Does neoadjuvant therapy contribute to increased risk in anastomotic leakage of esophageal cancer? A network meta-analysis.

AIM: Conflicting results have been reported about the impact of neoadjuvant therapy on anastomotic leakage (AL) after esophagectomy. We aimed to unravel the potential effect of neoadjuvant therapy on AL after esophagectomy through a network meta-analysis. METHODS: A Bayesian network meta-analysis was performed by retrieving relevant literature from PubMed, EMbase, The Cochrane Library and Web of Science Core Collection. Randomized clinical trials (RCTs) and retrospective studies (RS) comparing the following treatment modalities were included: neoadjuvant chemoradiation (nCRT), neoadjuvant chemotherapy (nCT), neoadjuvant radiotherapy (nR), neoadjuvant immunochemotherapy (nICT), and surgery alone (SA). Subgroup analyses by radiation dose, examined lymph nodes (ELN), route of reconstruction, site of anastomosis, and surgical approach were also conducted. RESULTS: A total of 62 studies with 12,746 patients were included for the present study, among which 17 were RCTs. There were no significantly statistical differences observed among the five treatment modalities in AL for both RCTs (nCRT-nICT: risk ratio 1.51, 95% confidence interval 0.52-4.4; nCT-nICT: 1.71, 0.56-5.08; nICT-nR: 0.79, 0.12-8.02; nICT-SA: 0.59, 0.2-1.84) and RS (nCRT-nICT: odds ratio 1.53, 95% confidence interval 0.84-2.84; nCT-nICT: 1.56, 0.87-2.88; nICT-SA: 0.6, 0.31-1.12; nICT-nR: 1.08, 0.09-36.02). Subgroup analysis revealed that no significant difference in AL was observed among the five treatment modalities except for the impact of nCRT versus nCT (0.21, 0.05-0.73) on AL with a radiation dose ≥41.4 Gy. CONCLUSIONS: Neoadjuvant therapy do not significantly increase the incidence of AL after esophagectomy. Administration of irradiation with a moderate dose is not associated with elevated risk in AL. Clinicians can be less apprehensive about prescribing nCRT.

Prognostic implications, genomic and immune characteristics of lung adenocarcinoma with lepidic growth pattern.

AIMS: Conflicting data were provided regarding the prognostic impact and genomic features of lung adenocarcinoma (LUAD) with lepidic growth pattern (LP+A). Delineation of the genomic and immune characteristics of LP+A could provide deeper insights into its prognostic implications and treatment determination. METHODS: We conducted a search of articles in PubMed, EMBASE and the Cochrane Library from inception to January 2024. A domestic cohort consisting of 52 LUAD samples was subjected to whole-exome sequencing as internal validation. Data from The Cancer Genomic Atlas and the Gene Expression Omnibus datasets were obtained to characterise the genomic and immune profiles of LP+A. Pooled HRs and rates were calculated. RESULTS: The pooled results indicated that lepidic growth pattern was either predominant (0.35, 95% CI 0.22 to 0.56, p<0.01) or minor (HR 0.50, 95% CI 0.36 to 0.70, p<0.01) histological subtype was associated with favourable disease-free survival. Pooled gene mutation rates suggested higher EGFR mutation (0.55, 95% CI 0.46 to 0.64, p<0.01) and lower KRAS mutation (0.14, 95% CI 0.02 to 0.25, p=0.02) in lepidic-predominant LUAD. Lepidic-predominant LUAD had lower tumour mutation burden and pooled positive rate of PD-L1 expression compared with other subtypes. LP+A was characterised by abundance in resting CD4+memory T cells, monocytes and γδ T cells, as well as scarcity of cancer-associated fibroblasts. CONCLUSIONS: LP+A was a unique histological subtype with a higher EGFR mutation rate, lower tumour mutation burden and immune checkpoint expression levels. Our findings suggested potential benefits from targeted therapy over immunotherapy in LP+A.

CXCL5 impedes CD8+ T cell immunity by upregulating PD-L1 expression in lung cancer via PXN/AKT signaling phosphorylation and neutrophil chemotaxis.

BACKGROUND: Lung cancer remains one of the most prevalent cancer types worldwide, with a high mortality rate. Upregulation of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) may represent a key mechanism for evading immune surveillance. Immune checkpoint blockade (ICB) antibodies against PD-1 or PD-L1 are therefore widely used to treat patients with lung cancer. However, the mechanisms by which lung cancer and neutrophils in the microenvironment sustain PD-L1 expression and impart stronger inhibition of CD8+ T cell function remain unclear. METHODS: We investigated the role and underlying mechanism by which PD-L1+ lung cancer and PD-L1+ neutrophils impede the function of CD8+ T cells through magnetic bead cell sorting, quantitative real-time polymerase chain reaction (RT-PCR), western blotting, enzyme-linked immunosorbent assays, confocal immunofluorescence, gene silencing, flow cytometry, etc. In vivo efficacy and safety studies were conducted using (Non-obeseDiabetes/severe combined immune deficiency) SCID/NOD mice. Additionally, we collected clinical and prognostic data from 208 patients who underwent curative lung cancer resection between 2017 and 2018. RESULTS: We demonstrated that C-X-C motif chemokine ligand 5 (CXCL5) is markedly overexpressed in lung cancer cells and is positively correlated with a poor prognosis in patients with lung cancer. Mechanistically, CXCL5 activates the phosphorylation of the Paxillin/AKT signaling cascade, leading to upregulation of PD-L1 expression and the formation of a positive feedback loop. Moreover, CXCL5 attracts neutrophils, compromising CD8+ T cell-dependent antitumor immunity. These PD-L1+ neutrophils aggravate CD8+ T cell exhaustion following lung cancer domestication. Combined treatment with anti-CXCL5 and anti-PD-L1 antibodies significantly inhibits tumor growth in vivo. CONCLUSIONS: Our findings collectively demonstrate that CXCL5 promotes immune escape through PD-L1 upregulation in lung cancer and neutrophils chemotaxis through autocrine and paracrine mechanisms. CXCL5 may serve as a potential therapeutic target in synergy with ICBs in lung cancer immunotherapy.

A Compensation Method for the Geomagnetic Measurement Error of an Underwater Ship-Borne Magnetometer Based on Constrained Total Least Squares.

When magnetic matching aided navigation is applied to an underwater vehicle, the magnetometer must be installed inside the vehicle, considering the navigation safety and concealment of the underwater vehicle. Then, the interference magnetic field will seriously affect the accuracy of geomagnetic field measurement, which directly affects the accuracy of geomagnetic matching aided navigation. Therefore, improving the accuracy of geomagnetic measurements inside the vehicle through error compensation has become one of the most difficult problems that requires an urgent solution in geomagnetic matching aided navigation. In order to solve this problem, this paper establishes the calculation model of the internal magnetic field of the underwater vehicle and the geomagnetic measurement error model of the ship-borne magnetometer. Then, a compensation method for the geomagnetic measurement error of the ship-borne magnetometer, based on the constrained total least square method, is proposed. To verify the effectiveness of the method proposed in this paper, a simulation experiment of geomagnetic measurement and compensation of a ship-borne three-axis magnetometer was constructed. Among them, to be closer to the real situation, a combination of the geomagnetism model, the elliptic shell model and the magnetic dipole model was used to simulate the internal magnetic field of the underwater vehicle. The experimental results indicated that the root mean square error of geomagnetic measurement in an underwater vehicle was less than 5 nT after compensation, and the accuracy of geomagnetic measurement met the requirements of geomagnetic matching aided navigation.

Temporal control in shell-core structured nanofilm for tracheal cartilage regeneration: synergistic optimization of anti-inflammation and chondrogenesis.

Cartilage tissue engineering offers hope for tracheal cartilage defect repair. Establishing an anti-inflammatory microenvironment stands as a prerequisite for successful tracheal cartilage restoration, especially in immunocompetent animals. Hence, scaffolds inducing an anti-inflammatory response before chondrogenesis are crucial for effectively addressing tracheal cartilage defects. Herein, we develop a shell-core structured PLGA@ICA-GT@KGN nanofilm using poly(lactic-co-glycolic acid) (PLGA) and icariin (ICA, an anti-inflammatory drug) as the shell layer and gelatin (GT) and kartogenin (KGN, a chondrogenic factor) as the core via coaxial electrospinning technology. The resultant PLGA@ICA-GT@KGN nanofilm exhibited a characteristic fibrous structure and demonstrated high biocompatibility. Notably, it showcased sustained release characteristics, releasing ICA within the initial 0 to 15 days and gradually releasing KGN between 11 and 29 days. Subsequent in vitro analysis revealed the potent anti-inflammatory capabilities of the released ICA from the shell layer, while the KGN released from the core layer effectively induced chondrogenic differentiation of bone marrow stem cells (BMSCs). Following this, the synthesized PLGA@ICA-GT@KGN nanofilms were loaded with BMSCs and stacked layer by layer, adhering to a 'sandwich model' to form a composite sandwich construct. This construct was then utilized to repair circular tracheal defects in a rabbit model. The sequential release of ICA and KGN facilitated by the PLGA@ICA-GT@KGN nanofilm established an anti-inflammatory microenvironment before initiating chondrogenic induction, leading to effective tracheal cartilage restoration. This study underscores the significance of shell-core structured nanofilms in temporally regulating anti-inflammation and chondrogenesis. This approach offers a novel perspective for addressing tracheal cartilage defects, potentially revolutionizing their treatment methodologies.

Inhaled immunoantimicrobials for the treatment of chronic obstructive pulmonary disease.

Effective therapeutic modalities and drug administration strategies for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations are lacking. Here, mucus and biofilm dual-penetrating immunoantimicrobials (IMAMs) are developed for bridging antibacterial therapy and pro-resolving immunotherapy of COPD. IMAMs are constructed from ceftazidime (CAZ)-encapsulated hollow mesoporous silica nanoparticles (HMSNs) gated with a charge/conformation-transformable polypeptide. The polypeptide adopts a negatively charged, random-coiled conformation, masking the pores of HMSNs to prevent antibiotic leakage and allowing the nebulized IMAMs to efficiently penetrate the bronchial mucus and biofilm. Inside the acidic biofilm, the polypeptide transforms into a cationic and rigid α helix, enhancing biofilm retention and unmasking the pores to release CAZ. Meanwhile, the polypeptide is conditionally activated to disrupt bacterial membranes and scavenge bacterial DNA, functioning as an adjuvant of CAZ to eradicate lung-colonizing bacteria and inhibiting Toll-like receptor 9 activation to foster inflammation resolution. This immunoantibacterial strategy may shift the current paradigm of COPD management.

Impact of CT-guided hookwire localization on tumor spread through air spaces in stage IA lung adenocarcinoma.

Background: It remains undetermined whether preoperative computed tomography (CT)-guided hookwire localization would result in elevated risk of tumor spread through air spaces (STAS) in stage IA lung adenocarcinoma. Methods: A total of 1836 patients who underwent lobectomy were included. To eliminate the potential impact of confounding factors on producing STAS, propensity score-matching (PSM) was used to create two balanced subgroups stratified by implementation of hookwire localization. We also introduced an external cohort including 1486 patients to explore the effect of hookwire localization on the incidence of STAS and patient survival after sublobar resection (SR). For proactive simulation of hookwire localization, 20 consecutive lobectomy specimens of p-stage IA lung adenocarcinoma were selected. Results: Ex vivo tests revealed that mechanical artifacts presenting as spreading through a localizer surface (STALS) could be induced by hookwire localization but be distinguished by CD68 and AE1/3 antibody-based immunohistochemistry. The distance of STALS dissemination tended to be shorter compared with real STAS (P = 0.000). After PSM, implementation of hookwire localization was not associated with elevated STAS incidence, nor worse survival in p-stage IA patients undergoing lobectomy irrespective of STAS. Conclusions: CT-guided hookwire localization might induce mechanical artifacts presenting as STALS which could be distinguished by immunohistochemistry, but would not affect survival in p-stage IA disease. Surgeons can be less apprehensive about performing hookwire localization in relation to STAS on stage IA disease suitable for SR.

GIMAP7 inhibits epithelial-mesenchymal transition and glycolysis in lung adenocarcinoma cells via regulating the Smo/AMPK signaling pathway.

BACKGROUND: GTPase immunity-associated protein 7 (GIMAP7) has been previously recognized as a prognostic marker in pan-cancer. Our objective was to explore the function of GIMAP7 in the progression of lung adenocarcinoma (LUAD). METHODS: GIMAP7 was overexpressed by transfection with GIMAP7 plasmid, and knocked down using siRNAs. The biological functions of GIMAP7 were examined by employing CCK-8, EdU, colony formation, flow cytometry, wound healing, and transwell assays. The effects of GIMAP7 on the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), lactate production, and glucose uptake were evaluated. In addition, the related mRNA and protein expression was detected employing immunohistochemical, western blot, and qRT-PCR. A xenograft tumor model was established in nude mice to evaluate the effects of GIMAP7 on tumor growth. RESULTS: GIMAP7 was lowly expressed in LUAD tissues and cells. GIMAP7 inhibited the proliferation, mobility, EMT, glycolysis, but promoted apoptosis in LUAD cells. Moreover, we also confirmed that GIMAP7 suppressed Smo/AMPK signaling in LUAD cells. By adding the Smo agonist SAG and AMPK agonist GSK621, the results of rescue experiments further verified that GIMAP7 played a role in LUAD inhibition through inhibition of the Smo/AMPK signaling pathway. Furthermore, the role of GIMAP7 in inhibiting tumor growth was verified in vivo. CONCLUSIONS: These results demonstrate that GIMAP7 could inhibit cell proliferation, mobility and glycolysis, but accelerate apoptosis via repressing the Smo/AMPK signaling pathway in LUAD.