Novel prognostic nomograms for postoperative patients with oral cavity squamous cell carcinoma in the central region of China.

BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) is the most common pathological type in oral tumors. This study intends to construct a novel prognostic nomogram model based on China populations for these resectable OCSCC patients, and then validate these nomograms. METHODS: A total of 607 postoperative patients with OCSCC diagnosed between June 2012 and June 2018 were obtained from two tertiary medical institutions in Xinxiang and Zhengzhou. Then, 70% of all the cases were randomly assigned to the training group and the rest to the validation group. The endpoint time was defined as overall survival (OS) and disease-free survival (DFS). The nomograms for predicting the 3-, and 5-year OS and DFS in postoperative OCSCC patients were established based on the independent prognostic factors, which were identified by the univariate analysis and multivariate analysis. A series of indexes were utilized to assess the performance and net benefit of these two newly constructed nomograms. Finally, the discrimination capability of OS and DFS was compared between the new risk stratification and the American Joint Committee on Cancer (AJCC) stage by Kaplan-Meier curves. RESULTS: 607 postoperative patients with OCSCC were selected and randomly assigned to the training cohort (n = 425) and validation cohort (n = 182). The nomograms for predicting OS and DFS in postoperative OCSCC patients had been established based on the independent prognostic factors. Moreover, dynamic nomograms were also established for more convenient clinical application. The C-index for predicting OS and DFS were 0.691, 0.674 in the training group, and 0.722, 0.680 in the validation group, respectively. Besides, the calibration curve displayed good consistency between the predicted survival probability and actual observations. Finally, the excellent performance of these two nomograms was verified by the NRI, IDI, and DCA curves in comparison to the AJCC stage system. CONCLUSION: The newly established and validated nomograms for predicting OS and DFS in postoperative patients with OCSCC perform well, which can be helpful for clinicians and contribute to clinical decision-making.

Nomogram based on immune-inflammatory indicators and age-adjusted charlson comorbidity index score to predict prognosis of postoperative parotid gland carcinoma patients.

BACKGROUND: Parotid gland carcinoma (PGC) is a rare malignant tumor. The purpose of this study was to investigate the role of immune-inflammatory-nutrition indicators and age-adjusted Charlson comorbidity index score (ACCI) of PGC and develop the nomogram model for predicting prognosis. METHOD: All patients diagnosed with PGC in two tertiary hospitals, treated with surgical resection, from March 2012 to June 2018 were obtained. Potential prognostic factors were identified by univariate and multivariate Cox regression analyses. The nomogram models were established based on these identified independent prognostic factors. The performance of the developed prognostic model was estimated by related indexes and plots. RESULT: The study population consisted of 344 patients with PGC who underwent surgical resection, 285 patients without smoking (82.8%), and 225 patients (65.4%) with mucoepidermoid carcinoma, with a median age of 50.0 years. American Joint Committee on Cancer (AJCC) stage (p < 0.001), pathology (p = 0.019), tumor location (p < 0.001), extranodal extension (ENE) (p < 0.001), systemic immune-inflammation index (SII) (p = 0.004), prognostic nutrition index (PNI) (p = 0.003), ACCI (p < 0.001), and Glasgow prognostic Score (GPS) (p = 0.001) were independent indicators for disease free survival (DFS). Additionally, the independent prognostic factors for overall survival (OS) including AJCC stage (p = 0.015), pathology (p = 0.004), tumor location (p < 0.001), perineural invasion (p = 0.009), ENE (p < 0.001), systemic immune-inflammation index (SII) (p = 0.001), PNI (p = 0.001), ACCI (p = 0.003), and GPS (p = 0.033). The nomogram models for predicting DFS and OS in PGC patients were generated based on these independent risk factors. All nomogram models show good discriminative capability with area under curves (AUCs) over 0.8 (DFS 0.802, and OS 0.825, respectively). Decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) show good clinical net benefit of the two nomograms in both training and validation cohorts. Kaplan-Meier survival analyses showed superior discrimination of DFS and OS in the new risk stratification system compared with the AJCC stage system. Finally, postoperative patients with PGC who underwent adjuvant radiotherapy had a better prognosis in the high-, and medium-risk subgroups (p < 0.05), but not for the low-risk subgroup. CONCLUSION: The immune-inflammatory-nutrition indicators and ACCI played an important role in both DFS and OS of PGC patients. Adjuvant radiotherapy had no benefit in the low-risk subgroup for PGC patients who underwent surgical resection. The newly established nomogram models perform well and can provide an individualized prognostic reference, which may be helpful for patients and surgeons in proper follow-up strategies.

Multivariate analysis of prognostic factors in patients with lip squamous cell carcinoma after surgery.

BACKGROUND: Lip squamous cell carcinoma (LSCC) was one of the most common cancer types of head and neck tumors. This study aimed to find more predictors of the prognosis in postoperative LSCC patients. METHODS: A total of 147 LSCC patients between June 2012 and June 2018 were collected from two tertiary care institutions. There were 21 clinicopathological factors included and analyzed in our study. The univariate and multivariate Cox regression analyses were performed to find the independent prognostic factors for predicting progression-free survival (PFS) and overall survival (OS) in postoperative LSCC patients. The role of adjuvant radiotherapy in various subgroups was displayed by Kaplan-Meier plots. RESULTS: The 1-, 3-, and 5-year PFS of postoperative LSCC patients were 88.4%, 70.1%, and 57.8%, respectively. Similarly, the 1-, 3-, and 5-year OS of postoperative LSCC patients were 94.6%, 76.9%, and 69.4%, respectively. The results suggested that postoperative LSCC patients with age at diagnosis ≥ 70 years, grade with moderate or poor differentiate, the American Joint Committee on Cancer (AJCC) stage IV, higher systemic immune-inflammation index (SII), surgical margin < 5, and age-adjusted Charlson Comorbidity Index (ACCI) ≥ 5 tend to have a poorer PFS (all P < 0.05). Besides, postoperative LSCC patients with age at diagnosis ≥ 70 years, AJCC stage IV, higher GPS, higher SII, and ACCI ≥ 5 tend to have a worse OS (all P < 0.05). Additionally, postoperative patients with LSCC in the subgroup of ACCI < 5 and AJCC III-IV stage was more likely to benefit from adjuvant radiotherapy, but not for the other subgroups. CONCLUSION: We identified a series of significant immune-inflammation-related and comorbidity-related clinicopathological factors associated with the prognosis of postoperative LSCC patients by local data from two tertiary care institutions in China, which can be helpful for patients and surgeons to pay more attention to nutrition, inflammation, and complications and finally obtained a better prognosis.

Gut microbiota: An emerging therapeutic approach of herbal medicine for prevention of colorectal cancer.

The gut dysbiosis has emerged as a prominent player in the pathogenesis and development of colorectal cancer (CRC), which in turn intensifies dysregulated gut microbiota composition and inflammation. Since most drugs are given orally, this dysbiosis directly and indirectly impinges the absorption and metabolism of drugs in the gastrointestinal tract, and subsequently affects the clinical outcome of patients with CRC. Herbal medicine, including the natural bioactive products, have been used traditionally for centuries and can be considered as novel medicinal sources for anticancer drug discovery. Due to their various structures and pharmacological effects, natural products have been found to improve microbiota composition, repair intestinal barrier and reduce inflammation in human and animal models of CRC. This review summarizes the chemo-preventive effects of extracts and/or compounds derived from natural herbs as the promising antineoplastic agents against CRC, and will provide innovative strategies to counteract dysregulated microbiota and improve the lives of CRC patients.

Implications of m6A methylation and microbiota interaction in non-small cell lung cancer: From basics to therapeutics.

N6-methyladenine (m6A) is one of the most common RNA epigenetic modifications in all higher eukaryotes. Increasing evidence demonstrated that m6A-related proteins, acted as oncogenes or tumor suppressors, are abnormally expressed in the cell lines and tissues of non-small cell lung cancer (NSCLC). In addition, lung as the special immune organ contacts with the outer environments and thereby inevitably suffers from different types of microbial pathogen attack. Those microbial pathogens affect the development, progression, and clinical outcomes of NSCLC via altering host m6A modification to disrupt pulmonary immune homeostasis and increase the susceptibility; conversely, host cells modulate m6A modification to repress bacterial colonization. Therefore, m6A harbors the potential to be the novel biomarkers and targets for predicting poor prognosis and chemotherapy sensitivity of patients with lung cancer. In this paper, we provided an overview of the biological properties of m6A-modifying enzymes, and the mechanistic links among lung microbiota, m6A modification and NSCLC. Although the flood of novel m6A-related inhibitors represents many dramatic improvements in NSCLC therapy, their efficacy and toxicity in NSCLC are explored to address these pivotal gaps in the field.

Potential Implications of the Lung Microbiota in Patients with Chronic Obstruction Pulmonary Disease and Non-Small Cell Lung Cancer.

Recently, chronic obstructive pulmonary disease (COPD) has been considered as a common risk factor of non-small cell lung cancer (NSCLC). However, very few studies have been conducted on the effects of COPD on the lung microbiota in patients with NSCLC. To identify the lung microbiota in patients with COPD and NSCLC (CN), the microbiome of the induced sputa of 90 patients was analyzed using 16S rDNA sequencing. The results showed no significant differences in the bacterial diversities of induced sputa among patients with COPD, NSCLC, and CN and no intrinsic differences among patients with different pathological types of lung cancer. After surgical operation, the diversities of the induced sputa in patients with CN significantly decreased. More remarkably, both the microbial community phenotypes and the components of the induced sputa in patients with CN obviously differed from those in patients with COPD or NSCLC. The relative abundances of Streptococcus, Veillonella, Moraxella, and Actinomyces significantly decreased, but those of Neisseria and Acinetobacter significantly increased in patients with CN compared with those in patients with COPD or NSCLC alone, resulting in increased Gram-negative microbiota and, therefore, in potential pathogenicity and stress tolerance, as well as in enhancement of microbial glycolipid metabolism, amino acid metabolism, and oxidative stress. Although COPD did not affect the number of pulmonary flora species in patients with NSCLC, these significant alterations in the microbial populations, phenotypes, and functions of induced sputa due to COPD would contribute to inflammation-derived cancer progression in patients with CN.

Polysaccharides from Platycodonis Radix ameliorated respiratory syncytial virus-induced epithelial cell apoptosis and inflammation through activation of miR-181a-mediated Hippo and SIRT1 pathways.

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in young children, but there are few safe and effective treatments for this disease. Platycodonis Radix is widely used as an antitussive and expectorant drug for preventing various diseases in lower respiratory tract, in which the polysaccharides are one of the main bioactivity constituents. In this study, the protective effects of the P. Radix polysaccharides (PRP) against RSV-induced bronchiolitis in juvenile mice and RSV-induced apoptosis of epithelial HEp-2 cells were investigated. The results showed that PRP obviously decreased the levels of IL-1ß, IL-4, IL-6, TNF-α, IFN-γ and TSLP in lung tissues, and reduced the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) of RSV-infected mice. Furthermore, it reduced the apoptosis of RSV-infected HEp-2 cells and remarkably inhibited the mRNA expressions of RSV L gene, which indicated that PRP affected transcription and replication of RSV in host cells. Compared with that in RSV-infected group, miR-181a-5p in the PRP-treated group presented the highest relative abundance and its expression was violently reduced by approximately 30%. Mechanistically, PRP had the similar effects as miR-181a-5p antagomir on RSV-induced apoptosis and inflammation in HEp-2 cells via upregulating BCL2, MLL3 and SIRT1, which could be reversed by miR-181a-5p mimic. Therefore, it demonstrated that PRP not only protected against RSV-induced lung inflammation in mice but also inhibited apoptosis of RSV-infected HEp-2 cells via suppressing miR-181a-5p and transcriptionally activating Hippo and SIRT1 pathways.

Isovitexin potentiated the antitumor activity of cisplatin by inhibiting the glucose metabolism of lung cancer cells and reduced cisplatin-induced immunotoxicity in mice.

The increased resistance and toxicity have become the main causes of chemotherapy failure for treating lung cancer. The combination of chemotherapeutic drugs with other agents has been recognized as a promising strategy to overcome these difficulties. Isovitexin (IVT) is a well-known flavone C-glycoside found in many plants and has attracted wide attention due to its obvious antitumor and antioxidant effects. In this study, we investigated the synergistic effects of IVX and cisplatin (DDP) in non-small cell lung cancer (NSCLC) A549 and H1975 cells. The results showed that the combined treatment with IVT and DDP markedly inhibited proliferation and induced apoptosis of the two NSCLC cells. Using a mouse model of A549 xenograft, IVT potentiated the inhibition of DDP on tumor growth, but reduced DDP-induced hepatotoxicity and nephrotoxicity in mice. Remarkedly, IVT promoted lipopolysaccharide (LPS)- and lectin- stimulated splenocyte proliferation, and enhance cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activities as well as the production of IL-2 and TNF-α. Furthermore, IVT significantly reduced glucose uptake, lactate production, and ATP production, and downregulated the protein expressions of pyruvate kinase M2 (PKM2)-mediated pathway in both A549 and H1975 cells. After the over-expression of PKM2 in the NSCLC cells, the synergistic antitumor effect of IVT and DDP was markedly weakened. Therefore, IVT not only inhibited cell proliferation and glucose metabolism via downregulating the expression of PKM2 to enhance the antitumor activity of DDP against lung cancer cells, and improved DDP-induced immunotoxicity in mice. It also presented a novel strategy to enhance the anti-tumor effect of platinum-based chemotherapy against NSCLC.

PRP1, a heteropolysaccharide from Platycodonis Radix, induced apoptosis of HepG2 cells via regulating miR-21-mediated PI3K/AKT pathway.

Two polysaccharides (PRP1 and PRP2) were isolated from Platycodonis Radix. Preliminary structural analysis indicated that PRP1 was composed of glucose, fructose, and arabinose in a molar ratio of 1:1.91:1.59 with a molecular weight of 440 kDa, whereas PRP2 was composed of arabinose, fructose, and galactose in a molar ratio of 1:1.39:1.18 with a molecular weight of 2.85 kDa. Compared with PRP2, PRP1 exerted stronger anticancer activity in vitro. Treatment with 5-30 µg/ml of PRP1 significantly inhibited the proliferation of HepG2 cells in vitro, and oral administration at the doses of 75-300 mg/kg also reduced the tumor growth in vivo. The miRNA expression patterns of human liver cancer cells HepG2 in vivo under PRP1 treatment were established, and microRNA-21 (miR-21) as the onco-miRNA was appreciably downregulated. PRP1 repressed the expression of miR-21, which directly targeted and suppressed PTEN (a negative regulator of the PI3K/Akt signaling cascade), and subsequently upregulated the expression of PTEN but downregulated the PI3K/AKT pathway, thereby promoting liver cancer cell apoptosis. These findings indicated that PRP1 inhibited the proliferation and induced the apoptosis of HepG2 mainly via inactivating the miR-21/PI3K/AKT pathway. Therefore, PRP1 could be used as a food supplement and candidate for the treatment of liver cancer.

The Inhibitory Effect of Eplerenone on Cell Proliferation in the Contralateral Kidneys of Rats with Unilateral Ureteral Obstruction.

BACKGROUND: The unilateral ureteral obstruction (UUO) model not only induces renal interstitial fibrosis in the obstructed kidney but also induces injury in the contralateral kidney. We hypothesized that activation of the mineralocorticoid receptor (MR) may induce fibrosis in the early stage of UUO. METHODS: Thirty male Sprague-Dawley rats weighting 200 ± 10 g were used in this study and randomly divided into 3 groups: a UUO group, a UUO and eplerenone group, and a sham group. The contralateral kidney and plasma were harvested for further study 10 days after surgery. RESULTS: The level of plasma aldosterone (869.95 ± 55.851 pg/mL) was significantly higher in the UUO group than that in the sham group (478.581 ± 36.186 pg/mL vs. UUO, p < 0.05). The infiltrated inflammatory cells (F4/80) and deposited collagens were increased significantly in the contralateral kidneys in the UUO group compared to those in the sham group, which were decreased by eplerenone. However, proliferating cell nuclear antigen was increased 2.47 times in the UUO group compared to the sham group in the contralateral kidney (p < 0.01), and those changes are attenuated by eplerenone. The expression of SGK-1 protein and mRNA was upregulated in the contralateral kidney in the UUO group, which is suppressed by eplerenone treatment. NF-κB pathway effecters were also changed markedly in the contralateral kidney in the UUO group and partly reversed by eplerenone. CONCLUSION: Aldosterone induces inflammatory cell proliferation via the MR/SGK-1 and NF-κB pathways and eventually leads to fibrosis in the contralateral kidney.