Efficacy and safety of pembrolizumab as first-line treatment for advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease: protocol for a prospective, single-arm, single-center, phase II clinical trial.

Background: The first-line standard treatment option for patients with NSCLC complicated with Chronic obstructive pulmonary disease (COPD) is still unclear and relies on the treatment option of NSCLC alone. To date, a limited number of retrospective studies have explored the efficacy and safety of immunotherapy in patients with NSCLC complicated with COPD. We therefore designed this study to further explore the efficacy and safety of first-line immunotherapy in patients with NSCLC complicated with COPD. Methods: This study was designed as a single-armed, single-center, prospective, phase II clinical study. It will include 30 advanced (stage IV) NSCLC combined with COPD primary treatment subjects. Each subject's diagnosis will be confirmed by clinical, radiographic, pathologic, and pulmonary function evaluation. A fixed dose of 200 mg pembrolizumab will be administered by intravenous infusion on day1 every 3 weeks (Q3W). The management of stable and acute exacerbations of COPD include home oxygen therapy, and the use of conventional medications are also administered. Imaging evaluation will be performed every 6 weeks for 6 months from the first pembrolizumab dose and approximately every 12 weeks thereafter until disease progression or early withdrawal. COPD status will be evaluated every 3 months by pulmonary function, GOLD grading, mMRC score, CAT score, ABCD grouping, and AECOPD severity. The primary outcome is Progression-free survival. The secondary outcome measures include objective response rate, overall survival, rate of acute exacerbations of COPD (times/year), lung function, mMRC score, CAT score, impact of treatment on patient's health-related quality of life, antibiotic use (including duration and classes), and adverse events associated with immune checkpoint inhibitors. Exploratory endpoint is to explore the association between COPD grade and the degree of immune cell (CD4+ T lymphocytes and CD8+ T lymphocytes) infiltration, as well as the association between COPD grade and the efficacy of immune checkpoint inhibitors. Clinical trial registration: ClinicalTrials.gov, identifier NCT05578222.

Impact of chronic obstructive pulmonary disease on the efficacy and safety of neoadjuvant immune checkpoint inhibitors combined with chemotherapy for resectable non-small cell lung cancer: a retrospective cohort study.

BACKGROUND: Neoadjuvant immune checkpoint inhibitors(ICIs) combined with chemotherapy can improve non-small cell lung cancer(NSCLC) patients' pathological responses and show promising improvements in survival. Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease, and its associated abnormal inflammatory response affects not only the immunotherapy efficacy but also immune-related adverse events. It remains unclear whether NSCLC patients with COPD can benefit from neoadjuvant ICIs combined with chemotherapy. METHODS: A retrospective observational clinical study was conducted on 105 consecutive NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy at the Department of Thoracic Surgery of Tianjin Chest Hospital between April 2020 and April 2023. RESULTS: A total of 74 NSCLC patients were included in the study, including 30 patients with COPD and 44 patients without COPD. The percentage of patients with a pathological complete response (PCR) was higher in the COPD group than in the non-COPD group (43.3% vs. 20.5%, P = 0.042). Multivariate logistic regression analysis of factors associated with PCR showed that the adjusted odds ratio (OR) was statistically significant for presence of COPD (OR = 3.020, 95%CI: 1.042-8.757; P = 0.042). Major pathological response (66.7% vs. 50%, P = 0.155), R0 resection rate (96.7% vs.93.2%, P = 0.642), N2 lymph node downstaging(92.3% vs. 66.7%, P = 0.182) and objective response rate (70% vs. 63.6%, P = 0.57) were not significantly different between the groups. Progression-free survival(PFS) was not reached in the COPD group and 17 months (95%CI: 12.1-21.9) in the non-COPD group, with statistically significance (χ2 = 6.247, P = 0.012). Multivariate Cox's regression analysis showed that the adjusted hazard ratio (HRadj) was statistically significant for presence of COPD (HRadj = 0.321, 95%CI: 0.111-0.930; P = 0.036). The grade 3 and grade 4 adverse events in the COPD group were leukopenia (3.3%, 6.7%), neutropenia (3.3%, 6.7%), fatigue (6.7%, 0%), gastrointestinal reactions (3.3%, 0%), and hypothyroidism (3.3%, 0%). In the non-COPD group, the corresponding adverse events were leukopenia (6.8%, 6.8%), neutropenia (3.3%, 6.8%), fatigue (2.3%, 0%), gastrointestinal reactions (2.3%, 0%), and hypothyroidism (2.3%, 0%), respectively. CONCLUSIONS: The present study indicates that the presence of COPD may improve PCR, prolong PFS, and have an acceptable safety profile in NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy.

Revisiting maize Brittle endosperm-2 reveals new insights in BETL development and starchy endosperm filling.

Rerouting the starch biosynthesis pathway in maize can generate specialty types, like sweet corn and waxy corn, with a drastically increasing global demand. Hence, a fine-tuning of starch metabolism is relevant to create diverse maize cultivars for end-use applications. Here, we characterized a new maize brittle endosperm mutant, referred to as bt1774, which exhibited decreased starch content but a dramatic increase of soluble sugars at maturity. Both endosperm and embryo development was impaired in bt1774 relative to the wild-type (WT), with a prominently arrested basal endosperm transfer layer (BETL). Map-based cloning revealed that BRITTLE ENDOSPERM2 (Bt2), which encodes a small subunit of ADP-glucose pyrophosphorylase (AGPase), is the causal gene for bt1774. A MuA2 element was found to be inserted into intron 2 of Bt2, leading to a severe decrease of its expression, in bt1774. This is in line with the irregular and loosely packed starch granules in the mutant. Transcriptome of endosperm at grain filling stage identified 1,013 differentially expressed genes in bt1774, which were notably enriched in the BETL compartment, including ZmMRP1, Miniature1, MEG1, and BETLs. Gene expression of the canonical starch biosynthesis pathway was marginally disturbed in bt1774. Combined with the residual 60 % of starch in this nearly null mutant of Bt2, this data strongly suggests that an AGPase-independent pathway compensates for starch synthesis in the endosperm. Consistent with the BETL defects, zein accumulation was impaired in bt1774. Co-expression network analysis revealed that Bt2 probably has a role in intracellular signal transduction, besides starch synthesis. Altogether, we propose that Bt2 is likely involved in carbohydrate flux and balance, thus regulating both the BETL development and the starchy endosperm filling.

Prognostic and Immunological Role of FAT Family Genes in Non-Small Cell Lung Cancer.

BACKGROUND: The FAT atypical cadherin 1/2/3/4 (FAT1/2/3/4) has been linked to the occurrence and development of various cancers. However, the prognostic and immunological role of FAT1/2/3/4 in non-small cell lung cancer (NSCLC) has not been clarified. METHODS: The association of FAT1/2/3/4 mutations with tumor mutation burden (TMB), tumor immunity in the microenvironment, and response to ICIs in NSCLC was investigated. Whole-exome sequencing data of lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) samples from the Cancer Genome Atlas (TCGA), and an immunotherapy data set comprising mutation and survival data of 75 NSCLC patients were analyzed. Two independent pan-cancer cohorts with large samples were used to validate the prognostic value of FAT1/2/3/4 mutations in immunotherapy. RESULTS: A high mutation rate of FAT1/2/3/4 (57.3%, 603/1052) was observed in NSCLC patients. TMB was significantly higher in samples with mutated FAT1/2/3/4 compared to samples with wildtype FAT1/2/3/4 (P < .05). FAT2 mutation was found to be an independent prognostic biomarker in LUAD. FAT1/2/3/4 were aberrantly expressed in LUAD and LUSC, and high FAT2 expression strongly correlated with high PD-L1 levels in LUAD. Moreover, LUAD patients with FAT1 mutations showed significantly high activated dendritic cells infiltration, whereas those with FAT2/3/4 mutations had high infiltration of CD8+ T-cells, M1 macrophages, activated memory CD4+ T-cells, and helper follicular T-cells. It was also observed that FAT1/2/4 mutations were significantly associated with better enhanced objective response and durable clinical benefit, whereas FAT1/2/3 mutations correlated with longer progression-free survival in ICI-treated NSCLC cohort. FAT1/4 mutations were related to better overall survival in pan-cancer patients treated with ICIs. CONCLUSIONS: FAT family genes are potential prognostic and immunological biomarkers and correlate with response to ICIs in NSCLC.

Identification of Recurrent Insertions and Deletions in Exon 18 and 19 of Human Epidermal Growth Factor Receptor 2 as Potential Drivers in Non-Small-Cell Lung Cancer and Other Cancer Types.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) belongs to the same family as epidermal growth factor receptor (EGFR) and is known as an important cancer driver gene. Insertions and deletions (indels) are frequent driver mutations in both EGFR and HER2. The most common HER2 indels are the exon 20 insertions within the kinase domain, while others are rarely reported. Our study aimed to investigate other indels of HER2 that may act as driver mutations in Chinese patients with different cancer types. METHODS: In this retrospective study, patient samples were subjected to targeted sequencing covering HER2 and other cancer-related genes. Mutation profiles of patients harboring HER2 exon 18/19 indels were described. Identified HER2 exon 18/19 indels in our study were compared with external data from COSMIC. In silico and in vitro analyses were performed on selected indels of HER2 exon 18 and 19, respectively. RESULTS: A total of 25 indels in HER2 exon 18/19, 17 of which being recurrent, were identified in 20 of 53,591 patients with lung cancer (0.037%), two of 5,888 patients with colorectal cancer (0.034%), two of 3,774 patients with breast cancer (0.053%), and one of 14 patients with urothelial carcinoma of the renal pelvis (7.1%). Most patients harboring HER2 exon 18/19 indels were absent of known driver mutations. In lung cancer, mutation profiles were comparable between patients carrying HER2 exon 18/19 indels and the two established HER2 drivers (exon 20 insertions and S310 mutations). The in silico and in vitro analyses suggested an activated state conferred by HER2 exon 18/19 indels, which could be targeted by different tyrosine kinase inhibitors. CONCLUSION: Our study revealed a class of rare but unique indels in HER2 exon 18/19, which may act as driver mutations in several cancer types.

How has the efficiency of China's green development evolved? An improved non-radial directional distance function measurement.

As a key choice for human sustainable development, green development is also one of China's five major vision points. To explore the level of green development in China since it was first written into national documents in 2011, this paper applies an improved non-radial distance function based on Data Envelopment Analysis method to analyze the progress against the development targets set in related national documents. The results show that: (1) China's green development efficiency has kept increasing in 2011-2017. (2) The growth in green development efficiency was significantly higher in the 13th Five-Year Plan period compared to the 12th Five-Year Plan period. (3) The green development efficiency shows a decreasing trend from south to north, east of the Hu line. This study provides a more practical idea for evaluating the quality of green development in mainland China.

Paclitaxel-loaded magnetic nanocrystals for tumor neovascular-targeted theranostics: an amplifying synergistic therapy combining magnetic hyperthermia with chemotherapy.

A combination of chemotherapy and targeted magnetic hyperthermia (TMH) via a designed magnetic nanocrystal (MNC) drug delivery system was considered as an effective tumor synergistic therapy strategy. In this paper, we successfully synthesized tumor neovascular-targeted Mn-Zn ferrite MNCs, which encapsulated paclitaxel (PTX) in a biocompatible PEG-phospholipid (DSPE-PEG2000) layer and surface, simultaneously coupled with a tripeptide of arginine-glycine-aspartic acid (RGD). The high-performance RGD-modified MNC loaded with PTX (MNCs-PTX@RGD) embodied excellent magnetic properties, including high-contrast magnetic resonance imaging (MRI) and remarkable magnetically induced heat generation ability. We established the mouse model bearing subcutaneous 4T1 breast tumor, and demonstrated that MNCs-PTX@RGD could be effectively located in the tumor neovascular epithelial cells under the guidance of in vivo MRI. Notably, MNCs-PTX@RGD could easily penetrate into the tumor tissue from the tumor-fenestrated vascular networks for capturing a sufficient temperature (around 43 °C) exposed to an alternative current magnetic field (ACMF, 2.58 kA m-1, 390 kHz), leading to an effective TMH effect. Subsequently, the TMH-mediated temperature elevation accelerated the PTX release from the inner lipid layer, promoting the synergetic thermo-chemotherapy in vivo. The amplifying synergistic treatment strategy obviously improved the anti-tumor efficacy of MNCs-PTX@RGD, and simultaneously increased the survival time of the mice to more than 46 days, which provided a broad development prospect in clinical applications.

The emergence of various genetic alterations mediated the Osimertinib resistance of a patient harboring heterozygous germline EGFR T790M: a case report.

Epidermal growth factor receptor (EGFR) T790M is the major mechanism mediating resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Despite the high frequency of EGFR activating mutations among East Asian lung cancer patients, germline T790M has been the subject of very little research. Questions remain as to whether germline T790M develops resistance to Osimertinib and if so, through which mechanisms. This study examined a patient harboring germline EGFR T790M who acquired resistance to Osimertinib therapy. After the failure of first-line icotinib therapy, which was administered for only 3 months, targeted next-generation sequencing of plasma samples collected at icotinib progression and the re-analysis of the baseline tissue biopsy sample revealed EGFR T790M with allelic frequencies approximating 50%. Lymphocyte genomic deoxyribonucleic acid (DNA) sequencing confirmed the germline heterozygous status of the T790M mutation. In addition to the EGFR T790M, a concurrent EGFR L858R was detected from the baseline tissue sample. Osimertinib therapy was initiated resulting in a partial response within 1 month of the commencement of the therapy. After 15.2 months of Osimertinib therapy, disease progression was evaluated due to the presence of pleural effusion. The targeted sequencing of plasma and pleural effusion samples revealed the emergence of EGFR G719A, tumor protein p53 (TP53) Q136X, and the co-amplification of Cyclin D1, fibroblast growth factor (FGF) 19, FGF3, and FGF4. This case highlights the importance of conducting next-generation sequencing-based molecular testing during both diagnostic and disease progression assessments to reveal sensitizing mutations and mutations that could mediate primary and acquired resistance to targeted therapeutics.

Case analysis of novel coronavirus pneumonia in the Second Hospital of Wuhan Iron and Steel Company, Qingshan District, Wuhan, China.

BACKGROUND: To analyze the clinical and infectious characteristics of new coronavirus pneumonia with diagnosed and suspected cases in the Second Hospital of WISCO(Wuhan Iron and Steel Company) of Qingshan District, Wuhan City, and further enhance the understanding of new coronavirus pneumonia. METHODS: According to the fifth and sixth editions of the new coronavirus pneumonia diagnosis and treatment plan issued by the National Health Commission of the People's Republic of China and National Administration of Traditional Chinese Medicine, we carried out the case analysis and infectious disease investigation and research on the confirmed and suspected cases of new coronavirus pneumonia admitted to the second-floor ward of the hospital from January 28th, 2020, to February 26th, 2020. RESULTS: From January 28th, 2020 to February 26th, 2020, 83 patients were admitted, 40 were cured, and 7 died. Before February 13th, 69 patients were admitted, including 22 confirmed patients and 47 suspected patients. After February 13th, the data of newly hospitalized suspected patients decreased to 2 people. The average time from onset to diagnosis was 5.38 days. About 57.1% of the confirmed patients were isolated at home before admission, and 53.2% of the suspected patients were isolated by hospital observation before admission. The proportion of fever and other clinical symptoms was 81.8%, 65.5% of the patients had the fastest heart rate of 90-120 rpm, and 11 of the patients had severe/critical illness, accounting for 20%. The count of leukocytes, neutrophils, and C-reactive proteins (CRPs) in severe patients was higher than those in light patients (P<0.05), and the count of lymphocytes was lower than that in mild patients (P=0.016). CONCLUSIONS: The novel coronavirus pneumonia in Qingshan District of Wuhan in February was diagnosed promptly, controlled,and treated effectively. The combination of traditional Chinese and western medicine in the treatment of new coronavirus pneumonia might help patients.

miR­144­3p regulates the resistance of lung cancer to cisplatin by targeting Nrf2.

Chemotherapeutic drug resistance is correlated with treatment failure and poor prognosis among lung cancer patients. Numerous studies indicate the relevance of miRNAs in inducing certain drug resistance. In the course of the study, we unexpectedly found that miR­144­3p could regulate the cisplatin resistance of lung cancer cells via Nrf2. However, Nrf2 also could reverse activate the expression of miR­144­3p by binding to the ARE box in the miR­144­3p promoter. This may be a self­protection mechanism of the body. In addition, we also found that in other cancer cell lines, such as HepG2, miR­144­3p also had the function of regulating cisplatin resistance. These findings may provide some theoretical reference for the clinical inhibition of cisplatin resistance.

Dexmedetomidine mitigates CLP-stimulated acute lung injury via restraining the RAGE pathway.

OBJECTIVE: RAGE pathway plays crucial effects in causing acute lung injury (ALI). Dexmedetomidine (DEX) is showed to mitigate sepsis-stimulated ALI. However, its mechanisms have not been verified. The study was to evaluate whether the RAGE pathway participated in the actions of DEX on sepsis-stimulated ALI in rats. METHODS: Male rats were administrated with intravenously DEX 30 min after sepsis. At 24 h of sepsis, lung myeloperoxidase (MPO) and macrophages in the bronchoalveolarlavage fluid (BALF) were observed. The actions of DEX on pro-inflammatory molecules and related mechanisms were determined by immunological methods. RESULTS: It was indicated that DEX markedly attenuated CLP-stimulated augment of lung inflammatory cells infiltration, along with significantly mitigated MPO activity. Besides, DEX obviously reduced lung wet/dry weight ratio and the levels of HMGB1 and RAGE in BALF and lung tissue. Moreover, DEX post-treatment apparently attenuated the histopathological lung injury compared with CLP model group. Furthermore, western blot analysis revealed that DEX efficiently restrained the activation of IκB-α, NF-κB p65, and MAPK. CONCLUSION: Our studies demonstrated that DEX attenuates the aggravation of sepsis-stimulated ALI via down regulation of RAGE pathway, which has a potential value in the clinical therapy.

Pulsed radiofrequency of the second cervical ganglion (C2) for the treatment of cervicogenic headache.

In this case series report, two patients with cervicogenic headache were selected. After initial positive response to the greater occipital nerve block, pulse radiofrequency (PRF) was performed on the position of the second cervical ganglion (C2). Two patients reported 100% pain relief lasting for 6 months. The lateral puncture is safer and more comfortable than the posterior site. This case study demonstrates the effectiveness of PRF to treat cervicogenic headache originating from the C2 nerve. However, we need to further evaluate the results using more samples.

[Stress analysis of separators with different specifications].

OBJECTIVE: To evaluate the shape and structure of different separators affecting the mechanical behavior. METHODS: The stress of different separators was analyzed by ANSYS software. Various separators were meshed into one-dimensional solid elements and the material character parameters were inputted. The loads were added gradually. RESULTS: The stress was related to the arm of force and the point of force application. CONCLUSIONS: The force applied can be controlled by selecting different separators.