Fabrication and properties of PLA/ß-TCP scaffolds using liquid crystal display (LCD) photocuring 3D printing for bone tissue engineering.

Introduction: Bone defects remain a thorny challenge that clinicians have to face. At present, scaffolds prepared by 3D printing are increasingly used in the field of bone tissue repair. Polylactic acid (PLA) has good thermoplasticity, processability, biocompatibility, and biodegradability, but the PLA is brittle and has poor osteogenic performance. Beta-tricalcium phosphate (ß-TCP) has good mechanical properties and osteogenic induction properties, which can make up for the drawbacks of PLA. Methods: In this study, photocurable biodegradable polylactic acid (bio-PLA) was utilized as the raw material to prepare PLA/ß-TCP slurries with varying ß-TCP contents (ß-TCP dosage at 0%, 10%, 20%, 30%, 35% of the PLA dosage, respectively). The PLA/ß-TCP scaffolds were fabricated using liquid crystal display (LCD) light-curing 3D printing technology. The characterization of the scaffolds was assessed, and the biological activity of the scaffold with the optimal compressive strength was evaluated. The biocompatibility of the scaffold was assessed through CCK-8 assays, hemocompatibility assay and live-dead staining experiments. The osteogenic differentiation capacity of the scaffold on MC3T3-E1 cells was evaluated through alizarin red staining, alkaline phosphatase (ALP) detection, immunofluorescence experiments, and RT-qPCR assays. Results: The prepared scaffold possesses a three-dimensional network structure, and with an increase in the quantity of ß-TCP, more ß-TCP particles adhere to the scaffold surface. The compressive strength of PLA/ß-TCP scaffolds exhibits a trend of initial increase followed by decrease with an increasing amount of ß-TCP, reaching a maximum value of 52.1 MPa at a 10% ß-TCP content. Degradation rate curve results indicate that with the passage of time, the degradation rate of the scaffold gradually increases, and the pH of the scaffold during degradation shows an alkaline tendency. Additionally, Live/dead staining and blood compatibility experiments suggest that the prepared PLA/ß-TCP scaffold demonstrates excellent biocompatibility. CCK-8 experiments indicate that the PLA/ß-TCP group promotes cell proliferation, and the prepared PLA/ß-TCP scaffold exhibits a significant ability to enhance the osteogenic differentiation of MC3T3-E1 cells in vitro. Discussion: 3D printed LCD photocuring PLA/ß-TCP scaffolds could improve surface bioactivity and lead to better osteogenesis, which may provide a unique strategy for developing bioactive implants in orthopedic applications.

Hi-MGT: A hybrid molecule graph transformer for toxicity identification.

Conventional toxicity testing methods that rely on animal experimentation are resource-intensive, time-consuming, and ethically controversial. Therefore, the development of alternative non-animal testing approaches is crucial. This study proposes a novel hybrid graph transformer architecture, termed Hi-MGT, for the toxicity identification. An innovative aggregation strategy, referred to as GNN-GT combination, enables Hi-MGT to simultaneously and comprehensively aggregate local and global structural information of molecules, thus elucidating more informative toxicity information hidden in molecule graphs. The results show that the state-of-the-art model outperforms current baseline CML and DL models on a diverse range of toxicity endpoints and is even comparable to large-scale pretrained GNNs with geometry enhancement. Additionally, the impact of hyperparameters on model performance is investigated, and a systematic ablation study is conducted to demonstrate the effectiveness of the GNN-GT combination. Moreover, this study provides valuable insights into the learning process on molecules and proposes a novel similarity-based method for toxic site detection, which could potentially facilitate toxicity identification and analysis. Overall, the Hi-MGT model represents a significant advancement in the development of alternative non-animal testing approaches for toxicity identification, with promising implications for enhancing human safety in the use of chemical compounds.

Clinical features and therapeutic outcomes of alveolar soft part sarcoma in children: A single-center, retrospective study.

Background: Alveolar soft part sarcoma (ASPS) is a rare sarcoma that has been shown to be highly effective to antiangiogenic agents and immune checkpoint inhibitors, but most reported studies about ASPS were concentrated on adult population. In this study, we aimed to describe the clinical features and therapeutic outcomes of ASPS in children. Methods: We retrospectively reviewed the records of patients with ASPS in our institution since Jan 2015. All patients included in this study were pathologically confirmed ASPS and aged under 12 years at the time of initial diagnosis. Demographic characteristics, tumor sizes, primary tumor sites, metastasis, treatments used, therapeutic responses and survivals were evaluated. Results: We identified a total of 56 patients to be initially diagnosed as ASPS since Jan 2015. A predisposition of high occurrence in head and neck (32.1%) was observed (versus 41.1% in limbs and 21.4% in trunk). 26 (46.4%) patients developed metastasis at the time of diagnosis or during follow-up. Tumors in tongue, pharynx and larynx had the least likelihood to metastasize (7.7%, P<0.05). Observation was recommended for 15 stage IV patients with only pulmonary metastasis. 7 (46.7%) patients remained stable until last follow up. The 1-year PFS rate was 83.3% and median progression-free survival time (PFS) was 29.4 months. 15 patients with progressive disease received mono or combined therapy. 11 patients received PD-1 monotherapy. 2 patients achieved partial response and 5 stable disease. The overall response rate was 18.2%. The median PFS of this group was 22.0 months, and the 1-year PFS rate was 70.0%. 4 patients received a combination therapy of PD-1 inhibitors plus tyrosine kinase inhibitors. All of them remained stable. No disease-related death occurred during follow-up. Conclusions: ASPS exhibits a higher occurrence in head and neck in children. ASPS originating from glossopharyngeal region tends to have a lower metastasis rate. ASPS displays a more indolent growth pattern in children, which makes observation a preferable choice for children with sole pulmonary metastasis. Pediatric ASPS appears to be less effective to targeted therapy and immunotherapy than adults. The treatment of progressive ASPS in children remains challenging.

Efficacy of PD-1 inhibitors combined with pegylated liposomal doxorubicin and dacarbazine compared with liposomal doxorubicin and dacarbazine in advanced leiomyosarcoma patients: a retrospective, single-institutional cohort study.

Background: PD-1 inhibitor monotherapy is ineffective for metastatic leiomyosarcoma (LMS), but it remains unclear whether PD-1 inhibitors demonstrate any efficacy when combined with chemotherapy. This study retrospectively evaluated pegylated liposomal doxorubicin (PLD) and dacarbazine (DTIC) with/without PD-1 inhibitors for advanced/metastatic LMS patients treated in our single institution. Methods: The inclusion criteria were a confirmed histological diagnosis of LMS, treatment between January 2020 and March 2022, measurable disease (evaluated by CT or MRI), an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and age ≥18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Results: A total of 41 patients were included in this study, among whom 21 received PLD and DTIC alone while 20 received PLD and DTIC with PD-1 inhibitors. There were no differences of clinical characteristics between the two groups. Although the chemo plus PD-1 group had a better ORR (30% vs. 4.8%, P=0.04), there were no benefits in terms of disease control rate (DCR) (80% vs. 66.7%, P=0.29), PFS (8.8 months, 95% CI: 4.57-13.0 vs. 6.1 months, 95% CI: 3.03-9.14, P=0.54), and OS (not reached in both groups, P=0.84) when compared to chemo alone. Multiple treatment lines and previous use of tyrosine kinase inhibitors (TKIs) seemed to be negative factors for PFS in the univariate analysis, but failed to be significant in the multivariate analysis. Conclusions: This retrospective, single-institutional study showed that PD-1 inhibitors combined with standard PLD and DTIC chemotherapy failed to exert benefits on survival for LMS patients. Considering the small sample size and retrospective clinical research design, further explorations are needed to verify the conclusion.

Phase II Study of TQB2450, a Novel PD-L1 Antibody, in Combination with Anlotinib in Patients with Locally Advanced or Metastatic Soft Tissue Sarcoma.

PURPOSE: To explore the efficacy and safety of TQB2450 combined with anlotinib in patients with locally advanced or metastatic soft-tissue sarcoma (LA/M STS). PATIENTS AND METHODS: This was a single arm phase II study (TQB2450-Ib-02 study) performed at two hospitals in China to assess the potency of TQB2450 combined with anlotinib in patients with LA/M STS. Patients were previously unresponsive to at least one chemotherapy regimen. Anlotinib (12 mg every day) was administered orally from day 1 to day 14 every 3 weeks. TQB2450 was administered by intravenous infusion at 1,200 mg on day 1 every 3 weeks. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. RESULTS: Between January 2019 and June 2020, 30 patients were enrolled. The ORR was 36.67% and the DCR was 76.67%. The median PFS was 7.85 months [95% confidence interval (CI), 2.89-23.06] and the median OS was not reached [95% CI, 10.58-not estimable (NE)]. Among the patients with alveolar soft part sarcoma (ASPS; 12/30, 40%), the ORR was 75% and the median PFS was 23.06 months (95% CI, 8.97-NE). The most common treatment related adverse events were hypothyroidism (76.67%), hypertriglyceridemia (63.33%), hypercholesterolemia (60.00%), and elevated blood lactate dehydrogenase (53.33%). CONCLUSIONS: The study showed the promising activity in patients with ASPS, also indicating the trend of treatment efficacy in other sarcomas. The toxicity was tolerable. More studies with larger sample size and controlled arm were warranted.

The efficacy of 99mTc-rituximab as a tracer for sentinel lymph node biopsy in cutaneous melanoma patients.

Background: The sentinel lymph node (SLN) status is a vital prognostic factor for malignant melanoma (MM) patients. There is increasing evidence that a radioactive agent, rather than its combination with blue dye, is sufficient for a SLN biopsy (SLNB). Thus, we discussed the efficacy of 99mTc-rituximab as a tracer in MM patients. Methods: A total of 502 consecutive patients with MM who underwent SLNB were enrolled in this study. All participants were peritumorally injected with 99mTc-rituximab before imaging, and scanned with single-photon emission computed tomography-computed tomography (SPECT-CT) to detect the number and location of the SLN. A gamma detection probe was employed to detect radioactive SLNs in operation. Follow up was conducted to observe whether nodal or distant recurrence occurred. Results: The SLNs were successfully imaged via SPECT-CT and harvested from all 502 participants. No drainage tube was indwelled and 32 (6.3%) participants experienced the following complications: seroma (n=26, 5.2%), wound infections or lymphangitis (n=6, 1.2%), sensory nerve injuries (n=4, 0.8%). There were 380 patients who were diagnosed as SLN-negative and 122 (24.2%) were SLN-positive. A total of 85 SLN-positive patients received complete lymph node dissection, and 28 (32.9%) had additional positive lymph nodes. During a median follow-up of 24 months, 28 participants were found to have a false negative (FN) SLN. The FN rate was 18.7%. A higher T stage was a predictive factor for FN [odds ratio (OR) 1.77; P<0.05]. There was no significant difference in the positive or FN rate between the acral and cutaneous groups. Conclusions: The radiopharmaceutical 99mTc-rituximab could be employed as a simple and safe tracer in acral and cutaneous melanoma SLN biopsies.

Real-world experience with pembrolizumab in patients with advanced soft tissue sarcoma.

BACKGROUND: The goal of this study was to retrospectively analyze the efficacy and safety of pembrolizumab in the real-world treatment of soft tissue sarcoma (STS). METHODS: We analyzed 38 patients who suffered from STS and received pembrolizumab treatment from July 2017 to December 2018 in our hospital. We investigated the influence of clinical characteristics, treatment timing, and treatment protocol on objective response rate (ORR). We also investigated the factors affecting overall survival (OS) and progression-free survival (PFS), as well as the occurrence of severe adverse events (SAEs). RESULTS: The overall ORR was 19.4% (7/36). The ORRs of patients who received pembrolizumab treatment as first-line, second-line, and third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). Four patients (11.1%) maintained a complete response (CR) or partial response (PR) for at least 6 months with pembrolizumab monotherapy, or after withdrawal of chemotherapy or targeted therapy regimens. The median PFS was 2.9 months [95% confidence interval (CI): 2.4-3.4 months] and the median OS was 12.0 months (95% CI: 10.2-13.8 months). Cox regression analysis showed that treatment time was an independent factor affecting PFS (P=0.041), while Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was the only independent factor affecting OS (P=0.028). CONCLUSIONS: In the real world, the effectiveness of pembrolizumab in the treatment of STS was low. Some subtypes showed a limited response to pembrolizumab, including alveolar soft part sarcoma (ASPS), undifferentiated pleomorphic sarcoma (UPS), exoskeletal chondrosarcoma (ESCS), and angiosarcoma (AS), while the response in leiomyosarcoma (LMS) was low. Combination therapy may increase the risk of SAEs, especially when combined with pazopanib.

Target therapy for metastatic alveolar soft part sarcoma: a retrospective study with 47 cases.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a translocation-associated soft-tissue tumor resistant to conventional cytotoxic agents. This report aims to compare the efficacy of anlotinib versus pazopanib as targeted monotherapy in metastatic ASPS and to determine the impact of drug dosage reduction on disease control. METHODS: Sixteen and 31 patients with metastatic ASPS were respectively treated with anlotinib and pazopanib monotherapy at a single institution. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were retrieved and compared between both therapeutic arms. Adverse events (AEs) within each group were recorded. Kaplan-Meier survivorship curves computed the impact of drug dosage reduction on PFS. RESULTS: The anlotinib group showed an ORR of 31.2%, compared to 35.5% in the pazopanib arm (P=0.772). Median PFS was 23.6 months [95% confidence interval (CI), 16.2-31.0 months] in patients treated with anlotinib, but dropped to 13.7 months (95% CI, 10.8-16.7 months) in those managed with pazopanib (P=0.023). One (6.3%) patient on anlotinib and 11 (35.5%) on pazopanib developed AEs requiring drug dosage reduction (P=0.029), which significantly reduced patients' PFS in the latter setting (10.5 vs. 15.8 months, P=0.012). In patients without dosage reduction, anlotinib showed a bordering advantage than pazopanib on median PFS (24.5 vs. 15.8 months, P=0.112). CONCLUSIONS: Compared to pazopanib, anlotinib yielded longer PFS and lower incidence of AEs in ASPS patients. Drug dosage reduction was more frequently encountered with the former agent and affected the disease control.

KIF18B promotes tumor progression in osteosarcoma by activating ß-catenin.

Objective: Osteosarcoma is a common primary highly malignant bone tumor. Kinesin family member 18B (KIF18B) has been identified as a potential oncogene involved in the development and metastasis of several cancer types. While KIF18B overexpression in osteosarcoma tissue is clearly detected, its specific function in the disease process remains to be established. Methods:KIF18B expression was assessed in osteosarcoma tissues and cells. We additionally evaluated the effects of KIF18B on proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. Results: Our results showed overexpression of KIF18B in osteosarcoma tissues and cells. Knockdown of KIF18B induced G1/S phase arrest and significantly inhibited proliferation, migration, and invasion of osteosarcoma cells, both in vitro and in vivo. KIF18B regulated ß-catenin expression at the transcriptional level by controlling nuclear aggregation of ATF2 and at the post-transcriptional level by interacting with the adenomatous polyposis coli (APC) tumor suppressor gene in osteosarcoma cells. Conclusions: KIF18B plays a carcinogenic role in osteosarcoma by regulating expression of ß-catenin transcriptionally via decreasing nuclear aggregation of ATF2 or post-transcriptionally through interactions with APC. Our collective findings support the potential utility of KIF18B as a novel prognostic biomarker for osteosarcoma.

Correction: Yan, Y.; et al. Building Extraction Based on an Optimized Stacked Sparse Autoencoder of Structure and Training Samples Using LIDAR DSM and Optical Images. Sensors 2017, 17, 1957.

The authors wish to make the following corrections to this paper [1]:[...].

Building Extraction Based on an Optimized Stacked Sparse Autoencoder of Structure and Training Samples Using LIDAR DSM and Optical Images.

In this paper, a building extraction method is proposed based on a stacked sparse autoencoder with an optimized structure and training samples. Building extraction plays an important role in urban construction and planning. However, some negative effects will reduce the accuracy of extraction, such as exceeding resolution, bad correction and terrain influence. Data collected by multiple sensors, as light detection and ranging (LIDAR), optical sensor etc., are used to improve the extraction. Using digital surface model (DSM) obtained from LIDAR data and optical images, traditional method can improve the extraction effect to a certain extent, but there are some defects in feature extraction. Since stacked sparse autoencoder (SSAE) neural network can learn the essential characteristics of the data in depth, SSAE was employed to extract buildings from the combined DSM data and optical image. A better setting strategy of SSAE network structure is given, and an idea of setting the number and proportion of training samples for better training of SSAE was presented. The optical data and DSM were combined as input of the optimized SSAE, and after training by an optimized samples, the appropriate network structure can extract buildings with great accuracy and has good robustness.