Long noncoding RNA UCA1 inhibits epirubicin-induced apoptosis by activating PPARα-mediated lipid metabolism.

Metabolic reprogramming is a hallmark of cancer, and abnormal lipid metabolism is associated with drug resistance in bladder cancer cells. The long noncoding RNA (lncRNA) UCA1 is overexpressed in bladder cancer, but its functional contribution to lipid metabolism remains uncharacterized. In this study, we demonstrated that lncRNA UCA1 inhibits epirubicin-induced cell apoptosis by supporting abnormal lipid metabolism in bladder cancer cells. Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPARα mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARα and downstream p-AKT/p-GSK-3ß/ß-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRα to the lncRNA UCA1 promoter. These findings were verified in a mouse xenograft model and are consistent with the expression patterns in human bladder cancer patients. Overall, these findings establish the role of lncRNA UCA1 in lipid metabolism and bladder cancer cell resistance to epirubicin, suggesting that lncRNA UCA1 may serve as a candidate target for enhancing bladder cancer chemotherapy.

Nonunion of the distal one-fourth of the tibia treated by retrograde tibial intramedullary nail.

OBJECTIVE: To evaluate the effectiveness of retrograde tibial intramedullary nail (RTN) in addressing nonunion in the distal one-fourth of the tibia. METHODS: This retrospective study included consecutive patients who were treated with RTN for nonunion in the distal one-fourth of the tibia between December 2020 and August 2023. Data regarding age, sex, injury mechanism, fracture type, initial fixation method, nonunion duration and type, risk factors, surgical duration, hospital stay, time to bone union, ankle function at final follow-up, and any complications were extracted from hospital records and analysed. RESULTS: Five patients in total were included, with previous treatments comprising locking plates and/or external fixation. The mean duration of RTN surgery was 94.0 ± 13.7 min, and mean duration of hospital stay was 9.8 ± 1.9 days. Patients were monitored for 10-18 months post RTN, achieving complete bone healing within a mean of 4.8 months. At the latest follow-up, the mean American Orthopedic Foot and Ankle Society (AOFAS) score was 84.4 ± 6.8 (range, 77-95). No complications, such as infection, reoperation, implant issues, rotational deformity, or shortening were reported. CONCLUSION: RTN emerges as a dependable, minimally invasive, and safe treatment modality for managing nonunion in the distal one-fourth of the tibia.

Promotion of hepatocellular carcinoma stemness and progression by abnormal spindle-like microcephaly-associated protein via the Wnt/ß-catenin pathway.

Background: Cancer stem cells (CSCs) play a crucial role in tumor recurrence and metastasis, which are the primary causes of death in patients with hepatocellular carcinoma (HCC). Currently, no drug effectively blocks the recurrence and metastasis of liver cancer, leading to a poor prognosis for patients. To enhance treatment outcomes, there is an urgent need to investigate the molecular mechanisms behind the recurrence and progression of liver cancer, with the aim of identifying effective therapeutic targets. Targeting HCC stemness can improve the prognosis of patients with HCC. Abnormal spindle-like microcephaly-associated protein (ASPM) plays a pivotal role in regulating neurogenesis and brain size, which is a centrosome protein. ASPM has been implicated in tumorigenesis and tumor progression, but its regulatory role in HCC stemness is not well understood. This study aims to investigate the role of ASPM in liver cancer stemness and elucidate its potential molecular mechanisms. Methods: Bioinformatics analysis was used to study the expression of ASPM and its clinical significance in HCC. In vitro and in vivo assays were conducted to clarify the impact of ASPM knockdown on HCC cell stemness. The correlation between ASPM and the Wnt/ß-catenin pathway was examined through analysis of online databases and in vitro experiments. Results: The bioinformatics analysis revealed significant upregulation of ASPM was significantly upregulated in HCC samples, with expression correlating with poor prognosis. In vitro experimental data confirmed elevated ASPM expression in HCC cells compared to normal hepatocytes. Knockdown of ASPM suppressed HCC cell growth, clone formation, spheroid formation, migration, invasion, and the expression of CSC markers CD133 and CD44. This also inhibited the activation of the Wnt/ß-catenin pathway. Reactivation of this pathway partially reversed the biological changes induced by ASPM knockdown in HCC cells. Additionally, in vivo data demonstrated that ASPM downregulation reduced the size and weight of xenografts in BALB/c mice, along with decreased expression of CSC markers. Conclusions: These findings suggest that ASPM promotes HCC stemness and progression through the Wnt/ß-catenin pathway. Targeting ASPM or the Wnt/ß-catenin pathway may be a promising strategy to prevent HCC chemoresistance and recurrence, ultimately improving patient prognosis.

The Inhibitory Effects of Propofol on Colorectal Cancer Progression through the NF-κB/HIF-1α Signaling Pathway.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is a neoplastic disease that gradually develops due to genetic variations and epigenetic changes. Surgical excision is the first-line treatment for CRC. Accumulating evidence has shown that total intravenous anesthesia has beneficial effects for CRC patients as it decreases the probability of tumor recurrence and metastasis. Propofol is one of the most frequently used intravenous anesthetics in clinical practice. However, it remains unknown whether it can reduce recurrence and metastasis after surgery in cancer patients. METHODS: CRC cell lines (HCT116 and SW480) were cultured in vitro, and different concentrations of propofol were added to the cell culture medium. The proliferation effect of propofol on CRC cell lines was evaluated by CCK-8 assay. The effect of propofol on the migration and invasion of CRC cells was evaluated by scratch healing and Transwell experiments. The inhibitory effects of propofol on NF-κB and HIF-1α expressions in CRC cell lines were determined by Western blotting and immunofluorescence assays to further clarify the regulatory effects of propofol on NF-κB and HIF-1α. RESULTS: Compared to the control, propofol significantly inhibited the proliferation, migration, and invasion abilities of CRC cells (HCT116 and SW480) (p < 0.0001). The expression levels of NF-κB and HIF-1α gradually decreased with increasing propofol concentration in both cell lines. After activation and inhibition of NF-κB, the expression of HIF-1α changed. Further studies showed that propofol inhibited LPS-activated NF-κB-induced expression of HIF-1α, similar to the NF-κB inhibitor Bay17083 (p < 0.0001). CONCLUSION: In vitro, propofol inhibited the proliferation, migration, and invasion of CRC cells (HCT116 and SW480) in a dose-dependent manner, possibly by participating in the regulation of the NF-κB/HIF-1α signaling pathway.

Construction and identification of lncRNA/circRNA-coregulated ceRNA networks in gemcitabine-resistant bladder carcinoma.

OBJECTIVES: To explore the regulatory networks that underlie the development of chemoresistance in bladder cancer. METHODS: We analyzed profiles of differentially expressed long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs) and messenger RNA (mRNAs) in gemcitabine-resistant/sensitive bladder cancer cells using next-generation sequencing data. RESULTS: Hundreds of differentially expressed lncRNAs and miRNAs and thousands of circRNAs and mRNAs were identified. Bioinformatics analysis revealed the chromosomal localizations, classification and coexpression of mRNAs, as well as candidates for cis and trans regulation by lncRNAs. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of differentially expressed mRNAs and circRNAs indicated important functional roles of coregulated RNAs, thus establishing competing endogenous RNA (ceRNA) and protein-protein interactions networks that may underlie chemoresistance in bladder cancer. We demonstrated that lncRNA LINP1 can act as a ceRNA by inhibiting miR-193a-5p to increase TP73 expression; and that lncRNA ESRG and hsa_circ_0075881 can simultaneously bind miR-324-3p to increase ST6GAL1 expression. Modulation of ceRNA network components using ablation and overexpression approaches contributed to gemcitabine resistance in bladder cancer cells. CONCLUSIONS: These results elucidate mechanisms by which lncRNAs and circRNAs coregulate the development of bladder cancer cell resistance to gemcitabine, thus laying the foundation for future research to identify biomarkers and disease targets.

Drug-eluting beads versus conventional transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis.

BACKGROUND: Transarterial chemoembolization (TACE) consists of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE). The benefits of the 2 treatments remain controversial. We conduct this meta-analysis to assess the efficacy and safety of the 2 methods for the patients with unresectable hepatocellular carcinoma. METHODS: In order to get a sound conclusion, we did thorough search all relevant studies with clear and stringent keyword criteria on the main databases. Objective tumor response rate, overall survival (OS) rate and adverse events were calculated and analyzed by RevMan 5.3 software. The random-effects or fixed-effects model was applied to pool the estimates according to Cochran Q test and I2 statistics. RESULTS: Twenty-four studies involving 2987 patients were eligible. DEB-TACE significantly improved objective tumor response rate (OR) (risk ratio [RR] = 1.27, 95% confidence interval [CI] [1.08, 1.48]; P = .003). While as for 1-year, 2-year, 3-year, 5-year OS rates, there were no evidences to indicate that DEB-TACE was significantly better than cTACE (RR = 1.05, 95% CI [0.99, 1.11]; P = .08), (RR = 1.02, 95% CI [0.93, 1.11]; P = .68), (RR = 0.92, 95% CI [0.77, 1.10]; P = .37), (RR = 0.92, 95% CI [0.47, 1.80]; P = .81), respectively. Adverse events rate (AE) was also similar in both groups (RR = 1.11, 95% CI [0.99,1.26]; P = .08). CONCLUSION: This meta-analysis demonstrates that DEB-TACE is not superior than cTACE regarding to OS and AE. However, DEB-TACE still be considered to provide a better objective tumor response rate for patients with unresectable hepatocellular carcinoma.

Effect of Individualized PEEP on Perioperative Pulmonary Complications in Elderly Patients with Prostate Cancer Undergoing General Anesthesia in Trendelenburg Position: A Single-Center Retrospective Study.

OBJECTIVE: This study aimed to explore the effect of individualized positive end-expiratory pressure (PEEP) on postoperative pulmonary complications (PPCs) in elderly patients with prostate cancer undergoing general anesthesia in Trendelenburg position (low-head and high-foot position at about 45° when patients were in supine position). METHODS: The clinical data of 96 elderly patients undergoing Leonardo's robotic-assisted laparoscopic radical prostatectomy in Zhejiang Provincial People's Hospital from October 2021, to April 2023, were selected for retrospective analysis. Sixteen patients who had interrupted follow-up or did not meet the inclusion criteria were excluded, and 80 patients were finally included. The patients were divided into group A (lung-protective strategy using routine PEEP value, n = 40) and group B (lung-protective strategy using individualized PEEP value, n = 40) on the basis of different inversion methods. The PEEP value of group A was set as 5 cmH2O, whereas that of group B was determined under the guidance of static lung compliance. The incidences of PPCs on postoperative day 7 were statistically analyzed, and the serum levels of interleukin (IL) 6 (IL-6) and IL-8 in both groups were measured by enzyme-linked immunoadsordent assay (ELISA). RESULTS: The incidence of pulmonary complications was obviously lower in group B than in group A on postoperative day 7 (p < 0.001). Group B had lower levels of serum IL-6 and IL-8 at the end of surgery (T1) and 12 h after surgery (T2, p < 0.001); Higher oxygenation index values 10 min after successful titration of individualized PEEP (A3), 1 h after individualized PEEP ventilation (A4), 2 h after individualized PEEP ventilation (A5), 10 min after recovery of supine position (A6), and 30 min after tracheal extubation (A7); And lower hospitalization time (all p < 0.001) than group A. CONCLUSIONS: Individualized PEEP for elderly patients with prostate cancer undergoing general anesthesia in Trendelenburg position effectively relieves the release of inflammatory factors, reduces the occurrence of PPCs, and shortens hospitalization time. Thus, it is an effective protection strategy and has certain clinical value.

Pan-Immune-Inflammatory Value in Patients with Non-Small-Cell Lung Cancer Undergoing Neoadjuvant Immunochemotherapy.

Background: We aimed to investigate the predictive value of a systematic serum inflammation index, pan-immune-inflammatory value (PIV), in pathological complete response (pCR) of patients treated with neoadjuvant immunotherapy to further promote ideal patients' selection. Methods: The clinicopathological and baseline laboratory information of 128 NSCLC patients receiving neoadjuvant immunochemotherapy between October 2019 and April 2022 were retrospectively reviewed. We performed least absolute shrinkage and selection operator (LASSO) algorithm to screen candidate serum biomarkers for predicting pCR, which further entered the multivariate logistic regression model to determine final biomarkers. Accordingly, a diagnostic model for predicting individual pCR was established. Kaplan-Meier method was utilized to estimate curves of disease-free survival (DFS), and the Log rank test was analyzed to compare DFS differences between patients with and without pCR. Results: Patients with NSCLC heterogeneously responded to neoadjuvant immunotherapy, and those with pCR had a significant longer DFS than patients without pCR. Through LASSO and the multivariate logistic regression model, PIV was identified as a predictor for predicting pCR of patients. Subsequently, a diagnostic model integrating with PIV, differentiated degree and histological type was constructed to predict pCR, which presented a satisfactory predictive power (AUC, 0.736), significant agreement between actual and our nomogram-predicted pathological response. Conclusion: Baseline PIV was an independent predictor of pCR for NSCLC patients receiving neoadjuvant immunochemotherapy. A significantly longer DFS was achieved in patients with pCR rather than those without pCR; thus, the PIV-based diagnostic model might serve as a practical tool to identify ideal patients for neoadjuvant immunotherapeutic guidance.

[Effect of multi-glycosides of Tripterygium wilfordii on renal injury in diabetic kidney disease rats through NLRP3/caspase-1/GSDMD pyroptosis pathway].

This study investigated the effect of multi-glycosides of Tripterygium wilfordii(GTW) on renal injury in diabetic kidney disease(DKD) rats through Nod-like receptor protein 3(NLRP3)/cysteine-aspartic acid protease-1(caspase-1)/gsdermin D(GSDMD) pyroptosis pathway and the mechanism. To be specific, a total of 40 male SD rats were randomized into the normal group(n=8) and modeling group(n=34). In the modeling group, a high-sugar and high-fat diet and one-time intraperitoneal injection of streptozotocin(STZ) were used to induce DKD in rats. After successful modeling, they were randomly classified into model group, valsartan(Diovan) group, and GTW group. Normal group and model group were given normal saline, and the valsartan group and GTW group received(ig) valsartan and GTW, respectively, for 6 weeks. Blood urea nitrogen(BUN), serum creatinine(Scr), alanine ami-notransferase(ALT), albumin(ALB), and 24 hours urinary total protein(24 h-UTP) were determined by biochemical tests. The pathological changes of renal tissue were observed based on hematoxylin and eosin(HE) staining. Serum levels of interleukin-1ß(IL-1ß) and interleukin-18(IL-18) were detected by enzyme-linked immunosorbent assay(ELISA). Western blot was used to detect the expression of pyroptosis pathway-related proteins in renal tissue, and RT-PCR to determine the expression of pyroptosis pathway-related genes in renal tissue. Compared with the normal group, the model group showed high levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1ß and IL-18(P<0.01), low level of ALB(P<0.01), severe pathological damage to kidney, and high protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01). Compared with the model group, valsartan group and GTW group had low levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1ß and IL-18(P<0.01), high level of ALB(P<0.01), alleviation of the pathological damage to the kidney, and low protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01 or P<0.05). GTW may inhibit pyroptosis by decreasing the expression of NLRP3/caspase-1/GSDMD in renal tissue, thereby relieving the inflammatory response of DKD rats and the pathological injury of kidney.

[The Relationship between Occurrence of aGVHD in Patients with Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation and Immune Cell Components in Graft].

OBJECTIVE: To explore the relationship between occurrence of acute graft-versus-host disease (aGVHD) and various immune cell composition in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The clinical data of 104 patients with AML undergoing allo-HSCT in our hospital were retrospectively analyzed, and the hematopoietic reconstitution and occurrence of GVHD were analyzed. Flow cytometry was used to detect the proportion of various types of immune cells in the grafts, the number of graft composition in patients with different degrees of aGVHD was calculated and compared, and to analyze the correlation between the severity of aGVHD in AML patients after allo-HSCT and the immune cell components in the graft. RESULTS: There was no significant difference in the time of hematopoietic reconstitution between the high number group of total number of nucleated cells (TNC) and the low number group, while the time of neutrophil and platelet reconstruction in the high number of CD34 group was significantly faster than that in the low number of CD34 group (P＜0.05), and the total hospital stay also tends to be shorten. Compared with patients in 0-Ι aGVHD group, both HLA-matched and HLA-haploidentical transplantation, the infusion amounts of CD3+ cells, CD3+CD4+ cells, CD3+CD8+ cells, NK cells and CD14+ monocytes were higher in patients of Ⅱ-Ⅳ aGVHD group， but the difference was not statistically significant (P>0.05); In addition, in patients with HLA-haploidentical transplantation, the number of CD4+CD25+ cells in Ⅱ-Ⅳ aGVHD group was significantly lower than that in 0-Ι aGVHD group (P<0.05), and the same trend was also observed in HLA-matched transplanted patients, but the difference was not significant (P=0.078). CONCLUSION: High number of CD34+ cells in the graft is beneficial to hematopoietic reconstitution in AML patients. To a certain degree, high number of CD3+ cells, CD3+CD4+ cells, CD3+CD8+ cells, NK cells and CD14+ cells tend to increase the occurrence of aGVHD, but high number of CD4+CD25+ regulatory T cells is beneficial to reduce the incidence of aGVHD in AML patients.

Distinct Prognostic Factors of Ground Glass Opacity and Pure-Solid Lesion in Pathological Stage I Invasive Lung Adenocarcinoma.

Background: Ground glass opacity (GGO) is associated with favorable survival in lung cancer. However, the relevant evidence of the difference in prognostic factors between GGO and pure-solid nodules for pathological stage I invasive adenocarcinoma (IAC) is limited. We aimed to identify the impact of GGO on survival and find prognostic factor for part-GGO and pure-solid patients. Methods: Between December 2007 and August 2018, patients with pathological stage I IAC were retrospectively reviewed and categorized into the pure-GGO, part-GGO, and pure-solid groups. Survival curves were analyzed by the Kaplan-Meier method and compared by log-rank tests. Least absolute shrinkage and selection operator and Cox regression models were used to obtained prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: The number of patients with pure-GGO, part-GGO, and pure-solid was 134, 540, and 396, respectively. Part-GGO patients with consolidation-tumor-ratio (CTR) > 0.75 had similar outcome to those with pure-solid nodules. In part-GGO patients, CTR was negatively associated with OS (P = 0.007) and solid tumor size (STS) was negatively associated with DFS (P < 0.001). Visceral pleural invasion (VPI) was negatively associated with OS (P = 0.040) and DFS (P = 0.002). Sublobectomy was negatively associated with OS (P = 0.008) and DFS (P = 0.005), while extended N1 stations examination was associated with improved DFS (P = 0.005) in pure-solid patients. Conclusions: Though GGO component is a positively prognostic factors of patients with pathological stage I IAC, a small proportion of GGO components is not associated with favorable survival. VPI, STS and CTR are the significant predictors for part-GGO patients. Sublobectomy, especially wedge resection should be used cautiously in pure-solid patients.

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer.

Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.

Response of primary tumor and lymph node in non-small cell lung cancer after neoadjuvant immunotherapy: a pooled analysis.

The good pathological response of primary tumors (PTs) to neoadjuvant immunotherapy has been acknowledged in non-small cell lung cancer (NSCLC), however, it remains unclear whether neoadjuvant immunotherapy shows consistent effects in metastatic lymph nodes (LNs). We compared the pathological response of PT and nodal downstaging using a pooled analysis to assess the effect of neoadjuvant immunotherapy on LNs. Original articles reporting the tumor major pathological response (ypT(MPR)), pathological complete response (ypT0) and nodal downstaging following neoadjuvant immunotherapy in NSCLC were retrieved. The OR and 95% CI were calculated by Review Manager V.5.3. Subgroup analysis was performed according to the neoadjuvant therapy regimen used. A total of 209 patients from 6 studies were included in this analysis. The frequency of nodal downstaging was comparable to that of ypT(MPR) (OR 1.31; 95% CI 0.84 to 2.05; p=0.24). Interestingly, ypN0 was observed more frequently than ypT0 (OR 3.26; 95% CI 2.06 to 5.16; p<0.0001). However, this difference was not observed in the subgroup of cN2 patients who underwent immune checkpoint inhibitor monotherapy (OR 1.58; 95% CI 0.56 to 4.48; p=0.39). Neoadjuvant immunotherapy results in satisfactory response in metastatic LN. Patients had a high probability of node clearance when ypT0 was confirmed, especially in patients treated with immunochemotherapy.

Effect of dexmedetomidine on the Montreal Cognitive Assessment in older patients undergoing pulmonary surgery.

OBJECTIVE: We investigated the effect of dexmedetomidine anesthesia on postoperative cognitive function after pulmonary surgery. METHODS: A blinded, prospective, randomized, placebo-controlled study was performed on 60 patients (age range 65-74 years) undergoing lobectomy by video-assisted thoracoscopic surgery (29 in the dexmedetomidine group; 31 in the placebo group). Dexmedetomidine group patients received dexmedetomidine, and placebo group patients received an equal volume of physiological saline 20 minutes before anesthesia induction. Cognitive function was evaluated using the Montreal Cognitive Assessment 1 day before surgery and on postoperative day (POD)1, POD3, and POD7. The regional cerebral oxygen saturation (rSO2) was monitored continuously by near-infrared spectroscopy before anesthesia. RESULTS: The Montreal Cognitive Assessment score was significantly different between the two groups on POD1 (dexmedetomidine 26.4 ± 0.73 vs. placebo 25.5 ± 0.96) and POD3 (dexmedetomidine 27.1 ± 0.79 vs. placebo 26.6 ± 0.80). Specifically, attention and orientation scores were increased in the dexmedetomidine group on POD1 and POD3. The rSO2 was not significantly different between the dexmedetomidine and placebo groups. CONCLUSION: Dexmedetomidine given before induction of anesthesia could reduce the risk of postoperative cognitive dysfunction and might not decrease rSO2. Hence, dexmedetomidine could be employed in pulmonary surgical procedures, especially for older patients with a high risk of cognitive dysfunction.

Integrative Analysis of Bioinformatics and Machine Learning Algorithms Identifies a Novel Diagnostic Model Based on Costimulatory Molecule for Predicting Immune Microenvironment Status in Lung Adenocarcinoma.

Costimulatory molecules are an indispensable signal for activating immune cells. However, the features of many costimulatory molecule genes (CMGs) in lung adenocarcinoma (LUAD) are poorly understood. This study systematically explored expression patterns of CMGs in the tumor immune microenvironment (TIME) status of patients with LUAD. Their expression profiles were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Two robust TIME subtypes ("hot" and "cold") were classified by K-means clustering and estimation of stromal and immune cells in malignant tumor tissues using expression data. The "hot" subtype presented higher infiltration in activated immune cells and enrichments in the immune cell receptor signaling pathway and adaptive immune response. Three CMGs (CD80, LTB, and TNFSF8) were screened as final diagnostic markers by means of Least Absolute Shrinkage Selection Operator and Support Vector Machine-Recursive Feature Elimination algorithms. Accordingly, the diagnostic nomogram for predicting individualized TIME status showed satisfactory diagnostic accuracy in The Cancer Genome Atlas training cohort as well as GSE31210 and GSE180347 validation cohorts. Immunohistochemistry staining of 16 specimens revealed an apparently positive correlation between the expression of CMG biomarkers and pathologic response to immunotherapy. Thus, this diagnostic nomogram provided individualized predictions in TIME status of LUAD patients with good predictive accuracy, which could serve as a potential tool for identifying ideal candidates for immunotherapy.

CircFGGY Inhibits Cell Growth, Invasion and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma via Regulating the miR-545-3p/Smad7 Axis.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Circular RNAs (circRNAs) play critical roles in the progression of HCC. However, the role of the newly identified circFGGY (hsa_circ_0006633) in the development and progression of HCC has not been explored. In this study, we found that circFGGY was significantly downregulated in tumor compared with that in adjacent normal liver tissues of patients with HCC. HCC patients with low circFGGY expression had poor overall survival after hepatectomy. Moreover, it was found that circFGGY could inhibit the proliferation, invasion and epithelial-mesenchymal transition of HCC both in vivo and in vitro. Mechanistically, circFGGY promoted the expression of Smad7, a well-known suppressor of the transforming growth factor-ß signaling pathway. In addition, miR-545-3p, a tumor promoter targeting both circFGGY and Smad7, suppressed the upregulation of Smad7 caused by circFGGY overexpression. Collectively, our data revealed that circFGGY inhibits the proliferation and invasion of HCC cells by sponging miR-545-3p and promote the expression of Smad7, indicating that circFGGY functions as a tumor suppressor and could be a prognostic biomarker for HCC.

An Aging-Related Gene Signature-Based Model for Risk Stratification and Prognosis Prediction in Lung Squamous Carcinoma.

Aging is an inevitable process characterized by a decline in many physiological activities, and has been known as a significant risk factor for many kinds of malignancies, but there are few studies about aging-related genes (ARGs) in lung squamous carcinoma (LUSC). We designed this study to explore the prognostic value of ARGs and establish an ARG-based prognosis signature for LUSC patients. RNA-sequencing and corresponding clinicopathological data of patients with LUSC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The ARG risk signature was developed on the basis of results of LASSO and multivariate Cox analysis in the TCGA training dataset (n = 492). Furthermore, the GSE73403 dataset (n = 69) validated the prognostic performance of this ARG signature. Immunohistochemistry (IHC) staining was used to verify the expression of the ARGs in the signature. A five ARG-based signature, including A2M, CHEK2, ELN, FOS, and PLAU, was constructed in the TCGA dataset, and stratified patients into low- and high-risk groups with significantly different overall survival (OS) rates. The ARG risk score remained to be considered as an independent indicator of OS in the multivariate Cox regression model for LUSC patients. Then, a prognostic nomogram incorporating the ARG risk score with T-, N-, and M-classification was established. It achieved a good discriminative ability with a C-index of 0.628 (95% confidence interval [CI]: 0.586-0.671) in the TCGA cohort and 0.648 (95% CI: 0.535-0.762) in the GSE73403 dataset. Calibration curves displayed excellent agreement between the actual observations and the nomogram-predicted survival. The IHC staining discovered that these five ARGs were overexpression in LUSC tissues. Besides, the immune infiltration analysis in the TCGA cohort represented a distinctly differentiated infiltration of anti-tumor immune cells between the low- and high-risk groups. We identified a novel ARG-related prognostic signature, which may serve as a potential biomarker for individualized survival predictions and personalized therapeutic recommendation of anti-tumor immunity for patients with LUSC.

Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer.

Multimodality treatment provides modest survival benefits for patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC). Nevertheless, preoperative immunotherapy has continuously been shown to be promising in treating resectable NSCLC.This phase 2 trial enrolled patients with AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC deemed surgically resectable. Patients received three cycles of neoadjuvant treatment with intravenous PD-1 inhibitor toripalimab (240 mg), carboplatin (area under the curve 5), and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for other subtypes) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks afterward. The primary endpoint was major pathological response (MPR), defined as less than 10% residual tumor remaining at the time of surgery.Thirty-three patients were enrolled, of whom 13 (39.4%) had T3-4N2 stage IIIB disease. Thirty (90.9%) patients underwent resection and all except one (96.7%) achieved R0 resection. Twenty patients (60.6%) in the intention-to-treat population achieved an MPR, including 15 patients (45.5%) who achieved a pathological complete response (pCR). The MPR and pCR rates in the per-protocol population were 66.7% and 50.0%, respectively. The surgical complications included three cases of arrhythmias, one case of a prolonged air leak, and one case of chylothorax. The most common grade 3 treatment-related adverse event (TRAE) was anemia (2, [6.1%]). Severe TRAEs included one (3.0%) case of grade 3 peripheral neuropathy that resulted in surgical cancellation.Toripalimab plus platinum-based doublet chemotherapy yields a high MPR rate, manageable toxicity, and feasible resection in stage III NSCLC.Trial ClinicalTrials.gov (NCT04304248).