Risks and Clinical Predictors of Hepatocellular Carcinoma in Chinese Populations: A Real-World Study of 10,359 Patients in Six Medical Centers.

Purpose: Early detection of hepatocellular carcinoma (HCC) through surveillance could reduce this cancer-associated mortality. We aimed to develop and validate algorithms using panel serum biomarkers to identify HCC in a real-world multi-center study in China. Patients and Methods: A total of 10,359 eligible subjects, including HCCs and benign liver diseases (BLDs), were recruited from six Chinese medical centers. The three nomograms were built using logistic regression and their sensitivities and specificities were carefully assessed in training and validation cohorts. HCC patients after surgical resection were followed to determine the prognostic values of these algorithms. Prospective surveillance performance was assessed in a cohort of chronic hepatitis B patients during 144 weeks follow-up. Results: Independent risk factors such as alpha-fetoprotein (AFP), lens cuinaris agglutinin-reactive fraction of AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), albumin (ALB), and total bilirubin (TBIL) obtained from train cohort were used to construct three nomograms (LAD, C-GALAD, and TAGALAD) using logistic regression. In the training and two validation cohorts, their AUCs were all over 0.900, and the higher AUCs appeared in TAGALAD and C-GALAD. Furthermore, the three nomograms could effectively stratify HCC into two groups with different survival and recurrence outcomes in follow-up validation. Notably, TAGALAD could predict HCC up to 48 weeks (AUC: 0.984) and 24 weeks (AUC: 0.900) before clinical diagnosis. Conclusion: The proposed nomograms generated from real-world Chinese populations are effective and easy-to use for HCC surveillance, diagnosis, as well as prognostic evaluation in various clinical scenarios based on data feasibility.

The efficacy and safety in radioactive iodine refractory thyroid cancer patients treated with sorafenib.

Background: Sorafenib included in Chinese medical insurance is the earliest targeted drug for radioactive iodine refractory differentiated thyroid cancer (RR-DTC). This study is to further demonstrate the clinical efficacy and safety of sorafenib used in Zhujiang Hospital of Southern Medical University. Methods: RR-DTC patients treated at our Department of Nuclear Medicine in Zhujiang Hospital of Southern Medical University (October 2017-May 2020) were retrospectively analyzed. Treatment effects, progression-free survival (PFS), and adverse effects (AEs) during medication were evaluated. Results: Of the 31 patients included, 26 patients were evaluated for efficacy with a median follow-up time of 17.5 months (4.0-51.0 months). The disease control rate (DCR) was 57.7% (n = 15) and the objective response rate (ORR) was 26.9% (n = 7). Most patients with disease control had thyroglobulin decreases of more than 60% (p = 0.004), ORRs were favorable in patients with lung metastasis and lung-only metastasis (p = 0.010 and 0.001, respectively). The PFS of the 26 patients analyzed was 16.5 months (95%CI: 14.41 -23.90 months). In the subgroup analysis, female, patients with lung-only metastasis, hand-foot skin syndrome (HFS), and thyroglobulin response ≥ 60% observed longer PFS (p = 0.038, 0.045, 0.035, and 0.000, respectively), while patients with bone metastasis had lower PFS (p = 0.035). The most common toxicity profile was HFS (93.5%), followed by diarrhea (83.9%), alopecia (74.2%). All the side effects were mainly grade 1-2. Grade 3-4 adverse reactions were more common in diarrhea and HFS. Conclusions: Sorafenib has promising efficacy in RR-DTC, especially in patients with lung metastasis and lung-only metastasis. The AEs of sorafenib were generally mild, and the main AE was HFS.

Corrigendum: Incorporation size of lymph node metastasis focus and pre-ablation stimulated Tg could more effectively predict clinical outcomes in differentiated thyroid cancer patients without distant metastases.

[This corrects the article DOI: 10.3389/fendo.2023.1094339.].

Incorporation size of lymph node metastasis focus and pre-ablation stimulated Tg could more effectively predict clinical outcomes in differentiated thyroid cancer patients without distant metastases.

Background: The size of lymph node metastasis (LNM) and pre-ablation stimulated Tg (ps-Tg) were key predictors of clinical prognosis in differentiated thyroid cancer (DTC) patients, however, very few studies combine the above two as predictors of clinical prognosis of DTC patients. Methods: Persistent/recurrent disease and clinicopathologic factors were analyzed in 543 DTC patients without distant metastases who underwent LN dissection, near-total/total thyroidectomy, and radioiodine ablation. Results: In the multivariate analysis, size of LNM, ps-Tg, and the activity of 131I significantly correlated with long-term remission. The optimal cutoff size of LNM 0.4 cm-1.4 cm (intermediate-risk patients) and >1.4cm (high-risk patients) increased the recurrence risk (hazard ratio [95% CI], 4.674 [2.881-7.583] and 13.653 [8.135-22.913], respectively). Integration of ps-Tg into the reclassification risk stratification showed that ps-Tg ≤ 10.0 ng/mL was relevant to a greatly heightened possibility of long-term remission (92.2%-95.4% in low-risk patients, 67.3%-87.0% in intermediate-risk patients, and 32.3%-57.7% in high-risk patients). Conclusion: The cutoff of 0.4 cm and 1.4 cm for a definition of size of LNM in DTC patients without distant metastases can reclassify risk assessment, and incorporating ps-Tg could more effectively predict clinical outcomes and modify the postoperative management plan.

Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin.

BACKGROUND: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance. AIM: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC. METHODS: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively. RESULTS: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone. CONCLUSION: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.

Outcome of patients with differentiated thyroid cancer treated with empirical radioiodine therapy on the basis of Thyroglobulin Elevation Negative Iodine Scintigraphy (TENIS) syndrome without structural disease: a retrospective cohort study.

BACKGROUND: For differentiated thyroid cancer (DTC) patients with thyroglobulin (Tg) elevation and negative iodine scintigraphy (commonly termed "TENIS" syndrome) after thyroidectomy, radioactive iodine (RAI) therapy, and thyroid-stimulating hormone (TSH) suppression therapy, empirical RAI therapy may be considered. However, the outcome data of TENIS syndrome without structural disease after empirical RAI therapy have not shown clear evidence of improvement in survival. We assessed the efficacy of such empirical RAI therapy in TENIS syndrome without structural disease and evaluated the progression-free survival (PFS). METHODS: A total of 80 papillary thyroid cancer (PTC) patients with TENIS syndrome without structural disease were included in this retrospective study. 52 patients were treated with empirical RAI therapy while another 28 patients were untreated. The progression-free survival (PFS) of both groups was defined as the main outcome. The secondary outcome was the comparison of serum Tg levels 12 months after being diagnosed as TENIS syndrome. RESULTS: The PFS of the empirical RAI therapy group was better than the untreated group (p < 0.001). Moreover, there was significant difference in Tg normalization between patients treated with empirical therapy and without treatment (p = 0.001). Empirical RAI therapy (p = 0.001) predicts better PFS. Male gender (p = 0.041) and empirical RAI therapy (p = 0.002) predict better remission in serum Tg level. CONCLUSION: Patients with TENIS syndrome without structural disease can benefit from empirical RAI therapy in both PFS and Tg normalization.

Locoregional progression-free survival of bone metastases from differentiated thyroid cancer.

To evaluate the locoregional progression-free survival (LPFS) of bone metastatic lesions from differentiated thyroid cancer (DTC) after radioiodine therapy (RAIT) and to define its influencing factors, we performed a retrospective cohort analysis of 89 patients with bone metastases from DTC who received RAIT in our department over a 17-year period. The median follow-up time was calculated using the reverse Kaplan-Meier method. The log-rank test and a multivariate Cox proportional hazards regression model were performed in the analysis of prognostic indicators for LPFS. In this research, the median follow-up time for all patients was 47 (95% CI, 35.752-58.248) months, and that for patients with no progression was 42 months. The longest follow-up time was 109 months. The median LPFS time was 58 (95% CI, 32.602-83.398) months, and the 3- and 5-year LPFS probabilities were 57.8 and 45.1%, respectively. Multivariate analysis revealed bone structural changes as an independent risk factor for LPFS (P= 0.004; hazard ratio, 49.216; 95% CI, 3.558-680.704). Furthermore, the non-total-lesion uptake subgroup presented a worse LPFS than the total-lesion uptake subgroup in patients with structural bone lesions (P = 0.027). RAIT can improve the LPFS of radioiodine-avid bone metastases from DTC, especially those without bone structural changes.

Progressive changes in the major salivary gland after radioiodine therapy for differentiated thyroid cancer: a single-center retrospective ultrasound cohort study.

This study aimed to determine the prevalence of radioiodine-induced salivary gland damage by evaluating progressive changes in salivary glands using ultrasound. Four hundred forty-six patients with differentiated thyroid carcinoma who underwent total or near-total thyroidectomy and postoperative radioiodine therapy were retrospectively reviewed. From the first to the fifth follow-up visits, the positive rate of major salivary gland changes on ultrasound gradually increased from 2.0% to 33.0% (P<0.001) and possibly stabilized at the fifth visit (approximately 36 months). The first positive result was detected at an average of 20.78±8.72 months. Only 21 of the 161 positive cases eventually achieved negative ultrasound results (Fisher's test, P<0.001), and the 21 cases simply showed a coarse echotexure. In conclusion, ultrasound changes appeared late, and most of these changes were not reversed.

Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons.

Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.

N-glycan fingerprint predicts alpha-fetoprotein negative hepatocellular carcinoma: A large-scale multicenter study.

Alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (ANHCC) patients account for more than 30% of the whole entity of HCC patients and are easily misdiagnosed. This three-phase study was designed to find and validate new ANHCC N-glycan markers which identified from The Cancer Genome Atlas (TCGA) database and noninvasive detection. Differentially expressed genes (DEGs) of N-glycan biosynthesis and degradation related genes were screened from TCGA database. Serum N-glycan structure abundances were analyzed using N-glycan fingerprint (NGFP) technology. Totally 1340 participants including ANHCC, chronic liver diseases and healthy controls were enrolled after propensity score matching (PSM). The Lasso algorithm was used to select the most significant N-glycan structures abundances. Three machine learning models [random forest (RF), support vector machine (SVM) and logistic regression (LR)] were used to construct the diagnostic algorithms. All 13N-glycan structure abundances analyzed by NGFP demonstrated significant and was enrolled by Lasso. Among the three machine learning models, LR algorithm demonstrated the best diagnostic performance for identifying ANHCC in training cohort (LR: AUC: 0.842, 95%CI: 0.784-0.899; RF: AUC: 0.825, 95%CI: 0.766-0.885; SVM: AUC: 0.610, 95%CI: 0.527-0.684). This LR algorithm achieved a high diagnostic performance again in the independent validation (AUC: 0.860, 95%CI: 0.824-0.897). Furthermore, the LR algorithm could stratify ANHCC into two distinct subgroups with high or low risks of overall survival and recurrence in follow-up validation. In conclusion, the biomarker panel consisting of 13N-glycan structures abundances using the best-performing algorithm (LR) was defined and indicative as an effective tool for HCC prediction and prognosis estimate in AFP negative subjects.

Serum N-glycan fingerprint nomogram predicts liver fibrosis: a multicenter study.

OBJECTIVES: Liver cirrhosis (LC) is the end-stage of fibrosis in chronic liver diseases, non-invasive early detection of liver fibrosis (LF) is particularly essential for therapeutic decision. Aberrant glycosylation of glycoproteins has been demonstrated to be closely related to liver abnormalities. METHODS: This study was designed to enroll a total of 1,565 participants with LC/LF, chronic hepatitis virus (CHB) and healthy controls. Fibrosis was confirmed by liver biopsy. Using capillary electrophoresis N-glycan fingerprint (NGFP) analysis, we developed a nomogram algorithm (FIB-G) to discriminate LC from non-cirrhotic subjects. RESULTS: The FIB-G demonstrated good diagnostic performances in identifying LC with the area under the curve (AUC) 0.895 (95%CI: 0.857-0.915). Furthermore, the diagnostic efficiencies of FIB-G were superior to that of log (P2/P8), procollagen III N-terminal (PIIINP), type IV collage (IV-C), laminin (LN), hyaluronic acid (HA), aspartate transaminase to platelets ratio index (APRI), and FIB-4 when detecting significant fibrosis (S0-1 vs. S2-4, AUC: 0.787, 95%CI: 0.701-0.873), severe fibrosis (S0-2 vs. S3-4, AUC: 0.844, 95%CI: 0.763-0.924), and LC (S0-3 vs. S4, AUC: 0.773, 95%CI: 0.667-0.880). Besides, changes of FIB-G were associated well with the regression of fibrosis and liver function Child-Pugh classification. CONCLUSIONS: FIB-G is an accurate multivariant N-glycomic algorithm for LC prediction and fibrosis progression/regression monitoring. The high throughput feasible NGFP using only 2 µL of serum could help physicians make the more precise non-invasive staging of LF or cirrhosis and reduce the need for invasive liver biopsy.

BRAF V600E and lymph node metastases in papillary thyroid cancer.

OBJECTIVE: To evaluate the relationship between the BRAF V600E mutation in lymph node metastasis (LNM) and its invasive characteristics in papillary thyroid cancer (PTC). MATERIAL AND METHODS: A total of 373 PTC patients were enrolled in this study conducted at Zhujiang Hospital of Southern Medical University between January 2017 and December 2018. PTCs with cervical lymph node metastases were verified pathohistologically, and primary tumors and LNM were examined for the BRAF V600E mutation. Patients were excluded from the study if the BRAF V600E mutation was examined only in primary tumors or only in LNM. RESULTS: Of the 373 patients examined, BRAF V600E mutation frequency in primary tumors was slightly higher than in LNM (81.5% vs 78.0%, P = 0.000), the intra-class correlation coefficient (ICC) was 0.865 (95% CI 0.835-0.890). The BRAF V600E mutation in both primary tumor and LNM negatively correlated with the size of the largest metastatic focus of LNM (Odds ratio, OR = 0.297, 95% CI 0.143-0.616, P = 0.001; OR = 0.242, 95% CI 0.119-0.492, P = 0.000, respectively). There was no relationship between BRAF V600E mutation in LNM and the number, extranodal extension or stage of LNM (P > 0.05). CONCLUSION: The BRAF V600E mutation in LNM may not be related to the invasive characteristics of LNM in PTC.

Postoperative thyroid remnants for differentiated thyroid cancer may not affect the outcome of high-dose radioiodine therapy.

OBJECTIVES: This study aims to provide a way to estimate the volume of the thyroid remnant and determine its relationship with the outcome of radioiodine (RAI) therapy in depth. MATERIALS AND METHODS: A retrospective analysis was performed on patients who underwent initial RAI therapy between January 2010 and January 2016. The patients were divided into five groups based on the thyroid remnant estimated by post-therapy whole-body scan(post-Rx WBS), thyroid scintigraphy and ultrasonography. The relationship between the volume of thyroid remnant and the outcome of RAI therapy were evaluated by univariate analysis and multivariate analysis. RESULTS: Of 703 patients, the majority could be found different size of thyroid remnants using the three imaging methods, and only few patients(2.1%) could reach no thyroid remnant. There was no association between the volume of thyroid remnant and the outcome of RAI therapy in univariate analysis (χ2 = 1.633, P = 0.652) and multivariate analysis (P > 0.05). In the subgroup of patients with high-risk factors, there was still no significant difference (intermediate risk subgroup: P = 0.338 vs high risk subgroup: P = 0.263). CONCLUSION: Different sizes of thyroid remnants were left after surgery. However, in high radioiodine activity, the volume of thyroid remnants may not affect the outcome of RAI therapy even in patients with some high-risk factors, so the high radioiodine activities may resolve the the problem caused by thyroid remnants in some cases.

Improving Tumor-to-Background Contrast through Hydrophilic Tetrazines: The Construction of 18 F-Labeled PET Agents Targeting Nonsmall Cell Lung Carcinoma.

Bioorthogonal reactions have been widely used in the biomedical field. 18 F-TCO/Tetrazine ligation is the most reactive radiolabelled inverse electron demand Diels-Alder reaction, but its application had been limited due to modest contrast ratios of the resulting conjugates. Herein, we describe the use of hydrophilic tetrazines to improve tumor-to-background contrast of neurotensin receptor targeted PET agents. PET agents were constructed using a rapid Diels-Alder reaction of the radiolabeled trans-cyclooctene (18 F-sTCO) with neurotensin (NT) conjugates of a 3,6-diaryltetrazine, 3-methyl-6-aryltetrazine, and a derivative of 3,6-di(2-hydroxyethyl)tetrazine. Although cell binding assays demonstrated all agents have comparable binding affinity, the conjugate derived from 3,6-di(2-hydroxyethyl)tetrazine demonstrated the highest tumor to muscle contrast, followed by conjugates of the 3-methyl-6-aryltetrazine and 3,6-diaryltetrazine.

The diagnostic value of serum DSA-TRF in hepatocellular carcinoma.

TRF is a glycoprotein mainly secreted by hepatocytes, The aim of this study was to explore the diagnostic value of aberrant glycosylated serum transferrin (TRF) especially containing multi-antennary glycans in hepatocellular carcinoma (HCC).A total of 581 subjects including HCC patients, liver cirrhosis (LC) patients, chronic hepatitis (CHB) patients and healthy controls (HC) were recruited. All the subjects were randomly assigned to training group (n = 411) and validation group (n = 170). We firstly analyzed the serum protein N-glycome profiling of HCC, LC, and HC by DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE) technology. We established a lectin-antibody sandwich ELISA (Lectin-ELISA) method to detect multi-antennary glycans-contained TRF (DSA-TRF) in serum, in which Datura stramonium Agglutinin (DSA) was used for specific recognition. Levels of serum DSA-TRF and TRF were analyzed respectively. The diagnostic efficacies of DSA-TRF and TRF of differentiating HCC patients from CHB, LC patients and HC within the training group were evaluated using receiver operating characteristic (ROC) curve and tested in the validation group.The result found that in training group, serum TRF and DSA-TRF levels differed significantly between HCC (1.86 ± 0.50, g/L, 0.285 ± 0.06), CHB + LC (2.39 ± 0.74, g/L, 0.189 ± 0.07) and HC (1.92 ± 0.69, g/L, 0.249 ± 0.09) (HCC vs. CHB + LC, P < 0.001; HCC vs. HC, P < 0.001; CHB + LC vs. HC, P < 0.001). The area under the ROC curve (AUC) of DSA-TRF was significantly superior to AFP (0.880, 95%CI: 0.834-0.925 vs. 0.776, 95%CI: 0.725-0.827, P = 0.003) in differentiating HCC from CHB + LC. The AUC of diagnostic model GlycoTRF1 (0.981, 95%CI: 0.969-0.993) was higher than DSA-TRF and AFP alone (P<0.001) in differentiating HCC from CHB + LC, which was verified in validation group.The results indicated that the serum DSA-TRF might serve as a potential glycan biomarker for distinguishing HCC from CHB and LC.

SIZE OF THE LARGEST METASTATIC FOCUS TO THE LYMPH NODE IS ASSOCIATED WITH INCOMPLETE RESPONSE OF PN1 PAPILLARY THYROID CARCINOMA.

Objective: To evaluate the influence of the size of the metastatic focus in lymph nodes (LNs) on therapeutic response among papillary thyroid cancer (PTC) and cervical pathologically proven LN metastases (pN1). Methods: Patients with pN1 PTC who underwent total or near-total thyroidectomy, LN dissection, and postoperative radioactive iodine therapy in a university hospital between 2014 and 2016 were retrospectively reviewed. Furthermore, 554 patients were assigned to three groups according to the size of the metastatic focus in the LNs (≤0.2 cm, 0.2 to 1.0 cm, ≥1.0 cm). Structural incomplete response (SIR) was defined as structural or functional evidence of disease with any thyroglobulin level and/or anti-thyroglobulin antibodies. Results: Among the 554 patients, the proportion of patients with SIR was 2.5% (4/161) in group 1, 13.9% (37/267) in group 2, and 46.8% (59/126) in group 3 (χ2 = 100.073; P<.001). The optimal cutoff value of the size of the largest metastatic focus to the LNs was 0.536 cm to predict SIR with a corresponding sensitivity of 0.82, a specificity of 0.716, and an area under the curve of 0.821 (95% confidence interval [CI], 0.777 to 0.864; P<.001). Size of the largest metastatic focus to the LNs was confirmed to be an independent predictive factor for SIR (odds ratio, 9.650; 95% CI, 4.925 to 18.909; P<.001). Conclusion: In patients with pN1 PTC, there is an association between the size of the largest metastatic focus to the LNs and incomplete response. Abbreviations: AJCC = American Joint Committee on Cancer; ATA = American Thyroid Association; BIR = biochemical incomplete response; CI = confidence interval; ER = excellent response; ETE = extranodal extension; 18F-FDG = 18F-fluorodeoxyglucose; IDR = indeterminate response; LN = lymph node; OR = odds ratio; PET/CT = positron emission tomography/computed tomography; pN1 = pathologically proven LN metastases; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SIR = structural incomplete response; sTg = stimulated thyroglobulin; TgAb = anti-thyroglobulin antibody; TSH = thyroid-stimulating hormone.

Modeling RNA-Binding Protein Specificity In Vivo by Precisely Registering Protein-RNA Crosslink Sites.

RNA-binding proteins (RBPs) regulate post-transcriptional gene expression by recognizing short and degenerate sequence motifs in their target transcripts, but precisely defining their binding specificity remains challenging. Crosslinking and immunoprecipitation (CLIP) allows for mapping of the exact protein-RNA crosslink sites, which frequently reside at specific positions in RBP motifs at single-nucleotide resolution. Here, we have developed a computational method, named mCross, to jointly model RBP binding specificity while precisely registering the crosslinking position in motif sites. We applied mCross to 112 RBPs using ENCODE eCLIP data and validated the reliability of the discovered motifs by genome-wide analysis of allelic binding sites. Our analyses revealed that the prototypical SR protein SRSF1 recognizes clusters of GGA half-sites in addition to its canonical GGAGGA motif. Therefore, SRSF1 regulates splicing of a much larger repertoire of transcripts than previously appreciated, including HNRNPD and HNRNPDL, which are involved in multivalent protein assemblies and phase separation.

Clinical significance of the BRAFV600E mutation in PTC and its effect on radioiodine therapy.

The goal of this study was to explore the relationship of the BRAFV600E mutation with clinicopathologic factors and evaluate the effect of radioactive iodine (RAI) therapy in a large group of intermediate- and high-risk papillary thyroid cancer (PTC) patients with the BRAFV600E mutation and without distant metastases. We collected data for PTC patients who underwent total or near-total thyroidectomy and RAI treatment in our hospital from January 2014-December 2017. There were 1220 PTC patients who met the criteria, and the BRAFV600E mutation was observed in 979 of them (80.2%). Multivariate analysis identified that the BRAFV600E mutation remained independently associated with age at diagnosis, and bilaterality (OR = 1.023, 95% CI = 1.012-1.039, P < 0.001; OR = 1.685, 95% CI = 1.213-2.341, P = 0.002, respectively). In addition, the patients with bilateral PTCs had a higher prevalence of extrathyroid invasion, capsular invasion and fusion of metastatic lymph nodes than the unilateral PTC patients. The response to RAI therapy was evaluated in both the entire series and the patients with a high recurrence risk; no significant difference was discerned between the BRAFV600E mutation and the wild-type groups (P = 0.237 and P = 0.498, respectively). To summarize, our results confirmed that PTC patients with the BRAFV600E mutation exhibit more aggressive characteristics. In addition, the patients with bilateral PTC have a higher incidence of extrathyroid invasion. Moreover, BRAFV600E mutation PTC patients did not show a poorer clinical response after postsurgical RAI therapy, suggesting that RAI therapy may improve the general clinical outcome of these patients.

A Nomogram Predicting Extrahepatic Metastases for Patients with Adjuvant Transarterial Chemoembolization after Hepatectomy.

Background: Prognosis remains poor for hepatocellular carcinoma (HCC) patients with extrahepatic metastases (EHMs). This study aimed to develop a nomogram to predict EHMs in HCC patients who underwent adjuvant transarterial chemoembolization (TACE) following hepatectomy. Methods: Data of 578 HCC patients who underwent TACE after hepatectomy at the Eastern Hepatobiliary Surgery Hospital was retrospectively reviewed. Cox regression analyses was used to select variables to construct the nomogram. Predictive accuracy and discriminative ability of the model were performed using concordance index (C-index), calibration curve and the area under time-dependent receiver operating characteristic (ROC) curve. Results: Postoperative EHMs were detected in 89 and 31 patients in the training cohort (n = 453) and validation cohort (n = 125), respectively. Multivariate analysis showed that tumor size (HR, 1.099; 95% CI, 1.049-1.152), coarse beam type of tumor histopathological structure (HR, 2.382; 95% CI, 1.030-5.512), presence of satellite nodules (HR, 1.936; 95% CI, 1.156-3.244) and alpha-fetoprotein (AFP) (HR, 1.399; 95% CI, 1.098-1.783) were independent risk factors for EHMs (all p < 0.05). The nomogram incorporated these factors achieved good agreement between prediction and actual observation with a concordance index (C-index) of 0.73 (95% CI, 0.68 to 0.78) and 0.71 (95% CI, 0.63 to 0.79) in the training cohort and validation cohort, respectively. In addition, patients who had a nomogram score > 17 were considered to have higher risk for EHMs compared with those scored ≤ 12. Furthermore, the time-dependent area under the ROC curve indicated comparative stability and adequate discriminative ability of the model. Conclusions: This novel nomogram can identify those with high risk of EHMs after adjuvant TACE following hepatectomy. The validation cohort showed a good performance, suggesting it could benefit surgeons on decision-making.

Characterization of kinase gene expression and splicing profile in prostate cancer with RNA-Seq data.

BACKGROUND: Alternative splicing is a ubiquitous post-transcriptional regulation mechanism in most eukaryotic genes. Aberrant splicing isoforms and abnormal isoform ratios can contribute to cancer development. Kinase genes are key regulators of multiple cellular processes. Many kinases are found to be oncogenic and have been intensively investigated in the study of cancer and drugs. RNA-Seq provides a powerful technology for genome-wide study of alternative splicing in cancer besides the conventional gene expression profiling. But this potential has not been fully demonstrated yet. METHODS: We characterized the transcriptome profile of prostate cancer using RNA-Seq data from viewpoints of both differential expression and differential splicing, with an emphasis on kinase genes and their splicing variations. We built a pipeline to conduct differential expression and differential splicing analysis, followed by functional enrichment analysis. We performed kinase domain analysis to identify the functionally important candidate kinase gene in prostate cancer, and calculated the expression levels of isoforms to explore the function of isoform switching of kinase genes in prostate cancer. RESULTS: We identified distinct gene groups from differential expression and splicing analyses, which suggested that alternative splicing adds another level to gene expression regulation. Enriched GO terms of differentially expressed and spliced kinase genes were found to play different roles in regulation of cellular metabolism. Function analysis on differentially spliced kinase genes showed that differentially spliced exons of these genes are significantly enriched in protein kinase domains. Among them, we found that gene CDK5 has isoform switching between prostate cancer and benign tissues, which may affect cancer development by changing androgen receptor (AR) phosphorylation. The observation was validated in another RNA-Seq dataset of prostate cancer cell lines. CONCLUSIONS: Our work characterized the expression and splicing profiles of kinase genes in prostate cancer and proposed a hypothetical model on isoform switching of CDK5 and AR phosphorylation in prostate cancer. These findings bring new understanding to the role of alternatively spliced kinases in prostate cancer and also demonstrate the use of RNA-Seq data in studying alternative splicing in cancer.