hydrogels find extensive application in the treatment of diabetic wound healing. However, traditional bulk hydrogels are significantly limited due to their nano-porous structure, which obstructs cell migration and tissue infiltration. Moreover, regulating inflammation and matrix metalloproteinase -9 (MMP-9) expression in diabetic wounds is crucial for enhancing wound healing. This study marks the first instance of introducing an efficient, scalable, and simple method for producing microfiber-gel granules encapsulating bioceramics powders. Utilizing this method, an injectable microporous granular microgel-fiber hydrogel (MFgel) is successfully developed by assembling microgel-fibers made from hyaluronic acid (HA) and sodium alginate (SA) loaded with small interfering RNA (siRNA) and bioglass (BG) particles. Compared to traditional hydrogels (Tgel), MFgel possesses a highly interconnected network with micron-sized pores, demonstrating favorable properties for cell adhesion and penetration in in vitro experiments. Additionally, MFgel exhibits a higher compressive modulus and superior mechanical stability. When implanted subcutaneously in mice, MFgel promotes cellular and tissue infiltration, facilitating cell proliferation. Furthermore, when applied to skin defects in diabetic rats, MFgel not only effectively regulates inflammation and suppresses MMP-9 expression but also enhances angiogenesis and collagen deposition, thereby significantly accelerating diabetic wound healing. Taken together, this hydrogel possesses great potential in diabetic wound healing applications.

Arthroscopic Autologous Iliac Crest Grafting Results in Similar Outcomes and Low Recurrence Compared to Remplissage Plus Bankart Repair for Anterior Shoulder Instability With Bipolar Bone Defects.

PURPOSE: To compare the functional outcomes, range of motion (ROM), recurrence rates, and complication rates of arthroscopic autologous iliac crest grafting (AICG) and Remplissage plus Bankart repair (RB) for anterior shoulder instability with bipolar bone defects. METHODS: This study enrolled patients undergoing arthroscopic AICG or RB with 13.5-25% glenoid bone defect combined with Hill-Sachs lesion between January 2013 and April 2020, who had a minimum 2-year follow-up. Patient-reported outcomes were evaluated by Subjective Shoulder Value (SSV), Oxford Shoulder Instability Score (OSIS), Rowe score, Constant score, and visual analog scale (VAS) for pain. Active ROM, return to sports, recurrence, self-reported apprehension, and complications were recorded. RESULTS: This study included 60 patients, including 28 AICG (Group A) and 32 RB (Group R). Mean glenoid bone defect was similar (17.7% ± 3.1% vs 16.6% ± 2.4%; P = .122). Both groups showed significant postoperative improvement in Rowe score, SSV, OSIS, and Constant score. No significant difference was found in postoperative Rowe Score (87.7 vs 85.2; P = .198). A total of 20/28 (71.4%) patients in Group A versus 26/32 (81.3%) patients in Group R met the Patient Acceptable Symptomatic State determined by VAS pain score (P = .370). Both groups showed high return-to-sports rates (67.8% vs 71.8%; P = .735) and slightly decreased ROM. There were two cases of recurrence in Group A versus one in Group R (P = .594). Group R had insignificantly higher positive self-reported apprehension rate (40.6% vs 17.9%; P = .055). CONCLUSIONS: For anterior shoulder instability with bipolar bone defects, both arthroscopic AICG and RB can result in satisfactory clinical outcomes, good postoperative ROM, and low recurrence and complication rates. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

The prevalence and parameters of fabella and its association with medial meniscal tear in China: a retrospective study of 1011 knees.

BACKGROUND: Fabella is a sesamoid bone of knee that has potential biomechanical function. We aimed to examine the fabellar prevalence and parameters in Chinese population and test the hypothesis that fabellar presence and morphology were associated with meniscus tear or ligament injury. METHODS: A total of 1011 knee magnetic resonance imaging scans from 979 patients with knee pain were analyzed retrospectively. The exclusion criteria are postsurgical scans, difficulty in fabella discrimination, conditions not suitable for measurement, and unsatisfied image. The fabellar presence and its parameters (length, width and thickness) were documented. The association between fabellar presence and meniscus tear or ligament injury were assessed by chi-square test, in all knees and subgroups (age, gender, side, lesion part). The correlation of fabellar presence and parameters with advancing age was assessed by Spearman correlation analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to investigate whether factors related with meniscus tear or ligament injury. Diagnostic performance of risk factors was assessed by receiver operating characteristic (ROC) analysis. RESULTS: The overall prevalence of fabellae was 39.8% (402/1011 knees) and increased with the increasing age (r = 0.237, P < 0.001). The size of the fabellae differed according to genders, age, and presence of articulating grooves. Fabella presented more often in knees with medial meniscus (MM) tears (66.7% vs 33.8%; P < 0.001) with a multivariate OR of 2.960 (95% CI, 1.853-3.903). The association remained in all tear parts (anterior, middle, and posterior), and in younger (age < 50 years) and older patients (age ≥ 50 years). Age, fabellar length, width, length/thickness ratio and width/thickness ratio yielded an area under the ROC curve (AUC) of 0.604-0.766 to predict an MM tear. In combination with age, fabellar width and length/thickness ratio, the AUC was improved 0.791 (95% CI, 0.744-0.837), with a sensitivity of 73.0% and a specificity of 74.6%. CONCLUSION: The presence of fabellae, increased fabellar length and width as well as flatter fabellar morphology, are significantly associated with an increased risk for MM tear. These findings might aid clinicians in identifying patients at risk for a MM tear and informing them.

The recombinant human fibroblast growth factor-18 (sprifermin) improves tendon-to-bone healing by promoting chondrogenesis in a rat rotator cuff repair model.

BACKGROUND: Rotator cuff healing is improved by reconstructing the fibrocartilaginous structure of the tendon-to-bone enthesis. Fibroblast growth factor (FGF)-18 (sprifermin) is a well-known growth factor that improves articular cartilage repair via its anabolic effect. This study aimed to investigate the effect of recombinant human FGF-18 (rhFGF-18) on the chondrogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) in vitro and tendon-to-bone healing in a rat model of rotator cuff repair. METHODS: Histological and reverse transcription-quantitative real-time polymerase chain reaction analyses of chondral pellets cultured with different concentrations of rhFGF-18 were performed. Bilateral detachment and repair of the supraspinatus tendon were performed on rats. The rats were administered 0.2 mL of sodium alginate (SA) hydrogel with (rhFGF-18/SA group, n = 12) or without (SA group, n = 12) 20 µg of rhFGF-18 into the repaired side. The simple repair group (n = 12) served as a control. At 4 and 8 weeks after surgery, histological analysis and biomechanical tests were performed. RESULTS: After chondrogenesis induction, compared with the control group, 10 ng/mL of rhFGF-18 increased pellet volume significantly (P = .002), with improved histological staining. It was noted that 10 ng/mL of rhFGF-18 upregulated the mRNA expression (relative ratio to control) of aggrecan (2.59 ± 0.29, P < .001), SRY-box transcription factor 9 (1.88 ± 0.05, P < .001), and type II collagen (1.46 ± 0.18, P = .009). At 4 and 8 weeks after surgery, more fibrocartilage and cartilaginous extracellular matrix was observed in rhFGF-18/SA-treated rats. The semiquantitative data from picrosirius red staining test were 31.1 ± 4.5 vs. 61.2 ± 4.1 at 4 weeks (P < .001) and 61.5 ± 2.8 vs. 80.5 ± 10.5 at 8 weeks (P = .002) (control vs. rhFGF-18/SA). Ultimate failure load (25.42 ± 3.61 N vs. 18.87 ± 2.71 N at 4 weeks and 28.63 ± 5.22 N vs. 22.15 ± 3.11 N at 8 weeks; P = .006 and P = .03, respectively) and stiffness (18.49 ± 1.38 N/mm vs. 14.48 ± 2.01 N/mm at 8 weeks, P = .01) were higher in the rhFGF-18/SA group than in the control group. CONCLUSION: rhFGF-18 promoted chondrogenesis in the hBMSCs in vitro. rhFGF-18/SA improved tendon-to-bone healing in the rats by promoting regeneration of the fibrocartilage enthesis. rhFGF-18 (sprifermin) may be beneficial in improving tendon-to-bone healing after rotator cuff repair.

Eribulin, Child-Pugh score, and liver-function tests: lessons from pivotal breast cancer studies 301 and 305.

BACKGROUND: The recommended starting dose of eribulin in patients with hepatic impairment is based on the Child-Pugh score, largely informed by a pharmacokinetic study of 18 patients. In the pivotal studies of eribulin in metastatic breast cancer (Study 301 and Study 305 [EMBRACE]), entry criteria and dose modifications were based on liver-function test (LFT) results rather than Child-Pugh score. In populations such as patients with metastatic breast cancer, in which metastatic infiltration is the predominant cause of hepatic impairment, using Child-Pugh score may be problematic; in clinical practice, it has been more common for oncologists to make dosing decisions based on LFTs. To address this, the effects of abnormal baseline LFT results on eribulin efficacy and safety were investigated. METHODS: In this pooled post hoc analysis, 1062 patients who were randomized to receive eribulin in Studies 301 and 305 were divided into 4 groups: (A) no elevated LFT results (no liver impairment); (B) increased levels of aspartate aminotransferase and/or alanine aminotransferase; (C) decreased albumin and/or increased levels of aspartate aminotransferase and/or alanine aminotransferase but not increased bilirubin; and (D) increased bilirubin. Patients were subcategorized by presence of liver metastasis. Drug exposure, dose intensity, and treatment-emergent adverse events (TEAEs) were analyzed. RESULTS: Eribulin mesylate mean dosage was 0.82 (group A)-0.65 mg/m2/week (group D). Group D had shorter treatment, more dose reductions/delays, more TEAEs leading to dose modifications, and numerically lower objective response rates and clinical benefit rates versus groups A-C. TEAE rates leading to dose modification were similar between group D (45.5%) and groups A-C (range, 43.5-54.9%) in the absence of liver metastases, but higher in group D (91.3%) compared with groups A-C (range, 41.7-54.3%) if liver metastases were present. CONCLUSIONS: Mild elevations in bilirubin levels were associated with increased toxicity and a greater requirement for dose modifications. Based both on these study data and existing recommendations, we propose a novel scheme to guide initial dose selection in patients with metastatic breast cancer and hepatic impairment that is based on LFTs rather than Child-Pugh score.

CY-09 attenuates the progression of osteoarthritis via inhibiting NLRP3 inflammasome-mediated pyroptosis.

Excessive activation of inflammation in chondrocyte has been considered to be a major reason cause of cellular death and degeneration in osteoarthritis (OA) development. The NLRP3 inflammasome-mediated pyroptosis pathway is closely related to inflammation regulation. This research was conducted to confirm whether NLRP3 expression and activity are impacted in the development of OA and to detect the role of CY-09, a selective and direct inhibitor of NLRP3 in the in vitro and in vivo models of OA. Our findings corroborated that the expression of NLRP3 is stimulated in OA cartilage. CY-09 can maintain extracellular matrix (ECM) homeostasis and regulate inflammation in TNF-α treated chondrocytes via inhibition of NLRP3 inflammasome-mediated pyroptosis. Moreover, the chondrocyte protective effects of CY-09 were further confirmed in vivo in a DMM-induced OA model. In conclusion, our research indicates that experimental OA activated the NLRP3 activity, and pharmacological inhibition of NLRP3 inflammasome activation by CY-09 protects chondrocytes against inflammation and attenuates OA development.

GPR35 regulates osteogenesis via the Wnt/GSK3ß/ß-catenin signaling pathway.

It is well known that osteoporosis is a significant chronic disease with the increase of the aging population. Here, we report that expression of G protein-coupled receptor 35 (GPR35) in bone marrow mesenchymal stem cells (BMSCs) is suppressed in diagnosed osteoporosis patients and osteoporotic mice. The expression of GPR35 on BMSCs is enhanced during osteogenic differentiation. GPR35 knockout suppresses the proliferation and osteogenesis of BMSCs and deteriorates bone mass in both sham-treated and ovariectomized mice. Moreover, GPR35 deficiency reduces ß-catenin activity in BMSCs. In contrast, the overexpression of GPR35 contributes to these processes in BMSCs. Finally, using zaprinast, a synthetic GPR35 agonist, we show that zaprinast rescues OVX-induced bone loss and promotes bone generation in mice. Thus, GPR35 may as a new target and its agonist zaprinast may serve as a novel treatment for osteoporosis.

A first-in-human phase I study of TAS0728, an oral covalent binding inhibitor of HER2, in patients with advanced solid tumors with HER2 or HER3 aberrations.

TAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 h and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: https://clinicaltrials.gov/ct2/show/NCT03410927 ; registered on January 25, 2018.

Amorphous calcium phosphate nanoparticles using adenosine triphosphate as an organic phosphorus source for promoting tendon-bone healing.

BACKGROUND: Rotator cuff tear (RCT) is a common problem of the musculoskeletal system. With the advantage of promoting bone formation, calcium phosphate materials have been widely used to augment tendon-bone healing. However, only enhancing bone regeneration may be not enough for improving tendon-bone healing. Angiogenesis is another fundamental factor required for tendon-bone healing. Therefore, it's necessary to develop a convenient and reliable method to promote osteogenesis and angiogenesis simultaneously, thereby effectively promoting tendon-bone healing. METHODS: The amorphous calcium phosphate (ACP) nanoparticles with dual biological activities of osteogenesis and angiogenesis were prepared by a simple low-temperature aqueous solution method using adenosine triphosphate (ATP) as an organic phosphorus source. The activities of osteogenesis and angiogenesis and the effect on the tendon-bone healing of ACP nanoparticles were tested in vitro and in a rat model of acute RCT. RESULTS: The ACP nanoparticles with a diameter of tens of nanometers were rich in bioactive adenosine. In vitro, we confirmed that ACP nanoparticles could enhance osteogenesis and angiogenesis. In vivo, radiological and histological evaluations demonstrated that ACP nanoparticles could enhance bone and blood vessels formation at the tendon-bone junction. Biomechanical testing showed that ACP nanoparticles improved the biomechanical strength of the tendon-bone junction and ultimately promoted tendon-bone healing of rotator cuff. CONCLUSIONS: We successfully confirmed that ACP nanoparticles could promote tendon-bone healing. ACP nanoparticles are a promising biological nanomaterial in augmenting tendon-bone healing.

Health-related quality of life in patients receiving first-line eribulin mesylate with or without trastuzumab for locally recurrent or metastatic breast cancer.

BACKGROUND: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor approved for second-line (European Union) or third-line (United States) treatment of metastatic breast cancer. Two phase 2 single trials, evaluating first-line eribulin as monotherapy (Study 206; NCT01268150) or in combination with trastuzumab (Study 208; NCT01269346) in locally recurrent or metastatic breast cancer, demonstrated objective response rates of 28.6 and 71.2%, respectively. Median progression-free survival was 6.8 and 11.6 months, respectively. Tolerability profiles were similar to those from previous studies. This secondary analysis was conducted to assess health-related quality of life (HRQoL) in both phase 2 trials. METHODS: Patients received eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of each 21-day cycle. Patients in Study 208 also received intravenous trastuzumab on day 1 of each cycle (8 mg/kg in cycle 1, then 6 mg/kg). HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life (QLQ-C30) assessment tool and the Quality-of-Life Questionnaire for Breast Cancer (QLQ-BR23) at baseline and cycles 2, 4, and 6. Results for clinically meaningful changes were based on previously published minimum important differences. RESULTS: Of the 108 patients (56 in Study 206 and 52 in Study 208) treated, 57 and 87%, respectively, completed 6 cycles. Completion rates for both questionnaires were 94 and 98%, respectively, at cycle 6. Most patients had stable/improved HRQoL scores with some exceptions; for example, more patients experienced a worsening in cognitive functioning and systemic therapy side effects than experienced improvement. Mean QLQ-C30 symptom scores correlated with corresponding adverse event rates for nausea/vomiting, dyspnea, appetite loss, constipation, and diarrhea in Study 206 and for fatigue, nausea/vomiting, pain, dyspnea, insomnia, constipation, and diarrhea in Study 208. CONCLUSIONS: First-line eribulin ± trastuzumab therapy did not lead to deterioration of overall HRQoL in most patients, with more than 60% of patients having stable/improved global health status/quality-of-life scores. Eribulin has been demonstrated to be comparable with other chemotherapy agents with an acceptable safety profile. Therefore, further evaluation is warranted to determine whether eribulin ± trastuzumab therapy may be a potential option for first-line treatment in some patients with metastatic breast cancer who were recently treated in the neoadjuvant setting. TRIAL REGISTRATION: NCT01268150 (December 29, 2010), NCT01269346 (January 4, 2011).

Porous Nanocomposite Comprising Ultralong Hydroxyapatite Nanowires Decorated with Zinc-Containing Nanoparticles and Chitosan: Synthesis and Application in Bone Defect Repair.

Hydroxyapatite nanowires exhibit a great potential in biomedical applications owing to their high specific surface area, high flexibility, excellent mechanical properties, and similarity to mineralized collagen fibrils of natural bone. In this work, zinc-containing nanoparticle-decorated ultralong hydroxyapatite nanowires (Zn-UHANWs) with a hierarchical nanostructure have been synthesized by a one-step solvothermal method. The highly flexible Zn-UHANWs exhibit a hierarchical rough surface and enhanced specific surface area as compared with ultralong hydroxyapatite nanowires (UHANWs). To evaluate the potential application of Zn-UHANWs in bone regeneration, the biomimetic Zn-UHANWs/chitosan (CS) (Zn-UHANWs/CS) composite porous scaffold with 80 wt % Zn-UHANWs was prepared by incorporating Zn-UHANWs into the chitosan matrix by the freeze-drying process. The as-prepared Zn-UHANWs/CS composite porous scaffold exhibits enhanced mechanical properties, highly porous structure, and excellent water retention capacity. In addition, the Zn-UHANWs/CS porous scaffold has a good biodegradability with the sustainable release of Zn, Ca, and P elements in aqueous solution. More importantly, the Zn-UHANWs/CS porous scaffold can promote the osteogenic differentiation of rat bone marrow derived mesenchymal stem cells and facilitate in vivo bone regeneration as compared with the pure CS porous scaffold or UHANWs/CS porous scaffold. Thus, both the Zn-UHANWs and Zn-UHANWs/CS porous scaffold developed in this work are promising for application in bone defect repair.

The Superior Glenohumeral Joint Capsule Alone Does Not Prevent Superior Translation of the Humeral Head: An In Vitro Biomechanical Study.

PURPOSE: To answer 2 questions: What is the main structure that prevents the superior translation of the humeral head, the supraspinatus or the superior capsule (SC)? And what mechanism does the principal structure rely on to prevent the superior translation of the humeral head, the spacer effect or the tensional hammock effect? METHODS: Eight shoulder specimens were assessed using a custom biomechanical testing system. Glenohumeral superior translation and subacromial peak pressure were compared using 6 models: the intact joint model, supraspinatus dysfunction model, supraspinatus defect model, SC tear model, SC defect model, and irreparable rotator cuff tear (IRCT) model. RESULTS: Compared with the intact joint model, the supraspinatus defect model significantly increased the superior translation (by 2.6 mm; P < .001) and subacromial peak pressure (by 0.43 MPa; P = .013) at 0° glenohumeral abduction, while the SC defect model unremarkably altered the superior translation at 0° (by 0.6 mm; P = .582) and 45° (by 0.3 mm; P = .867) of glenohumeral abduction and the subacromial peak pressure at 0° (by 0.11 MPa; P = .961), 30° (by -0.03 MPa; P = .997), and 45° (by -0.33 MPa; P = .485) of glenohumeral abduction. The supraspinatus dysfunction model significantly increased the superior translation at 0° (by 1.7 mm; P < .001), 30° (by 1.2 mm; P = .005), and 45° (by 0.8 mm; P = .026) of glenohumeral abduction, but not the subacromial peak pressure compared with the intact joint model. However, no significant differences were found between the supraspinatus defect model and the supraspinatus dysfunction model with respect to the superior translation or subacromial peak pressure (all P > .05). CONCLUSIONS: The anatomic SC has a negligible role in preventing the superior translation of the humeral head. CLINICAL RELEVANCE: SC reconstruction is not a simple anatomic reconstruction, and its promising clinical outcome may be due to tensional fixation technique and choice of graft.

Platelet-Rich Plasma-Loaded Poly(d,l-lactide)-Poly(ethylene glycol)-Poly(d,l-lactide) Hydrogel Dressing Promotes Full-Thickness Skin Wound Healing in a Rodent Model.

Traditional therapeutic methods for skin wounds have many disadvantages, and new wound dressings that can facilitate the healing process are thus urgently needed. Platelet-rich plasma (PRP) contains multiple growth factors (GFs) and shows a significant capacity to heal soft tissue wounds. However, these GFs have a short half-life and deactivate rapidly; we therefore need a sustained delivery system to overcome this shortcoming. In this study, poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA: PLEL) hydrogel was successfully created as delivery vehicle for PRP GFs and was evaluated systematically. PLEL hydrogel was injectable at room temperature and exhibited a smart thermosensitive in situ gel-formation behavior at body temperature. In vitro cell culture showed PRP-loaded PLEL hydrogel (PRP/PLEL) had little cytotoxicity, and promoted EaHy926 proliferation, migration and tube formation; the factor release assay additionally indicated that PLEL realized the controlled release of PRP GFs for as long as 14 days. When employed to treat rodents' full-thickness skin defects, PRP/PLEL showed a significantly better ability to raise the number of both newly formed and mature blood vessels compared to the control, PLEL and PRP groups. Furthermore, the PRP/PLEL-treated group displayed faster wound closure, better reepithelialization and collagen formation. Taken together, PRP/PLEL provides a promising strategy for promoting angiogenesis and skin wound healing, which extends the potential of this dressing for clinical application.

Prevalence of bilateral Discoid Lateral Menisci (DLM) in patients operated for symptomatic DLM with a follow-up study on their asymptomatic contralateral knees: a Magnetic Resonance Imaging (MRI) assessment.

BACKGROUND: The purpose was to investigate prevalence of bilateral discoid lateral menisci (DLM) in Han Chinese patients who received surgery for symptomatic DLM, as well as a follow-up study of their asymptomatic contralateral knees using magnetic resonance imaging (MRI). METHODS: A total of 110 patients [50 males and 60 females; average age: 21.95 ± 12.77 years (range: 6 to 67 years)] admitted to our hospital with symptomatic DLM were treated with arthroscopic surgery. The contralateral asymptomatic knees were evaluated for DLM by MRI. Postoperative clinical evaluation was performed using the Lysholm knee scoring scale and International Knee Documentation Committee subjective knee evaluation. RESULTS: Eighty (72.73%) of 110 symptomatic DLM patients had bilateral DLM, of which 68 (85%) were of homotype (same type). Fourteen of 80 bilateral DLM patients were symptomatic and received operations in both knees. Twelve of remaining 66 bilateral DLM patients with asymptomatic one knee underwent a second arthroscopic surgery as their asymptomatic knees became symptomatic over the five-year interim. Of these 12 cases, seven exhibited no shift and five showed posterocentral meniscal shift. Furthermore, at least two cases showed progression from asymptomatic grade II to symptomatic grade III over the interim. All patients showed significant improvement after surgery. CONCLUSIONS: The bilateral DLM rate of Han Chinese patients with symptomatic DLM was relatively high at 72.7 %, and 85 % of those were of homotype.

Apixaban with antiplatelet therapy after acute coronary syndrome.

BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats.

BACKGROUND: Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study. METHODS: Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats. RESULTS: We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence. CONCLUSION: In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.

Adipose-derived stem cell-based optimization strategies for musculoskeletal regeneration: recent advances and perspectives.

Musculoskeletal disorders are the leading causes of physical disabilities worldwide. The poor self-repair capacity of musculoskeletal tissues and the absence of effective therapies have driven the development of novel bioengineering-based therapeutic approaches. Adipose-derived stem cell (ADSC)-based therapies are being explored as new regenerative strategies for the repair and regeneration of bone, cartilage, and tendon owing to the accessibility, multipotency, and active paracrine activity of ADSCs. In this review, recent advances in ADSCs and their optimization strategies, including ADSC-derived exosomes (ADSC-Exos), biomaterials, and genetic modifications, are summarized. Furthermore, the preclinical and clinical applications of ADSCs and ADSC-Exos, either alone or in combination with growth factors or biomaterials or in genetically modified forms, for bone, cartilage, and tendon regeneration are reviewed. ADSC-based optimization strategies hold promise for the management of multiple types of musculoskeletal injuries. The timely summary and highlights provided here could offer guidance for further investigations to accelerate the development and clinical application of ADSC-based therapies in musculoskeletal regeneration.