Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.
Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current TNM or Veterans Administration Lung Study Group (VALG) staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent center, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggest potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better Progression Free Survival (PFS) and Overall Survival (OS) after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.
To the Editor: Current guidelines recommended that patients with acute coronary syndrome (ACS) should receive dual anti-platelet therapy of aspirin plus P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor) if without contraindication. Up to now, information on the clinical efficacy and safety of potent anti-platelet drugs in the elderly patients with ACS is limited, especially in very older people (age ≥75 years). We searched PubMed, the Cochrane library, Web of Science, EMBASE (Excerpt Medical Database) from January 2000 to December 2019. Analysis of the data was performed using Stata software, Version 12.0 (StataCorp LP, College Station, TX, USA). The overall polled results were recorded as risk ratios (RRs) and 95% confidence intervals (CIs) with two-sided P values. Finally, seven clinical studies included 8848 patients of potent oral P2Y12-inhibitors versus clopidogrel in elderly patients (age ≥65 years old) with ACS were included in this meta-analysis.[1–7] Patients older than 65 years in the included trials were mainly treated with aspirin combined with ticagrelor, and those over 75 years were mainly treated with aspirin plus prasugrel. Five thousand six hundred and forty-eight (63.8%) received aspirin plus prasugrel, and 3839 patients (43.4%) received reduced maintenance dose prasugrel (<10 mg). The seven included studies were all high-quality studies. All seven included studies discussed the effect of anti-platelet therapy on the incidence of major adverse cardiovascular events (MACEs) in elderly ACS patients. There was no significantly difference between the group treated with potent P2Y12 inhibitors and that with clopidogrel in reducing MACEs, whether it was older than 65 years or 75 years (RR = 0.95, 95% confidence interval [CI] 0.86–1.05) [Table 1]. In the sub-group analysis, there was no significant difference in MACEs between the group treated with the standard-dose potent ticagrelor and that with clopidogrel (RR = 0.81, 95% CI 0.30–1.31, P = 0.026). Reduced-dose prasugrel did not increase the incidence of MACE (RR = 1.02, 95% CI 0.86–1.18, P = 0.921). Data on all-cause mortality was provided in five studies,[1,2,4–6] and one was patients older than 65 years. No significant heterogeneity was presented in these studies (I2 = 31%; P = 0.215). As expected, aspirin plus potent P2Y12 inhibitors may reduce all-cause mortality, with a RR = 0.82, 95% CI: 0.66 to 0.97. Six randomized controlled studies[1,5–7] reported the risk of major bleeding. Patients treated with potent anti-platelet P2Y12 inhibitors (ticagrelor or clopidogrel) showed a strong tendency to increase the risk of major bleeding (RR 1.25, 95% CI 0.99–1.51) compared with those with clopidogrel. In the sub-group analysis, patients received reduced-dose prasugrel did not differ significantly in the bleeding risk from those received clopidogrel (RR 1.23, 95% CI 0.68–1.78, P = 0.422).Table 1: Ischemia and bleeding outcomes from randomization to the end of follow-up in elderly ACS patients (n = 8848).The choice of anti-platelet drugs in elderly patients is extremely interesting and requires more effective treatment strategies to reduce thrombotic events without increasing the risk of bleeding complication.[8] The principal findings from this meta-analysis, available to date to examine the outcomes of more potent P2Y12 inhibitors vs. clopidogrel in elderly ACS patients, are as follows: (1) Dual anti-platelet therapy with more potent P2Y12 receptor antagonists compared with clopidogrel demonstrated a similar protective ischemic effect determined by MACEs and all-cause mortality in elderly patients presenting with ACS. (2) The dosage of potent P2Y12 inhibitors (both standard and reduced dose) did not affect the protective ischemic effects, compared with that of clopidogrel. (3) Potent P2Y12 inhibitors indeed showed a strong tendency to increase the risk of major bleeding, compared with clopidogrel. In addition, this analysis included the maintenance of different dosage of prasugrel as a sub-group, which showed that the reduced dose of prasugrel had no significant difference in the occurrence of MACEs and all-cause mortality in comparison with clopidogrel, but it did have the tendency to reduce the risk of major bleeding. There was no sufficient data to confirm this effect, so it still needs to be further explored. Experts consensus clearly expresses that the patients with high risk of bleeding is cautious with prasugrel, which is also a proof of this meta-analysis. Although the sub-group analysis showed no significant increase in the risk of bleeding at lower maintenance doses, the tendency of overall risk of major bleeding from potent anti-platelet agents was still increased. Therefore, the use of potent anti-platelet drugs in high-risk elderly patients should be cautious. Certainly, this study has common potential limitations, potent P2Y12 inhibitors refers to two different drugs that may have different biological and clinical effects, and only 17.2% of patients included in the study received ticagrelor. It is necessary to conduct special tests to confirm these results and increase the sample size as appropriate. Funding This work was partially supported by the grants from the National Natural Science Foundation of China (No. 81471021 and No. 81873512) and the Hu Bei Health and Family Planning Commission (No. WJ2015MB006). Conflict of interest None.
Beta blockers are a recommended therapy in patients with heart failure with reduced ejection fraction(HFrEF). Beta blockers markedly and unequivocally reduce mortality in patients with heart failure with reduced ejection fraction. However, the beneficial effects of beta blockers in patients with heart failure with preserved ejection fraction(HFpEF) are not well established. In this review, we will assess the evidence basis of the recommendations for beta blockers and discuss emerging concerns about the use of beta blockers in patients with HFpEF. The available evidence for beta blockers is limited and it remains uncertain whether beta blockers have a beneficial role in the treatment of HFpEF in the absence of an alternative indication for their use.
Small cell lung cancer (SCLC) is a malignant and heterogeneous cancer with limited therapeutic options and insufficient prognostic models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current TNM or VALG staging methods. The subtyping result could be further validated using FFPE biopsy samples from an independent center, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggest potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better PFS and OS time after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction as well as precise treatments including targeted and immunotherapies.Funding: This work was supported by the National Natural Science Foundation of China (No.82072597, No.62131009, No. 31770892, No. 31970725, No. 31870828, No. 81874237 and No. 81974016), Beijing Municipal Natural Science Foundation (No. 7192199), National Key Research and Development Program of China (No. 2018YFA0507503, No. 2017YFA0505102, No. 2017YFA0505103 and No. 2017YFA0505104), and State Key Laboratory of Proteomics (No. SKLP-K202002). Kaifeng science and technology development grant (No. 1806005).Declaration of Interest: Jun Qin is the cofounder and co-owner of the Beijing Pineal Diagnostics Co. Ltd.; Dongdong Zhan and Fang Cheng are employees of Beijing Pineal Diagnostics Co. Ltd.. All other authors declare no competing interests.Ethical Approval: This study was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Tumors in the discovery cohort (diagnosed between 2012-2018) were obtained with informed consent from archival sources at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Tumors in the second cohort (diagnosed between 2018-2021) were biopsy samples obtained from First Affiliated Hospital of Henan University.
Objective To determine the enact gene location hab-1 ( en308) which effects C elagans abnormal habituation using SNPs methods. Methods (1) To retrieve the SNP markers of Y71A12B which chained at the first autosome the CB4856 (22. 330MU) and SNP markers of C37A5 (22. 330MU) in C. elegans gene bank,its genotype was set to YC/YC,the genotypes of hab-1 (cn308) was set to h/h. (2) By means of Synchronized processing, the size of worms was unified. (3) Wild-type CB4856 male was three-factor hybridized with her-maphroditism cn308. F1 generation were tested by Tap test, recording the distance of response of the worms, statistical processing, screening habituation and retaining the Normal Heterozygote (YC/h) , suboulturing to F2. (4) Then F2 generation were tested by Tap test,C. elegans with slow habitualion were selected, processed by PCR, digested by restriction enzyme , separated target fragment with 2% agarose gel electrophoresis. Results After the first Tap test, the formation of habituation of the wild-type was significantly faster than the cn308. (the average of habituation for Tap stimulation( Moving distance, unit;mm) ,the wild-type' s was (0.414 ±0. 049)mm,cn308 was (0.777 ±0.062)mm, ( = 10.08, P<0.001) ,in the habituation retention test 1 hour later,the habituation of wild-type was found that it retained significantly longer than cn308 (the average of habituation retention, wild-type was (0.307 ±0.041)mm,cn308 was (0. 815 ±0. 054) mm, : = 11.54, P< 0.001). (2) SNP fragments were analyzed, the genetic recombination number between SNP marker of Y71A12B and hab-1 and the genetic recombination number between SNP marker of C37A5 and hab-1 were gathered, observing the phenotype of H non C-type, namely, Ch/h:20, Yh/h:6 ,by reckoning the restructuring proportion it was determined that the distance between hab-1 and SNP marker of Y71A12B was 0. 831MU. The distance between hab-1 and SNP marker of C37A5 was 0. 249MU. So it could be ascertained that hab-1 located between the SNP marker of Y71A12B and SNP marker of C37A5. Conclusion The gene location of hab-1 which influence C. elegans abnormal habituation by harmless mechanical tap stimulation is 23. 161MU.
Key words:
Tap stimulation; Habitualion; SNPs; Hab-1
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)