Angelica gigas polysaccharide induces CR3-mediated macrophage activation and the cytotoxicity of natural killer cells against HCT-116 cells via NF-κB and MAPK signaling pathways.

Angelica gigas (A. gigas) is traditional medicinal herb that mainly exists in Korea and northeastern China. There have been relatively few studies conducted thus far on its polysaccharides and their bioactivities. We purified and described a novel water-soluble polysaccharide derived from A. gigas and investigated its immunoenhancing properties. The basic components of crude and purified polysaccharides (F1 and F2) were total sugar (41.07% - 70.55%), protein (1.12-10.33%), sulfate (2.9-5.5%), and uronic acids (0.5-31.05%) in total content. Our results demonstrated that the crude and fractions' molecular weights (Mw) varied from 42.2 to 285.2 × 103 g/mol. As the most effective polysaccharide, F2 significantly stimulated RAW264.7 cells to release nitric oxide (NO) and express several cytokines. Furthermore, F2 increased the expression of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-É£), natural killer cytotoxicity receptors (NKp44), and granzyme-B in NK-92 cells and enhanced the cytotoxicity against HCT-116 cells. In our experiments, we found that F2 stimulated RAW264.7 cells and NK-92 cells via MAPK and NF-κB pathways. The monosaccharide and methylation analysis of the high immunostimulant F2 polysaccharide findings revealed that the polysaccharide was primarily composed of 1 â†’ 4, 1 â†’ 6, 1 â†’ 3, 6, 1 â†’ 3 and 1 â†’ 3, 4, 6 galactopyranose residues, 1 â†’ 3 arabinofuranose residues, 1 â†’ 4 glucopyranose residues. These results demonstrated that the F2 polysaccharide of A. gigas which possesses potential immunostimulatory attributes, could be used to create a novel functional food.

Comparison of Partial Versus Superficial or Total Parotidectomy for Superficial T1-2 Primary Parotid Cancers.

OBJECTIVES: This study aimed to compare the oncological outcomes of partial versus superficial or total parotidectomy for superficial T1 or T2 primary parotid cancers and investigate their prognostic factors and recurrence patterns. METHODS: The medical records of 77 patients with T1-2 primary parotid malignancies between May 2003 and March 2022 were retrospectively reviewed. Univariate and multivariate analyses were performed to evaluate the prognostic factors associated with overall survival, disease-free survival, and local and distant recurrence. RESULTS: The average follow-up duration was 70.2 months (range, 12-202 months). The 5-year overall and disease-free survival rates were 88.7% and 77.1%, respectively. Twenty-two patients underwent partial parotidectomy, and 55 underwent superficial or total parotidectomy. There were no significant differences in the disease recurrence (P=0.320) and mortality rates (P=0.884) of the partial and superficial or total parotidectomy groups. The mean duration of surgery was shorter and the overall complication rates were significantly lower in the partial group than in the superficial or total parotidectomy group (P=0.049). Sixteen cases of recurrence occurred during the study period (20.8%). Univariate analyses showed that high-grade tumors (P=0.006), lymphovascular invasion (P=0.046), and regional lymph node metastasis (P=0.010) were significant risk factors for disease recurrence. Multivariate analysis identified regional lymph node metastasis as an independent prognostic factor for disease recurrence (P=0.027), and lymphovascular invasion as an independent prognostic factor for overall survival (P=0.033). CONCLUSION: The conservative surgical approach of partial parotidectomy can yield oncological outcomes comparable to those of superficial or total parotidectomy with careful patient selection in T1-2 parotid cancers.

A novel sulfated mannan-carboxymethyl-5-fluorouracil-folic acid conjugates for targeted anticancer drug delivery.

CFP2 is a sulfated polysaccharide isolated from Codium fragile that shows excellent immunomodulatory activity. To reduce the side effects of 5-fluorouracil (5-FU), CFP2 was used as a macromolecular carrier to react with carboxymethyl-5-fluorouracil (C-5-FU) to form CFP2-C-5-FU, which further reacted with folic acid (FA) via an ester bond to form novel conjugates (CFP2-C-5-FU-FA). CFP2-C-5-FU-FA was confirmed by nuclear magnetic resonance (NMR) analysis. In vitro drug release results showed that the cumulative release rate of C-5-FU was 49.9% in phosphate buffer (pH 7.4) after 96 h, which was much higher than that of the other groups, indicating that CFP2-C-5-FU-FA showed controlled drug release behavior. CFP2-C-5-FU-FA also exhibited enhanced apoptosis and cellular uptake in vitro. Further, intravenous administration of CFP2-C-5-FU-FA in an HCT-116 cell-bearing xenograft mouse showed that the conjugates were safe and effective drug delivery systems. These results suggest that folate-targeted conjugates can be used effectively for efficient chemotherapy of colorectal cancer.

Factors influencing bactericidal efficacy using atmospheric cold plasma (ACP) against Escherichia coli in wheat flour.

This study aimed to evaluate operating factors that influence the bactericidal efficacy of atmospheric cold plasma (ACP) using wheat flour contaminated with Escherichia coli. It also investigated how non-optimized operating factors of ACP could affect wheat flour properties. Five operating factors (container volume, flour weight, shaking RPM, treatment time, and gas flow rate) were evaluated for the bactericidal effect of ACP using the Box-Behnken design. In addition, thermal and pasting properties were measured to assess the effect of non-optimized ACP operating conditions on wheat flour quality. ACP operating factors (volume of the container, shaking RPM, and treatment time) had significant effects on reducing E. coli in wheat flour (p < 0.05). The bactericidal effect also depended on the distance and contact area between the plasma jet and sample. The temperature at the flour surface increased (max. 70 ℃) when ACP treatment didn't provide sufficient space and optimized duration. Thermal, pasting, and gelling properties of ACP treated-wheat flour in a 10 mL container increased significantly compared to untreated wheat flour. Large amounts of samples, long processing time, and insufficient space contributed to overheating which leads to denaturation or change of the wheat flour properties. The present study proposed important data for industrial sterilization of wheat flour using ACP.

Evaluation of Combined Cancer Markers With Lactate Dehydrogenase and Application of Machine Learning Algorithms for Differentiating Benign Disease From Malignant Ovarian Cancer.

BACKGROUND: The differential diagnosis of ovarian cancer is important, and there has been ongoing research to identify biomarkers with higher performance. This study aimed to evaluate the diagnostic utility of combinations of cancer markers classified by machine learning algorithms in patients with early stage ovarian cancer, which has rarely been reported. METHODS: In total, 730 serum samples were assayed for lactate dehydrogenase (LD), neutrophil-to-lymphocyte ratio (NLR), human epididymis protein 4 (HE4), cancer antigen 125 (CA125), and risk of ovarian malignancy algorithm (ROMA). Among them, 53 were diagnosed with early stage ovarian cancer, and the remaining 677 were diagnosed with benign disease. RESULTS: The areas under the receiver operating characteristic curves (ROC-AUCs) of the ROMA, HE4, CA125, LD, and NLR for discriminating ovarian cancer from non-cancerous disease were .707, .680, .643, .657, and .624, respectively. ROC-AUC of the combination of ROMA and LD (.709) was similar to that of single ROMA in the total population. In the postmenopausal group, ROC-AUCs of HE4 and CA125 combined with LD presented the highest value (.718). When machine learning algorithms were applied to ROMA combined with LD, the ROC-AUC of random forest was higher than that of other applied algorithms in the total population (.757), showing acceptable performance. CONCLUSION: Our data suggest that the combinations of ovarian cancer-specific markers with LD classified by random forest may be a useful tool for predicting ovarian cancer, particularly in clinical settings, due to easy accessibility and cost-effectiveness. Application of an optimal combination of cancer markers and algorithms would facilitate appropriate management of ovarian cancer patients.

Genomic analysis of pancreatic cancer reveals 3 molecular subtypes with different clinical outcomes.

ABSTRACT: Pancreatic cancer has a very high mortality with a 5-year survival of <5%. The purpose of this study was to classify specific molecular subtypes associated with prognosis of pancreatic cancer using The Cancer Genome Atlas (TCGA) multiplatform genomic data.Multiplatform genomic data (N = 178), including gene expression, copy number alteration, and somatic mutation data, were obtained from cancer browser (https://genome-cancer.ucsc.edu, cohort: TCGA Pancreatic Cancer). Clinical data including survival results were analyzed. We also used validation cohort (GSE50827) to confirm the robustness of these molecular subtypes in pancreatic cancer.When we performed unsupervised clustering using TCGA gene expression data, we found three distinct molecular subtypes associated with different survival results. Copy number alteration and somatic mutation data showed different genomic patterns for these three subtypes. Ingenuity pathway analysis revealed that each subtype showed differentially altered pathways. Using each subtype-specific genes (200 were selected), we could predict molecular subtype in another cohort, confirming the robustness of these molecular subtypes of pancreatic cancer. Cox regression analysis revealed that molecular subtype is the only significant prognostic factor for pancreatic cancer (P = .042, 95% confidence interval 0.523-0.98).Genomic analysis of pancreatic cancer revealed 3 distinct molecular subtypes associated with different survival results. Using these subtype-specific genes and prediction model, we could predict molecular subtype associated with prognosis of pancreatic cancer.

The occult nodal metastasis rate of early tongue cancer (T1-T2): A protocol for a systematic review and meta-analysis.

OBJECTIVES: In this study, a meta-analysis was conducted to evaluate the occult lymph node metastasis rate in patients with early-stage (T1-T2) oral tongue squamous cell carcinoma. Also, the correlation between occult lymph node metastasis rate and T2 ratio among T1-T2 or the reported year of each study was analyzed to adjust other confound variables. STUDY DESIGN: Literature search. METHODS: A systematic computerized search of the electronic databases was carried out for articles published between January 1, 1980, and December 31, 2018, which reported occult nodal metastasis rate in T1 and T2 (separately) tongue cancer patients. Statistical analysis was performed using Comprehensive Meta Analysis version 3.3.070. Publication bias was assessed by the Egger test and Begg funnel plot method. The correlation between occult nodal metastasis rate and T2 ratio or reported year, respectively, was assessed by meta-regression analysis. RESULTS: From 19 studies, a total of 1567 cases were included in the meta-analysis. By random effects model, the mean occult cervical lymph node metastasis was 24.4% (95% confidence interval; 0.205-0.248). The meta-regression revealed that the T2 ratio and the reported year of the studies did not have a significant effect on the occult metastasis rate (correlation coefficient = 0.531 and 0.002, respectively, and P = .426 and 0.921, respectively). CONCLUSION: The meta-analysis revealed that the early-stage oral tongue squamous cell carcinoma had a rate of 24.4% for occult nodal metastasis. The occult nodal metastasis rate was not significantly affected by neither T2 ratio among T1-T2 nor reported year of the studies.

Whole-genome, transcriptome, and methylome analyses provide insights into the evolution of platycoside biosynthesis in Platycodon grandiflorus, a medicinal plant.

Triterpenoid saponins (TSs) are common plant defense phytochemicals with potential pharmaceutical properties. Platycodon grandiflorus (Campanulaceae) has been traditionally used to treat bronchitis and asthma in East Asia. The oleanane-type TSs, platycosides, are a major component of the P. grandiflorus root extract. Recent studies show that platycosides exhibit anti-inflammatory, antiobesity, anticancer, antiviral, and antiallergy properties. However, the evolutionary history of platycoside biosynthesis genes remains unknown. In this study, we sequenced the genome of P. grandiflorus and investigated the genes involved in platycoside biosynthesis. The draft genome of P. grandiflorus is 680.1 Mb long and contains 40,017 protein-coding genes. Genomic analysis revealed that the CYP716 family genes play a major role in platycoside oxidation. The CYP716 gene family of P. grandiflorus was much larger than that of other Asterid species. Orthologous gene annotation also revealed the expansion of ß-amyrin synthases (bASs) in P. grandiflorus, which was confirmed by tissue-specific gene expression. In these expanded gene families, we identified key genes showing preferential expression in roots and association with platycoside biosynthesis. In addition, whole-genome bisulfite sequencing showed that CYP716 and bAS genes are hypomethylated in P. grandiflorus, suggesting that epigenetic modification of these two gene families affects platycoside biosynthesis. Thus whole-genome, transcriptome, and methylome data of P. grandiflorus provide novel insights into the regulation of platycoside biosynthesis by CYP716 and bAS gene families.

The value of CT, MRI, and PET-CT in detecting retropharyngeal lymph node metastasis of head and neck squamous cell carcinoma.

BACKGROUND: The diagnostic accuracies of the imaging studies should be clearly acknowledged in managing head and neck cancer patients; however, the accuracies of preoperative imaging studies in detecting retropharyngeal lymph node (RPLN) metastasis are still not clarified. This study was to evaluate diagnostic accuracies of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT) in detecting RPLN metastasis of head and neck squamous cell carcinomas. METHODS: For 123 patients who had performed RPLN dissection during the surgery of their squamous cell carcinoma of the head and neck, preoperative CT, MRI, and/or PET-CT were reviewed for RPLN metastasis in a blinded fashion by one experienced radiologist. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of each imaging modality were assessed, by comparing with the histopathologic findings of the resected RPLNs that served as the standard of reference. RESULTS: RPLNs were pathologically positive for metastasis in 43 of the 123 patients (35%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy in detecting metastasis to RPLN were 65, 94, 85, 83, and 84% for CT; 74, 94, 87, 87 and 87% for MRI; 83, 93, 89, 89 and 89% for PET-CT, respectively. When all the three imaging modalities were considered together (n = 74), they offered sensitivity of 90%, specificity of 91%, positive predictive value of 87%, negative predictive value of 93%, and accuracy of 91%. CONCLUSIONS: The preoperative imaging studies offered relatively high specificity rates, but rather low sensitivity rates. The three imaging modalities altogether increased diagnostic accuracies, which highlights the potential of the three studies when used altogether can minimize missed diagnoses of RPLN metastasis.

Silence of Hippo Pathway Associates with Pro-Tumoral Immunosuppression: Potential Therapeutic Target of Glioblastomas.

The critical role of the Hippo pathway has been recently investigated in various cancers, but little is known about its role in glioblastoma (GBM). In order to evaluate the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature from four different previously-established silence of Hippo pathway (SOH) signatures. Based on a newly generated core SOH signature, a SOH and active Hippo pathway (AH) was predicted in GBM samples from The Cancer Genome Atlas (TCGA) and validated in a separate cohort. A comparative analysis was performed on multi-panel genomic datasets from TCGA and the possible association of SOH with immune activity and epithelial mesenchymal transition was also evaluated. The SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1, were markedly increased in the SOH subgroup of GBM patients. SOH signature was strongly associated with a high immune signature score and mesenchymal features. Genes differentially expressed between SOH and AH groups revealed many markers for inhibitory immune checkpoints and M2-polarized macrophages were upregulated in the SOH subgroup, suggesting that SOH may induce the resistance of cancer cells to host immune response in GBM. In summary, SOH is significantly associated with the poor prognosis of GBM patients and is possibly mediated by pro-tumoral immunosuppression.

A case of mammary analogue secretory carcinoma of the parotid gland: A case report.

RATIONALE: Mammary analogue secretory carcinoma is a low grade salivary gland malignancy, first described by Skalova et al in 2010. The histological, immunohistochemical, and molecular characteristics of this tumor resemble those of secretory carcinoma of the breast. PATIENT CONCERNS: A 40-year-old male patient without any specific past history came with complaints of 4 cm-sized hard, fixed, right infra-auricular mass without tenderness. There was no enlarged or enhancing lymph node in both neck. DIAGNOSES: Fine needle aspiration biopsy was done for right parotid mass and pathologic report was "lymphocytes only" that suggested benign or low-grade malignant parotid tumor. INTERVENTIONS: Partial parotidectomy including mass excision was performed. Operative finding showed hard bluish mass located in deep lobe of right parotid gland. OUTCOMES: Final pathologic report revealed secretory carcinoma of parotid gland. Homogenous eosinophilic secretions were identified inside microcystic structure. The immunophenotype was positive for epithelial membrane antigen, vimentin, S-100 protein. After 15 months of the surgery, the patient showed negative evidence of disease state. LESSONS: We present here a case of mammary analogue secretory carcinoma of the parotid gland to help further characterize this rare tumor.

Transcriptome Analysis Reveals Significant Differences in Gene Expression of Malignant Pheochromocytoma or Paraganglioma.

Prediction of malignant behavior of pheochromocytoma (PC) or paraganglioma (PG) is of limited value. The Cancer Genome Atlas (TCGA) and the French 'Cortico et Médullosurrénale: les Tumeurs Endocrines' (COMETE) network in Paris (France) facilitate accurate differentiation of malignant PC/PG based on genetic information. Therefore, the objective of this transcriptome analysis is to identify the prognostic genes underlying the differentiation of malignant PC/PG in the TCGA and COMETE databases. TCGA carries data pertaining to multigenomic analysis of 173 PC/PG surgical resection samples while the COMETE cohort contains data involving 188 PC/PG surgical resection samples. Clinical information and mRNA expression datasets were downloaded from TCGA and COMETE databases. Based on eligibility criteria, 58 of 173 PC/PG samples in TCGA and 171 of 188 PC/PG samples collected by the COMETE network were selected. Using Ingenuity Pathway Analysis, the mRNA expression of malignant and benign PC/PG was compared. The 58 samples in TCGA included 11 malignant and 47 benign cases. Among the 171 samples obtained from the COMETE cohort, 19 were malignant and 152 were benign. A comparative analysis of the mRNA expression data of the two databases revealed that 11 up/downregulated pathways involved in malignant PC/PG were related to cancer signaling, metabolic alteration, and prominent mitosis, whereas 6 upregulated genes and 1 downregulated gene were significantly enriched in the functional annotation pathways. The TCGA and COMETE databases showed differences in mRNA expression associated with malignant and benign PC/PG. Improved recognition of prognostic genes facilitates the diagnosis and treatment of PC/PG.

Runx3 inhibits endothelial progenitor cell differentiation and function via suppression of HIF-1α activity.

Endothelial progenitor cells (EPCs) are bone marrow (BM)­derived progenitor cells that can differentiate into mature endothelial cells, contributing to vasculogenesis in the blood vessel formation process. Runt­related transcription factor 3 (RUNX3) belongs to the Runt domain family and is required for the differentiation of specific immune cells and neurons. The tumor suppressive role of RUNX3, via the induction of apoptosis and cell cycle arrest in a variety of cancers, and its deletion or frequent silencing by epigenetic mechanisms have been studied extensively; however, its role in the differentiation of EPCs is yet to be investigated. Therefore, in the present study, adult BM­derived hematopoietic stem cells (HSCs) were isolated from Runx3 heterozygous (Rx3+/­) or wild­type (WT) mice. The differentiation of EPCs from the BM­derived HSCs of Rx3+/­ mice was found to be significantly increased compared with those of the WT mice, as determined by the number of small or large colony­forming units. The migration and tube formation abilities of Rx3+/­ EPCs were also observed to be significantly increased compared with those of WT EPCs. Furthermore, the number of circulating EPCs, defined as CD34+/vascular endothelial growth factor receptor 2 (VEGFR2)+ cells, was also significantly increased in Rx3+/­ mice. Hypoxia­inducible factor (HIF)­1α was upregulated in Rx3+/­ EPCs compared with WT EPCs, even under normoxic conditions. Furthermore, in a hindlimb ischemic mouse models, the recovery of blood flow was observed to be highly stimulated in Rx3+/­ mice compared with WT mice. Also, in a Lewis lung carcinoma cell allograft model, the tumor size in Rx3+/­ mice was significantly larger than that in WT mice, and the EPC cell population (CD34+/VEGFR2+ cells) recruited to the tumor was greater in the Rx3+/­ mice compared with the WT mice. In conclusion, the present study revealed that Runx3 inhibits vasculogenesis via the inhibition of EPC differentiation and functions via the suppression of HIF­1α activity.

The 100 most influential manuscripts on hepatocellular carcinoma: a bibliometric analysis.

OBJECTIVE: Citation analysis represents one of the best available methods to identify the most influential articles. This study aimed to identify and characterize the top 100 highly cited articles (T100) that focus on hepatocellular carcinoma and to reveal the trends in accomplishments within this field. METHODS: A search of the Thomson Reuters Web of Science citation indexing database was conducted using terms related to hepatocellular carcinoma. The T100 were selected and analyzed further based on the number of citations, authorship, year of publication, journal, country of origin, institution, and article type. RESULTS: Hepatology published the highest number of papers (n = 15), and the United States produced the highest number of contributions (n = 31). Barcelona University was the institution with the highest number of articles in the T100 (n = 9). The T100 articles included 35 observational studies, 13 randomized control studies, 25 basic research articles, 18 reviews, seven clinical guidelines, and two meta-analyses. CONCLUSIONS: This is the first bibliometric study to identify the most influential papers in hepatocellular carcinoma research. This report presents major advances and changes in research regarding hepatocellular carcinoma and can serve as a guide for writing a citable article.

Prognostic significance of high metabolic activity in breast cancer: PET signature in breast cancer.

High metabolic activity, reflected in increased glucose uptake, is one of the hallmarks of many cancers including breast cancer. However, not all cancers avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus, we aim to generate a genomic signature of glucose hypermetabolism in breast cancer and examine its clinical relevance. To identify genes significantly associated with glucose uptake, gene expression data were analyzed together with the standardized uptake values (SUVmax) of 18F-fluorodeoxy-glucose on positron emission tomography (PET) for 11 breast cancers. The resulting PET signature was evaluated for prognostic significance in four large independent patient cohorts (n = 5417). Potential upstream regulators accountable for the high glucose uptake were identified by gene network analysis. A PET signature of 242 genes was significantly correlated with SUVmax in breast cancer. In all four cohorts, high PET signature was significantly associated with poorer prognosis. The prognostic value of this PET signature was further supported by Cox regression analyses (hazard ratio 1.7, confidential interval 1.48-2.02; P < 0.001). The PET signature was also strongly correlated with previously established prognostic genomic signatures such as PAM50, Oncotype DX, and NKI. Gene network analyses suggested that MYC and TBX2 were the most significant upstream transcription factors in the breast cancers with high glucose uptake. A PET signature reflecting high glucose uptake is a novel independent prognostic factor in breast cancer. MYC and TBX2 are potential regulators of glucose uptake.

Characterization and quantification of flavonoid glycosides in the Prunus genus by UPLC-DAD-QTOF/MS.

Widely distributed in plants, flavonoids reduce the incidence of cancer and cardiovascular disease. In this study, flavonoid content and composition in members of the Prunus genus were evaluated using liquid chromatography with diode array and electrospray ionization mass spectrometric detection (UPLC-DAD-ESI/QTOF-MS). Flavonoids in plants of the Prunus genus include the basic structures of kaempferol, quercetin, and catechin, and exist as mono-, di-, or tri-glycoside compounds mono-acylated with acetic acid. A total of 23 individual flavonoids were isolated and confirmed, three of which appear to be newly identified compounds: quercetin 3-O-(2″-O-acetyl)neohesperidoside, quercetin 3-O-(4″-O-acetyl)rutinoside, and kaempferol 3-O-(4″-O-acetyl)rutinoside. Japanese apricot and Chinese plum contained the highest amounts of flavonoids in the Prunus genus. During the ripening stage of Japanese apricot, the total flavonol content was reduced, while the catechin content was increased.

MicroRNA-107 Targets IKBKG and Sensitizes A549 Cells to Parthenolide.

BACKGROUND/AIM: Patients with advanced non-small cell lung cancer (NSCLC) frequently face a dismal prognosis because of lack of curative therapies. We, therefore, conducted a preclinical investigation of the therapeutic efficacy of microRNA-107 (miR-107). MATERIALS AND METHODS: The effects of miR-107 on cell proliferation and target gene expression were studied. Combinatorial effects of miR-107 and parthenolide were evaluated. RESULTS: Cell proliferation was repressed in A549 NSCLC cells transfected with miR-107. Inhibitor of nuclear factor kappa B kinase subunit gamma was directly targeted by miR-107. Overexpression of miR-107 in A549 cells sensitized them to parthenolide along with a marked reduction of cyclin-dependent kinase 2. CONCLUSION: Our findings unveil an important biological function of miR-107 in regulating lung cancer cell proliferation and elevating an antiproliferative effect of parthenolide on lung cancer cells, suggesting that miR-107 could be beneficial benefit treatment for advanced NSCLC.

Three distinct genomic subtypes of head and neck squamous cell carcinoma associated with clinical outcomes.

OBJECTIVES: Heterogeneity of head and neck squamous cell carcinomas (HNSCCs) results in unpredictable outcomes for patients with similar stages of cancer. Beyond the role of human papilloma virus (HPV), no validated molecular marker of HNSCCs has been established. Thus, clinically relevant molecular subtypes are needed to optimize HNSCC therapy. The purpose of this study was to identify subtypes of HNSCC that have distinct biological characteristics associated with clinical outcomes and to characterize genomic alterations that best reflect the biological and clinical characteristics of each subtype. MATERIALS AND METHODS: We analyzed gene expression profiling data from pan-SCC tissues including cervical SCC, esophageal SCC, lung SCC, and HNSCC (n = 1346) to assess the similarities and differences among SCCs and to identify molecular subtypes of HNSCC associated with prognosis. Subtype-specific gene expression signatures were identified and used to construct predictive models. The association of the subtypes with prognosis was validated in two independent cohorts of patients. RESULTS: Pan-SCC analysis identified three novel subtypes of HNSCC. Subtype 1 had the best prognosis and was similar to cervical SCC, whereas subtype 3 had the worst prognosis and was similar to lung SCC. Subtype 2 had a moderate prognosis. The 600-gene signature associated with the three subtypes significantly predicted prognosis in two independent validation cohorts. These three subtypes also were associated with potential benefit of immunotherapy. CONCLUSION: We identified three clinically relevant HNSCC molecular subtypes. Independent prospective studies to assess the clinical utility of the subtypes and associated gene signature are warranted.

Integrated Genomic Comparison of Mouse Models Reveals Their Clinical Resemblance to Human Liver Cancer.

Hepatocellular carcinoma (HCC) is a heterogeneous disease. Mouse models are commonly used as preclinical models to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Here, integration of genomic signatures from molecularly and clinically defined human HCC (n = 11) and mouse models of HCC (n = 9) identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 knockout (KO), Sav1 KO, and SV40 T antigen mouse models effectively recapitulated subtypes of human HCC with a poor prognosis, whereas the Myc transgenic model best resembled human HCCs with a more favorable prognosis. The Myc model was also associated with activation of ß-catenin. E2f1, E2f1/Myc, E2f1/Tgfa, and diethylnitrosamine (DEN)-induced models were heterogeneous and were unequally split into poor and favorable prognoses. Mst1/2 KO and Sav1 KO models best resemble human HCC with hepatic stem cell characteristics. Applying a genomic predictor for immunotherapy, the six-gene IFNγ score, the Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis showed that elevated expression of immune-inhibitory genes (Cd276 and Nectin2/Pvrl2) in Mst1/2 KO, Sav1 KO, and SV40 models and decreased expression of immune stimulatory gene (Cd86) in the DEN model might be accountable for the lack of predictive response to immunotherapy.Implication: The current genomic approach identified the most relevant mouse models to human liver cancer and suggests immunotherapeutic potential for the treatment of specific subtypes. Mol Cancer Res; 16(11); 1713-23. ©2018 AACR.