Correlation analysis between BRAFV600E mutation and ultrasonic and clinical features of papillary thyroid cancer.

Purpose: The study investigates the value of the BRAFV600E mutation in determining the aggressiveness of papillary thyroid cancer (PTC) and its correlation with ultrasound features. Methods: The study selected 176 patients with BRAFV600E mutation and 80 without the mutation who underwent surgery at Guangxi Medical University Cancer Hospital. Clinical and pathological data were collected, focusing on BRAFV600E mutations and associated ultrasonic features. Correlation analysis, as well as univariate and multivariate logistic regression analysis, were conducted to identify independent risk factors for BRAFV600E mutation. The results were verified using a nomogram model. Results: The analysis results indicate that the BRAFV600E mutation correlates with tumor size, nodule size, taller-than-wide shape, margin, and shape of papillary thyroid cancer. The receiver operating characteristic curve was used to analyze the diagnostic effect of these features on BRAFV600E mutation. The results showed that nodule size had the most significant area under the curve (AUC = 0.665). Univariate and multivariate logistic regression analyses revealed that taller-than-wide shape ≥1, ill-defined margin, irregular shape, nodule size (≤1.40 cm), TT4 (>98.67 nmol/L), and FT3 (<4.14 pmol/L) were independent risk factors for BRAFV600E mutation. While considering all these factors in the nomogram, the Concordance index (C-index) remained high at 0.764. This suggests that the model has a good predictive effect. Conclusion: Ultrasound features including nodule size, taller-than-wide shape ≥1, ill-defined margins, irregular shape, higher TT4 levels, and lower FT3 levels were associated with papillary thyroid cancer aggressiveness and BRAFV600E mutation.

Deep learning system for malignancy risk prediction in cystic renal lesions: a multicenter study.

OBJECTIVES: To develop an interactive, non-invasive artificial intelligence (AI) system for malignancy risk prediction in cystic renal lesions (CRLs). METHODS: In this retrospective, multicenter diagnostic study, we evaluated 715 patients. An interactive geodesic-based 3D segmentation model was created for CRLs segmentation. A CRLs classification model was developed using spatial encoder temporal decoder (SETD) architecture. The classification model combines a 3D-ResNet50 network for extracting spatial features and a gated recurrent unit (GRU) network for decoding temporal features from multi-phase CT images. We assessed the segmentation model using sensitivity (SEN), specificity (SPE), intersection over union (IOU), and dice similarity (Dice) metrics. The classification model's performance was evaluated using the area under the receiver operator characteristic curve (AUC), accuracy score (ACC), and decision curve analysis (DCA). RESULTS: From 2012 to 2023, we included 477 CRLs (median age, 57 [IQR: 48-65]; 173 men) in the training cohort, 226 CRLs (median age, 60 [IQR: 52-69]; 77 men) in the validation cohort, and 239 CRLs (median age, 59 [IQR: 53-69]; 95 men) in the testing cohort (external validation cohort 1, cohort 2, and cohort 3). The segmentation model and SETD classifier exhibited excellent performance in both validation (AUC = 0.973, ACC = 0.916, Dice = 0.847, IOU = 0.743, SEN = 0.840, SPE = 1.000) and testing datasets (AUC = 0.998, ACC = 0.988, Dice = 0.861, IOU = 0.762, SEN = 0.876, SPE = 1.000). CONCLUSION: The AI system demonstrated excellent benign-malignant discriminatory ability across both validation and testing datasets and illustrated improved clinical decision-making utility. CRITICAL RELEVANCE STATEMENT: In this era when incidental CRLs are prevalent, this interactive, non-invasive AI system will facilitate accurate diagnosis of CRLs, reducing excessive follow-up and overtreatment. KEY POINTS: The rising prevalence of CRLs necessitates better malignancy prediction strategies. The AI system demonstrated excellent diagnostic performance in identifying malignant CRL. The AI system illustrated improved clinical decision-making utility.

Nomogram to predict prognosis of head and neck rhabdomyosarcoma patients in children and adolescents.

Purpose: This study aims to explore the prognostic factors of head and neck rhabdomyosarcoma (HNRMS) in children and adolescents and construct a simple but reliable nomogram model for estimating overall survival (OS) of patients. Methods: Data of all HNRMS patients during 2004-2018 were identified from the Surveillance, Epidemiology, and End Result database. Kaplan-Meier method was performed to calculate OS stratified by subgroups and comparison between subgroups was completed by log-rank test. Univariate and multivariate Cox regressions analysis were employed for identifying independent predictors, which subsequently were used for a predictive model by R software, and the efficacy of the model was evaluated by applying receiver operating curve (ROC), calibration and decision curve analysis (DCA). Results: A total of 446 patients were included in the study. The 1-, 3-, and 5-year OS rate of the whole cohort was 90.6%, 80.0%, and 75.5%, respectively. The results of univariate and multivariate Cox regression analysis indicated that the primary site in parameningeal region, alveolar RMS histology, M1 stage, IRS stage 4, surgery, and chemotherapy were significant prognostic factors (all P<0.05). The performance of nomogram model was validated by discrimination and calibration, with AUC values of 1, 3, and 5 years OS of 0.843, 0.851, and 0.890, respectively. Conclusion: We constructed a prognostic nomogram model for predicting the OS in HNRMS patients in children and adolescents and this model presented practical and applicable clinical value to predict survival when choosing treatment strategies.

NR5A2 gene affects the overall survival of LUAD patients by regulating the activity of CSCs through SNP pathway by OCLR algorithm and immune score.

Objective: Differentially expressed genes (DEGs) in lung adenocarcinoma (LUAD) tumor stem cells were screened, and the biological characteristics of NR5A2 gene were investigated. Methods: The expression and prognosis of NR5A2 in human LUAD were predicted and analyzed through bioinformatics analysis from a human cancer database. Gene expression and clinical data of LUAD tumor and normal lung tissues were obtained from The Cancer Genome Atlas (TCGA) database, and DEGs associated with lung cancer tumor stem cells (CSCs) were screened. Univariate and multivariate Cox regression models were used to screen and establish prognostic risk prediction models. The immune function of the patients was scored according to the model, and the relative immune functions of the high- and low-risk groups were compared to determine the difference in survival prognosis between the two groups. In addition, we calculated the index of stemness based on the transcriptome of the samples using one-class linear regression (OCLR). Results: Bioinformatics analysis of a clinical cancer database showed that NR5A2 was significantly decreased in human LUAD tissues than in normal lung tissues, and the decrease in NR5A2 gene expression shortened the overall survival and progression-free survival of patients with LUAD. Conclusion: The NR5A2 gene may regulate LUAD tumor stem cells through selective splicing mutations, thereby affecting the survival and prognosis of patients with lung cancer, and the NR5A2 gene may regulate CSCs through single nucleotide polymorphism.

Effect of bi-enzyme hydrolysis on the properties and composition of hydrolysates of Manchurian walnut dreg protein.

Walnut dreg (WD) active peptides are an important source of dietary antioxidants; however, the products of conventional hydrolysis have limited industrial output owing to poor flavour and low bioactivity. To this end, in this study, we aimed to employ bvLAP, an aminopeptidase previously identified in our research, as well as commercially available Alcalase for bi-enzyme digestion. The flavour, antioxidant activity, and structures of products resulting from various digestion methods were compared. The results showed that the bi-enzyme digestion products had enhanced antioxidant activity, increased ß-sheet content, and reduced bitterness intensity from 9.65 to 6.93. Moreover, bi-enzyme hydrolysates showed a more diverse amino acid composition containing 1640 peptides with distinct sequences. These results demonstrate that bi-enzyme hydrolysis could be a potential process for converting WD into functional food ingredients. Additionally, our results provide new concepts that can be applied in waste processing and high-value utilisation of WD.

Biochemical component analysis of human myopic corneal stroma using the Raman spectrum.

PURPOSE: This study aimed to measure the Raman spectrum of the human corneal stroma lens obtained from small incision lenticule extraction surgery (SMILE) in Asian myopic eyes using a confocal Raman micro-spectrometer built in the laboratory. METHODS: Forty-three myopic patients who underwent SMILE with equivalent diopters between - 4.00 and - 6.00 D were selected, and the right eye data were collected. Corneal stroma lenses were obtained during surgery, and the Raman spectra were measured after air drying. The complete Raman spectrum of human myopic corneal stroma lens tissue was obtained within the range of 700-4000 cm-1. RESULTS: Thirteen characteristic peaks were found, with the stronger peaks appearing at 937 cm-1, corresponding to proline, valine, and the protein skeleton of the human myopic corneal stroma lens; 1243 cm-1, corresponding to collagen protein; 1448 cm-1, corresponding to the collagen protein and phospholipids; and 2940 cm-1, corresponding to the amino acid and lipids, which was the strongest Raman peak. CONCLUSION: These results demonstrated that Raman spectroscopy has much potential as a fast, cost-effective, and reliable diagnostic tool in the diagnosis and treatment of eye diseases, including myopia, keratoconus, and corneal infection.

Nasofacial Groove Pedicled Flap for the Reconstruction of Lateral Alar Defect.

BACKGROUND: The repair of nasal alar defects is challenging for plastic surgeons, and there is currently no standard operation. Herein, the authors reported the clinical outcomes of a nasofacial groove pedicled flap for the reconstruction of alar defect. METHODS: This retrospective study included patients who underwent the nasofacial groove pedicled flap for the reconstruction of alar defect between January 2018 and June 2020. Photographs of standard facial postures were taken before and after surgery to record the surgical results of the patients. The patient's medical history was reviewed retrospectively. Self-reported satisfaction of patients on scar morphology and reconstructive effect were evaluated with a questionnaire survey. RESULTS: There were 26 eligible patients enrolled, and all patients were followed up for more than 1 year after surgery. All flaps were free of ischemia and necrosis and healed well. No patient experienced restricted nostril ventilation. Eight patients underwent reoperation to trim the flap pedicle and the scar. Eight patients (8/26) reported "very satisfied," and 17 patients (17/26) reported "satisfied" with the repair effect and scar morphology. One patient went through multiple laser treatments to improve her scars but still remained visible hyperpigmentation. She was dissatisfied with postoperative flap pigmentation but was satisfied with the correction effect. CONCLUSIONS: The clinical results indicated that the nasal groove flap was safe for the treatment of the lateral alar defect, and the patients were satisfied with the clinical results. The authors believe that this flap can be used as an alternative method for repairing the lateral alar defect. LEVEL OF EVIDENCE: Level -IV, therapeutic study.

Curcumin Inhibits Bladder Cancer by Inhibiting Invasion via AKT/MMP14 Pathway.

BACKGROUND: Bladder cancer is a malignant tumor of the urinary and reproductive tract that seriously threatens human health. It is urgent to develop new drugs for bladder cancer. This study aims to explore whether curcumin could inhibit bladder cancer and the potential mechanism. METHODS: Firstly, network pharmacology was applied to explore the potential target of curcumin in bladder cancer. Among the potential target of curcumin on bladder cancer, the role of matrix metalloproteinase-14 (MMP14) was further explored by bioinformatic analysis and the expression of MMP14 was confirmed by immunohistochemistry staining. The effect of curcumin on bladder cancer was then studied using the cell counting kit-8 (CCK-8) assay, clone formation assay, apoptosis assay, and Transwell assay. Finally, AKT, MMP14, E-cadherin and N-cadherin were analyzed by Western blot assay to confirm whether curcumin could inhibit bladder cancer by inhibiting invasion via AKT/MMP14 pathway. RESULTS: In the present study, we found that the target of curcumin for bladder cancer includes signal transducer and activator of transcription 3 (STAT3), AKT, cyclin A2 (CCNA2), epidermal growth factor receptor (EGFR), E1A binding protein p300 (EP300) and MMP14. MMP14 was highly expressed in bladder cancer than in normal tissues and was associated with a worse prognosis (p < 0.05). Curcumin could inhibit the proliferation and migration of bladder cancer cells (p < 0.05), while promoting cell apoptosis by inhibiting the AKT/MMP14 pathway (p < 0.05). CONCLUSION: Curcumin could inhibit bladder cancer by inhibiting invasion through the AKT/MMP14 pathway.

Cathepsin V drives lung cancer progression by shaping the immunosuppressive environment and adhesion molecules cleavage.

Cathepsin V (CTSV) is a cysteine cathepsin protease that plays a crucial role in extracellular matrix degradation. CTSV is correlated with poor prognosis in various cancers, but the underlying mechanism remains elusive. Here, we observed that CSTV is upregulated in lung cancer and is a poor prognosis factor for lung cancer. CTSV acts as a driver in the metastasis of lung cancer both in vitro and in vivo. CTSV promotes lung cancer metastasis by downregulating adhesion molecules, including fibronectin, E-cadherin, and N-cadherin. Our data revealed that CTSV functions by mediating the fragmentation of fibronectin, E-cadherin, and N-cadherin in cleavage, remodeling the extracellular matrix (ECM). The rationally designed antibody targeting CTSV blocks its cleaving ability towards fibronectin, E-cadherin, and N-cadherin, suppressing migration and invasion. Furthermore, we found that CTSV expression is negatively correlated with immune cell infiltration and immune scores and inhibits T cell activity. Targeting CTSV with specific antibodies effectively suppressed lung cancer metastasis in a mouse model. Our study demonstrates the critical role of CTSV in the immunity and metastasis of lung cancer, suggesting that the CTSV-targeting approach is a promising strategy for lung cancer.

Engineered Nanovesicles Expressing Bispecific Single Chain Variable Fragments to Protect against SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in high morbidity and mortality rates worldwide. Although the epidemic has been controlled in many areas and numerous patients have been successfully treated, the risk of reinfection persists due to the low neutralizing antibody titers and weak immune response. To provide long-term immune protection for infected patients, novel bispecific CB6/dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (SIGN) nanovesicles (NVs) were constructed to target both the SARS-CoV-2 spike protein (S) and the DC receptors for virus neutralization and immune activation. Herein, we designed NVs expressing both CB6 and DC-SIGN single chain variable fragments (scFvs) on the surface to block SARS-CoV-2 invasion and activate DC function. Monophosphoryl lipid A (MPLA) was loaded into the CB6/DC-SIGN NVs as an adjuvant to promote this process. The CB6/DC-SIGN NVs prevented a pseudovirus expressing the S protein from infecting the target cells expressing high levels of angiotensin-converting enzyme 2 in vitro. Additionally, CB6/DC-SIGN NVs admixed with S-expressing pseudoviruses activated the DCs, which was promoted by the adjuvant MPLA loaded in the NVs. Using a mouse model, we also confirmed that the CB6/DC-SIGN NVs effectively improved the neutralizing antibody titer and inhibited the growth of tumors expressing the S protein after 3 weeks of treatment. This potential NV-based treatment not only exerts a blocking effect by binding the S protein in the short term but may also provide patients with long-term protection against secondary infections.

Effects of long-term blue light irradiation on carotenoid biosynthesis and antioxidant activities in Chinese cabbage (Brassica rapa L. ssp. pekinensis).

The aim of this study was to investigate the impact of long-term exposure to blue light-emitting diodes (LEDs) on the accumulation of indolic glucosinolates and carotenoids, as well as the plant growth and antioxidant activities in both orange and common Chinese cabbage (Brassica rapa L. ssp. pekinensis). Blue light treatment also induced higher ferric-reducing antioxidant power and 2,2-diphenyl-1-picrylhydrazyl by 20.66 % and 30.82 % and antioxidant enzyme activities catalase, peroxidase, superoxide dismutase, and the accumulation of non-enzymatic antioxidant substances (total phenols and total flavonoids) in the orange Chinese cabbage. Furthermore, long-term exposure to blue light had negative effects on the net photosynthetic rate and chlorophyll fluorescence levels. Meanwhile, blue light promoted accumulation of Indol-3-ylmethyl glucosinolate (I3M), ß-carotene, lutein and zeaxanthin due to the high expression of regulatory and biosynthetic genes of the above metabolic pathways. In particular, lycopene and ß-carotene content in orange Chinese cabbage increased by 60.14 % and 65.33 % compared to the ones in common line. The accumulation of carotenoid and increasing antioxidant levels in the orange cabbage line was influenced by long-term blue light irradiation, leading to better tolerance to low temperature and drought stresses. The up-regulation of transcription factors such as BrHY5-2, BrPIF4 and BrMYB12 may also contribute to the increased tolerance in orange Chinese cabbage to extreme environmental stresses. The BrHY5-2 gene could activate carotenoid biosynthetic genes and induce the accumulation of carotenoids. These findings suggested that long-term blue light irradiation could be a promising technique for increasing the nutrition value and enhancing tolerance to low temperature and drought stresses in Chinese cabbage.

The Association Between Serum Glutathione Peroxidase-3 Concentration and Risk of Acute Kidney Injury After Cardiac Surgery: A Nested Case-Control Study.

Oxidative stress has an integral role in the pathophysiology of cardiac surgery-associated acute kidney injury (CSA-AKI). Glutathione peroxidase 3 (GPx3) is an important antioxidant enzyme in circulation and is mainly secreted by the kidney. This study aimed to evaluate the relation between GPx3 protein and CSA-AKI. This study is a nested case-control study in Zhongshan Hospital affiliated with Fudan University. We examined serum samples from 80 CSA-AKI patients and 80 age- and gender-matched non-AKI patients who underwent cardiac surgery. AKI was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) 2012 criteria. We measured serum GPx3 concentration using the enzyme-linked immunosorbent assay. GPx3 ratio is the ratio of preoperative and 6 hours postoperative of GPx3 protein concentration. We applied dose-response relation analyses to odds ratio in different GPx3 ratio levels and integrated it into the logistic model to predict the risk of AKI. The receiver operating characteristic curve and area under the curve (AUC) was used to assess the prediction models. Postoperative serum GPx3 concentrations were significantly lower in the AKI group compared with the non-AKI group (1.78 ± 0.33 vs 2.03 ± 0.27, p <0.001). Malondialdehyde was higher in the AKI than in the non-AKI group (17.74 ± 8.65 vs 7.48 ± 4.59, p <0.001). The AKI risk increased in a dose-dependent manner, which was flat in the first half of the GPx3 ratio and then tended to be faster. The peaking odds ratio of CSA-AKI was 2.615 at the GPx3 ratio of 1.21 to 1.40. The AUC value to predict CSA-AKI only included the GPx3 ratio was 72.3%. After gradually integrating other covariates (body mass index, aortic crossclamp time, and cardiopulmonary bypass), the model showed an AUC of 82.6%. The serum GPx3 concentration was significantly lower in the CSA-AKI group. GPx3 ratio has a good predictive value for CSA-AKI, which may be a potential early diagnostic marker for AKI.

Robot-assisted thoracoscopic surgery for mediastinal tumours in children: a single-centre retrospective study of 149 patients.

OBJECTIVES: The purpose of this retrospective study was to summarize our experience in performing robot-assisted thoracoscopic surgery (RATS) for mediastinal tumours in children to investigate its safety and feasibility. METHODS: This retrospective study involved 149 patients with mediastinal tumours who were hospitalized in the Department of Thoracic Surgery of Beijing Children's Hospital, Capital Medical University, and underwent RATS for tumour resection from March 2021 to November 2022. Information on patient age, weight, tumour size, surgical incision selection, operative time, intraoperative bleeding, intraoperative complications, length of hospital stay, rate of conversion to thoracotomy and follow-up conditions were summarized. RESULTS: All 149 surgeries were successfully completed with no cases of mortality. There were 77 male and 72 female patients, with a mean age of 5.9 years (range: 6 months-16 years, 8 months) and a mean weight of 23.6 kg (8.0-72.0 kg). The mean maximum tumour diameter was 5.5 cm (2.0-12.0 cm), the mean operative time was 106.7 min (25.0-260.0 min), the mean intraoperative bleeding volume was 11.3 ml (1.0-400.0 ml) and the mean hospital stay was 7.2 days (4.0-14.0 days). All patients recovered well with no cases of tumour recurrence or mortality during the postoperative follow-up period (3-23 months). CONCLUSIONS: RATS is safe and feasible to apply in children with mediastinal tumours who are >6 months of age and weigh more than 8 kg in terms of short-term outcomes, but longer-term follow-up is needed to fully evaluate the benefits. For cases that are associated with greater surgical difficulty and risk, a comprehensive surgical plan should be fully prepared in advance of surgery.

Paenimyroides aestuarii gen. nov. sp. nov., a novel bacterium isolated from sediment in the Pearl River Estuary and reclassification of five Flavobacterium and four Myroides species.

An aerobic, Gram-negative, non-motile, yellow-to-orange pigmented and round bacterium, designated strain SCSIO 72103T, was isolated from sediment collected in the Pearl River Estuary, Guangdong Province, PR China and subjected to a polyphasic taxonomic study. Growth occurred at 20-37 °C (optimum, 28 °C), pH 6-8 (optimum, pH 7) and with 1-5.5% NaCl (optimum, 1-3 %). Comparative 16S rRNA gene analysis indicated that strain SCSIO 72103T had the highest similarities to Flavobacterium baculatum SNL9T (94.7 %) and Myroides aquimaris SW105T (94.2 %). Phylogenetic analysis based 16S rRNA gene sequences showed that strain SCSIO 72103T formed a single clade with M. aquimaris SW105T. Strain SCSIO 72103T contained iso-C15 : 0 as the major fatty acid and the predominant respiratory quinone was menaquinone MK-6. These characteristics are consistent with those of F. baculatum SNL9T and M. aquimaris SW105T. Phosphatidylethanolamine, most notably, unidentified aminolipid and unidentified aminophospholipid were major polar lipids. Strain SCSIO 72103T had a single circular chromosome of 2.96 Mb with a DNA G+C content of 35.1 mol%. The average nucleotide identity, average amino acid identity (AAI) and digital DNA-DNA hybridization values showed that the pairwise similarities between SCSIO 72103T and the type strains of F. baculatum SNL9T and M. aquimaris SW105T were 78.5-80.5 %, 79.0-81.4 % and 22.7-22.8 %, respectively. The AAI values between species in this clade and the type species of Flavobacterium and Myroides were below the 65 % threshold, indicating that these species belong to a novel genus. On the basis of phylogenetic, physiological and chemotaxonomic characteristics, strain SCSIO 72103T represents a new species of a novel genus, for which the name Paenimyroides aestuarii gen. nov. sp. nov. is proposed. The type strain is SCSIO 72103T (=KCTC 92043T=MCCC 1K06659T). It is also proposed that nine known species in the genera Flavobacterium and Myroides are reclassified as Paenimyroides species.

Transcriptome analysis reveals molecularly distinct subtypes in retinoblastoma.

Retinoblastoma is the most frequent intraocular malignancy in children. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using gene expression profiles, we demonstrate the existence of two major retinoblastoma subtypes that can be divided into six subgroups. Subtype 1 has higher expression of cone related genes and higher percentage of RB1 germline mutation. By contrast, subtype 2 tumors harbor more genes with ganglion/neuronal features. The dedifferentiation in subtype 2 is associated with stemness features including low immune infiltration. Gene Otology analysis demonstrates that immune response regulations and visual related pathways are the key molecular difference between subtypes. Subtype 1b has the highest risk of invasiveness across all subtypes. The recognition of these molecular subtypes shed a light on the important biological and clinical perspectives for retinoblastomas.

Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody.

Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients.

Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in colorectal cancer.

BACKGROUND: Chimeric antigen receptor (CAR) -T cell therapy is an efficient therapeutic strategy for specific hematologic malignancies. However, positive outcomes of this novel therapy in treating solid tumors are curtailed by the immunosuppressive tumor microenvironment (TME), wherein signaling of the checkpoint programmed death-1 (PD-1)/PD-L1 directly inhibits T-cell responses. Although checkpoint-targeted immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy. METHODS: We constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with an autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs. RESULTS: We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. PD-1-TREM2 scFv-secreting CAR-T cells resulted in highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Moreover, the PD-1-TREM2 scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life. CONCLUSIONS: Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.

Efficacy and safety of nab-paclitaxel plus platinum in non-small cell lung cancer: a meta-analysis.

Purpose: This meta-analysis was exerted in assessing the anticancer efficacy and safety of nab-paclitaxel (nab-P) when combined with platinum compound agents for therapy in patients with non-small cell lung cancer (NSCLC). Method: We systematically searched the following seven electronic databases: PubMed, Cochrane Library, Web of Science, Embase, CNKI, Wan Fang, and China Science and Technology Journal Data. Randomized comparative clinical [randomized controlled clinical trial (RCT)] studies on nab-P plus platinum and carboplatin or cisplatin in combination with conventional chemotherapy agents or traditional paclitaxel were searched. Results: A total of 19 RCT studies involving 6,011 patients were analyzed. The primary outcome includes the overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The secondary outcome includes adverse events (AEs). Nab-P combined with platinum (carboplatin/cisplatin) had a better ORR [odds ratio (OR) = 1.66, 95% confidence interval (CI) (1.34, 2.05), p < 0.001] and improved PFS [hazard ratio (HR) = 0.84, 95% CI: (0.74, 0.94), p = 0.01] and OS [HR = 0.86, 95% CI: (0.78, 0.96), p = 0.008] in NSCLC patients. ORR [OR = 2.18, 95% CI: (1.07, 4.43)], PFS [HR = 0.62, 95% CI: (0.40, 0.97)], and OS [HR = 0.63, 95% CI: (0.49, 0.81)] were significantly improved among patients aged >70 years, and ORR [OR = 1.80, 95% CI: (1.20, 2.70)] and PFS [HR = 0.74, 95% CI: (0.56, 0.97)] were significantly elevated with SCC rate ≥65% in NSCLC patients (all p > 0.05). Among the adverse effects, the prevalence of neutropenia, neuralgia, and arthralgia/myalgia (≥ grade 3) compared to that of the control group. On the other hand, the prevalence of anemia and thrombocytopenia was higher in the nab-P plus platinum (carboplatin/cisplatin) compared to that of controls. It is worth noting that fatigue did not show statistical significance. Conclusion: Nab-P in combination with carboplatin/cisplatin regimen improves efficacy and tolerability in patients with NSCLC. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022288499.

Anti-tumor effects of novel alkannin derivatives with potent selectivity on comprehensive analysis.

BACKGROUND: Therapeutic approaches based on glycolysis and energy metabolism of tumor cells are new promising strategies for the treatment of cancer. Currently, researches on the inhibition of pyruvate kinase M2, a key rate limiting enzyme in glycolysis, have been corroborated as an effective cancer therapy. Alkannin is a potent pyruvate kinase M2 inhibitor. However, its non-selective cytotoxicity has affected its subsequent clinical application. Thus, it needs to be structurally modified to develop novel derivatives with high selectivity. PURPOSE: Our study aimed to ameliorate the toxicity of alkannin through structural modification and elucidate the mechanism of the superior derivative 23 in lung cancer therapy. METHODS: On the basis of the principle of collocation, different amino acids and oxygen-containing heterocycles were introduced into the hydroxyl group of the alkannin side chain. We examined the cell viability of all derivatives on three tumor cells (HepG2, A549 and HCT116) and two normal cells (L02 and MDCK) by MTT assay. Besides, the effect of derivative 23 on the morphology of A549 cells as observed by Giemsa and DAPI staining, respectively. Flow cytometry was performed to assess the effects of derivative 23 on apoptosis and cell cycle arrest. To further assess the effect of derivative 23 on the Pyruvate kinase M2 in glycolysis, an enzyme activity assay and western blot assay were performed. Finally, in vivo the antitumor activity and safety of the derivative 23 were evaluated by using Lewis mouse lung cancer xenograft model. RESULTS: Twenty-three novel alkannin derivatives were designed and synthesized to improve the cytotoxicity selectivity. Among these derivatives, derivative 23 showed the highest cytotoxicity selectivity between cancer and normal cells. The anti-proliferative activity of derivative 23 on A549 cells (IC50 = 1.67 ± 0.34 µM) was 10-fold higher than L02 cells (IC50 = 16.77 ± 1.44 µM) and 5-fold higher than MDCK cells (IC50 = 9.23 ± 0.29 µM) respectively. Subsequently, fluorescent staining and flow cytometric analysis showed that derivative 23 was able to induce apoptosis of A549 cells and arrest the cell cycle in the G0/G1 phase. In addition, the mechanistic studies suggested derivative 23 was an inhibitor of pyruvate kinase; it could regulate glycolysis by inhibiting the activation of the phosphorylation of PKM2/STAT3 signaling pathway. Furthermore, studies in vivo demonstrated derivative 23 significantly inhibited the growth of xenograft tumor. CONCLUSION: In this study, alkannin selectivity is reported to be significantly improved following structural modification, and derivative 23 is first shown to be able to inhibit lung cancer growth via the PKM2/STAT3 phosphorylation signaling pathway in vitro, indicating the potential value of derivative 23 in treating lung cancer.