The Clinical Characteristics and Treatments for Large Cell Carcinoma Patients Older than 65 Years Old: A Population-Based Study.

Background: Pulmonary large cell carcinoma, a type of non-small cell lung cancer (NSCLC), is a rare neoplasm with poor prognosis. In this study, our aim was to investigate the impact of radiation sequences with surgery for stage III/IV LCC patients between different age groups, especially in the elderly patients. Patients and Methods: The patients with LCC and other types of NSCLC in the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2015 were retrospectively analyzed. Then we divided the LCC patients into two age groups: <65 years old group and ≥65 years old group. Propensity score method (PSM) was used to control potential differences between different groups. The overall survival (OS) of LCC patients and other types of NSCLC patients were evaluated by Kaplan−Meier analysis. Univariate and multivariate Cox regression analysis were employed to explore the independent risk factors of OS. The forest plots of HRs for OS were generated to show the above outcomes more visually. Results: In total, 11,349 LCC patients and 129,118 other types of NSCLC patients were enrolled in this study. We divided LCC patients into <65 years old group (4300) and ≥65 years old group (7049). LCC patients was more common in whites (81.4%), males (58.3%), elderly (≥65 years old: 62.1%), east regions (52.7%), upper lobe (51.6%), right-origin of primary (55.4%), with advanced grade (54.2%) or stage (76.7%). After PSM, Kaplan−Meier analysis and multivariate Cox analysis showed significantly worse survival prognosis for LCC patients compared to other types of NSCLC, especially in the group ≥65 years old (HR: 1.230; 95% CI: 1.171−1.291; p < 0.001). For LCC patients, there were some risk survival factors including whites, males, not upper lobe, advanced stage, elder age at diagnosis, bone metastasis, liver metastasis, singled status, no lymphadenectomy, no surgery, and no chemotherapy (p < 0.05). In LCC patients ≥65 years old, radiation after surgery had significantly better impact on overall survival outcomes (HR: 0.863, 95% CI: 0.765−0.973, p = 0.016), whereas radiation prior to surgery (HR: 1.425, 95% CI: 1.059−1.916, p = 0.019) had significantly worse impact on prognosis of patients. In LCC patients <65 years old, radiation sequences with surgery had no significant impact on the OS of patients (p = 0.580), but ≥4 LNRs had significantly survival benefits to prognosis (HR:0.707, 95% CI: 0.584−0.855). Elderly LCC patients had worse malignant tumors than young patients, of which the majority were diagnosed as stage III/IV tumors. Conclusions: Postoperative radiotherapy may achieve a better prognosis for stage III/IV LCC patients older than 65 years old compared to other radiation sequences with surgery.

Exploration of the optimal number of regional lymph nodes removed for resected N0 NSCLC patients: A population-based study.

Background: The aim of our study was to explore the optimal number of regional lymph nodes removed (LNRs) in resected N0 non-small cell lung cancer (NSCLC) patients and identify potential risk factors. Methods: Included in this study were 55,024 N0 NSCLC patients between 2004 and 2015 based on the Surveillance, Epidemiology, and End Results database (SEER). All the patients were divided into No LNR group (57.8%), 1-3 LNRs group (8.1%) and ≥4 LNRs group (31.4%). Relevant clinical and patient parameters including overall survival (OS), lung cancer-specific survival (LCSS), gender, race, year of diagnosis, primary site, T stage, AJCC stage, laterality, histological type, lymphadenectomy, radiation, chemotherapy, age at diagnosis, insurance status, marital status, family income. Results: Kaplan-Meier analysis demonstrated LNRs had significantly better OS and LCSS than No LNRs in all the N0 NSCLC patients with different T stages (Logrank p<.001). Univariate and multivariate analysis showed that both OS and LCSS in ≥ 4 LNRs group were better than those in <1-3 LNRs group (OS: ≥4 LNRs group: HR, 0.583; 95%CI, 0.556-0.610; P<.001 vs.1-3 LNRs group: HR, 0.726; 95%CI, 0.687-0.769; P<.001; LCSS: ≥4 LNRs group: HR, 0.514; 95%CI, 0.480-0.550; P<.001 vs.1-3 LNRs group: HR, 0.647; 95%CI, 0.597-0.702; P<.001). In addition, whites, males, not upper lobe, large cell carcinoma and others, advance T stage or AJCC stage, no surgery, no LNR, no radiation, no chemotherapy, elder age at diagnosis, singled marital status and low family income had negative impact on prognosis of N0 NSCLC patients. Conclusions: Our study suggests that ≥ 4 LNRs can yield better survival outcomes compared with 1-3 LNRs in N0 NSCLC patients.

Epigallocatechin-3-gallate, an active ingredient of Traditional Chinese Medicines, inhibits the 3CLpro activity of SARS-CoV-2.

SARS-CoV-2 is the etiological agent responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19). The main protease of SARS-CoV-2, 3CLpro, is an attractive target for antiviral inhibitors due to its indispensable role in viral replication and gene expression of viral proteins. The search of compounds that can effectively inhibit the crucial activity of 3CLpro, which results to interference of the virus life cycle, is now widely pursued. Here, we report that epigallocatechin-3-gallate (EGCG), an active ingredient of Chinese herbal medicine (CHM), is a potent inhibitor of 3CLpro with half-maximum inhibitory concentration (IC50) of 0.874 ± 0.005 µM. In the study, we retrospectively analyzed the clinical data of 123 cases of COVID-19 patients, and found three effective Traditional Chinese Medicines (TCM) prescriptions. Multiple strategies were performed to screen potent inhibitors of SARS-CoV-2 3CLpro from the active ingredients of TCMs, including network pharmacology, molecular docking, surface plasmon resonance (SPR) binding assay and fluorescence resonance energy transfer (FRET)-based inhibition assay. The SPR assay showed good interaction between EGCG and 3CLpro with KD ~6.17 µM, suggesting a relatively high affinity of EGCG with SARS-CoV-2 3CLpro. Our results provide critical insights into the mechanism of action of EGCG as a potential therapeutic agent against COVID-19.

Protein interactome of the deamidase phosphoribosylformylglycinamidine synthetase (PFAS) by LC-MS/MS.

Phosphoribosylformylglycinamidine synthase (PFAS) is an essential enzyme in de novo synthesis of purine. Previously, PFAS has been reported to modulate RIG-I activation during viral infection via deamidation. In this study, we sought to identify potential substrates that PFAS can deamidate. Flag-PFAS was transfected into HEK-293T cells and PFAS associated proteins were purified with anti-Flag M2 magnetic beads. PFAS associated proteins were identified using mass spectrometry and were analyzed using bioinformatics tools including KEGG pathway analysis, gene ontology annotation, and protein interaction network analysis. A total of 441 proteins is suggested to potentially interact with PFAS. Of this number, 12 were previously identified and 429 are newly identified. The interactions of PFAS with CAD, CCT2, PRDX1, and PHGDH were confirmed by co-immunoprecipitation and western blotting. This study is first to report the interaction of PFAS with several proteins which play physiological roles in tumor development including CAD, CCT2, PRDX1, and PHGDH. Furthermore, we show here that PFAS is able to deamidate PHGDH, and induce other posttranslational modification into CAD, CCT2 and PRDX1. The present data provide insight on the biological function of PFAS. Further study to explore the role of these protein interactions in tumorigenesis and other diseases is recommended.

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development.

Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 (DISC1), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.