Single-cell atlas of healthy vocal folds and cellular function in the endothelial-to-mesenchymal transition.

The vocal fold is an architecturally complex organ comprising a heterogeneous mixture of various layers of individual epithelial and mesenchymal cell lineages. Here we performed single-cell RNA sequencing profiling of 5836 cells from the vocal folds of adult Sprague-Dawley rats. Combined with immunostaining, we generated a spatial and transcriptional map of the vocal fold cells and characterized the subpopulations of epithelial cells, mesenchymal cells, endothelial cells, and immune cells. We also identified a novel epithelial-to-mesenchymal transition-associated epithelial cell subset that was mainly found in the basal epithelial layers. We further confirmed that this subset acts as intermediate cells with similar genetic features to epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma. Finally, we present the complex intracellular communication network involved homeostasis using CellChat analysis. These studies define the cellular and molecular framework of the biology and pathology of the VF mucosa and reveal the functional importance of developmental pathways in pathological states in cancer.

Circ-DTL sponges miR-758-3p to accelerate cervical cancer malignant progression by regulating DCUN1D1 expression.

Circular RNAs (circRNAs) play important roles in regulating various cancer progression. However, the function and clinical significance of circ-denticleless E3 ubiquitin proteinligase homolog (DTL) in cervical cancer (CC) have not been studied. The present work explored the function and mechanism of circ-DTL in CC development. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the expression of circ-DTL, miR-758-3p, and DCUN1D1. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to detect cell proliferation. Cell cycle and cell apoptosis were investigated by flow cytometry. Wound-healing assay and transwell assay were conducted to assess cell migration and cell invasion. Western blot assay was carried out to determine protein expression. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to identify the relationship between miR-758-3p and circ-DTL or DCUN1D1. Xenograft mouse model assay was conducted to explore the role of circ-DTL in CC progression in vivo. Circ-DTL and DCUN1D1 expression were upregulated in CC tissues and CC cells, but miR-758-3p expression was downregulated. Knockdown of circ-DTL inhibited CC cell growth, migration, and invasion and promoted cell cycle arrest and cell apoptosis. Circ-DTL could sponge miR-758-3p to modulate CC cell progression. Moreover, miR-758-3p inhibited CC malignant development by suppressing DCUN1D1 expression. In addition, circ-DTL knockdown repressed CC cell tumor properties in vivo. Circ-DTL acted as a tumor promoter in CC development by regulating the miR-758-3p/DCUN1D1 pathway.

Circ_0005615 promotes cervical cancer cell growth and metastasis by modulating the miR-138-5p/KDM2A axis.

Cervical cancer (CC) is a highly fatal gynecological malignancy due to its high metastasis and recurrence rate. Circular RNA (circRNA) has been regarded as a regulator of CC. However, the underlying molecular mechanism of circ_0005615 in CC remains unclear. The levels of circ_0005615, miR-138-5p, and lysine demethylase 2A (KDM2A) were measured using qRT-PCR or western blot. Cell proliferation was assessed by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, and colony formation experiments. Cell invasion and migration were tested by transwell assay and wound healing assay. Flow cytometry and Caspase-Glo 3/7 Assay kit were used to analyze cell apoptosis. The expression of proliferation-related and apoptosis-related markers was detected by western blot. The binding relationships among circ_0005615, miR-138-5p, and KDM2A were verified by dual-luciferase reporter assay or RNA immunoprecipitation assay. Xenograft assay was applied to detect the effect of circ_0005615 in vivo. Circ_0005615 and KDM2A were upregulated, while miR-138-5p was downregulated in CC tissues and cells. Circ_0005615 knockdown retarded cell proliferation, migration, and invasion, while promoting apoptosis. Besides, circ_0005615 sponged miR-138-5p, and miR-138-5p could target KDM2A. miR-138-5p inhibitor reversed the regulation of circ_0005615 knockdown on CC cell growth and metastasis, and KDM2A overexpression also abolished the inhibitory effect of miR-138-5p on CC cell growth and metastasis. In addition, we also discovered that circ_0005615 silencing inhibited CC tumor growth in vivo. Circ_0005615 acted as a tumor promoter in CC by regulating the miR-138-5p/KDM2A pathway.

PrMYB5 activates anthocyanin biosynthetic PrDFR to promote the distinct pigmentation pattern in the petal of Paeonia rockii.

Paeonia rockii is well-known for its distinctive large dark-purple spot at the white petal base and has been considered to be the main genetic source of spotted tree peony cultivars. In this study, the petal base and petal background of Paeonia ostii (pure white petals without any spot), P. rockii, and other three tree peony cultivars were sampled at four blooming stages from the small bell-like bud stage to the initial blooming stage. There is a distinct difference between the pigmentation processes of spots and petal backgrounds; the spot pigmentation was about 10 days earlier than the petal background. Moreover, the cyanin and peonidin type anthocyanin accumulation at the petal base mainly contributed to the petal spot formation. Then, we identified a C1 subgroup R2R3-MYB transcription factor, PrMYB5, predominantly transcribing at the petal base. This is extremely consistent with PrDFR and PrANS expression, the contents of anthocyanins, and spot formation. Furthermore, PrMYB5 could bind to and activate the promoter of PrDFR in yeast one-hybrid and dual-luciferase assays, which was further verified in overexpression of PrMYB5 in tobacco and PrMYB5-silenced petals of P. rockii by comparing the color change, anthocyanin contents, and gene expression. In summary, these results shed light on the mechanism of petal spot formation in P. rockii and speed up the molecular breeding process of tree peony cultivars with novel spot pigmentation patterns.

Integrating full-length transcriptomics and metabolomics reveals the regulatory mechanisms underlying yellow pigmentation in tree peony (Paeonia suffruticosa Andr.) flowers.

Tree peony (Paeonia suffruticosa Andr.) is a popular ornamental plant in China due to its showy and colorful flowers. However, yellow-colored flowers are rare in both wild species and domesticated cultivars. The molecular mechanisms underlying yellow pigmentation remain poorly understood. Here, petal tissues of two tree peony cultivars, "High Noon" (yellow flowers) and "Roufurong" (purple-red flowers), were sampled at five developmental stages (S1-S5) from early flower buds to full blooms. Five petal color indices (brightness, redness, yellowness, chroma, and hue angle) and the contents of ten different flavonoids were determined. Compared to "Roufurong," which accumulated abundant anthocyanins at S3-S5, the yellow-colored "High Noon" displayed relatively higher contents of tetrahydroxychalcone (THC), flavones, and flavonols but no anthocyanin production. The contents of THC, flavones, and flavonols in "High Noon" peaked at S3 and dropped gradually as the flower bloomed, consistent with the color index patterns. Furthermore, RNA-seq analyses at S3 showed that structural genes such as PsC4Hs, PsDFRs, and PsUFGTs in the flavonoid biosynthesis pathway were downregulated in "High Noon," whereas most PsFLSs, PsF3Hs, and PsF3'Hs were upregulated. Five transcription factor (TF) genes related to flavonoid biosynthesis were also upregulated in "High Noon." One of these TFs, PsMYB111, was overexpressed in tobacco, which led to increased flavonols but decreased anthocyanins. Dual-luciferase assays further confirmed that PsMYB111 upregulated PsFLS. These results improve our understanding of yellow pigmentation in tree peony and provide a guide for future molecular-assisted breeding experiments in tree peony with novel flower colors.

Prediction of Hepatocellular Carcinoma Response to Transcatheter Arterial Chemoembolization: A Real-World Study Based on Non-Contrast Computed Tomography Radiomics and General Image Features.

OBJECTIVE: To construct a predictive model of short-term response and overall survival for transcatheter arterial chemoembolization (TACE) treatment in hepatocellular carcinoma (HCC) patients based on non-contrast computed tomography (NC-CT) radiomics and clinical features. METHODS: Ninety-four HCC patients who underwent CT scanning 1 week before the first TACE treatment were retrospectively recruited and divided randomly into a training group (n = 47) and a validation group (n = 47). NC-CT radiomics data were extracted using MaZda software, and the compound model was calculated from radiomics and clinical features by logistic regression. The performance of the different models was compared by examining the area under the receiver operating characteristic curve (AUC). The prediction of prognosis was evaluated using survival analysis. RESULTS: Thirty NC-CT radiomic features were extracted and analyzed. The compound model was formed using four NC-CT run-length matrix (RLM) features and general image features, which included the maximum diameter (cm) of the tumor and the number of tumors (n). The AUCs of the model for TACE response were 0.840 and 0.815, whereas the AUCs of the six-and-twelve grade were 0.754 and 0.750 in the training and validation groups, respectively. HCC patients were divided into two groups using the cutoff value of the model: a group in which the TACE-response led to good survival and a group in which TACE-nonresponse caused poor prognosis. CONCLUSION: Radiomic features from NC-CT predicted TACE-response. The compound model generated by NC-CT radiomics and clinical features is effective and directly predicts TACE-response and overall survival. The model may be used repeatedly and is easy to operate.

Cytotoxic and targeted systemic therapy in patients with advanced cutaneous squamous cell carcinoma in the head and neck.

BACKGROUND: The outcomes of patients treated with cytotoxic or targeted systemic therapy is not well defined for cutaneous squamous cell carcinoma of the head and neck (cSCCHN). METHODS: Patients with cSCCHN treated with cytotoxic or targeted systemic therapy were included. Patients were divided into two groups based on the presence of distant metastasis (M1 vs. M0) at presentation. A proportional hazards model was used to assess for independent predictors of overall survival. RESULTS: Of 129 patients with cSCCHN, 20 (16%) were M1 and 109 (84%) were M0. Independent predictors of improved survival were M0 status, treatment of locally advanced disease with radiotherapy, and lower Eastern Cooperative Oncology Group (ECOG) score. CONCLUSIONS: Survival was worse in M1 patients treated with cytotoxic or targeted systemic therapy and poor baseline performance status but improved in those receiving radiotherapy. These data can serve as historical controls for future systemic therapy trials, including immunotherapy.

TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2.

Colorectal cancer (CRC) is a common cancer worldwide, and its treatment strategies are limited. The underlying mechanism of CRC progression remains to be determined. Telomere maintenance 2 (TELO2) is a mTOR­interacting protein. Both the role and molecular mechanism of TELO2 in cancer progression remain unknown. In this study, the gene expression database of normal and tumor tissue, in addition to western blot analysis, and immunohistochemistry (IHC) were used to determine the expression and location of TELO2 in CRC and normal tissues. Clinical features of a tissue array were collected and analyzed. WST­1, soft agar, flow cytometry, wound healing, and invasion assays were employed to verify the role of TELO2 in the growth, cell cycle, migration, and invasion of CRC cells. The correlation between TELO2 and RICTOR (rapamycin­insensitive companion of mTOR) was analyzed by bioinformatics, IHC, and immunoprecipitation. Normal and serum­deprived cells were collected to detect the protein level of TELO2 and its downstream effectors. The results revealed that TELO2 was significantly upregulated in CRC, and TELO2 inhibition significantly restrained the growth, cell cycle, and metastasis of CRC cells. TELO2 overexpression correlated with age, lymph node metastasis, and TNM stage of CRC patients. In addition, TELO2 was positively correlated with RICTOR in CRC and induced tumor progression mainly via RICTOR with serum in culture. RICTOR induced the degradation of TELO2 upon serum deprivation in an mTOR­independent manner. These findings indicate that TELO2 promotes tumor progression via RICTOR in a serum­dependent manner, which may be a potential therapeutic target for CRC.

Genome-Wide Identification and Comparative Profiling of MicroRNAs Reveal Flavonoid Biosynthesis in Two Contrasting Flower Color Cultivars of Tree Peony.

MicroRNA (miRNA)-mediated gene regulation is involved in various physiological processes in plants. Flower color is one of the vital ornamental traits of tree peony (Paeonia suffruticosa Andr.). However, the yellow-flowered tree peony cultivars are particularly rare. To elucidate the miRNA-mediated gene regulatory mechanism underlying yellow pigmentation in tree peony, we combined pigment assessment, miRNA identification, expression analysis, and gene functional verification in two contrasting flower color cultivars "High Noon" and "Roufurong." Flavones/flavonols and anthocyanins were found to be the main contributors to the coloration of "High Noon" and "Roufurong" petals, respectively. Subsequently, miRNA analysis based on available genome data identified 9 differentially expressed miRNAs and 12 relevant target genes implicated in flavonoid biosynthesis. Their dynamic expression patterns determined the key role of mdm-miR156b-PsSPL2 module in yellow pigmentation of tree peony flowers. The sequence analysis and subcellular localization validated that PsSPL2 might function as a nuclear-localized transcription factor. Overexpression of PsSPL2 in tobacco resulted in a decrease of anthocyanin content and down-regulation of NtF3'H and NtDFR transcripts. PsSPL2-silenced petals exhibited lighter yellow color, and the contents of THC, Ap, and Ch decreased significantly. Meanwhile, expression levels of PsCHS, PsCHI, and PsF3H were significantly decreased in the petals with PsSPL2 silencing, while those of PsF3'H and PsDFR were remarkably increased. This study offers a novel insight into yellow pigmentation-related miRNA regulation network in tree peony, and further provides the valuable information on physiological changes during yellow coloring process of tree peony.

MiR-125a-5p inhibits cell proliferation, cell cycle progression, and migration while promoting apoptosis in head and neck cancers by targeting ERBB3.

OBJECTIVE: Head and neck cancer is one of the most common cancer types worldwide. MicroRNAs play a vital regulatory role in the occurrence and development of cancer. The objective of this study is to explore the mechanism of miR-125a-5p in the proliferation, migration and apoptosis of head and neck cancer cells and define its target genes. METHODS: The effects of miR-125a-5p on head and neck cancer cells proliferation, cell cycle distribution, apoptosis and migration were evaluated by colony formation, BrdU assay, flow cytometry and transwell assays. The potential target gene of miR-125a-5p was determined by luciferase activity assay and western blot analysis. RESULTS: In this study, overexpression of miR-125a-5p significantly inhibited the proliferation of head and neck cancer cells, whereas inhibition of miR-125a-5p enhanced their proliferation. BrdU assay and flow cytometry revealed that miR-125a-5p might inhibit the proliferation of cancer cells by causing cell cycle arrest. Cell apoptosis assay and Transwell assay indicated that miR-125a-5p induced cell apoptosis and inhibited cell migration of cancer cells. Other experiments confirmed that miR-125a-5p could significantly downregulate its expression by binding to ERBB3 to inhibit proliferation and ERBB3 could at least partially mediate the inhibition of miR-125a-5p on the proliferation of head and neck cancer cells. CONCLUSION: The findings of this study suggested that the miR-125a-5p/ERBB3 axis might play a role in the proliferation, regulation of cell cycle, migration and apoptosis of head and neck cancer cells, potentially offering a new target for treatments of head and neck cancers.

OTX1 exerts an oncogenic role and is negatively regulated by miR129-5p in laryngeal squamous cell carcinoma.

BACKGROUND: Orthodenticle homeobox 1 (OTX1) is a transcription factor that plays an important role in various human cancers. However, the function of OTX1 in laryngeal squamous cell carcinoma (LSCC) is largely unknown. We aimed to explore the roles of OTX1 in LSCC and its possible molecular mechanism. METHODS: The expression levels of OTX1 were assessed in LSCC cell lines and tissue samples. We further examined the effect of OTX1 on LSCC progression. The upstream regulator of OTX1 was identified using a computer algorithm and confirmed experimentally. RESULTS: OTX1 was highly expressed in 70.7% (70/99) of LSCC tissue samples. The OTX1 expression in LSCC was significantly correlated with lymph node metastasis. High OTX1 expression in patients with LSCC was correlated with poor prognosis. Knockdown of OTX1 inhibited proliferation, colony formation, migration and invasion in LSCC cells. Knockdown of OTX1 inhibited tumor growth in a xenograft mouse model. Mechanistically, OTX1 might act as a direct target of miR-129-5p. OTX1 enhanced tumorigenicity and tumor growth both in vitro and in vivo. CONCLUSIONS: Our findings support that OTX1 is an oncogene in LSCC tumorigenesis and progression. Furthermore, OTX1 is a direct target of miR-129-5p in LSCC cells. Taken together, OTX1 is a promising diagnostic and therapeutic marker for LSCC.

Long noncoding RNA FOXD2-AS1 enhances chemotherapeutic resistance of laryngeal squamous cell carcinoma via STAT3 activation.

Laryngeal squamous cell carcinoma (LSCC) is a common head and neck cancer. Despite recently improved management of LSCC, chemotherapy resistance of patients remains a challenge. In this study, we identified that long noncoding RNA FOXD2-AS1 regulates LSCC therapeutic resistance by augmenting LSCC stemness. LSCC chemotherapy-resistant patients showed increased FOXD2-AS1 expression compared with that in chemotherapy-sensitive patients, which predicted poor prognosis. Gain- or loss-of-function experiments showed that upregulated FOXD2-AS1 maintained cancer stemness, reducing the response to chemotherapy, while FOXD2-AS1 downregulation had the opposite effects. FOXD2-AS1 acted as a scaffold for STAT3 and PRMT5, promoting STAT3 transcriptional activity, which is essential to maintain cancer stemness and promote chemotherapeutic resistance. Interfering with FOXD2-AS1 using short hairpin RNA rescued LSCC's chemotherapeutic sensitivity. Thus, FOXD2-AS1 promotes LSCC chemotherapeutic resistance and is an upstream activator of STAT3, making FOXD2-AS1 a potential therapeutic target to improve the chemotherapy effect in LSCC patients.

Prognostic value of the radiomics-based model in progression-free survival of hypopharyngeal cancer treated with chemoradiation.

PURPOSE: To develop a radiomics-based model to stratify the risk of early progression (local/regional recurrence or metastasis) among patients with hypopharyngeal cancer undergoing chemoradiotherapy and modify their pretreatment plans. MATERIALS AND METHODS: We randomly assigned 113 patients into two cohorts: training (n = 80) and validation (n = 33). The radiomic significant features were selected in the training cohort using least absolute shrinkage and selection operator and Akaike information criterion methods, and they were used to build the radiomic model. The concordance index (C-index) was applied to evaluate the model's prognostic performance. A Kaplan-Meier analysis and the log-rank test were used to assess risk stratification ability of models in predicting progression. A nomogram was plotted to predict individual risk of progression. RESULTS: Composed of four significant features, the radiomic model showed good performance in stratifying patients into high- and low-risk groups of progression in both the training and validation cohorts (log-rank test, p = 0.00016, p = 0.0063, respectively). Peripheral invasion and metastasis were selected as significant clinical variables. The combined radiomic-clinical model showed good discriminative performance, with C-indices 0.804 (95% confidence interval (CI), 0.688-0.920) and 0.756 (95% CI, 0.605-0.907) in the training and validation cohorts, respectively. The median progression-free survival (PFS) in the high-risk group was significantly shorter than that in the low-risk group in the training (median PFS, 9.5 m and 19.0 m, respectively; p [log-rank] < 0.0001) and validation (median PFS, 11.3 m and 22.5 m, respectively; p [log-rank] = 0.0063) cohorts. CONCLUSIONS: A radiomics-based model was established to predict the risk of progression in hypopharyngeal cancer with chemoradiotherapy. KEY POINTS: • Clinical information showed limited performance in stratifying the risk of progression among patients with hypopharyngeal cancer. • Imaging features extracted from CECT and NCCT images were independent predictors of PFS. • We combined significant features and valuable clinical variables to establish a nomogram to predict individual risk of progression.

Association of Immunosuppression With Outcomes of Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck.

Importance: Patients with immunosuppression have a higher incidence of cutaneous squamous cell carcinoma (cSCC) and often present with more aggressive, multifocal disease. Objectives: To determine the risks for mortality in patients with cSCC and immunosuppression compared with nonimmunosuppression and to compare the difference in mortality risk based on the cause of immunocompromise. Design, Setting, and Participants: This retrospective cohort study of patients with cSCC of the head and neck recruited participants from a tertiary cancer care center. Patients who underwent no treatment, wide local excision, or biopsy of the lesions were eligible for inclusion from January 1, 1995, to September 30, 2015. Data were analyzed from March 21, 2018, to April 4, 2019. Exposures: Immunocompromise, defined as having solid organ transplant, stem cell transplant, hematopoetic malignant disease, autoimmune disease requiring treatment with immunosuppressive therapy, type 1 or 2 diabetes treated with insulin, HIV or AIDS, or other hematoproliferative disorder. Main Outcomes and Measures: Patients were divided into 2 groups according to their immune status (immunosuppression vs no immunosuppression). The primary outcome measure was disease-specific survival. A Cox proportional hazards regression model was used to determine the association of immune status with disease outcome. Results: A total of 796 patients (680 men [85.4%]; median age, 69 [range, 27-98] years), including 147 with and 649 without immunosuppression (IS and non-IS groups, respectively), constituted the final cohort. In the IS group, 77 (52.4%) had diabetes, 39 (26.5%) had lymphoma or leukemia, 25 (17.0%) had an organ or stem cell transplant, and 3 (2.0%) had HIV. Five-year disease-specific survival was 68.2% in the IS group compared with 84.1% in the non-IS group (difference, 15.9%; 95% CI, 3.5%-27.4%). Immunosuppression was independently associated with worse disease-specific survival (hazard ratio, 2.32; 95% CI, 1.53-3.50). Conclusions and Relevance: This study's findings suggest that immunosuppression is independently associated with a worse outcome in cSCC, with a 2.32 times increased risk of disease-specific death after adjusting for age, history of skin cancer, recurrent or persistent disease status, disease stage, and treatment.

High Notch1 expression affects chemosensitivity of head and neck squamous cell carcinoma to paclitaxel and cisplatin treatment.

BACKGROUND: Notch1 expression has been reported to be associated with chemotherapy resistance and poor prognosis, but the role of Notch1 in head and neck squamous cell carcinoma (HNSCC) sensitivity to anticancer drugs remains unclear. The aim of this study was to evaluate HNSCC sensitivity to paclitaxel and cisplatin in vitro and the chemotherapeutic response of HNSCC to these two drugs in vivo. METHODS: We used immunohistochemistry to assess Notch1 expression in fresh HNSCC samples treated by PF (cisplatin+5- fluorouracil) and TPF (paclitaxel + cisplatin+5- fluorouracil). We also assessed the sensitivity of two HNSCC cell lines to the Notch1 inhibitor of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The overall and progression-free survival were assessed. RESULTS: High Notch1 expression was significantly associated with paclitaxel resistance (P < 0.01). DAPT increased sensitivity to paclitaxel and cisplatin in vitro (P < 0.05). Compared with patients with Notch1 expression, patients without Notch1 expression were more likely to have a response to neoadjuvant chemotherapy with PF (P < 0.01) or TPF (P < 0.01) and had significantly better overall survival (P < 0.05) and progression-free survival (P < 0.05). Among patients without Notch1 expression (but not among patients with Notch1 expression), those who received TPF had significantly better survival than those who received PF (P < 0.05). CONCLUSION: Taken together, our findings may provide some evidence to partially support the predictive value of Notch1 expression in the therapeutic response to paclitaxel and cisplatin.

Radiomic Nomogram: Pretreatment Evaluation of Local Recurrence in Nasopharyngeal Carcinoma based on MR Imaging.

Background: To develop and validate a radiomic nomogram incorporating radiomic features with clinical variables for individual local recurrence risk assessment in nasopharyngeal carcinoma (NPC) patients before initial treatment. Methods: One hundred and forty patients were randomly divided into a training cohort (n = 80) and a validation cohort (n = 60). A total of 970 radiomic features were extracted from pretreatment magnetic resonance (MR) images of NPC patients from May 2007 to December 2013. Univariate and multivariate analyses were used for selecting radiomic features associated with local recurrence, and multivariate analyses was used for building radiomic nomogram. Results: Eight contrast-enhanced T1-weighted (CET1-w) image features and seven T2-weighted (T2-w) image features were selected to build a Cox proportional hazard model in the training cohort, respectively. The radiomic nomogram, which combined radiomic features and multiple clinical variables, had a good evaluation ability (C-index: 0.74 [95% CI: 0.58, 0.85]) in the validation cohort. The radiomic nomogram successfully categorized those patients into low- and high-risk groups with significant differences in the rate of local recurrence-free survival (P <0.05). Conclusions: This study demonstrates that MR imaging-based radiomics can be used as an aid tool for the evaluation of local recurrence, in order to develop tailored treatment targeting specific characteristics of individual patients.

PLOD2 contributes to drug resistance in laryngeal cancer by promoting cancer stem cell-like characteristics.

BACKGROUND: Advanced stage laryngeal squamous cell carcinoma (LSCC) presents a poor prognosis; thus, there is a great need to identify novel prognostic molecular markers. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is thought to be a novel prognostic factor in several cancers, but its role in LSCC remains unknown. Cancer stem cells (CSCs) are responsible for most instances of tumor recurrence and the development of drug resistance and have been proven to be present in head and neck cancers. Our preliminary study indicated that PLOD2 was elevated in LSCC tissues; therefore, we hypothesized that PLOD2 is related to the prognosis of LSCC patients and aimed to explore the role and underlying mechanism of PLOD2 in LSCC. METHODS: We validated the prognostic role of PLOD2 in 114 LSCC patients by immunohistochemistry. Stable PLOD2-overexpressing Hep-2 and FaDu cells were established and assessed by molecular biology and biochemistry methods both in vitro and in vivo. RESULTS: We confirmed that PLOD2 overexpression was correlated with poor prognosis in LSCC patients. PLOD2 overexpression strengthened the CSC-like properties of Hep-2 and FaDu cells, activated the Wnt signaling pathway and conferred drug resistance in LSCC in vitro and in vivo. CONCLUSIONS: We found that PLOD2 could serve as a prognostic marker in patients with LSCC and confer drug resistance in LSCC by increasing CSC-like traits; in addition, a Wnt-responsive CSC pathway was identified.

Lymphocyte telomere length predicts clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy.

Because lymphocyte telomere length (LTL) plays critical roles in the maintenance of genomic stability and integrity, LTL thus may influence the etiology and prognosis of squamous cell carcinoma of the oropharynx (SCCOP). However, given the association between LTL and risk of human papillomavirus (HPV)-associated SCCOP and between LTL and tumor HPV status of SCCOP, we hypothesized that LTL is associated with SCCOP prognosis, particularly in HPV-positive patients after definitive radiotherapy. LTL and tumor HPV type 16 (HPV16) status were determined in 564 incident SCCOP patients before radiotherapy or chemoradiation. Both univariate and multivariable Cox regression analyses were performed to estimate the association between LTL and prognosis. Eighty-five percent patients had HPV16-positive tumors. Patients with shorter telomeres had significantly better overall, disease-specific and disease-free survival than did those with longer telomeres (log-rank P < 0.001). Moreover, patients with shorter telomeres had significantly lower risk of death overall [hazard ratio (HR) = 0.2; 95% confidence interval (CI) = 0.1-0.4], death due to SCCOP (HR = 0.2; 95% CI = 0.1-0.4) and SCCOP recurrence (HR = 0.3; 95% CI = 0.2-0.5) after adjusting for other important prognostic confounders. Finally, we found more pronounced effects of LTL on survival in HPV16-positive SCCOP patients after stratified analysis according to tumor HPV status. These findings indicate that LTL plays a significant role in the survival of patients with SCCOP, especially HPV16-positive patients who undergo definitive radiotherapy. Therefore, pretreatment LTL may be an independent prognostic biomarker for HPV16-positive SCCOP. Prospective studies with larger sample sizes are needed to confirm these findings.

Development and validation of a magnetic resonance imaging-based model for the prediction of distant metastasis before initial treatment of nasopharyngeal carcinoma: A retrospective cohort study.

BACKGROUND: We aimed to identify a magnetic resonance imaging (MRI)-based model for assessment of the risk of individual distant metastasis (DM) before initial treatment of nasopharyngeal carcinoma (NPC). METHODS: This retrospective cohort analysis included 176 patients with NPC. Using the PyRadiomics platform, we extracted the imaging features of primary tumors in all patients who did not exhibit DM before treatment. Subsequently, we used minimum redundancy-maximum relevance and least absolute shrinkage and selection operator algorithms to select the strongest features and build a logistic model for DM prediction. The independent statistical significance of multiple clinical variables was tested using multivariate logistic regression analysis. FINDINGS: In total, 2780 radiomic features were extracted. A DM MRI-based model (DMMM) comprising seven features was constructed for the classification of patients into high- and low-risk groups in a training cohort and validated in an independent cohort. Overall survival was significantly shorter in the high-risk group than in the low-risk group (P < 0·001). A radiomics nomogram based on radiomic features and clinical variables was developed for DM risk assessment in each patient, and it showed a significant predictive ability in the training [area under the curve (AUC), 0·827; 95% confidence interval (CI), 0.754-0.900] and validation (AUC, 0.792; 95% CI, 0.633-0.952) cohorts. INTERPRETATION: DMMM can serve as a visual prognostic tool for DM prediction in NPC, and it can improve treatment decisions by aiding in the differentiation of patients with high and low risks of DM. FUND: This research received financial support from the National Natural Science Foundation of China (81571664, 81871323, 81801665, 81771924, 81501616, 81671851, and 81527805); the National Natural Science Foundation of Guangdong Province (2018B030311024); the Science and Technology Planning Project of Guangdong Province (2016A020216020); the Scientific Research General Project of Guangzhou Science Technology and Innovation Commission (201707010328); the China Postdoctoral Science Foundation (2016M600145); and the National Key R&D Program of China (2017YFA0205200, 2017YFC1308700, and 2017YFC1309100).