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.

Applications of Circulating Tumor DNA in Myelodysplastic Syndromes and Acute Myeloid Leukemia: Promises and Challenges.

The term 'liquid biopsy' has become widely used by clinicians with the development of non-invasive diagnostic and monitoring techniques for malignancies. Liquid biopsy can provide genetic information for early diagnosis, risk stratification, treatment selection and postoperative follow-up. In the era of personalized medicine, liquid biopsy is an important research direction. In recent years, research on circulating tumour DNA (ctDNA) in hematological malignancies has also made great progress. This review provides an overview of the current understanding of circulating tumour DNA in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Additionally, recent advancements in the monitoring of minimal/measurable residual disease (MRD) through ctDNA are discussed.

Pan-mediastinal neoplasm diagnosis via nationwide federated learning: a multicentre cohort study.

BACKGROUND: Mediastinal neoplasms are typical thoracic diseases with increasing incidence in the general global population and can lead to poor prognosis. In clinical practice, the mediastinum's complex anatomic structures and intertype confusion among different mediastinal neoplasm pathologies severely hinder accurate diagnosis. To solve these difficulties, we organised a multicentre national collaboration on the basis of privacy-secured federated learning and developed CAIMEN, an efficient chest CT-based artificial intelligence (AI) mediastinal neoplasm diagnosis system. METHODS: In this multicentre cohort study, 7825 mediastinal neoplasm cases and 796 normal controls were collected from 24 centres in China to develop CAIMEN. We further enhanced CAIMEN with several novel algorithms in a multiview, knowledge-transferred, multilevel decision-making pattern. CAIMEN was tested by internal (929 cases at 15 centres), external (1216 cases at five centres and a real-world cohort of 11 162 cases), and human-AI (60 positive cases from four centres and radiologists from 15 institutions) test sets to evaluate its detection, segmentation, and classification performance. FINDINGS: In the external test experiments, the area under the receiver operating characteristic curve for detecting mediastinal neoplasms of CAIMEN was 0·973 (95% CI 0·969-0·977). In the real-world cohort, CAIMEN detected 13 false-negative cases confirmed by radiologists. The dice score for segmenting mediastinal neoplasms of CAIMEN was 0·765 (0·738-0·792). The mediastinal neoplasm classification top-1 and top-3 accuracy of CAIMEN were 0·523 (0·497-0·554) and 0·799 (0·778-0·822), respectively. In the human-AI test experiments, CAIMEN outperformed clinicians with top-1 and top-3 accuracy of 0·500 (0·383-0·633) and 0·800 (0·700-0·900), respectively. Meanwhile, with assistance from the computer aided diagnosis software based on CAIMEN, the 46 clinicians improved their average top-1 accuracy by 19·1% (0·345-0·411) and top-3 accuracy by 13·0% (0·545-0·616). INTERPRETATION: For mediastinal neoplasms, CAIMEN can produce high diagnostic accuracy and assist the diagnosis of human experts, showing its potential for clinical practice. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth.

Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC). SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 potently inhibited cell proliferation, cell cycle progression, migration and viability. The dual inhibitor induced mitochondrial depolarization and apoptosis activation in NSCLC cells, but it was non-cytotoxic to human lung epithelial cells. SKI-349 inhibited SphK activity and induced ceramide accumulation in primary NSCLC cells, without affecting SphK1/2 expression. SKI-349-induced NSCLC cell death was attenuated by sphingosine-1-phosphate and by the SphK activator K6PC-5, but was potentiated by the short-chain ceramide C6. Moreover, SKI-349 induced Akt-mTOR inactivation, JNK activation, and oxidative injury in primary NSCLC cells. In addition, SKI-349 decreased bromodomain-containing protein 4 (BRD4) expression and downregulated BRD4-dependent genes (Myc, cyclin D1 and Klf4) in primary NSCLC cells. At last, SKI-349 (10 mg/kg) administration inhibited NSCLC xenograft growth in nude mice. Akt-mTOR inhibition, JNK activation, oxidative injury and BRD4 downregulation were detected in SKI-349-treated NSCLC xenograft tissues. Taken together, targeting SphK1/2 by SKI-349 potently inhibits NSCLC cell growth in vitro and in vivo.

Nickel-Catalyzed Ipso/Ortho Difunctionalization of Aryl Bromides with Alkynes and Alkyl Bromides via a Vinyl-to-Aryl 1,4-Hydride Shift.

Polysubstituted arenes are ubiquitous structures in a myriad of medicinal agents and complex molecules. Herein, we report a new catalytic blueprint that merges the modularity of nickel catalysis for bond formation with the ability to enable a rather elusive 1,4-hydride shift at arene sp2 C-H sites, thus allowing access to ipso/ortho-difunctionalized arenes from readily available aryl halides under mild conditions and exquisite selectivity profile.

Nickel-catalysed migratory hydroalkynylation and enantioselective hydroalkynylation of olefins with bromoalkynes.

α-Chiral alkyne is a key structural element of many bioactive compounds, chemical probes, and functional materials, and is a valuable synthon in organic synthesis. Here we report a NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that delivers the corresponding benzylic alkynylation products in high yields with excellent regioselectivities. Catalytic enantioselective hydroalkynylation of styrenes has also been realized using a simple chiral PyrOx ligand. The obtained enantioenriched benzylic alkynes are versatile synthetic intermediates and can be readily transformed into synthetically useful chiral synthons.

Extracapsular lymph node involvement is a robust survival predictor in esophageal cancer patients: A pooled analysis.

BACKGROUND: Although extracapsular lymph node involvement (EC-LNI) has been proposed to be incorporated into the staging system of esophageal cancer, the prognostic value of EC-LNI remains controversial with conflicting data available, especially in the era of neoadjuvant therapy. METHODS: An electronic literature search was undertaken using four public databases. Studies investigating the effects of EC-LNI on survival were included. In addition to analysis of the entire cohort, subset analyses were also performed to assess the impact of EC-LNI on patients receiving different treatment modalities. RESULTS: A total of 20 studies were included in this meta-analysis. Pooling 13 studies on overall survival (OS), we observed that presence of EC-LNI was associated with significantly worse OS (HR = 2.09, 95%CI: 1.63-2.68; p < 0.01). Nine studies describing disease-free survival (DFS) included, the pooled data revealed that presence of EC-LNI was associated with significantly worse DFS (HR = 1.89, 95%CI: 1.63-2.20; p < 0.001). Subset analyses of patients receiving neoadjuvant therapy demonstrated a survival disadvantage of EC-LNI on OS (HR = 1.928, 95%CI: 1.196-3.107; p = 0.007) and DFS (HR = 1.985, 95%CI: 1.585-2.487; p < 0.001). Similar result was also seen in patients receiving primary surgery (OS: HR = 2.219, 95%CI: 1.720-2.864; p < 0.001; DFS: HR = 1.659, 95%CI: 1.285-2.141; p < 0.001). CONCLUSION: EC-LNI is a strong prognostic predictor of inferior survival in patients with esophageal cancer irrespective of treatment modality. The currently pooled evidence indicates that EC-LNI has great potential to be incorporated into the future staging system.

Characterization of Tumor Microenvironment in Lung Adenocarcinoma Identifies Immune Signatures to Predict Clinical Outcomes and Therapeutic Responses.

BACKGROUND AND OBJECTIVE: Increasing evidence has elucidated the clinicopathological significance of individual TME component in predicting outcomes and immunotherapeutic efficacy in lung adenocarcinoma (LUAD). Therefore, we aimed to investigate whether comprehensive TME-based signatures could predict patient survival and therapeutic responses in LUAD, and to assess the associations among TME signatures, single nucleotide variations and clinicopathological characteristics. METHODS: In this study, we comprehensively estimated the TME infiltration patterns of 493 LUAD patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathological features of LUADs using two proposed computational algorithms. A TMEscore was then developed based on the TME signature genes, and its prognostic value was validated in different datasets. Bioinformatics analysis was used to evaluate the efficacy of the TMEscore in predicting responses to immunotherapy and chemotherapy. RESULTS: Three TME subtypes were identified with no prognostic significance exhibited. Among them, naïve B cells accounted for the majority in TMEcluster1, while M2 TAMs and M0 TAMs took the largest proportion in TMEcluster2 and TMEcluster3, respectively. A total of 3395 DEGs among the three TME clusters were determined, among which 217 TME signature genes were identified. Interestingly, these signature genes were mainly involved in T cell activation, lymphocyte proliferation and mononuclear cell proliferation. With somatic variations and tumor mutation burden (TMB) of the LUAD samples characterized, a genomic landscape of the LUADs was thereby established to visualize the relationships among the TMEscore, mutation spectra and clinicopathological profiles. In addition, the TMEscore was identified as not only a prognosticator for long-term survival in different datasets, but also a predictive biomarker for the responses to immune checkpoint blockade (ICB) and chemotherapeutic agents. Furthermore, the TMEscore exhibited greater accuracy than other conventional biomarkers including TMB and microsatellite instability in predicting immunotherapeutic response (p < 0.001). CONCLUSION: In conclusion, our present study depicted a comprehensive landscape of the TME signatures in LUADs. Meanwhile, the TMEscore was proved to be a promising predictor of patient survival and therapeutic responses in LUADs, which might be helpful to the future administration of personalized adjuvant therapy.

Comparison of Ivor Lewis and Sweet esophagectomy for middle and lower esophageal squamous cell carcinoma: A systematic review and pooled analysis.

BACKGROUND: Lack of robust evidence highlights the important need to address the controversy on the clinical safety and effectiveness between Ivor Lewis versus Sweet procedure for middle and lower esophageal squamous cell carcinoma (ESCC). METHODS: Search results were filtered according to certain criteria and were analyzed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. FINDINGS: The inter-study heterogeneity was high. Ivor Lewis procedure might be associated with longer operation time (p < 0.01) and higher lymph node yield (p < 0.01) compared with Sweet procedure. There was no significant difference in the length of hospital stay and postoperative complications with similar reoperation rate between the two procedures (p > 0.05). As the combined analysis of survival data revealed, there was no statistical difference in the oncologic efficacy of them (p = 0.97). INTERPRETATION: The present study based on retrospective data with high heterogeneity indicated that Ivor Lewis esophagectomy might be associated with increased lymph node yield but longer operation time than Sweet. Prospective studies are warranted to compare the long-term survival of Ivor Lewis esophagectomy versus Sweet for middle and lower ESCC.

Does the lymph node yield affect survival in patients with esophageal cancer receiving neoadjuvant therapy plus esophagectomy? A systematic review and updated meta-analysis.

BACKGROUND: Conflicting data have been reported on the prognostic impact of the extent of lymphadenectomy during esophagectomy for esophageal cancer (EC) after neoadjuvant therapy, especially after neoadjuvant chemoradiotherapy (nCRT). METHODS: A comprehensive online search was performed to explore the association between increased lymph node yield (LNY) and survival of patients with EC, in which the overall survival (OS) was set as the primary outcome. In addition to analysis of the entire cohort, subgroup analyses of different induction therapy and different populations were also performed. FINDINGS: A total of 19528 patients from twelve studies were included in our study. The pooled data revealed that more lymph node harvested was associated with better OS (HR = 0·87; 95% CI: 0·79-0·95, p < 0·001). Notably, a higher LNY was associated with better OS if the threshold was less than 18. However, more thorough lymphadenectomy might not bring additional survival benefits when it came to a cutoff value more than 18. The subgroup analysis further revealed that a higher LNY after nCRT was associated favorable survival. In terms of subset analysis of different populations, increased LNY was associated with longer OS in Western populations but not in Eastern. INTERPRETATION: Increased LNY during esophagectomy after neoadjuvant therapy, especially after nCRT, might be associated with improved OS. More studies are warranted to assess the survival benefits of a higher LNY receiving neoadjuvant therapy plus esophagectomy, especially in Eastern populations. FUNDING: Supported by the projects from Suzhou Key Laboratory of Thoracic Oncology (SZS201907), Suzhou Key Discipline for Medicine (SZXK201803), the Science and Technology Research Foundation of Suzhou Municipality (SYS2018063, SYS2018064), Municipal Program of People's Livelihood Science and Technology in Suzhou (SS2019061) and Major Project for Social Development, Jiangsu Provincial Department of Science and Technology (SBE2020750085).

Comparison of sublobar resection and lobectomy for patients with small (≤2cm) second primary non-small-cell lung cancer.

BACKGROUND: This study aimed to investigate whether sublobar resection (SR) is equivalent to lobectomy for small (≤ 2 cm) second primary lung cancer (SPLC). METHODS: We identified 834 patients with T1aN0M0 SPLC from the Surveillance, Epidemiology, and End Results (SEER) database during 2000-2016. Overall survival (OS) was compared between lobectomy and SR after propensity-score matching. A total of 228 patients with SPLC were identified from three institutions in China as the validation set. RESULTS: SR was an independent risk factor for patients with 1 to 2 cm SPLC (SR vs Lob: hazard ratio [HR], 1.593; 95% confidence interval [CI], 1.186-2.141; P = .002) but not for patients with SPLC ≤ 1 cm (SR vs Lob: HR, 1.206; 95% CI, 0.790-1.841; P = .385). Subgroup analysis on the SEER data indicated that OS favored lobectomy compared with SR for contralateral SPLC ≤ 2 cm but not for ipsilateral ones (ipsilateral: P = .692; contralateral: P = .030). Our multi-institutional data also revealed that SR was equivalent to lobectomy for patients with ≤2 cm ipsilateral SPLC. CONCLUSIONS: SR is equivalent to lobectomy for SPLC ≤ 1 cm but not for SPLC > 1 to 2 cm. SR might be recommended for patients with ipsilateral small SPLC considering the difficulty in reoperations.

Postoperative short-term outcomes of minimally invasive versus open esophagectomy for patients with esophageal cancer: An updated systematic review and meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis to synthesize the available evidence regarding short-term outcomes between minimally invasive esophagectomy (MIE) and open esophagectomy (OE). METHODS: Studies were identified by searching databases including PubMed, EMBASE, Web of Science and Cochrane Library up to March 2019 without language restrictions. Results of these searches were filtered according to a set of eligibility criteria and analyzed in line with PRISMA guidelines. RESULTS: There were 33 studies included with a total of 13 269 patients in our review, out of which 4948 cases were of MIE and 8321 cases were of OE. The pooled results suggested that MIE had a better outcome regarding all-cause respiratory complications (RCs) (OR = 0.56, 95% CI = 0.41-0.78, P = <0.001), in-hospital duration (SMD = -0.51; 95% CI = -0.78-0.24; P = <0.001), and blood loss (SMD = -1.44; 95% CI = -1.95-0.93; P = <0.001). OE was associated with shorter duration of operation time, while no statistically significant differences were observed regarding other outcomes. Additionally, subgroup analyses were performed for a number of different postoperative events. CONCLUSIONS: Our study indicated that MIE had more favorable outcomes than OE from the perspective of short-term outcomes. Further large-scale, multicenter randomized control trials are needed to explore the long-term survival outcomes after MIE versus OE.

Nickel-Catalyzed Asymmetric Reductive 1,2-Carboamination of Unactivated Alkenes.

Starting from diverse alkene-tethered aryl iodides and O-benzoyl-hydroxylamines, the enantioselective reductive cross-electrophilic 1,2-carboamination of unactivated alkenes was achieved using a chiral pyrox/nickel complex as the catalyst. This mild, modular, and practical protocol provides rapid access to a variety of ß-chiral amines with an enantioenriched aryl-substituted quaternary carbon center in good yields and with excellent enantioselectivities. This process reveals a complementary regioselectivity when compared to Pd and Cu catalysis.