Real-world data on the first-line immune checkpoint inhibitors or in combination with chemotherapy in older patients (aged ≥ 75 years) with advanced non-small cell lung cancer.

Purpose: The purpose of this study is to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) or plus with chemotherapy in older patients. Methods: We enrolled 110 older patients with non-small cell lung cancer (NSCLC ≥75 years) who received either chemotherapy alone (chemo), ICI plus chemotherapy (ICI + chemo), or ICI alone and ICI plus other therapies, which included anti-angiogenesis drugs or other novel ICI (ICIs). Patient characteristics, treatment response, survival, and toxicity were evaluated. Results: In total population, the ICIs group has the highest disease control rate (DCR 75%). There were no significant differences in progression-free survival (PFS) and overall survival (OS) among older patients between ICI + chemo and ICIs groups (PFS: 5.3 months vs. 5.5 months, p = 0.70, OS: 10.7 months vs. 20.3 months, p = 0.995). Meanwhile, we observed ICIs had a longer PFS and OS than chemo group (PFS: 3.9 months vs. 5.5 months, p = 0.01, OS: 10.9 months vs. 20.3 months, p = 0.05). Subgroup analysis showed that patients with programmed death ligand-1 (PD-L1) ≥ 1% had a distinct longer trend toward OS in ICIs group compared to ICI + chemo group (22.4 months vs. 10.7 months, p = 0.605), even though there was no significant difference. In terms of safety, ICIs was more tolerable and had a lower discontinuation rate than ICI + chemo group. Conclusion: In the real world, ICI + chemo is more likely to be discontinued due to adverse effects and does not significantly improve patient survival compared with ICIs treatment in total population and subgroup. Therefore, ICI alone or ICIs plus other therapies, such as anti-angiogenesis drugs or other novel ICI (ICIs) could be recommended for older cases with PD-L1 positive NSCLC.

Nivolumab combined docetaxel versus nivolumab in patients with previously treated nonsmall cell lung cancer: a phase 2 study.

The current standard second-line treatment is immune checkpoint inhibitors monotherapy for nonsmall cell lung cancer (NSCLC) patients. The objective of this phase 2 study was to evaluate the efficacy and safety of nivolumab plus docetaxel compared with nivolumab monotherapy for second-line therapy in immunotherapy-naive patients with advanced NSCLC. Progression-free survival (PFS) was the primary endpoint of this phase 2 study. Patients were randomized to receive nivolumab plus docetaxel or nivolumab monotherapy. From July 2019 to June 2022, a total of 22 patients were recruited, with significantly longer median PFS observed in the nivolumab plus docetaxel group (4.0 months) compared to the nivolumab group (2.0 months), P  = 0.0019. The study was closed in June 2022 due to slow recruitment. The objective response rate was 10.0% [95% confidence interval (CI), 0-28.6] in the nivolumab group and 25% (95% CI, 0.5-49.5) in the nivolumab + docetaxel group ( P  = 0.346). Disease control was significantly higher in the nivolumab plus docetaxel arm (40.0% versus 83.3%, P  = 0.035). There was also an improvement in overall survival (OS) in the nivolumab + docetaxel arm, but this was not statistically significant (10.0 months versus 7.2 months, P  = 0.129). The addition of docetaxel to nivolumab was well-tolerated, with adverse events more common in the combination group. Despite the small sample size, the results suggest that the addition of docetaxel to nivolumab may be a promising treatment option for NSCLC patients progressing on platinum-based chemotherapy, with trends towards improved OS observed.

Unilateral levator avulsion increases the risk of de novo stress urinary incontinence after cystocele repair.

INTRODUCTION: Patients without concurrent baseline stress urinary incontinence (SUI) can develop de novo SUI after transvaginal mesh surgery (TVM) for cystocele repair. Surgeons should be aware of de novo SUI risk factors after TVM. METHODS: A total of 1124 women who were underwent TVM surgeries were recruited and assessed for eligibility from January 1, 2012 to April 30, 2021. All data related to patients and surgeries was collected, which included general conditions, clinical examination, surgery records, and follow-up results. Patients were divided into three groups according to follow-up results and data were compared with each group. The relative risk (RR) of de novo SUI with levator avulsion was also calculated. RESULTS: Three hundred thirty-six patients were included in this study. They were divided into no complication group (n = 249), de novo SUI group (n = 68), and other complications group (n = 19). It seemed elder or obese women had a higher risk of de novo SUI after TVM (p < 0.05). In de novo SUI group, incidence of levator avulsion before surgery were higher than the other two groups (p = 0.001). TVM can significantly change a prolapse to point Aa and Ba on POP-Q quantification system (p < 0.05). RR ratios of de novo SUI with unilateral avulsion group is 2.60 (95% confidence interval [CI] 1.39-4.87), and 2.58 (95%CI 0.82-8.15) for bilateral group. CONCLUSION: Unilateral levator avulsion, instead of bilateral levator avulsion, is a risk factor of de novo SUI after cystocele repair surgery.

Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers in the world. The therapeutic outlook for HCC patients has significantly improved with the advent and development of systematic and targeted therapies such as sorafenib and lenvatinib; however, the rise of drug resistance and the high mortality rate necessitate the continuous discovery of effective targeting agents. To discover novel anti-HCC compounds, we first constructed a deep learning-based chemical representation model to screen more than 6 million compounds in the ZINC15 drug-like library. We successfully identified LGOd1 as a novel anticancer agent with a characteristic levoglucosenone (LGO) scaffold. The mechanistic studies revealed that LGOd1 treatment leads to HCC cell death by interfering with cellular copper homeostasis, which is similar to a recently reported copper-dependent cell death named cuproptosis. While the prototypical cuproptosis is brought on by copper ionophore-induced copper overload, mechanistic studies indicated that LGOd1 does not act as a copper ionophore, but most likely by interacting with the copper chaperone protein CCS, thus LGOd1 represents a potentially new class of compounds with unique cuproptosis-inducing property. In summary, our findings highlight the critical role of bioavailable copper in the regulation of cell death and represent a novel route of cuproptosis induction.

Novel beagle model of gastric local fibrotic target lesions for the evaluation and training of endoscopic techniques.

BACKGROUND: Novel endoscopic techniques used in the treatment of gastric lesions with local submucosal fibrosis need preclinical evaluation and training due to safety limitations. Therefore, the purpose of our study was to establish an animal model of gastric local fibrotic target lesions and assess its feasibility in the evaluation and training of endoscopic techniques. METHODS: In six experimental beagles, a 50% glucose solution was injected into three submucosal areas of the fundus, body, and antrum of the stomach to create gastric local fibrotic target lesions (experimental group). On post-injection day (PID) 7, the injection sites were assessed endoscopically to confirm the presence of submucosal fibrosis formation, and the dental floss clip traction assisted endoscopic submucosal dissection (DFC-ESD) procedure was performed on the gastric local fibrotic target lesions to confirm its feasibility after endoscopic observation. The normal gastric mucosa of six control beagles underwent the same procedure (control group). All the resected specimens were evaluated by histological examination. RESULTS: All 12 beagles survived without postoperative adverse events. On PID 7, 16 ulcer changes were observed at the injection sites (16/18) under the endoscope, and endoscopic ultrasonography confirmed the local submucosal fibrosis formation in all ulcer lesions. The subsequent DFC-ESD was successfully performed on the 32 gastric target lesions, and the mean submucosal dissection time in the ulcer lesions was greater than that in the normal gastric mucosa (15.3 ± 5.6 vs. 6.8 ± 0.8 min; P < 0.001). There was no difference in rates of en bloc resection, severe hemorrhage, or perforation between the two groups. Histological analysis of the ulcer lesions showed the absence of epithelial or muscularis mucosae and extensive submucosal fibrous tissue proliferations compared with normal gastric mucosa. Overall, endoscopists had high satisfaction with the realism and feasibility of the animal model. CONCLUSION: We developed a novel animal model of gastric local fibrotic target lesions to simulate difficult clinical situations, which strongly appeared to be suitable for the preclinical evaluation and learning of advanced endoscopic techniques.

[Postoperative Delirium in Patients on Cardiopulmonary Bypass for Cardiovascular Surgeries: Incidence and Influencing Factors].

Objective: To investigate the incidence and influencing factors of postoperative delirium (POD) and subsyndromal delirium (SSD) in patients connected to cardiopulmonary bypass during cardiovascular surgeries. Methods: We collected the general data and the data for the perioperative hematological, physiological, and biochemical indicators and the surgical and therapeutic conditions of patients connected to cardiopulmonary bypass during the course of cardiovascular surgeries conducted at a tertiary-care hospital in Hubei province between May 2022 and September 2022. The outcome indicators, including the incidence of POD and SSD, were assessed with the Nursing Delirium Screening Scale (Nu-DESC). Multinomial logistic regression was performed to analyze the influencing factors of patients with different statuses of POD and SSD. Results: Among the 202 patients, the incidence of SSD, SSD progressing to POD, and no POD or SSD (ND) progressing to POD were 13.4%, 6.4%, and 34.2%, respectively. Regression analysis showed that, with ND patients as the controls, the influencing factors for SSD were preoperative blood glucose (odds ratio [ OR]=0.38, 95% confidence interval [ CI]: 0.19-0.76), intraoperative platelet transfusion ( OR=0.37, 95% CI: 0.15-0.92), intraoperative etomidate ( OR=0.93, 95% CI: 0.87-0.98), and postoperative total bilirubin level ( OR=1.04, 95% CI: 1.01-1.07). For the progression of SSD to POD, the influencing factors were age ( OR=1.09, 95% CI: 1.01-1.17), ASA classification of IV and above ( OR=10.72, 95% CI: 1.85-62.08), intraoperative dexmedetomidine ( OR=1.01, 95% CI: 1.003-1.02), and the duration of mechanical ventilation ( OR=1.04, 95% CI: 1.01-1.07). For the progression of ND to POD, the influencing factors were age ( OR=1.06, 95% CI: 1.02-1.10), middle or high school education ( OR=0.35, 95% CI: 0.15-0.83), and the duration of mechanical ventilation ( OR=1.04, 95% CI: 1.01-1.07). Conclusion: Age, education, ASA classification, preoperative blood glucose, intraoperative platelet transfusion, intraoperative etomidate, intraoperative dexmedetomidine, postoperative total bilirubin, and the duration of mechanical ventilation are influencing factors for different statuses of POD and SSD among patients connected to cardiopulmonary bypass when they are undergoing cardiovascular surgeries. The influencing factors vary across groups of patients with different statuses of POD and SSD. Therefore, we should accurately assess the risk factors of patients with different statuses of POD and SSD and carry out corresponding interventions, thereby preventing or reducing the occurrence of POD and SSD, and ultimately promoting enhanced recovery after surgery.

TMEM41A overexpression correlates with poor prognosis and immune alterations in patients with endometrial carcinoma.

BACKGROUND: Expression levels of transmembrane protein 41A (TMEM41A) are related to the progression of malignant tumors. However, the association between TMEM41A expression and endometrial carcinoma (EC) remains unclear. This study aims to identify the roles of TMEM41A expression in the prognosis of patients with EC and its correlation with EC progression. METHODS: The TMEM41A expression and its correlation with the survival of patients with EC were assessed. Cox regression analysis was used to identify the prognostic factors, while nomograms were used to examine the association between the prognostic factors and the survival of patients with EC. Finally, the link between TMEM41A level and immune microenvironment and RNA modifications was investigated in EC. RESULTS: TMEM41A was overexpressed in EC. TMEM41A overexpression could diagnose the EC and evaluate the poor prognosis of patients. Overexpression of TMEM41A was associated with clinical stage, age, weight, histological subtype, tumor grade, and survival status of patients with EC. Clinical stage, age, tumor grade, radiotherapy, and TMEM41A overexpression were factors of poor prognosis in patients with EC. The nomograms revealed the correlation between the TMEM41A level and survival time of patients with EC at 1, 3, and 5 years. Furthermore, TMEM41A overexpression was significantly correlated with the level of the stromal score, immune score, estimate score, NK CD56 bright cells, iDC, NK cells, eosinophils, pDC, T cells, TReg, cytotoxic cells, mast cells, Th17 cells, neutrophils, aDC, NK CD56 dim cells, TFH, Th2 cells, CD8 T cells, macrophages, immune cell markers, and RNA modifications. CONCLUSIONS: TMEM41A is overexpressed in EC tissues and is associated with the prognosis, immune microenvironment, and RNA modification. Our preliminary studies indicate that overexpression of TMEM41A can potentially serve as a biomarker for EC treatment.

Construction of an endoplasmic reticulum stress-related signature in lung adenocarcinoma by comprehensive bioinformatics analysis.

BACKGROUND: Lung Adenocarcinoma (LUAD) is a major component of lung cancer. Endoplasmic reticulum stress (ERS) has emerged as a new target for some tumor treatments. METHODS: The expression and clinical data of LUAD samples were downloaded from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database, followed by acquiring ERS-related genes (ERSGs) from the GeneCards database. Differentially expressed endoplasmic reticulum stress-related genes (DE-ERSGs) were screened and used to construct a risk model by Cox regression analysis. Kaplan-Meier (K-M) curves and receiver operating characteristic (ROC) curves were plotted to determine the risk validity of the model. Moreover, enrichment analysis of differentially expressed genes (DEGs) between the high- and low- risk groups was conducted to investigate the functions related to the risk model. Furthermore, the differences in ERS status, vascular-related genes, tumor mutation burden (TMB), immunotherapy response, chemotherapy drug sensitivity and other indicators between the high- and low- risk groups were studied. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA expression levels of prognostic model genes. RESULTS: A total of 81 DE-ERSGs were identified in the TCGA-LUAD dataset, and a risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was constructed by Cox regression analysis. K-M and ROC analyses showed that the high-risk group had a low survival, and the Area Under Curve (AUC) of ROC curves of 1-, 3- and 5-years overall survival was all greater than 0.6. In addition, functional enrichment analysis suggested that the risk model was related to collagen and extracellular matrix. Furthermore, differential analysis showed vascular-related genes FLT1, TMB, neoantigen, PD-L1 protein (CD274), Tumor Immune Dysfunction and Exclusion (TIDE), and T cell exclusion score were significantly different between the high- and low-risk groups. Finally, qRT-PCR results showed that the mRNA expression levels of 6 prognostic genes were consistent with the analysis. CONCLUSION: A novel ERS-related risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was developed and validated, which provided a theoretical basis and reference value for ERS-related fields in the study and treatment of LUAD.

Aneuploid subtypes of circulating tumor cells and circulating tumor-derived endothelial cells predict the overall survival of advanced lung cancer.

Objective: This study aimed to detect circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) in patients with advanced lung cancer, for describing the distribution characteristics of CTC and CTEC subtypes, exploring the correlation between CTC/CTEC subtypes and novel prognostic biomarkers. Methods: A total of 52 patients with advanced lung cancer were enrolled in this study. Using the subtraction enrichment-immunofluorescence in situ hybridization (SE-iFISH) system, CTCs and CTECs derived from these patients were identified. Results: Based on cell size, there were 49.3% small and 50.7% large CTCs, and 23.0% small and 77.0% large CTECs. Triploidy, tetraploidy, and multiploidy varied in the small and large CTCs/CTECs. Besides these three aneuploid subtypes, monoploidy was found in the small and large CTECs. Triploid and multiploid small CTCs and tetraploid large CTCs were associated with shorter overall survival (OS) in patients with advanced lung cancer. However, none of the CTECs subtypes showed a significant correlation with patient prognosis. In addition, we found strong positive correlations (P<0.0001) in the four groups including triploid small cell size CTCs and multiploid small cell size CTECs, and multiploid small cell size CTCs and monoploid small cell size CTECs. Furthermore, combined detection of the specific subtypes, including triploid small CTC and monoploid small CTEC, triploid small CTC and triploid small CTEC, and multiploid small CTC and monoploid small CTEC, were associated with poor prognosis in advanced lung cancer. Conclusions: Aneuploid small CTCs are associated with the outcome of patients with advanced lung cancer. In particular, the combined detection of triploid small CTCs and monoploid small CTECs, triploid small CTCs and triploid small CTECs, and multiploid small CTCs and monoploid small CTECs has clinical significance for predicting prognosis in patients with advanced lung cancer.

Magnetic ring-assisted endoscopic submucosal dissection for gastric lesions with submucosal fibrosis: A preliminary study in beagle model.

BACKGROUND: During endoscopic submucosal dissection (ESD) for gastric lesions with fibrosis, appropriate traction could provide clear submucosal dissection visualization to improve safety and efficiency of procedures. Therefore, the aim of this study was to evaluate the feasibility of magnetic ring-assisted ESD (MRA-ESD) for gastric fibrotic lesions. METHOD: In the eight healthy beagles, 2-3 mL of 50% glucose solution was injected into submucosal layer of the stomach to induce gastric fibrotic lesions. A week after submucosal injection, two endoscopists at different levels performed MRA-ESD or standard ESD (S-ESD) for gastric simulated lesions, respectively. The magnetic traction system consisted of external handheld magnet and internal magnetic ring. The feasibility and procedure outcomes of the magnetic traction system were mainly evaluated. RESULTS: Forty-eight gastric simulated lesions with ulceration were confirmed to have submucosal fibrosis formation by preoperative endoscopic ultrasonography. The magnetic traction system could be easily established, only took 1.57 min, and allowed excellent submucosal visualization. The total procedure time was significantly shorter in the MRA-ESD group than in the S-ESD group for both endoscopists (mean: 46.83 vs. 25.09 min, p < 0.001), and this difference was accentuated in non-skilled endoscopist. There was significant difference between two groups in bleeding and perforation rates. Histological analysis showed the depth of resected specimens was a little deeper around the fibrotic portion in the S-ESD group (p < 0.001). CONCLUSION: The magnetic ring-assisted ESD technique may be an effective and safe treatment for gastric fibrotic lesions and may shorten the endoscopic learning curve for non-skilled endoscopists.

Single-cell transcriptomic dissection of the cellular and molecular events underlying the triclosan-induced liver fibrosis in mice.

BACKGROUND: Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol, TCS], a common antimicrobial additive in many personal care and health care products, is frequently detected in human blood and urine. Therefore, it has been considered an emerging and potentially toxic pollutant in recent years. Long-term exposure to TCS has been suggested to exert endocrine disruption effects, and promote liver fibrogenesis and tumorigenesis. This study was aimed at clarifying the underlying cellular and molecular mechanisms of hepatotoxicity effect of TCS at the initiation stage. METHODS: C57BL/6 mice were exposed to different dosages of TCS for 2 weeks and the organ toxicity was evaluated by various measurements including complete blood count, histological analysis and TCS quantification. Single cell RNA sequencing (scRNA-seq) was then carried out on TCS- or mock-treated mouse livers to delineate the TCS-induced hepatotoxicity. The acquired single-cell transcriptomic data were analyzed from different aspects including differential gene expression, transcription factor (TF) regulatory network, pseudotime trajectory, and cellular communication, to systematically dissect the molecular and cellular events after TCS exposure. To verify the TCS-induced liver fibrosis, the expression levels of key fibrogenic proteins were examined by Western blotting, immunofluorescence, Masson's trichrome and Sirius red staining. In addition, normal hepatocyte cell MIHA and hepatic stellate cell LX-2 were used as in vitro cell models to experimentally validate the effects of TCS by immunological, proteomic and metabolomic technologies. RESULTS: We established a relatively short term TCS exposure murine model and found the TCS mainly accumulated in the liver. The scRNA-seq performed on the livers of the TCS-treated and control group profiled the gene expressions of > 76,000 cells belonging to 13 major cell types. Among these types, hepatocytes and hepatic stellate cells (HSCs) were significantly increased in TCS-treated group. We found that TCS promoted fibrosis-associated proliferation of hepatocytes, in which Gata2 and Mef2c are the key driving TFs. Our data also suggested that TCS induced the proliferation and activation of HSCs, which was experimentally verified in both liver tissue and cell model. In addition, other changes including the dysfunction and capillarization of endothelial cells, an increase of fibrotic characteristics in B plasma cells, and M2 phenotype-skewing of macrophage cells, were also deduced from the scRNA-seq analysis, and these changes are likely to contribute to the progression of liver fibrosis. Lastly, the key differential ligand-receptor pairs involved in cellular communications were identified and we confirmed the role of GAS6_AXL interaction-mediated cellular communication in promoting liver fibrosis. CONCLUSIONS: TCS modulates the cellular activities and fates of several specific cell types (including hepatocytes, HSCs, endothelial cells, B cells, Kupffer cells and liver capsular macrophages) in the liver, and regulates the ligand-receptor interactions between these cells, thereby promoting the proliferation and activation of HSCs, leading to liver fibrosis. Overall, we provide the first comprehensive single-cell atlas of mouse livers in response to TCS and delineate the key cellular and molecular processes involved in TCS-induced hepatotoxicity and fibrosis.

Outcomes in Patients with Global Pincer Versus Focal Pincer Femoroacetabular Impingement Treated with Hip Arthroscopy: A Retrospective Study with a Minimum 2-Year Follow-Up.

OBJECTIVE: Global pincer is a relatively rare form of pincer deformity and is typically associated with technical challenges during surgery. So far, controversy remains whether patients with global pincer have equivalent surgical outcomes compared to patients with focal pincer. This study compares the clinical outcomes of arthroscopic treatment between patients with global pincer femoroacetabular impingement (FAI) and focal pincer FAI in the Chinese population. METHODS: Data were retrospectively collected from patients with global and focal pincer FAI who underwent hip arthroscopy with a minimum two-year follow-up between April 2016 and December 2018. Radiographic measurements, arthroscopic procedures, preoperative and postoperative patient-reported outcomes (PROs) including modified Harris hip score (mHHS), hip outcome score-activities of daily living (HOS-ADL), international hip outcome tool-12 (iHOT-12), and visual analogue scale (VAS) scores, rates of revision surgery and conversion to total hip arthroplasty (THA) were recorded. Achievement of minimal clinically important difference (MCID) and patient acceptable symptomatic state (PASS) was compared for the VAS, mHHS, HOS-ADL, and iHOT-12 scores between groups. RESULTS: The total of 33 and 167 patients were included in the global and focal group, respectively. There were no intergroup differences in age, gender, body mass index or follow-up times. Lateral center-edge angle (LCEA) was reduced in both groups postoperatively. Both groups demonstrated significant improvements in PROs compared with preoperative levels at the final follow-up. The preoperative scores showed significant differences in terms of mHHS (60.34 vs 62.90, P = 0.031) and HOS-ADL (61.45 vs 64.74, P = 0.022) scores between two groups, and the improvement of HOS-ADL score was significantly higher in global group (P = 0.027). However, the postoperative scores, including VAS, mHHS, HOS-ADL, and iHOT-12 scores, showed no significant differences between two groups. And there were no significant differences in the rate of meeting the PASS and MCID between groups. One (3.0%) in the global group and six (3.6%) patients in the focal group underwent revision arthroscopy respectively, with no significant difference (P = 0.876). There were no conversions to THA in both groups. CONCLUSIONS: Arthroscopic management of global pincer FAI can achieve excellent functional scores at minimum 2-year follow-up. The outcomes were similar to focal pincer FAI patients with a low rate of secondary procedure.

Second-line treatment options in advanced thymic carcinoma after failure of platinum-based chemotherapy: A multicenter retrospective study.

BACKGROUND: Currently there is no standard therapy recommended for second-line treatment for thymic carcinoma. Our study compared multidrug chemotherapy, single-agent chemotherapy, and PD-1 inhibitors in patients diagnosed with advanced thymic carcinoma who had previous platinum-based chemotherapy at the clinic. METHODS: The study included patients with thymic carcinoma who failed first-line platinum-based chemotherapy. Kaplan-Meier methods were applied in the study for estimating the progression-free survival (PFS) and overall survival (OS) curves. Pearson chi-square or Fisher's exact chi-square test was adopted to make comparisons of the objective response rate (ORR) between treatment groups. Cox regression was used for the multivariate analyses in PFS and OS. RESULTS: Among the 92 patients enrolled, multidrug chemotherapy was used in 51 (55.4%) patients for second-line therapy. Thirty-six patients (35.9%) received single-agent chemotherapy, and eight patients (8.7%) underwent PD-1 inhibitors. The multidrug chemotherapy group showed better efficacy than the other two groups, with an ORR of 35.3% (p = 0.006). The median PFS of multidrug chemotherapy, single-agent chemotherapy and PD-1 inhibitors were 5.0 months, 3.0 months, and 4.0 months, respectively (p = 0.008). Patients in the multidrug chemotherapy group also showed an advantage in OS in comparison with the other two treatment groups (p = 0.045), with a median OS of 30.4 months. Multivariate analysis showed that second-line treatment was independent factor for both PFS (p = 0.035) and OS (p = 0.037). Grade 3-4 AEs were mostly detected in patients receiving multidrug chemotherapy and were primarily hematologic. Treatment-related mortality was not found in any of the groups. CONCLUSIONS: Multidrug chemotherapy had a trend toward a more positive response rate and outcomes in longer survival time than single-agent chemotherapy and PD-1 inhibitors. Multidrug chemotherapy is a choice worth considering for second-line therapy in patients with thymic carcinoma if tolerable.

The overall survival benefit in Chinese ALK+ NSCLC patients received targeted therapies.

Background: Anaplastic lymphoma kinase (ALK) gene rearrangement is a series of mutations of non-small cell lung cancer (NSCLC) patients. Since 2011, multiple ALK inhibitors (ALKis) have been developed and launched for targeted therapy. In this study, we sought to investigate different strategies of sequential applying the ALKis and their clinical benefits to the overall survival (OS). Methods: A total of 176 patients with advanced NSCLC (stage IIIB-IV) harboring the ALK rearrangement were included in this cohort study. They were diagnosed between February 1, 2012 and November 19, 2019 at Peking University Cancer Hospital. Clinical characters were reviewed from patients' records. Strategies of drugs, progression-free survival (PFS) and OS were collected during the follow-ups. The Kaplan-Meier method and multivariate Cox proportional-hazard analysis were used to conduct the analyses survival and to examine the relationship between the variables and OS. Results: A significantly longer OS was observed either in patients treated with crizotinib [N=106, median OS (mOS): 32.9 months] or in patients treated with a next-generation ALKi [N=34, mOS: not reached (NR)] as the initial ALKi, compared with patients treated with conventional chemotherapy but no ALKi (N=36, mOS: 10.3 months, P<0.001). After disease progression with initial crizotinib, patients who received no ALKi had shorter OS than those who received only crizotinib beyond progressive disease (CBPD) (mOS: 9.7 vs. 20.3 months; P=0.015), only subsequent next-generation ALKis (mOS: 9.7 vs. 41.1 months; P<0.001), and CBPD followed with subsequent next-generation ALKis (mOS: 9.7 months vs. NR; P<0.001). Patients treated with 2 types of ALKi had better survival than those treated with 1 ALKi (mOS: 45.8 vs. 21.3 months, P=0.003), but no such survival benefit was observed in patients treated with ≥3 ALKis (P=0.366). Conclusions: ALKis have been shown to be clinically effective in treating NSCLC patients with ALK rearrangements. In the case of disease progression with crizotinib, either of CBPD or sequential other ALKis can extend patients' OS. The sequential application of multiple ALKis was found to be better than it of single ALKi in prolonging OS. However, the question of which inhibitor to select as the initial inhibitor needs to be examined further in future studies.

Identification of an Immune Classification and Prognostic Genes for Lung Adenocarcinoma Based on Immune Cell Signatures.

Objective: Current advances in immunotherapy requires accurate tumor sub-classification due to the heterogeneity of lung adenocarcinoma (LUAD). This study aimed to develop a LUAD sub-classification system based on immune cell signatures and identified prognostic gene markers. Methods: Signatures related to the prognosis of TCGA-LUAD and 4 GSE cohorts were screened and intersected from 184 previously published immune cell signatures. The LUAD samples in the TCGA were clustered by ConsensusClusterPlus. Molecular characteristics, immune characteristics and sensitivity to immunotherapies/chemotherapies were compared. LDA score was established through Linear Discriminant Analysis (LDA). Co-expression module was constructed by Weighted Gene Co-Expression Network Analysis (WGCNA). Results: Four LUAD subtypes with different molecular and immune characteristics were identified. Significant differences in prognosis among the four subtypes were observed. The IS1 subtype with the worst prognosis showed the highest number of TMB, mutant genes, IFN γ score, angiogenesis score and immune score. Twenty co-expression modules were generated by WGCNA. Blue module, sky blue module and light yellow module were significantly correlated with LUAD prognosis. The hub genes (CCDC90B, ARNTL2, RIPK2, SMCO2 and ADA and NBN) showing great prognostic significance were identified from the blue module. A total of 8 hub genes (NLRC3, CLEC2D, GIMAP5, CXorf65, PARP15, AKNA, ZC3H12D, and ARRDC5) were found in the light yellow module. Except for CXorf65, the expression of the other seven genes were significantly correlated with LUAD prognosis. Conclusion: This study determined four LUAD subtypes with different molecular and immune characteristics and 13 genes closely related to the prognosis of LUAD. The current findings could help understand the heterogeneity of LUAD immune classes.

Dietary sinapic acid attenuated high-fat diet-induced lipid metabolism and oxidative stress in male Syrian hamsters.

The current study investigated the effects of sinapic acid on high-fat diet (HFD)-induced lipid metabolism and oxidative stress in male Syrian hamsters. Sinapic acid treatment significantly reduced body weight, epididymal fat, and perirenal fat mass in HFD hamsters. Sinapic acid also improved dyslipidemia levels (reducing the serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol, and increasing the high-density lipoprotein cholesterol) and increased T-AOC levels to mitigate oxidative stress injury. Moreover, sinapic acid intervention increased the activations of PPAR-γ, CPT-1, and CYP7A1 and decreased the activations of FAS, ACC1, SREBP1, SREBP2, and HMGCR in the livers of HFD hamsters. In addition, sinapic acid intervention also significantly inhibited the intestinal mRNA levels of Srebp2 and Npc1l1 in HFD hamsters. In conclusion, sinapic acid can significantly attenuate abnormal lipid metabolism in the development of HFD-induced obesity and reduce the level of oxidative stress to exert its anti-obesity effect. PRACTICAL APPLICATIONS: Obesity is the main cause of some chronic metabolic syndromes, such as dyslipidemia, nonalcoholic fatty liver disease, diabetes, and hyperuricemia. Searching for new, safe, and effective natural products in weight loss and fat reduction has become one of the hot research topics. As a natural source of simple phenolic acids, sinapic acid is present in fruits, vegetables, and grains and has been indicated to have anti-inflammatory, antioxidant, antihyperuricemic, lipid homeostasis regulation, and anticancer activities. However, the lipid metabolism- and oxidative stress-regulating activities of sinapic acid are not clear. Here, the current study investigated the lipid metabolism and oxidative stress regulating activities of sinapic acid in male Syrian hamsters fed a high-fat diet.

Oral administration of Lactobacillus plantarum CQPC11 attenuated the airway inflammation in an ovalbumin (OVA)-induced Balb/c mouse model of asthma.

This study investigated the antiasthmatic and anti-inflammatory effects of Lactobacillus plantarum-CQPC11 (LP-CQPC11) on ovalbumin (OVA)-induced asthmatic Balb/c mice. Administration of different doses of LP-CQPC11 (105 , 107 , and 109 colony-forming unit [CFU]/mouse) effectively reduced airway hyperresponsiveness (AHR) and the lung W/D ratio in asthmatic mice. LP-CQPC11 treatment reduced the accumulation of inflammatory cells in the BALF and attenuated histologic edema in asthmatic mice. Administration of LP-CQPC11 decreased the serum levels of OVA-specific IgE, IgE, and OVA-specific IgG1. LP-CQPC11 treatment decreased the levels of inflammatory cytokines (TNF-α, IL-4, IL-13, IL-5, and IL-6) in the BALF of asthmatic mice. In addition, LP-CQPC11 also elevated the mRNA levels of Foxp3 and T-bet and decreased the mRNA levels of Gata3 and RORγt in asthmatic mice lungs. Administration of LP-CQPC11 also reduced OVA-induced oxidative stress by improving the activities of GSH-Px, SOD, and catalase in the lungs. Finally, LP-CQPC11 treatment also significantly decreased the activation of the NF-κB pathway to modulate the inflammatory reaction in the lungs of asthmatic mice. The results from this study clearly demonstrated that oral administration of LP-CQPC11 exhibited outstanding activity in attenuating OVA-induced asthma in a mouse model. Furthermore, LP-CQPC11 may be an effective microecologic agent in preventing allergic asthma in the future. PRACTICAL APPLICATIONS: Allergic asthma is a common chronic inflammation-associated respiratory disease. Lactic acid bacteria (LAB) are known as a health product involved in modulating immune tolerance and play important roles in disease prevention and treatment. Many studies have reported that LAB, as probiotics, exhibits great antioxidation, anticancer, and anti-inflammatory activities and have health benefits in gastrointestinal disorders. In fact, human studies have confirmed that Lactobacillus rhamnosus strains have an effective activity to reduce the risk of allergic asthma. LP-CQPC11 was isolated from Sichuan pickled cabbages (a type of LAB-fermented vegetable product, also called Sichuan paocai) and was reported to reduce d-galactose-induced aging in mice in our previous study. However, the antiasthmatic and anti-inflammatory activities of LP-CQPC11 are unclear. The current study investigated the antiasthmatic and anti-inflammatory effects of LP-CQPC11 on OVA-induced asthmatic Balb/c mice.

Multi-view manifold regularized compact low-rank representation for cancer samples clustering on multi-omics data.

BACKGROUND: The identification of cancer types is of great significance for early diagnosis and clinical treatment of cancer. Clustering cancer samples is an important means to identify cancer types, which has been paid much attention in the field of bioinformatics. The purpose of cancer clustering is to find expression patterns of different cancer types, so that the samples with similar expression patterns can be gathered into the same type. In order to improve the accuracy and reliability of cancer clustering, many clustering methods begin to focus on the integration analysis of cancer multi-omics data. Obviously, the methods based on multi-omics data have more advantages than those using single omics data. However, the high heterogeneity and noise of cancer multi-omics data pose a great challenge to the multi-omics analysis method. RESULTS: In this study, in order to extract more complementary information from cancer multi-omics data for cancer clustering, we propose a low-rank subspace clustering method called multi-view manifold regularized compact low-rank representation (MmCLRR). In MmCLRR, each omics data are regarded as a view, and it learns a consistent subspace representation by imposing a consistence constraint on the low-rank affinity matrix of each view to balance the agreement between different views. Moreover, the manifold regularization and concept factorization are introduced into our method. Relying on the concept factorization, the dictionary can be updated in the learning, which greatly improves the subspace learning ability of low-rank representation. We adopt linearized alternating direction method with adaptive penalty to solve the optimization problem of MmCLRR method. CONCLUSIONS: Finally, we apply MmCLRR into the clustering of cancer samples based on multi-omics data, and the clustering results show that our method outperforms the existing multi-view methods.

Evaluation of efficacy and toxicity of nivolumab combined with or without docetaxel in patients with advanced NSCLC.

BACKGROUND: The combination of PD-1/PD-L1 inhibitor and chemotherapy has been clinically confirmed to be beneficial as the first-line treatment of patients with advanced NSCLC. This study aimed to assess the effect of nivolumab + docetaxel versus nivolumab monotherapy in patients with NSCLC after the failure of platinum doublet chemotherapy. MATERIALS AND METHODS: The efficacy and toxicity of nivolumab + docetaxel combination therapy versus nivolumab monotherapy were compared in this retrospective study. Primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and toxicity. RESULTS: Between November 2017 and December 2019, 77 patients were included in this study, with 58 patients in the nivolumab group and 19 in the nivolumab + docetaxel group. The median follow-up was 18 months, and the PFS was 8 months for patients receiving nivolumab + docetaxel and 2 months for those receiving nivolumab alone (p = 0.001), respectively. Nivolumab + docetaxel showed superior OS compared with nivolumab, with the median OS unreached versus 7 months (p = 0.011). Among patients without EGFR/ALK variation, compared to nivolumab monotherapy, nivolumab + docetaxel showed better PFS (p = 0.04) and OS (p = 0.05). There was no significant difference in grade 3-4 adverse events (AEs) between the two groups (p = 0.253). CONCLUSIONS: The combination of nivolumab and docetaxel demonstrated a meaningful improvement in progression-free survival and overall survival compared to nivolumab monotherapy, in patients with NSCLC after the failure of platinum doublet chemotherapy, irrespective of EGFR/ALK variation status.

Pembrolizumab or Bevacizumab Plus Chemotherapy as First-Line Treatment of Advanced Nonsquamous Nonsmall Cell Lung Cancer: A Retrospective Cohort Study.

Objective: Pembrolizumab and bevacizumab both have antitumor activity. According to NCCN updated guideline the benefit of pembrolizumab or bevacizumab as a first line in management of advanced nonsmall cell lung cancer (NSCLC) is documented in randomized controlled studies. The study aimed to evaluate the response and complications of patients with advanced NSCLC treated with pembrolizumab or bevacizumab plus chemotherapy. Methods: This study was a retrospective cohort study of patients with advanced nonsquamous NSCLC who received cisplatin with pemetrexed combined with pembrolizumab (A group) or bevacizumab (B group) from 07/02/2018 to 07/03/2021 at Peking University Cancer Hospital. Progression-free survival (PFS) was the primary outcome. The secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and adverse events (AEs). Results: This study included 66 patients, 34 in A group and 32 in B group. There were no differences in median PFS (7.6 vs 9.9 months, P = .601). There were no differences in median OS (23.1 vs 24.2 months, P = .782). There were no differences in ORR (57.6% vs 41.9%, P = .211) and DCR (93.9% vs 100.0%, P = .164) between 2 groups. The occurrence of AEs was similar. No new safety signals were observed. Grade 3 to 4 treatment-related AEs occurred in 17 (50.0%) patients of A group and in 12 (37.5%) of B group (P > .05). Conclusion: The addition of pembrolizumab or bevacizumab to pemetrexed plus cisplatin was well tolerated and resulted in a clinically meaningful treatment benefit in advanced nonsquamous NSCLC. When pembrolizumab is not suitable, bevacizumab plus chemotherapy may be an option.