The efficacy and safety of adding PD-1 blockade to induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) for locoregionally advanced nasopharyngeal carcinoma: an observational, propensity score-matched analysis.

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.

Effects of titanium dioxide nanoparticle exposure on the gut microbiota of pearl oyster (Pinctada fucata martensii).

With the advancement of nanotechnology and the growing utilization of nanomaterials, titanium dioxide (TiO2) has been released into aquatic environments, posing potential ecotoxicological risks to aquatic organisms. In this study, the toxicological effects of TiO2 nanoparticles were investigated on the intestinal health of pearl oyster (Pinctada fucata martensii). The pearl oysters were subjected to a 14-day exposure to 5-mg/L TiO2 nanoparticle, followed by a 7-day recovery period. Subsequently, the intestinal tissues were analyzed using 16S rDNA high-throughput sequencing. The results from LEfSe analysis revealed that TiO2 nanoparticle increased the susceptibility of pearl oysters to potential pathogenic bacteria infections. Additionally, the TiO2 nanoparticles led to alterations in the abundance of microbial communities in the gut of pearl oysters. Notable changes included a decrease in the relative abundance of Phaeobacter and Nautella, and an increase in the Actinobacteria, which could potentially impact the immune function of pearl oysters. The abundance of Firmicutes and Bacteroidetes, as well as the expression of genes related to energy metabolism (AMPK, PK, SCS-1, SCS-2, SCS-3), were down-regulated, suggesting that TiO2 nanoparticles exposure may affect the digestive and energy metabolic functions of pearl oysters. Furthermore, the short-term recovery of seven days did not fully restore these levels to normal. These findings provide crucial insights and serve as an important reference for understanding the toxic effects of TiO2 nanoparticles on bivalves.

The AP2/ERF transcription factor MdDREB2A regulates nitrogen utilisation and sucrose transport under drought stress.

Drought stress is one of the main environmental factors limiting plant growth and development. Plants adapt to changing soil moisture by modifying root architecture, inducing stomatal closure, and inhibiting shoot growth. The AP2/ERF transcription factor DREB2A plays a key role in maintaining plant growth in response to drought stress, but the molecular mechanism underlying this process remains to be elucidated. Here, it was found that overexpression of MdDREB2A positively regulated nitrogen utilisation by interacting with DRE cis-elements of the MdNIR1 promoter. Meanwhile, MdDREB2A could also directly bind to the promoter of MdSWEET12, which may enhance root development and nitrogen assimilation, ultimately promoting plant growth. Overall, this regulatory mechanism provides an idea for plants in coordinating with drought tolerance and nitrogen assimilation to maintain optimal plant growth and development under drought stress.

Osseointegration of functionally graded Ti6Al4V porous implants: Histology of the pore network.

The additive manufacturing of titanium into porous geometries offers a means to generate low-stiffness endosseous implants with a greater surface area available for osseointegration. In this work, selective laser melting was used to produce gyroid-based scaffolds with a uniform pore size of 300 µm or functionally graded pore size from 600 µm to 300 µm. Initial in vitro assessment with Saos-2 cells showed favourable cell proliferation at pore sizes of 300 and 600 µm. Following implantation into rabbit tibiae, early histological observations at four weeks indicated some residual inflammation alongside neovessel infiltration into the scaffold interior and some early apposition of mineralized bone tissue. At twelve weeks, both scaffolds were filled with a mixture of adipocyte-rich marrow, micro-capillaries, and mineralized bone tissue. X-ray microcomputed tomography showed a higher bone volume fraction (BV/TV) and percentage of bone-implant contact (BIC) in the implants with 300 µm pores than in the functionally graded specimens. In functionally graded specimens, localized BV/TV measurement was observed to be higher in the innermost region containing smaller pores (estimated at 300-400 µm) than in larger pores at the implant exterior. The unit cell topology of the porous implant was also observed to guide the direction of bone ingrowth by conducting along the implant struts. These results suggest that in vivo experimentation is necessary alongside parametric optimization of functionally graded porous implants to predict short-term and long-term bone apposition.

Integrated Bone Formation Through In Vivo Endochondral Ossification Using Mesenchymal Stem Cells.

Conventional bone regeneration therapy using mesenchymal stem cells (MSCs) is difficult to apply to bone defects larger than the critical size because it does not have a mechanism to induce angiogenesis. Implanting artificial cartilage tissue fabricated from MSCs induces angiogenesis and bone formation in vivo via endochondral ossification (ECO). Therefore, this ECO-mediated approach may be a promising bone regeneration therapy in the future. An important aspect of the clinical application of this ECO-mediated approach is establishing a protocol for preparing enough cartilage to be implanted to repair the bone defect. It is especially not practical to design a single mass of grafted cartilage of a size that conforms to the shape of the actual bone defect. Therefore, the cartilage to be transplanted must have the property of forming bone integrally when multiple pieces are implanted. Hydrogels may be an attractive tool for scaling up tissue-engineered grafts for endochondral ossification to meet clinical requirements. Although many naturally derived hydrogels support MSC cartilage formation in vitro and ECO in vivo, the optimal scaffold material to meet the needs of clinical applications has yet to be determined. Hyaluronic acid (HA) is a crucial component of the cartilage extracellular matrix and is a biodegradable and biocompatible polysaccharide. Here, we show that HA hydrogels have excellent properties to support in vitro differentiation of MSC-based cartilage tissue and promote endochondral bone formation in vivo.

The feasibility of reduced-dose radiotherapy in childhood nasopharyngeal carcinoma with favorable response to neoadjuvant chemotherapy.

BACKGROUND: To assess the feasibility of adjusting radiation dose (RD) in childhood NPC with favorable tumor response after neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Using an NPC-specific database, children and adolescents (≤18 years) with locoregionally advanced NPC (CA-LANPC) were retrospectively analyzed. Enrolled patients were those who received favorable tumor response after 2-4 cycles of NAC followed by concurrent chemoradiotherapy. Survival outcomes and treatment-related toxicities were compared for the standard RD on primary tumors (PT-RDstandard, 66-72 Gy) and the reduced RD on primary tumors (PT-RDreduced, 60-65.9 Gy). RESULTS: A total of 132 patients were included, and the median follow-up time was 75.2 months (IQR, 53.2-98.7 months) for the entire cohort. The PT-RDreduced group had a significantly decreased incidence of severe mucositis (51.3 % vs 32.1 %; P = 0.034) when compared to the PT-RDstandard group. The total incidence of severe sequela in the PT-RDstandard group were significantly higher than those in the PT-RDreduced group (31.8 % vs 13.7 %; P = 0.029). In the propensity-matched analysis, the PT-RDreduced group resulted in parallel 5-year survival with the PT-RDstandard group from the matched cohort (disease-free survival, 82.7 % vs 80.3 %, P = 0.841; overall survival, 91.7 % vs 91.3 %, P = 0.582; distant metastasis-free survival, 87.5 % vs 82.8 %, P = 0.573; and locoregional relapse-free survival, 95.6 % vs 97.3 %, P = 0.836). In multivariate analysis, the impact of PT-RDreduced on all survival end points remained insignificant. CONCLUSIONS: Chemoradiotherapy with RD at levels of 60-65.9 Gy may be a reasonable strategy for CA-LANPC with favorable tumor response after NAC.

Small nodules (≤ 6 mm in diameter) of multiple primary lung cancers: prevalence and management.

BACKGROUND: Synchronous multiple primary lung cancers associated with small non-dominant nodules are commonly encountered. However, the incidence, follow-up, and treatment of small non-dominant tumors have been but little studied. We explored the prevalence and management of small non-dominant tumors and factors associated with interval growth. METHODS: This observational, consecutive, retrospective single-center study enrolled patients diagnosed with synchronous multiple primary lung cancers and small non-dominant tumors (≤ 6 mm in diameter) who underwent resection of the dominant tumor. The incidence, follow-up, and management of small non-dominant tumors and predictors of nodule growth were analyzed. RESULTS: There were 88 patients (12% of all lung cancer patients) with pathological diagnoses of synchronous multiple primary lung cancers. A total of 131 (18%) patients were clinically diagnosed with at least one small (≤ 6 mm in diameter) multiple primary lung cancer non-dominant tumor. 94 patients with 125 small-nodule non-dominant tumors clinically diagnosed as multiple primary lung cancers were followed-up for at least 6 months. A total of 29 (29/125, 23.2%) evidenced small pulmonary nodules (≤ 6 mm in diameter) that exhibited interval growth on follow-up computed tomography (CT). On multivariate analysis, a part-solid nodule (compared to a pGGN) (OR 1.23; 95% CI 1.08-1.40) or a solid nodule (compared to a pGGN) (OR 3.50; 95% CI 1.94-6.30) predicted small nodule interval growth. CONCLUSION: We found a relatively high incidence of multiple primary lung cancers with small non-dominant tumors exhibiting interval growth on follow-up CT, suggesting that resection of non-dominant tumors at the time of dominant tumor resection, especially when the nodules are part-solid or solid, is the optimal treatment.

Micro/Nanostructured Topography on Titanium Orchestrates Dendritic Cell Adhesion and Activation via ß2 Integrin-FAK Signals.

Background and Purpose: In clinical application of dental implants, the functional state of dendritic cells (DCs) has been suggested to have a close relationship with the implant survival rate or speed of osseointegration. Although microscale surfaces have a stable osteogenesis property, they also incline to trigger unfavorable DCs activation and threaten the osseointegration process. Nanoscale structures have an advantage in regulating cell immune response through orchestrating cell adhesion, indicating the potential of hierarchical micro/nanostructured surface in regulation of DCs' activation without sacrificing the advantage of microscale topography. Materials and Methods: Two micro/nanostructures were fabricated based on microscale rough surfaces through anodization or alkali treatment, the sand-blasted and acid-etched (SA) surface served as control. The surface characteristics, in vitro and in vivo DC immune reactions and ß2 integrin-FAK signal expression were systematically investigated. The DC responses to different surface topographies after FAK inhibition were also tested. Results: Both micro/nano-modified surfaces exhibited unique composite structures, with higher hydrophilicity and lower roughness compared to the SA surface. The DCs showed relatively immature functional states with round morphologies and significantly downregulated ß2 integrin-FAK levels on micro/nanostructures. Implant surfaces with micro/nano-topographies also triggered lower levels of DC inflammatory responses than SA surfaces in vivo. The inhibited FAK activation effectively reduced the differences in topography-caused DC activation and narrowed the differences in DC activation among the three groups. Conclusion: Compared to the SA surface with solely micro-scale topography, titanium surfaces with hybrid micro/nano-topographies reduced DC inflammatory response by influencing their adhesion states. This regulatory effect was accompanied by the modulation of ß2 integrin-FAK signal expression. The ß2 integrin-FAK-mediated adhesion plays a critical role in topography-induced DC activation, which represents a potential target for material-cell interaction regulation.

The role and interaction between transcription factor NAC-NOR and DNA demethylase SlDML2 in the biosynthesis of tomato fruit flavor volatiles.

Flavor-imparting volatile chemicals accumulate as fruits ripen, making major contributions to taste. The NAC transcription factor nonripening (NAC-NOR) and DNA demethylase 2 (SlDML2) are essential for tomato fruit ripening, but details of the potential roles and the relationship between these two regulators in the synthesis of volatiles are lacking. Here, we show substantial reductions in fatty acid and carotenoid-derived volatiles in tomato slnor and sldml2 mutants. An unexpected finding is the redundancy and divergence in volatile profiles, biosynthetic gene expression, and DNA methylation in slnor and sldml2 mutants relative to wild-type tomato fruit. Reduced transcript levels are accompanied by hypermethylation of promoters, including the NAC-NOR target gene lipoxygenase (SlLOXC) that is involved in fatty acid-derived volatile synthesis. Interestingly, NAC-NOR activates SlDML2 expression by directly binding to its promoter both in vitro and in vivo. Meanwhile, reduced NAC-NOR expression in the sldml2 mutant is accompanied by hypermethylation of its promoter. These results reveal a relationship between SlDML2-mediated DNA demethylation and NAC-NOR during tomato fruit ripening. In addition to providing new insights into the metabolic modulation of flavor volatiles, the outcome of our study contributes to understanding the genetics and control of fruit ripening and quality attributes in tomato.

NIR-II Navigation with an EGFR-Targeted Probe Improves Imaging Resolution and Sensitivity of Detecting Micrometastases in Esophageal Squamous Cell Carcinoma Xenograft Models.

The survival rate of esophageal squamous carcinoma (ESCC) after surgical resection is estimated to be only 30.3% due to the difficulty in identifying microinfiltration and subtle metastases. In this study, we explored the value of near-infrared fluorescence in the second window (NIR-II) using an epidermal growth factor receptor (EGFR)-targeted probe (cetuximab-IR800) for the intraoperative navigation of ESCC in xenograft mouse models. Immunohistochemical results showed that EGFR was aberrantly expressed in 94.49% (120/127) of ESCC tissues and 90.63% (58/64) of metastatic lymph nodes. Western blot results demonstrated that EGFR protein was highly expressed in ESCC cell lines. Flow cytometry data revealed that cetuximab-IR800 showed a stronger binding specificity in EGFR-positive KYSE-30 cells than in A2780 control cells (P < 0.01). In vivo imaging data showed that the ratio of mean fluorescent intensity (MFI) and tumor to background (TBR) was significantly higher in KYSE-30 subcutaneous tumors with the infusion of cetuximab-IR800 than in those with the infusion of IgG1-IR800 (P < 0.05). Surgical navigation with NIR-II imaging showed that the TBR in orthotopic ESCC was significantly higher than that of NIR in the first window (NIR-I) (2.11 ± 0.46 vs 1.58 ± 0.31, P < 0.05), and NIR-II was more sensitive than NIR-I in detecting subcentimeter metastases (94.87% (37/39) vs 58.97% (23/39), P < 0.001). In conclusion, cetuximab-IR800 with high specificity for ESCC was first used in NIR-II surgical navigation. This probe showed better imaging resolution and higher sensitivity in detecting subtle metastases derived from an orthotopic ESCC model than NIR-I, which indicates that NIR-II has promise in guiding precise surgery for ESCC patients.

Self-control protects Tibetan adolescent orphans from mental problems: A mediating role of self-esteem.

INTRODUCTION: Orphans are usually adopted by eligible families or raised by the government and organizations mutually. Although their basic needs are taken care of, the absence of parents in life makes orphans face higher risks of mental health problems, such as anxiety and depression, leading to lower levels of self-esteem and happiness. Previous studies have shown that self-control may have an effect on improving self-esteem; thus, it could become a way to protect mental health. Building on the structural equation model, the current study tested the possible effects of self-control on levels of self-esteem and mental problems among Tibetan orphans. METHODS: Participants were 143 adolescents from age 16 to 22 years (Mage = 18.77, 54.8% female) from an institutionalized orphanage in Tibet and they completed questionnaires measuring self-esteem, self-control, and clinical symptoms (Symptom Checklist-90-Revised). RESULTS AND CONCLUSIONS: Self-control was negatively associated with psychological illness through improved self-esteem. The present study suggested that self-control was a protective factor for the mental health of adolescent orphans through influencing the levels of self-esteem. Limitations and future directions were discussed.

FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-κB pathway in airway epithelial cells.

BACKGROUND: Airway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined. Recently, fibroblast growth factor 2 (FGF2) has been reported to be an inflammatory regulator; however, its role in asthma remains elusive. This study aimed to investigate the immunomodulatory role of FGF2 in asthma. METHODS: First, FGF2 expression was characterised in clinical asthma samples and the house dust mite (HDM)-induced mouse chronic asthma model. Second, recombinant mouse FGF2 (rm-FGF2) protein was intranasally delivered to determine the effect of FGF2 on airway inflammatory cell infiltration. Third, human airway epithelium-derived A549 cells were stimulated with either HDM or recombinant human interleukin-1ß (IL-1ß) protein combined with or without recombinant human FGF2. IL-1ß-induced IL-6 or IL-8 release levels were determined using enzyme-linked immunosorbent assay, and the involved signalling transduction was explored via Western blotting. RESULTS: Compared with the control groups, the FGF2 protein levels were significantly upregulated in the bronchial epithelium and alveolar areas of clinical asthma samples (6.70 ± 1.79 vs. 16.32 ± 2.40, P = 0.0184; 11.20 ± 2.11 vs. 21.00 ± 3.00, P = 0.033, respectively) and HDM-induced asthmatic mouse lung lysates (1.00 ± 0.15 vs. 5.14 ± 0.42, P < 0.001). Moreover, FGF2 protein abundance was positively correlated with serum total and anti-HDM IgE levels in the HDM-induced chronic asthma model (R2 = 0.857 and 0.783, P = 0.0008 and 0.0043, respectively). Elevated FGF2 protein was mainly expressed in asthmatic bronchial epithelium and alveolar areas and partly co-localised with infiltrated inflammatory cell populations in HDM-induced asthmatic mice. More importantly, intranasal instillation of rm-FGF2 aggravated airway inflammatory cell infiltration (2.45 ± 0.09 vs. 2.88 ± 0.14, P = 0.0288) and recruited more subepithelial neutrophils after HDM challenge [(110.20 ± 29.43) cells/mm2 vs. (238.10 ± 42.77) cells/mm2, P = 0.0392] without affecting serum IgE levels and Th2 cytokine transcription. In A549 cells, FGF2 was upregulated through HDM stimulation and promoted IL-1ß-induced IL-6 or IL-8 release levels (up to 1.41 ± 0.12- or 1.44 ± 0.14-fold change vs. IL-1ß alone groups, P = 0.001 or 0.0344, respectively). The pro-inflammatory effect of FGF2 is likely mediated through the fibroblast growth factor receptor (FGFR)/mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. CONCLUSION: Our findings suggest that FGF2 is a potential inflammatory modulator in asthma, which can be induced by HDM and acts through the FGFR/MAPK/NF-κB pathway in the airway epithelial cells.

Pathological and genomic phenotype of second neuroendocrine carcinoma during long-term follow-up after radical radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: Second head and neck neuroendocrine carcinoma (NEC) after radical radiotherapy for nasopharyngeal carcinoma (NPC) treatment is rarely reported. The prognosis of second cancer is poor, and our research focuses on finding a breakthrough in the treatment. In this study, we aimed to investigate clinicopathological characteristics and to identify the genomic landscape of second head and neck NECs. METHODS: We collected five second head and neck NEC cases in the recent three years from our patient database. Clinicopathological data and images were obtained. Genomic analysis was performed using high-throughput second generation sequencing. KEGG pathway enrichment analyses between high-frequency mutations were performed using the STRING database. RESULTS: All patients had been diagnosed with second NEC, according to the pathological observations. The interval between diagnosis of NPC and NEC ranged from 10 to 18 years. Two patients had brain or liver metastasis at three and nine months, respectively, after the diagnosis of NEC. Three patients died of the disease with the overall survival time ranging from three to nine months. Commonly altered genes (50%) in second head and neck NECs included TP53, RB1, NOTCH2, PTEN, POLG, KMT2C, U2AF1, EPPK1, ELAC2, DAXX, COL22A1, and ABL1. Those genetic lesions might affect p53 signaling, MAPK signaling, PI3K-Akt signaling, sphingolipid signaling, and neurotrophin signaling pathways. CONCLUSIONS: Second head and neck NECs had poor prognosis. We revealed, for the first time, the mutational landscape, high-frequency somatic mutations, and potential signaling pathways of second head and neck NECs. Its optimal treatment model needs to be further studied in future clinical trials.

Analysis of Codon Usage Patterns of Six Sequenced Brachypodium distachyon Lines Reveals a Declining CG Skew of the CDSs from the 5'-ends to the 3'-ends.

Brachypodium distachyon, a new monocotyledonous model plant, has received wide attention in biological research due to its small genome and numerous genetic resources. Codon usage bias is an important feature of genes and genomes, and it can be used in transgenic and evolutionary studies. In this study, the nucleotide compositions and patterns of codon usage bias were calculated using Codon W. Additionally, an ENC plot, Parity rule 2 and correspondence analyses were used to explore the major factors influencing codon usage bias patterns. The numbers of hydrogen bonds and skews were used to analyze the GC trend in the 5'-ends of the coding sequences. The results showed that minor differences in the codon usage bias patterns were revealed by the ENC plot, Parity rule 2 and correspondence analyses. The analyses of the CG-skew and the number of hydrogen bonds showed a declining trend in the number of cytosines at the 5'-ends of the CDSs (from the 5'-ends to the 3'-ends), indicating that GC may play a major role in codon usage bias. In addition, our results laid a foundation for the study of codon usage bias patterns in Brachypodium genus and suggested that the GC plays a major role in determining these patterns.

The Role of Pretreatment 18F-FDG PET/CT for Early Prediction of Neoadjuvant Chemotherapy Response in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.

INTRODUCTION: To evaluate the role of maximal standardized uptake values (SUVmax) and total lesion glycolysis (TLG) from serial 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for early prediction of neoadjuvant chemotherapy (NAC) response in locoregionally advanced nasopharyngeal carcinoma (LANPC). METHODS: A total of 121 LANPC patients who completed pretreatment 18F-FDG PET/CT between June 2017 and July 2020 were retrospectively included. The median age of all the participants was 50 years old (range: 19-74 years), with 94 (77.7%) males and 27 (22.3%) females. The SUVmax from the primary tumor site (SUVmax-PT) and the total lesion glycolysis from the primary tumor site (TLG-PT) were recorded. Tumor response was calculated according to the Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 Criteria at two-week post-secondary NAC cycle. Patients who achieved an objectively partial or full reaction after two cycles of NAC were defined as 'responders', and patients who obtained stability or progression were classified as 'non-responders'. RESULTS: After two cycles of NAC, 96 patients were categorized as "responders" and 25 patients as "non-responders". The optimal thresholds of the SUVmax-PT were 11.8 and 38.5 for the TLG-PT. Non-responders were significantly associated with high SUVmax-PT (HR, 3.49; 95% CI, 1.17-10.36; p = 0.024) and TLG-PT (HR, 4.45; 95% CI, 1.44-13.78; p = 0.010) in multivariate analysis. Recursive partitioning analysis (RPA) categorized patients into three prognostic groups based on SUVmax-PT and TLG-PT: high-response group, intermediate-response group, and low-response group, with corresponding favorable response rates of 94%, 80%, and 55%, respectively. Moreover, a nomogram was created based on metabolic parameters that precisely projected an individual's response of NAC (C-index, 0.787; 95% CI, 0.533-1.000). CONCLUSION: Pretreatment 18F-FDG PET/CT to measure SUVmax-PT and TLG-PT could be a useful non-invasive method for early indication of NAC efficacy. The nomogram based on PET/CT parameters may potentially provide direction for treatment decisions based on NAC levels.

c-Met-targeted near-infrared fluorescent probe for real-time depiction and dissection of perineural invasion and lymph node metastasis lesions in pancreatic ductal adenocarcinoma xenograft models.

Pancreatic ductal adenocarcinoma (PDAC), a fatal malignant tumour, has a high postoperative recurrence rate, mainly due to the difficulty of discerning occult lesions, including those related to perineural invasion (PNI) and lymph node metastasis (LNM). Cellular mesenchymal-epithelial transition factor (c-Met), an excellent imaging marker, is aberrantly expressed in the majority of PDACs. Thus, we plan to utilize a c-Met-targeted near-infrared fluorescent (NIRF) probe for real-time visualization and dissection of PDAC, and corresponding PNI and LNM lesions. Immunohistochemistry showed c-Met expression in PDAC, PNI and LNM reached 94.3% (100/106), 88.3% (53/60), and 71.4% (25/35), respectively, and its expression in PNI and LNM was significantly correlated with that in primary PDAC (r = 0.66, p < 0.0001 and r = 0.44, p < 0.01, respectively). SHRmAb-IR800 was successfully synthesized using an anti-c-Met antibody and a NIRF dye. The in vitro targeting ability of SHRmAb-IR800 was higher in CFPAC1 cells (c-Met positive) than in Miapaca-2 cells (c-Met negative) (p < 0.05). In vivo NIRF imaging of CFPAC1 subcutaneous tumours demonstrated higher accumulation of SHRmAb-IR800 than the control probe (p < 0.05). The signal-to-background ratio (TBR) of an orthotopic PDAC tumour was 3.38 ± 0.46, and imaging with SHRmAb-IR800 facilitated the resection of metastatic lesions with sensitivity and specificity values of 93.3% (56/60) and 87.1% (27/31), respectively. Furthermore, tiny PNI and LNM lesions in xenograft models were detected by NIRF imaging, with TBRs measuring 2.59 ± 0.19 and 2.88 ± 0.72, respectively. Therefore, the clinical translation of this probe might shed new light on NIRF-guided pancreatectomy and improve the surgical prognosis of PDAC patients.

Correction: Micro/nano-net guides M2-pattern macrophage cytoskeleton distribution via Src-ROCK signalling for enhanced angiogenesis.

Correction for 'Micro/nano-net guides M2-pattern macrophage cytoskeleton distribution via Src-ROCK signalling for enhanced angiogenesis' by Yang Yang et al., Biomater. Sci., 2021, DOI: 10.1039/d1bm00116g.

Micro/nano-net guides M2-pattern macrophage cytoskeleton distribution via Src-ROCK signalling for enhanced angiogenesis.

Implant surface topography has been proven to determine the fate of adhered macrophage polarization, which is closely related to the cytoskeletal arrangement during adhesion. Our purpose was to establish a topography that is favourable to M2 macrophage switching by regulating macrophage cytoskeleton distribution. Two micro/nano-net structures with different pore sizes were generated by alkali bathing at medium (SAM) or high (SAH) temperature based on the micro-level surface. Their surface characteristics, in vitro macrophage polarization and impact on endothelial cells were analysed. The in vivo macrophage response and osseointegration were also tested. The results showed that the micro/nano-net has high hydrophilicity and moderate roughness. In the SAH and SAM groups, macrophages exhibited an elongated cytoskeleton with tiny protrusions and had a high M2/M1 polarization ratio with enhanced angiogenic ability, and in vivo studies also showed faster angiogenesis and bone formation in these groups. SAH showed even better results than SAM. For cytoskeleton related pathway explanation, ROCK expression was upregulated and Src expression was downregulated at the early or late adhesion stage in both the SAH and SAM groups. These results indicated that the micro/nano-net structure guides elongated macrophage adhesion states via Src-ROCK signalling and switches macrophages towards the M2 phenotype, which provides a cytoskeleton-oriented topography design for an ideal immune response.

A new 7-gene survival score assay for pancreatic cancer patient prognosis prediction.

Gene expression features that are valuable for pancreatic ductal adenocarcinoma (PDAC) prognosis are still largely unknown. We aimed to explore pivotal molecular signatures for PDAC progression and establish an efficient survival score to predict PDAC prognosis. Overall, 163 overlapping genes were identified from three statistical methods, including differentially expressed genes (DEGs), coexpression network analysis (WGCNA), and target genes for miRNAs that were significantly related to PDAC patients' overall survival (OS). Then, according to the optimal value of the cross-validation curve (lambda = 0.031), 7 non-zero coefficients (ARNTL2, DSG3, PTPRR, ANLN, S100A14, ANKRD22, and TSPAN7) were selected to establish a prognostic prediction model of PDAC patients. We further confirmed the expression level of 7 genes using RT-PCR, western blot, and immunohistochemistry staining in PDAC patients' tissues. Our results showed that the ROC curve of the 7-mRNA model indicated good predictive ability for 1- and 2-year OS in three datasets (TCGA: 0.71, 0.69; ICGC: 0.8, 0.74; GEO batch: 0.61, 0.7, respectively). The hazard ratio (HR) of the low-risk group had a similar significant result (TCGA: HR = 0.3723; ICGC: HR = 0.2813; GEO batch: HR = 0.4999; all P < 0.001). Furthermore, Log-rank test results in three cohorts showed that the 7-mRNA assay excellently predicted the prognosis and metastasis, especially in TNM stage I&II subgroups of PDAC. In conclusion, the strong validation of our 7-mRNA signature indicates the promising effectiveness of its clinical application, especially in patients with TNM stages I&II.

Near-infrared fluorescence-guided resection of micrometastases derived from esophageal squamous cell carcinoma using a c-Met-targeted probe in a preclinical xenograft model.

The postoperative survival of esophageal squamous cell carcinoma (eSCC) is notably hindered by cancer recurrence due to difficulty in identifying occult metastases. Cellular mesenchymal-epithelial transition factor (c-Met), which is highly expressed in different cancers, including eSCC, has become a target for the development of imaging probes and therapeutic antibodies. In this study, we synthesized an optical probe (SHRmAb-IR800) containing a near-infrared fluorescence (NIRF) dye and c-Met antibody, which may help in NIRF-guided resection of micrometastases derived from eSCC. Cellular uptake of SHRmAb-IR800 was assessed by flow cytometry and confocal microscopy. In vivo accumulation of SHRmAb-IR800 and the potential application of NIRF-guided surgery were evaluated in eSCC xenograft tumor models. c-Met expression in human eSCC samples and lymph node metastases (LNMs) was analyzed via immunohistochemistry (IHC). Cellular accumulation of SHRmAb-IR800 was higher in c-Met-positive EC109 eSCC cells than in c-Met-negative A2780 cells. Infusion of SHRmAb-IR800 produced higher fluorescence intensity and a higher tumor-to-background ratio (TBR) than the control probe in EC109 subcutaneous tumors (P < 0.05). The TBRs of orthotopic EC109 tumors and LNMs were 3.01 ± 0.17 and 2.77 ± 0.56, respectively. The sensitivity and specificity of NIRF-guided resection of metastases derived from orthotopic cancers were 92.00% and 89.74%, respectively. IHC results demonstrated positive staining in 97.64% (124/127) of eSCC samples and 91.67% (55/60) of LNMs. Notably, increased c-Met expression was observed in LNMs compared to normal lymph nodes (P < 0.0001). Taken together, the results of this study indicated that SHRmAb-IR800 facilitated the resection of micrometastases of eSCC in the xenograft tumor model. This c-Met-targeted probe possesses translational potential in NIRF-guided surgery due to the high positive rate of c-Met protein in human eSCCs.