Efficacy of befotertinib in non-small cell lung cancer harboring uncommon compound EGFR mutations G719X and S768I: a case report.

The discovery of epidermal growth factor receptor (EGFR) somatic mutations and the availability of tyrosine kinase inhibitors (TKIs) as targeted therapies have transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC). p.G719X and p.S768I mutations, often present in the form of complex mutations, are considered rare. This study firstly reported the treatment outcome of a locally advanced unresectable NSCLC patient with a rare complex EGFR p.G719X/p.S768I mutations who received befotertinib. After treatment, the patient achieved partial response (PR), and no severe adverse events were observed. This case report supported befotertinib as a promising treatment option for advanced NSCLC patients with the rare p.G719X/p.S768I complex mutations.

NeoSCORE II: three vs four cycles of neoadjuvant sintilimab + chemotherapy for squamous non-small-cell lung cancer.

Immune checkpoint inhibitors (ICIs) plus chemotherapy has demonstrated efficacy in resectable non-small-cell lung cancer (NSCLC), yet the optimal period of neoadjuvant immunochemotherapy is undetermined. In a phase II study (neoSCORE, NCT04459611), more neoadjuvant therapy cycles appeared to provide greater pathological remission, and patients with squamous NSCLC had a better major pathological response rate than those with nonsquamous NSCLC. Sintilimab, a monoclonal anti-PD-1 antibody, has shown encouraging antitumor activity and safety in multiple cancers, including NSCLC. Here, we describe the study design of neoSCORE II (NCT05429463), a randomized, open-label, multicenter phase III trial comparing the efficacy and safety of three cycles with four cycles of neoadjuvant sintilimab plus platinum-based chemotherapy in resectable stage IIA-IIIB squamous NSCLC. Trial registration number: NCT05429463 (ClinicalTrials.gov).

Research progress on plant functional traits in agroecosystems.

Plant functional traits have an essential role in community formation and ecosystem function. Unlike natu-ral ecosystems, agroecosystems are affected by natural conditions and human management. Plant (i.e., crop)functional traits in the agroecosystems are thus shaped by natural and human selection. We reviewed the development of functional trait research, focusing on crop functional traits, research methods of agroecosystems based on traits, and the application of functional traits in agriculture. We then elaborated on the effect of domestication on crop trait trade-offs, the relationship between community functional structure and agroecosystem services, and the application of functional traits in weed management, cover cropping, and intercropping systems. Future research directions of crop functional traits include enriching the types of agroecosystems and crop species in studies, buil-ding up a crop functional trait database, and focusing on agroecosystem multifunctionality.

Tissue-resident CD69+ CXCR6+ Natural Killer cells with exhausted phenotype accumulate in human non-small cell lung cancer.

Natural killer (NK) cells with tissue-residency features (trNK cells) are a new subpopulation of NK cells, which plays an important role in tissue homeostasis. However, the characteristics of trNK cells in the tumor microenvironment (TME) of human cancers remain unclear. Using multicolor flow cytometry, we investigated the quantity, phenotype, and function of trNK cells in biospecimens freshly resected from 60 non-small cell lung cancer (NSCLC) patients. We successfully identified a new CD69+ CXCR6+ trNK subset with an immunomodulatory-like and exhausted phenotype, specifically accumulated in the TME of NSCLC. In vitro experiments showed that CD69+ CXCR6+ trNK cells more readily secreted IFN-γ and TNF-α spontaneously. Furthermore, the production of IFN-γ and TNF-α by tumor-infiltrating CD69+ CXCR6+ trNK cells was not induced by their reactivation in vitro, which is analogous to T-cell exhaustion. Finally, we demonstrated that the dysfunction of CD69+ CXCR6+ trNK cells could be partly ameliorated by PD-1 and CTLA-4 blockade. In summary, we identified a new dysfunctional CD69+ CXCR6+ trNK cell subset that specifically accumulates in the TME of NSCLC. Our findings suggest that CD69+ CXCR6+ trNK cells are a promising target for immune checkpoint inhibitors in the treatment of NSCLC.

Using aquatic animals as partners to increase yield and maintain soil nitrogen in the paddy ecosystems.

Whether species coculture can overcome the shortcomings of crop monoculture requires additional study. Here, we show how aquatic animals (i.e. carp, crabs, and softshell turtles) benefit paddy ecosystems when cocultured with rice. Three separate field experiments and three separate mesocosm experiments were conducted. Each experiment included a rice monoculture (RM) treatment and a rice-aquatic animal (RA) coculture treatment; RA included feed addition for aquatic animals. In the field experiments, rice yield was higher with RA than with RM, and RA also produced aquatic animal yields that averaged 0.52-2.57 t ha-1. Compared to their corresponding RMs, the three RAs had significantly higher apparent nitrogen (N)-use efficiency and lower weed infestation, while soil N contents were stable over time. Dietary reconstruction analysis based on 13C and 15N showed that 16.0-50.2% of aquatic animal foods were from naturally occurring organisms in the rice fields. Stable-isotope-labeling (13C) in the field experiments indicated that the organic matter decomposition rate was greater with RA than with RM. Isotope 15N labeling in the mesocosm experiments indicated that rice used 13.0-35.1% of the aquatic animal feed-N. All these results suggest that rice-aquatic animal coculture increases food production, increases N-use efficiency, and maintains soil N content by reducing weeds and promoting decomposition and complementary N use. Our study supports the view that adding species to monocultures may enhance agroecosystem functions.

Monoculture, where only one type of crop is grown to the exclusion of any other organism, is a pillar of modern agriculture. Yet this narrow focus disregards how complex inter-species interactions can increase crop yield and biodiversity while decreasing the need for fertilizers or pesticides. For example, many farmers across Asia introduce carps, crabs, turtles or other freshwater grazers into their rice paddies. This coculture approach yields promising results but remains poorly understood. In particular, it is unclear how these animals' behaviours and biological processes benefit the ecosystem. To examine these questions, Guo, Zhao et al. conducted three separate four-year field experiments; they compared rice plots inhabited by either carp, mitten crabs or Chinese softshell turtles with fields where these organisms were not present. With animals, the rice paddies had less weeds, better crop yields and steady levels of nitrogen (a natural fertiliser) in their soil. These ecosystems could breakdown organic matter faster, use it better and had a reduced need for added fertilizer. While animal feed was provided in the areas that were studied, carp, crabs and turtles obtained up to half their food from the field itself, eating weeds, algae and pests and therefore reducing competition for the crops. This work helps to understand the importance of species interactions, showing that diversifying monocultures may boost yields and make agriculture more sustainable.

A multidisciplinary collaborative model based on single-port thoracoscopy for the treatment of giant mediastinal lymph node hyperplasia: a case report.

Mediastinal unicentric Castleman disease (UCD) frequently manifests as a hyper-enhancing lymph node mass and is often surgically curable. However, because of excessive vascularisation and adhesion to important surrounding structures, surgery is often associated with severe haemorrhage that is often difficult to control thoracoscopically. Therefore, thoracotomy is often preferred, which increases the trauma to the patient and affects postoperative recovery. Here, we describe the case of a 30-year-old male patient with a large upper mediastinal lymph node (7 × 5 × 4 cm) that was compressing his superior vena cava. The distribution of nutritive arteries of the mass was analysed in detail, and the main branches were embolised prior to surgery. With the assistance of preoperative isovolumetric haemodilution, we achieved complete resection through single-port thoracoscopy, with only minor haemorrhage, which enabled the patient to recover rapidly. This multidisciplinary collaborative model, based on single-port thoracoscopic surgery, may be of wide practical use for the treatment of mediastinal UCD.

ZNF655 is involved in development and progression of non-small-cell lung cancer.

AIMS: Non-small cell lung cancer (NSCLC) is a malignant tumor with high mortality, which seriously endangers human health. The clinical significance, biological function and potential mechanism of Zinc finger protein 655 (ZNF655) in NSCLC are discussed in this study. MATERIALS AND METHODS: The expression level of ZNF655 in NSCLC was clarified by immunohistochemical (IHC) staining. Subsequently, lentivirus-mediated shRNA was used to construct ZNF655 knock down NSCLC cells NCI-H1299 and A549. In vitro and in vivo loss of function assays were used to evaluate the malignant behaviors of the cells. KEY FINDINGS: The expression level of ZNF655 was abnormally abundant in NSCLC. The decrease of ZNF655 expression led to the inhibition of the malignant behaviors of NSCLC, which was manifested by weakened proliferation, increased sensitivity to apoptosis, cycle repression at G2 and weakened migration. Consistently, downregulation of ZNF655 reduced tumorigenesis in mouse xenograft model. Moreover, decreased expression of ZNF655 resulted in upregulated expression of Bad, Bax, Fas, p21, p27, Caspase 3 and Caspase 8 in NSCLC cells. NCI-H1299 cells with ZNF655 knockdown resulted in decreased phosphorylation of Akt, downregulation of CDK6 and PIK3CA, and upregulation of MAPK9. Collectively, ZNF655 may regulate apoptosis of NSCLC cells through PI3K/Akt and p53 signaling pathways. SIGNIFICANCE: ZNF655 possessed a promoting effect in the progression of NSCLC, which may serve as a promising molecular target for clinical treatment.

CD38 identifies pre-activated CD8+ T cells which can be reinvigorated by anti-PD-1 blockade in human lung cancer.

BACKGROUND: CD38 has been observed expressing in activated T cells, while the features and functions of CD38+ T cells in human NSCLC are still unclear. METHODS: Here we uncovered the correlation between CD38 expression and survival and immune infiltration levels in tumor of NSCLC. Then, we collected samples from 51 NSCLC patients to study the biological feature and response to anti-PD-1 of tumor-infiltrating CD38+ CD8+ T cells in vitro. RESULTS: We found CD38 expression correlated with the survival and immune infiltration levels of NSCLC. It is interesting that CD38+ CD8+ T cells enriched in the tumors expressed higher level of cytotoxic molecule, cytokines and PD-1 than CD38- CD8+ T cells. Moreover, PD-1+ subset in tumor-infiltrating CD38+ CD8+ T cells expressed higher level of activated markers than PD-1+ CD38- CD8+ T cells. Next, we found tumor-infiltrating CD38+ CD8+ T cells expressed higher level of CD103, IFN-γ, TNF-α and perforin than CD38- CD8+ T cells when were reactivated in vitro. Finally, we observed that CD38+ CD8+ T cells isolated from tumors could be reinvigorated by anti-PD-1 in vitro. CONCLUSIONS: Our findings demonstrate that CD38 expression defines a subset of CD8+ T cells enriched in tumors of NSCLC which have paradoxical phenotypes and response to anti-PD-1. Our results suggest a pre-priming of these cells is may exist in tumor and consequentially facilitate it acquiring both anti-tumor potency and exhausted phenotype which can be reinvigorated by PD-1 blockade.

The maintenance of stable yield and high genetic diversity in the agricultural heritage torreya tree system.

BACKGROUND: Understanding how traditional agriculture systems have been maintained would help design sustainable agriculture. In this study, we examined how farmers have used two types of local trees (Torreya grandis) for stable yield and maintaining genetic diversity in the "globally important agricultural heritage torreya tree system". The two type of torreya trees are grafted torreya (GT) tree and non-grafted-torreya (NGT) tree. The GT tree has only female and was used to produced seed yields. The NGT tree has both male and female and was used to support GT tree by providing pollens and rootstocks. We first tested the ratio of GT tree to NGT tree, their age groups, ratio of female trees (including GT and NGT trees) to male, and the flowering period of GT and NGT trees. We then tested seed yields and genetic diversity of GT and NGT trees. We further tested gene flow among NGT trees, and the relationship of gene flow with exchange rates of pollens and seeds. RESULTS: GT and NGT trees (male and female) were planted in a mosaic pattern with a ratio of 4:1 (GT:NGT). In this planting pattern, one NGT male trees provided pollen for 20 female trees of GT and NGT. The trees were classified into four age groups (I = 100-400 years old; II = 400-700 years old; III = 700-1000 years old; and IV = 1000-1300 years old) based on basal diameter. The entire flowering period was longer for NGT trees than for GT trees that ensured GT trees (which lack of males) being exposed to pollens. GT tree had high and stable seed yield that increased with age groups. High genetic diversity has been maintained in both rootstocks of the GT trees and NGT trees. There was a strong gene flow among NGT trees, which positive correlated with the exchange rates of pollens and seeds. CONCLUSIONS: Our results suggest that farmers obtain stable seed yields, and maintain high genetic diversity by ingeniously using the local GT tree as yield producer and NGT tree as supporter. These GT and NGT trees together ensure sustainable torreya production.

Mechanism of VIPR1 gene regulating human lung adenocarcinoma H1299 cells.

The vasoactive intestinal peptide receptor-1(VIPR1) has prominent growth effects on a number of common neoplasms. However, there were contradictions in the effect cross different cancers. We aimed to explore the effect of VIPR1 overexpression on a human lung adenocarcinoma cell line H1299. GEO dataset was used to screen differentially expressed genes in lung adenocarcinoma tissues. The expression of VIPR1 mRNA was determined in the cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to determine VIPR1 protein expression in lung adenocarcinoma and corresponding adjacent tissues (n = 22). Fluorescence real-time quantitative PCR detected the expression of VIPR1 in human normal lung epithelial cell line BEAS-2B and lung adenocarcinoma cell line H1299. Overexpression strategies were employed to assess functions of VIPR1 expression on several malignant phenotypes in H1299. The expression of VIPR1 was lower in lung adenocarcinoma tissues than that in adjacent tissues. Compared with the normal lung epithelial cells BEAS-2B, VIPR1 was down-regulated in lung cancer cells H1299 (P < 0.05). After the overexpression of VIPR1, we found that VIPR1 significantly inhibited growth, migration, and invasion of H1299 cells (P < 0.05). Our findings point out the tumor suppressor roles of VIPR1 in human LUAD pathogenesis.

CD8+ T Cells Form the Predominant Subset of NKG2A+ Cells in Human Lung Cancer.

Background: NKG2A is an inhibitory receptor of both T cells and natural killer (NK) cells. Persistent activation promotes T cells and NK cells to express NKG2A and results in the progression of chronic infection and cancer. However, the characteristics and subsets of NKG2A+ lymphocytes in human lung cancer are still unclear. Methods: Here, we used the Tumor Immune Estimation Resource database and immune profiling of paired biospecimens to uncover the correlation between NKG2A expression and immune infiltration levels in human cancer as well as the characteristics of NKG2A+ lymphocytes in human lung cancer. Results: We found that KLRC1 expression was especially correlated with CD8+ T-cell infiltration levels in 34 types of human cancer through the Tumor Immune Estimation Resource database. Moreover, NKG2A+ CD8+ T cells were the predominant subset of NKG2A+ lymphocytes in human lung cancer. In contrast, the NKG2A+ NK cells were decreased in tumors compared with the paired normal lung tissue. Tumor-infiltrating NKG2A+ CD8+ T cells expressed tissue-resident memory T cell (TRM cell) and exhausted T-cell markers. Cytokines and cytotoxic molecules secreted by tumor-infiltrating NKG2A+ CD8+ T cells were significantly lower than those secreted by NKG2A- CD8+ T cells in vitro. When stimulated with T-cell receptor activator, tumor-infiltrating NKG2A+ CD8+ T cells could secrete large amounts of granzyme B. Conclusions: Our findings demonstrate that tumor-infiltrating NKG2A+ CD8+ T cells form the predominant subset of NKG2A+ cells in human lung cancer and suggest that targeting NKG2A+ CD8+ T cells is a promising approach for future anti-lung cancer immunotherapy.

Risk factors of lymph node metastasis in lung squamous cell carcinoma of 3 cm or less in diameter.

Through literature review we cannot find an efficient risk factor of lymph node metastasis in lung squamous cell carcinoma (SCC). This study aimed to investigate the risk factors of pathological lymph node status in patients with lung SCC of 3 cm or less in diameter, to provide some reference for the fellow surgeons in the decision of operative option.In total, we analyzed 154 patients with lung SCC of 3 cm or less in diameter who underwent lobectomy or bilobectomy or pneumonectomy with systematic lymph node dissection. The relationship between lymph node status and clinical characteristics were examined.Lymph node metastases were present in 48 patients (31.2%) of the study subjects. Multivariate analysis indicated that, age <60 years old (P = .007), tumor location of central-type (P = .003), tumor long axis >2 cm but ≤3 cm (P = .047) were associated with lymph node metastasis, and their odd ratios (OR) were 3.120, 3.359, and 5.196, respectively. Group analysis of the 74 peripheral lung SCC showed that those with the tumor long axis ≤2 cm had a lower rate of lymph node metastasis (7.9% vs 27.8%, P = .025).Age <60 years old, tumor location of central-type, and tumor long axis >2 cm but ≤3 cm are risk factors of lymph node metastasis in lung SCC. Systematic lymph node dissection or sampling is recommended when tumor central-type location and/or long axis >2 cm in lung SCC are present.

Left bronchial isomerism in a lung cancer patient undergoing right upper pulmonary lobectomy via a thoracoscope.

Left bronchial isomerism is a rare condition characterized by a bronchial structure on the right side that is a mirror image of the left side. In this report, we record our experience with a 62-year-old female lung cancer patient in whom left bronchial isomerism was discovered during surgery using a thoracoscope. A right upper pulmonary lobectomy was successfully completed, the key to which was successful separation of the right upper and middle lobes. As there is a risk of excising the wrong bronchi in such cases, thoracic surgeons need to identify bronchus variations. The optimal method to do this is to use a bronchoscope and computed tomography images of the bronchial tree reconstruction prior to surgery.

Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis: a meta-analysis.

BACKGROUND: Tumor-associated macrophages (TAMs) play a crucial role in the regulation of local inflammatory and immune response of tumor microenvironment, being associated with worse outcome of several solid tumors. But the prognostic value of tumor-infiltrating TAMs in lung cancer is still controversial. METHODS: We conduct a meta-analysis of 3055 patients in 21 studies searched from PubMed and Medline to investigate the correlation between tumor-infiltrating TAMs, including distinct TAM subsets and tissue distribution, and survival of lung cancer. Survival data were computed into odds ratios (ORs) and pooled using Mantel-Haenszel random-effect model. All statistical tests were two-sided. RESULTS: High density of tumor-infiltrating TAMs was significantly associated with worse overall survival (OS) at 3 years (OR = 2.45, 95% CI = 1.25 to 4.80, P = 0.009) and 5 years (OR = 2.04, 95% CI = 1.03 to 4.01, P = 0.04) of lung cancer. Results for disease free survival (DFS) were similar. M2 subset was associated with worse 3 year-OS and 5 year-OS, whereas M1 subset was associated with better 3-year OS and 5-year OS. Elevated TAM density in tumor stroma was associated with worse OS at 3 years and 5 years, while elevated TAMs in tumor islet/tumor stroma were associated with better OS at 3 years and 5 years. CONCLUSIONS: Increased tumor-infiltrating TAMs are associated with poor prognosis of lung cancer. M2 subset and TAMs in tumor stroma were associated with worse survival, while M1 subset and TAMs in tumor islet were associated with favorable survival of lung cancer.

Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis.

Accumulated studies have provided controversial evidences of the association between signal transducer and activator of transcription proteins 3 (STAT3) expression and survival of human solid tumors. To address this inconsistency, we performed a meta-analysis with 63 studies identified from PubMed, Medline and EBSCO. We found STAT3 overexpression was significantly associated with worse 3-year overall survival (OS) (OR = 2.06, 95% CI = 1.57 to 2.71, P < 0.00001) and 5-year OS (OR = 2.00, 95% CI = 1.53 to 2.63, P < 0.00001) of human solid tumors. Similar results were observed when disease free survival (DFS) were analyzed. Subgroup analysis showed that elevated STAT3 expression was associated with poor prognosis of gastric cancer, lung cancer, gliomas, hepatic cancer, osteosarcoma, prostate cancer, pancreatic cancer but better prognosis of breast cancer. The correlation between STAT3 and survival of solid tumors was related to its phosphorylated state. High expression level of STAT3 was also associated with advanced tumor stage. In conclusion, elevated STAT3 expression is associated with poor survival in most solid tumors. STAT3 is a valuable biomarker for prognosis prediction and a promising therapeutic target in human solid tumors.

NF-κB Expression and Outcomes in Solid Tumors: A Systematic Review and Meta-Analysis.

Nuclear factor-kappaB (NF-κB) is a key inflammatory transcription factor expressed frequently in tumors. Numerous studies have investigated the correlation between NF-κB expression and prognosis in solid tumors, but the conclusions are still in contradiction. Here, we conduct a meta-analysis to explore the overall association of NF-κB overexpression and survival in human solid tumors. Pubmed and EBSCO databases were searched for studies evaluating expression of NF-κB (as measured by immunohistochemistry) and overall survival (OS) and disease-free survival (DFS) in solid tumors. Published data were extracted and computed into odds ratios (ORs) for death at 3, 5, and 10 years. Data were pooled using the Mantel-Haenszel random-effect model. All statistical tests were two-sided. Forty-four studies with a total of 4418 patients were included in this meta-analysis. NF-κB overexpression was associated with worse OS at 3 years (OR = 3.40, 95% confidence interval [CI]  = 2.41-4.79, P < 0.00001), 5 years (OR = 2.72, 95% CI = 1.92-3.85, P < 0.00001), and 10 years (OR = 2.63, 95% CI =  .34-5.16, P = 0.005) of solid tumors. Results for 3- and 5-year DFS were similar. NF-κB expression was associated with poor 3-year OS in both Tumor, Lymph Node, Metastasis stage I-II (OR = 9.11, 95% CI = 2.90-28.68, P = 0.0002) and III-IV (OR = 2.59, 95% CI = 1.61-4.15, P < 0.0001). There is no correlation between cellular localization of NF-kB overexpression and OS of solid tumors. Among the tumor types, NF-κB was associated with worse 3 year-OS of colorectal cancer (OR = 2.70, 95% CI = 1.64-4.46, P < 0.0001), esophageal carcinoma (OR = 6.00, 95% CI = 3.29-10.94, P < 0.0001) and worse 5 year-OS of colorectal cancer (OR = 2.72, 95% CI = 1.92-3.85, P < 0.00001), esophageal carcinoma (OR = 5.96, 95% CI = 3.48-10.18, P = 0.03), and nonsmall cell lung cancer (OR = 1.69, 95% CI = 1.20-2.38, P = 0.002). Expression of NF-κB is associated with worse survival in most solid tumors irrespective of NF-κB localization.

Minimally invasive esophageal resection and intrathoracic anastomosis for lower thoracic esophageal cancer with single position.

There are various esophagectomy approaches for lower thoracic esophageal cancer, and the minimally invasive esophagectomy (MIE) approach shows the advantages of less discomfort, shorter length of stay and a faster recovery to baseline status than open approaches. The current study reports a case of lower thoracic esophageal cancer was treated using a single-position, minimally invasive surgical technique with laparoscopy and thoracoscopy. A 68-year-old man, whose gastroscopy identified the esophageal carcinoma, came to our medical center due to dysphagia for over 1 year. The patient underwent tumor radical resection and intrathoracic anastomosis by laparoscopy and thoracoscopy with single position. The patient has recovered well after the surgery.