Lysosome-related genes: A new prognostic marker for lung adenocarcinoma.

Currently, a reliable early prognostic marker has not been identified for lung adenocarcinoma (LUAD), the most common malignancy. Recent studies demonstrated that lysosomal rupture is involved in cancer migration, progression, and immune microenvironment formation. We performed a bioinformatics analysis of lysosomal rupture to investigate whether lysosome-related genes (LRGs) are key in LUAD. The analysis identified 23 LRGs. Cytoscape visualization identified 10 core genes (CCNA2, DLGAP5, BUB1B, KIF2C, PBK, CDC20, NCAPG, ASPM, KIF4A, ANLN). With the 23 LRGs, we established a new risk scoring rule to classify patients with LUAD into high- and low-risk groups and verified the accuracy of the risk score by receiver operating characteristic curves and established a nomogram to evaluate clinical patients. Immunotherapy effectiveness between the high- and low-risk groups was evaluated based on the tumor mutational burden and analyses of immune cell infiltration and drug sensitivity. Pathway enrichment analysis revealed that lysosomes were closely associated with glucose metabolism, amino acid metabolism, and the immune response in patients with LUAD. Lysosomes are a likely new therapeutic target and provide new directions and ideas for treating and managing patients with LUAD.

Construction of an algorithm based on oncosis-related LncRNAs comprising the molecular subtypes and a risk assessment model in lung adenocarcinoma.

BACKGROUND: As an important non-apoptotic cell death method, oncosis has been reported to be closely associated with tumors in recent years. However, few research reported the relationship between oncosis and lung cancer. METHODS: In this study, we established an oncosis-based algorithm comprised of cluster grouping and a risk assessment model to predict the survival outcomes and related tumor immunity of patients with lung adenocarcinomas (LUAD). We selected 11 oncosis-related lncRNAs associated with the prognosis (CARD8-AS1, LINC00941, LINC01137, LINC01116, AC010980.2, LINC00324, AL365203.2, AL606489.1, AC004687.1, HLA-DQB1-AS1, and AL590226.1) to divide the LUAD patients into different clusters and different risk groups. Compared with patients in clsuter1, patients in cluster2 had a survival advantage and had a relatively more active tumor immunity. Subsequently, we constructed a risk assessment model to distinguish between patients into different risk groups, in which low-risk patients tend to have a better prognosis. GO enrichment analysis revealed that the risk assessment model was closely related to immune activities. In addition, low-risk patients tended to have a higher content of immune cells and stromal cells in tumor microenvironment, higher expression of PD-1, CTLA-4, HAVCR2, and were more sensitive to immune checkpoint inhibitors (ICIs), including PD-1/CTLA-4 inhibitors. The risk score had a significantly positive correlation with tumor mutation burden (TMB). The survival curve of the novel oncosis-based algorithm suggested that low-risk patients in cluster2 have the most obvious survival advantage. CONCLUSION: The novel oncosis-based algorithm investigated the prognosis and the related tumor immunity of patients with LUAD, which could provide theoretical support for customized individual treatment for LUAD patients.

The effect of combined TPF and intensity modulated radiotherapy after TPF induction chemotherapy on locally advanced nasopharyngeal carcinoma: a retrospective analysis.

BACKGROUND: To evaluate the efficacy and toxicity of docetaxel, cisplatin, and fluorouracil (TPF) regimen followed by intensity modulated radiotherapy (IMRT) on locally advanced nasopharyngeal carcinoma (NPC). METHODS: A total of 150 patients with locally advanced NPC [American Joint Committee on Cancer (AJCC) 2009 stage IIIa-IVb] received 2 or 3 cycles of a TPF regimen as induction chemotherapy. A group of 67 participants (TPF group) continued to receive TPF chemotherapy and radiotherapy, and the remaining 83 participants (P group) received cisplatin chemotherapy and radiotherapy. RESULTS: A median follow-up of 35 months (4-66 months) showed that there was no significant difference between P group and TPF group in progression-free survival (PFS) and overall survival (OS). The incidence rate of myelosuppression at 3-4 degrees was 16.9% and 34.3% in the P group and TPF group (P=0.029), respectively, and the oral mucosa reaction at 3-4 degrees was 18.1% and 37.3% in the P group and TPF group, respectively (P=0.007). The 3-4-degree skin reaction in the P group and TPF group was 15.7% and 29.9% (P=0.030), respectively. The rate of liver function injury in the P group was significantly lower than that in TPF group (P<0.05). CONCLUSIONS: Compared with concurrent cisplatin chemotherapy and radiotherapy, the concurrent TPF regimen and IMRT showed no significant improvement in OS and PFS in patients with advanced NPC, but exhibited more severe hematologic toxicity, oral mucosal responses, skin reactions, and liver functional impairment.

Baseline Serum Cholesterol Levels Predict the Response of Patients with Advanced Non-Small Cell Lung Cancer to Immune Checkpoint Inhibitor-Based Treatment.

PURPOSE: Although predictive markers of immune checkpoint inhibitor (ICI)-based treatments have been extensively studied, with the exception of programmed death ligand 1 (PD-L1), most are not widely used in the clinic due to poor effects or defective practicability. The aim of this study was to identify those patients with high baseline serum cholesterol who benefit from ICI-based treatments. PATIENTS AND METHODS: Patients with advanced non-small cell lung cancer (NSCLC) treated at Ningbo Medical Center, Li Huili Hospital between August 2017 and December 2019 were enrolled in this retrospective study. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to evaluate the efficacy of the ICI-based treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier survival curves and compared using the log rank test. Univariate and multivariate analyses were conducted using the logistic regression analysis and Cox proportional hazards model. A receiver operating characteristic curve was created, and the area under the curve (AUC) was calculated to compare the predictive value of baseline serum cholesterol with PD-L1 expression for patient response to ICI-based treatment. RESULTS: In our cohort of 169 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) of the treatment were significantly higher in patients with hypercholesterolemia (>5.18 mmol/L) than in those with hypocholesterolemia (ORR: 33.67% vs 14.08%, P=0.004; DCR: 68.37% vs 42.25%, P=0.001). The median PFS was 7.9 months in the hypercholesterolemia group, significantly longer than in the hypocholesterolemia group (4.4 months, 95% CI: 4.620-7.380, P<0.001). The median OS in the two groups were 11 months and 8 months, with 95% CIs of 8.980-10.420 (P<0.001). The AUC for the baseline level of cholesterol was 0.706 (P<0.001), while it was 0.643 (P=0.001) for PD-L1 expression. CONCLUSION: The baseline serum cholesterol level is predictive of a clinical benefit for advanced NSCLC patients who undergo ICI-based treatment, and hence it is a promising prognostic indicator for ICI-based treatment of NSCLC.

Optimal Empiric Treatment for Klebsiella pneumoniae Infections in Short-Stay ICU Patients During Continuous Renal Replacement Therapy: Results from a Population Pharmacokinetic/Pharmacodynamic Analysis.

OBJECTIVE: There is a paucity of published data to evaluate the efficacy and safety of imipenem (IPM) and piperacillin-tazobactam (PT) dosing regimens in the treatment of septic patients acquiring continuous renal replacement therapy (CRRT). METHODS AND MATERIALS: Critically-ill patients were grouped into short-stay and long-stay intensive care unit (ICU) patients. Pathogens were isolated from bloodstream infections in these patients. Minimum inhibitory concentration (MIC) value was determined by agar dilution method. Population PK models were introduced in this study, and differences in the likelihood of achieving efficacious and toxic exposures of IPM and PT for critically-ill patients were assessed. RESULTS: A total of 86 K. pneumoniae bloodstream infection associated isolates were collected, and the MIC50 and MIC90 for short-stay ICU patients were 0.5/4 mg/L and 32/128 mg/L, respectively. IMP 0.5g q8h reached 90% probability of target attainment (PTA) against isolates with MICs ≤2 mg/L and was recommended to empirically treat short-stay ICU patients during CRRT based on the target of 40% ƒT>MIC. However, based on a more aggressive target of 100% ƒT>MIC, all the simulated IMP regimens except for IMP 1g q6h failed to achieve >80% cumulative fraction of response (CFR) in such patients. Unfortunately, the risk of drug-related toxicity for IMP 1g q6h was relatively high (50-85%). For PT, even the regimen of 4/0.5g q6h failed to provide sufficient antimicrobial exposure in short-stay ICU patients acquiring CRRT. CONCLUSION: No dose adjustment was required for the conventional IMP and PT regimens in the critically-ill population acquiring CRRT. Empirical treatment of IMP 0.5g q8h/q6h, not for PT, may provide sufficient antimicrobial exposure for short-stay ICU patients during CRRT. PT should be used in the knowledge of MIC results.

Overexpression of microRNA-122 re-sensitizes 5-FU-resistant colon cancer cells to 5-FU through the inhibition of PKM2 in vitro and in vivo.

5-Fluorouracil (5-FU) is one of the most commonly used anticancer drugs in the treatment of colon cancer. However, acquired chemoresistance is becoming one of the major challenges for patients with advanced stages of colon cancer. Currently, the mechanisms underlying cancer cell resistance to 5-FU are not fully understood. MicroRNAs (miRNA) have been suggested to play important roles in tumorigenesis and drug resistance in colon cancer. In this study, we generated 5-FU-resistant colon cancer cell lines from which we found that miR-122 was downregulated in 5-FU-resistant cells compared with sensitive cells. Meanwhile, the glucose metabolism is significantly upregulated in 5-FU-resistant cells. We report that PKM2 is a direct target of miR-122 in colon cancer cell. Importantly, overexpression of miR-122 in 5-FU-resistant cells resensitizes 5-FU resistance through the inhibition of PKM2 both in vitro and in vivo. In summary, these findings reveal that the dysregulated glucose metabolism contributes to 5-FU resistance, and glycolysis inhibition by miR-122 might be a promising therapeutic strategy to overcome 5-FU resistance.

Synergistic antitumor effect of dichloroacetate in combination with 5-fluorouracil in colorectal cancer.

Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been recently demonstrated as a promising nontoxic antineoplastic agent that promotes apoptosis of cancer cells. In the present study, we aimed to investigate the antitumor effect of DCA combined with 5-Fluorouracil (5-FU) on colorectal cancer (CRC) cells. Four human CRC cell lines were treated with DCA or 5-FU, or a combination of DCA and 5-FU. The cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The interaction between DCA and 5-FU was evaluated by the median effect principle. Immunocytochemistry with bromodeoxyuridine (BrdU) was carried out to determine the proliferation of CRC cells. Cell cycle and apoptosis were measured by flow cytometry, and the expression of apoptosis-related molecules was assessed by western blot. Our results demonstrated that DCA inhibited the viability of CRC cells and had synergistic antiproliferation in combination with 5-FU. Moreover, compared with 5-FU alone, the apoptosis of CRC cells treated with DCA and 5-FU was enhanced and demonstrated with the changes of Bcl-2, Bax, and caspase-3 proteins. Our results suggest that DCA has a synergistic antitumor effect with 5-FU on CRC cell lines in vitro.