The Transcription Factor Tbx5-Dependent Epigenetic Modification Contributes to Neuropathic Allodynia by Activating TRPV1 Expression in the Dorsal Horn.

Nerve injury can induce aberrant changes in the spine; these changes are due to, or at least partly governed by, transcription factors that contribute to the genesis of neuropathic allodynia. Here, we showed that spinal nerve ligation (SNL, a clinical neuropathic allodynia model) increased the expression of the transcription factor Tbx5 in the injured dorsal horn in male Sprague Dawley rats. In contrast, blocking this upregulation alleviated SNL-induced mechanical allodynia, and there was no apparent effect on locomotor function. Moreover, SNL-induced Tbx5 upregulation promoted the recruitment and interaction of GATA4 and Brd4 by enhancing its binding activity to H3K9Ac, which was enriched at the Trpv1 promotor, leading to an increase in TRPV1 transcription and the development of neuropathic allodynia. In addition, nerve injury-induced expression of Fbxo3, which abates Fbxl2-dependent Tbx5 ubiquitination, promoted the subsequent Tbx5-dependent epigenetic modification of TRPV1 expression during SNL-induced neuropathic allodynia. Collectively, our findings indicated that spinal Tbx5-dependent TRPV1 transcription signaling contributes to the development of neuropathic allodynia via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic allodynia by targeting Tbx5.

Protein Arginine Methyltransferase 5 Contributes to Paclitaxel-Induced Neuropathic Pain by Activating Transient Receptor Potential Vanilloid 1 Epigenetic Modification in Dorsal Root Ganglion.

BACKGROUND: Paclitaxel (PTX), which is a first-line chemotherapy drug used to treat various types of cancers, exhibits peripheral neuropathy as a common side effect that is difficult to treat. Protein arginine methyltransferase 5 (PRMT 5) is a key regulator of the chemotherapy response, as chemotherapy drugs induce PRMT5 expression. However, little is known about the PRMT5-mediated epigenetic mechanisms involved in PTX-induced neuropathic allodynia. METHODS: Sprague-Dawley rats were intraperitoneally given PTX to induce neuropathic pain. Biochemical analyses were conducted to measure the protein expression levels in the dorsal root ganglion (DRG) of the animals. The von Frey test and hot plate test were used to evaluate nociceptive behaviors. RESULTS: PTX increased the PRMT5 (mean difference [MD]: 0.68, 95% confidence interval [CI], 0.88-0.48; P < .001 for vehicle)-mediated deposition of histone H3R2 dimethyl symmetric (H3R2me2s) at the transient receptor potential vanilloid 1 ( Trpv1 ) promoter in the DRG. PRMT5-induced H3R2me2s recruited WD repeat domain 5 (WDR5) to increase trimethylation of lysine 4 on histone H3 (H3K4me3) at Trpv1 promoters, thus resulting in TRPV1 transcriptional activation (MD: 0.65, 95% CI, 0.82-0.49; P < .001 for vehicle) in DRG in PTX-induced neuropathic pain. Moreover, PTX increased the activity of NADPH oxidase 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 for vehicle), PRMT5-induced H3R2me2s, and WDR5-mediated H3K4me3 in the DRG in PTX-induced neuropathic pain. Pharmacological antagonism and the selective knockdown of PRMT5 in DRG neurons completely blocked PRMT5-mediated H3R2me2s, WDR5-mediated H3K4me3, or TRPV1 expression and neuropathic pain development after PTX injection. Remarkably, NOX4 inhibition not only attenuated allodynia behavior and reversed the above-mentioned signaling but also reversed NOX4 upregulation via PTX. CONCLUSIONS: Thus, the NOX4/PRMT5-associated epigenetic mechanism in DRG has a dominant function in the transcriptional activation of TRPV1 in PTX-induced neuropathic pain.

Phosphorylated Upstream Frameshift 1-dependent Nonsense-mediated µ-Opioid Receptor mRNA Decay in the Spinal Cord Contributes to the Development of Neuropathic Allodynia-like Behavior in Rats.

BACKGROUND: Nonsense-mediated messenger RNA (mRNA) decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. The authors hypothesized that nonsense-mediated µ-opioid receptor mRNA decay in the spinal cord is involved in the development of neuropathic allodynia-like behavior in rats. METHODS: Adult Sprague-Dawley rats of both sexes received spinal nerve ligation to induce neuropathic allodynia-like behavior. The mRNA and protein expression contents in the dorsal horn of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by the von Frey test and the burrow test. RESULTS: On Day 7, spinal nerve ligation significantly increased phosphorylated upstream frameshift 1 (UPF1) expression in the dorsal horn (mean ± SD; 0.34 ± 0.19 in the sham ipsilateral group vs. 0.88 ± 0.15 in the nerve ligation ipsilateral group; P < 0.001; data in arbitrary units) and drove allodynia-like behaviors in rats (10.58 ± 1.72 g in the sham ipsilateral group vs. 1.19 ± 0.31 g in the nerve ligation ipsilateral group, P < 0.001). No sex-based differences were found in either Western blotting or behavior tests in rats. Eukaryotic translation initiation factor 4A3 (eIF4A3) triggered SMG1 kinase (0.06 ± 0.02 in the sham group vs. 0.20 ± 0.08 in the nerve ligation group, P = 0.005, data in arbitrary units)-mediated UPF1 phosphorylation, leading to increased nonsense-mediated mRNA decay factor SMG7 binding and µ-opioid receptor mRNA degradation (0.87 ± 0.11-fold in the sham group vs. 0.50 ± 0.11-fold in the nerve ligation group, P = 0.002) in the dorsal horn of the spinal cord after spinal nerve ligation. Pharmacologic or genetic inhibition of this signaling pathway in vivo ameliorated allodynia-like behaviors after spinal nerve ligation. CONCLUSIONS: This study suggests that phosphorylated UPF1-dependent nonsense-mediated µ-opioid receptor mRNA decay is involved in the pathogenesis of neuropathic pain.

Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates Paclitaxel-Induced Neuropathic Pain.

BACKGROUND: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established. METHODS: Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests. RESULTS: PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain. CONCLUSIONS: pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches.

Efficacy and safety of combined targeted therapy and immunotherapy versus targeted monotherapy in unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Cancer therapy has evolved from non-specific cytotoxic agents to a selective, mechanism-based approach that includes targeted agents and immunotherapy. Although the response to targeted therapies for unresectable hepatocellular carcinoma (HCC) is acceptable with the improved survival, the high tumor recurrence rate and drug-related side effects continue to be problematic. Given that immune checkpoint inhibitor alone are not robust enough to improve survival in unresectable HCC, growing evidence supports the combination of targeted therapy and immunotherapy with synergistic effect. METHODS: Online databases including PubMed, EMBASE, Cochrane Library, and Web of Science were searched for the studies that compared targeted monotherapy with the combination therapy of targeted drug and checkpoint inhibitors in unresectable HCC patients. Eligibility criteria were the presence of at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (version 1.1) for unresectable HCC patients, an Eastern Cooperative Oncology Group performance status of 0-2, and a Child-Pugh score ≤ 7. Outcome measurements include overall survival (OS), progression-free survival (PFS), and treatment-related adverse event (TRAE). RESULTS: Three phase II/III randomized controlled trials were included in this study. The pooled results showed that combination therapy significantly improved survival than targeted monotherapy, in terms of OS (hazard ratio (HR) = 0.67; 95% confidence interval [CI]: 0.50-0.91) and PFS (HR = 0.58; 95% CI: 0.51-0.67), respectively. In the incidence of grade 3-5 TRAEs, the combination therapy was significantly higher than targeted monotherapy (odds ratio = 1.98; 95% CI: 1.13-3.48). CONCLUSION: For unresectable HCC, combined targeted drug and immunotherapy significantly improved survival compared with targeted monotherapy. However, the incidences of AEs of combinational therapy were higher than targeted monotherapy.

Dihydrolipoic acid-coated gold nanocluster bioactivity against senescence and inflammation through the mitochondria-mediated JNK/AP-1 pathway.

Cellular senescence is the progressive impairment of function and proliferation in response to various regulators. Dihydrolipoic acid-coated gold nanoclusters (DHLA-Au NCs), which are molecular clusters with covalently linked dihydroxyl lipoic acid, preserve cellular activities for long-term incubation. DHLA-Au NC delivery was characterized, and we determined the role of growth supplements on internalization, allowing the optimization of DHLA-Au NC bioactivity. In the optimized medium, DHLA-Au NCs attenuated the levels of the senescence-associated phenotype. Molecular mechanism analysis further indicated that during DHLA-Au NC treatment, the activation of the stress signal JNK and its downstream c-Jun were impaired under LPS induction, which led to a decline in AP-1-mediated TNF-α transactivation. Confocal microscopy and subcellular fractionation analysis suggested that DHLA-Au NCs interacted with mitochondria through their lipid moiety and attenuated mitochondria-derived reactive oxygen species. With adequate treatment, DHLA-Au NCs show protection against cellular senescence and inflammation in vitro and in vivo.

Spinal RNF20-Mediated Histone H2B Monoubiquitylation Regulates mGluR5 Transcription for Neuropathic Allodynia.

To date, histone H2B monoubiquitination (H2Bub), a mark associated with transcriptional elongation and ongoing transcription, has not been linked to the development or maintenance of neuropathic pain states. Here, using male Sprague Dawley rats, we demonstrated spinal nerve ligation (SNL) induced behavioral allodynia and provoked ring finger protein 20 (RNF20)-dependent H2Bub in dorsal horn. Moreover, SNL provoked RNF20-mediated H2Bub phosphorylated RNA polymerase II (RNAPII) in the promoter fragments of mGluR5, thereby enhancing mGluR5 transcription/expression in the dorsal horn. Conversely, focal knockdown of spinal RNF20 expression reversed not only SNL-induced allodynia but also RNF20/H2Bub/RNAPII phosphorylation-associated spinal mGluR5 transcription/expression. Notably, TNF-α injection into naive rats and specific neutralizing antibody injection into SNL-induced allodynia rats revealed that TNF-α-associated allodynia involves the RNF20/H2Bub/RNAPII transcriptional axis to upregulate mGluR5 expression in the dorsal horn. Collectively, our findings indicated TNF-α induces RNF20-drived H2B monoubiquitination, which facilitates phosphorylated RNAPII-dependent mGluR5 transcription in the dorsal horn for the development of neuropathic allodynia.SIGNIFICANCE STATEMENT Histone H2B monoubiquitination (H2Bub), an epigenetic post-translational modification, positively correlated with gene expression. Here, TNF-α participated in neuropathic pain development by enhancing RNF20-mediated H2Bub, which facilitates phosphorylated RNAPII-dependent mGluR5 transcription in dorsal horn. Our finding potentially identified neuropathic allodynia pathophysiological processes underpinning abnormal nociception processing and opens a new avenue for the development of novel analgesics.

DNA primase polypeptide 1 (PRIM1) involves in estrogen-induced breast cancer formation through activation of the G2/M cell cycle checkpoint.

The DNA primase polypeptide 1 (PRIM1) is responsible for synthesizing small RNA primers for Okazaki fragments generated during discontinuous DNA replication. PRIM1 mRNA expression levels in breast tumor samples were detected by real-time PCR analysis. Xenografted tumor model was established to study the carcinogenic role of PRIM1 and its potential therapeutic applications. The average PRIM1 mRNA (copy number × 103 /µg) expression was 4.7-fold higher in tumors than in normal tissue (*p = 0.005, n = 254). PRIM1 was detected preferentially at a higher level (>40-fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0.005). Poor overall survival rate was correlated to the estrogen receptor positive (ER+, n = 20) patients with higher PRIM1 expression when compare to the ER- (n = 10) patients (Chi Square test, p = 0.03). Stable expression of PRIM1-siRNA in the ER+ BT-474 cells-xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti-tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT-474-xenografted tumor growth volume compared with control (n =5 per group, *p < 0.05). This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose.

Targeting histone deacetylase 4/ubiquitin-conjugating enzyme 9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells in mice.

Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiation's effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5-10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; γH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin-conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation-induced cell death and reduced homologous recombination repair of DNA double-strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation-treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4-dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. Conclusion: HDAC4 signaling blockade enhances radiation-induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2018;67:586-599).

A preliminary report of head-to-head comparison of 18-gene-based clinical-genomic model and oncotype DX 21-gene assay for predicting recurrence of early-stage breast cancer.

BACKGROUND: The information of Oncotype DX applied in Asian breast cancer patients is limited. A recurrence index for distant recurrence (RI-DR) has been developed for early-stage breast cancer (EBC) from tumor samples in Chinese patients. In this study, we compared the prognostic performance of the Oncotype DX (ODx) recurrence score (RS) with the RI-DR for any recurrence risk type. MATERIALS AND METHODS: One hundred thirty-eight (138) patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative EBC who were previously tested with ODx were included for testing with the RI-DR. The cutoff score to partition the low- and high-risk patients was 26 for RS and 36 for RI-DR. The primary endpoint was recurrence-free survival (RFS). RESULTS: The concordance between the RI-DR and RS was 83% in N0 patients and 81% in node-positive patients when the RS score cutoff was set at 26. With a median follow-up interval of 36.8 months, the 4-year RFS for the high- and low-risk groups categorized by the RS were 61.9% and 95.0%, respectively (hazard ratio: 10.6, 95.0% confidence interval [CI]: 1.8-62.9). The 4-year RFS in the high- and low-risk groups categorized by the RI-DR were 72.6% and 98.5%, respectively (hazard ratio: 18.9, 95% CI: 1.8-138.8). CONCLUSION: This paper illustrated the performance of RI-DR and ODx RS in breast cancer women in Taiwan. There was high concordance between the RI-DR and RS. The RI-DR is not inferior to the RS in predicting RFS in EBC patients. This study will fill the gap between the current and best practice in Chinese patients.

A Novel Prediction Model for Bloodstream Infections in Hepatobiliary-Pancreatic Surgery Patients.

BACKGROUND: Bloodstream infections (BSI) are an important source of postoperative mortality in hepatobiliary-pancreatic surgery (HBPS) patients, and no prediction model has been analyzed before. METHODS: Using big data from the electronic medical records of the administrative and culture databases of MacKay Memorial Hospital, we identified the potential risk factors for community-acquired and healthcare-associated BSI and mortality of patients who received HBPS. Subsequently, we analyzed the microorganisms' profiles and antimicrobial susceptibility patterns for these BSI. RESULTS: BSI were found in 6.3% patients (349 of 5513 HBPS patients), and hospital mortality was 1.48% (82 of 5513). Dividing patients into low-, intermediate-, and high-risk groups on the basis of sex, age, status of comorbidity (renal failure, peptic ulcer disease, fluid and electrolyte disorders, and acute cholecystitis), a predictive BSI risk score model was developed. According to this model, BSI risk ranged from 1.43% to 11.95%; AUROC to predict BSI risk was 0.72 (95% CI 0.69-0.75). From this retrospective study, Enterobacteriaceae were the most common microorganisms that were isolated from BSI. For both community-acquired and healthcare-associated BSI, imipenem and colistin are the most successful. CONCLUSION: This novel model can be useful to predict who is at risk of BSI after HBPS, and new prophylactic protocols for these patients are needed.

Expression of serine peptidase inhibitor Kunitz type 1 in differentiated thyroid cancer.

SPINT1, also known as HAI-1, is a Kunitz-type serine protease inhibitor that inhibits multiple proteases including hepatocyte growth factor (HGF) activator and matriptase. SPINT1 has been shown to modulate HGF/MET activation in certain cancer types. In the present study, we analyzed microarray datasets and found that SPINT1 was consistently upregulated in differentiated thyroid cancer. SPINT1 protein expression was investigated using tissue microarrays and independent samples of our 143 patients. Strong SPINT1 expression was observed in 61-68% of papillary thyroid cancer and 41-50% of follicular thyroid cancer. The overexpression diminished in anaplastic thyroid cancer. The SPINT1 expression in normal thyroid tissues and benign thyroid lesions was low. Furthermore, we noted that the SPINT1 expression was associated with extrathyroidal invasion, lymphovascular invasion, lymph node metastasis, advanced TNM stage, and a higher risk of recurrence in differentiated thyroid cancer. The results were in accordance with our analysis of The Cancer Genome Atlas data. In conclusion, an overexpression of SPINT1 appears to be associated with an invasive phenotype in differentiated thyroid cancer.

Parathyroidectomy decreases neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios.

BACKGROUND: Systemic inflammation has been implicated in complications and heightened mortality of patients with secondary hyperparathyroidism. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are widely available surrogate markers of inflammation. This study sought to delineate the changes in NLR and PLR after parathyroidectomy. METHODS: A total of 213 patients undergoing initial parathyroidectomy from 2010 to 2015 for secondary hyperparathyroidism were identified from a prospectively maintained clinical database. Among 183 patients free of persistent or recurrent disease, follow-up NLR and PLR were available for analysis in 85 patients. RESULTS: In the whole study population, the baseline NLR was positively correlated with male sex, total white blood cell count, height, serum phosphorus, and calcium-phosphorus product levels. The baseline PLR was positively correlated with platelet count, serum phosphorus, and calcium-phosphorus product levels and negatively associated with patient age. Postoperative parathyroid hormone levels were positively correlated with NLR and PLR at follow-up. For patients who had successful parathyroidectomy, there was a decrease in NLR (P = 0.0006), PLR (P = 0.0003), and platelet count (P = 0.033), whereas hemoglobin significantly increased (P = 0.0002) after surgery. Those with persistent or recurrent hyperparathyroidism had no change in NLR, PLR, hemoglobin, total white blood cell, or platelet count. CONCLUSIONS: Successful parathyroidectomy is associated with a decrease in NLR and PLR. The modulatory effects of parathyroidectomy on systemic inflammation may partially explain the benefits of surgery in secondary hyperparathyroidism.

An Increased Neutrophil-to-Lymphocyte Ratio Predicts Incomplete Response to Therapy in Differentiated Thyroid Cancer.

Background: Previously we have shown that an elevated baseline neutrophil-to-lymphocyte ratio (NLR) was associated with a high risk of recurrence in patients with differentiated thyroid cancer. The clinical significance of the longitudinal changes in NLR following treatment remained unestablished. Methods: Adults patients with differentiated thyroid cancer were included in the study if the follow-up NLR data at 6 to 18 months after initial treatment were available. The response to treatment was categorized as excellent, indeterminate, biochemical incomplete, and structural incomplete as per guidelines of the American Thyroid Association. Results: Among 151 patients with thyroid cancer, a significant decrease in NLR following treatment was observed in those with stage I disease, those with low risk of recurrence, and those with an excellent response to therapy. Patients with a structural incomplete response had a significant increase in NLR at follow-up (p = 0.012). On multivariate analysis, incomplete response to therapy was associated with male sex (odds ratio [OR] = 3.35), tumor size (OR = 1.63), lymph node metastasis (OR = 4.80), distant metastasis (OR = 12.95), and increased NLR (OR = 13.68). Conclusions: An increase in systemic inflammation following treatment as measured by NLR is independently associated with an incomplete response to therapy in differentiated thyroid cancer.

Heme Oxygenase-1 Inhibitors Induce Cell Cycle Arrest and Suppress Tumor Growth in Thyroid Cancer Cells.

Heme oxygenase-1 (HO-1) is induced by a variety of stimuli and plays a multifaceted role in cellular protection. We have shown that HO-1 is overexpressed in thyroid cancer and is associated with tumor aggressiveness. Therefore, we set out to assess the effects of HO-1 inhibitors on the biology of thyroid cancer cells. Two different classes of HO-1 inhibitors were used, including a metalloporphyrin, zinc protoporphyrin-IX (ZnPP), and an azole antifungal agent, ketoconazole. The viability and colony formation of thyroid cancer cells decreased in a concentration- and time-dependent fashion following treatment with HO-1 inhibitors. Cancer cells exhibited a higher sensitivity to HO-1 inhibitors than non-malignant cells. HO-1 inhibitors induced a G0/G1 arrest accompanied by decreased cyclin D1 and CDK4 expressions and an increase in levels of p21 and p27. HO-1 inhibitors significantly increased intracellular ROS levels and suppressed cell migration and invasion. Oxygen consumption rate and mitochondrial mass were increased with ZnPP treatment. Mice treated with ZnPP had a reduced xenograft growth and diminished cyclin D1 and Ki-67 staining in tumor sections. Taken together, HO-1 inhibitors might have therapeutic potential for inducing cell cycle arrest and promoting growth suppression of thyroid cancer cells in vitro and in vivo.

Effect of Perioperative Intravenous Lidocaine Infusion on Acute and Chronic Pain after Breast Surgery: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Intravenous lidocaine infusion has been shown to reduce postoperative pain among patients undergoing abdominal surgery. This study aimed to evaluate the effects of perioperative lidocaine administration in breast surgery. METHODS: A meta-analysis of randomized controlled trials comparing lidocaine infusion vs. placebo/routine treatment was performed. Standardized mean difference (SMD) or risk ratio (RR) with 95% confidence intervals (CIs) was calculated from pooled data. Random-effects models were used, and heterogeneity was assessed. RESULTS: A total of 4 reports (3 primary studies and 1 extension) with 84 patients randomized to the lidocaine group and 83 patients randomized to the control group were included. There was no difference in pain scores at rest or during activity between the 2 groups from postoperative 2 hours to 3 days. At postoperative 72 hours, the lidocaine group had fewer analgesics consumed (SMD, -0.479; 95% CI, -0.914 to -0.043; P = 0.031). Chronic pain was assessed 3 to 6 months after breast surgery in 51 patients of the lidocaine group and 46 patients of the control group. Patients in the lidocaine group had significantly lower risk for the development of chronic pain (RR, 0.332; 95% CI, 0.141 to 0.781; P = 0.012). CONCLUSION: The results indicate no significant benefits of intravenous lidocaine infusion in terms of acute postoperative pain. Although lidocaine seems to attenuate the risk of chronic pain after breast surgery, there is insufficient evidence to conclude that lidocaine infusion is of proved benefit because the results were based on a limited number of small trials.

Aberrant expression of tumor-associated carbohydrate antigen Globo H in thyroid carcinoma.

BACKGROUND AND OBJECTIVES: The induction of tumor-associated carbohydrate antigen results from altered glycosylation in transformed cells. Globo H is a hexasaccharide glycosphingolipid overexpressed on malignancies of epithelial origin and has become an attractive vaccine target. We aimed to investigate the expression patterns and prognostic value of Globo H in thyroid neoplasms. METHODS: Globo H expression was examined by immunohistochemical analysis using commercial and in-house tissue microarrays. The expression was correlated with clinicopathologic characteristics in papillary thyroid cancer. RESULTS: Normal or benign thyroid lesions were negative for Globo H expression. Globo H was positive in 33% medullary, 24% papillary, 11% undifferentiated, and 8% follicular thyroid cancer. Globo H expression in papillary thyroid cancer was associated with extrathyroidal invasion (P = 0.017), BRAF mutation (P = 0.010), AMES high risk (P = 0.045), and increased ATA risk of recurrence (P = 0.022). CONCLUSIONS: Globo H is specifically expressed in a subset of thyroid malignancies. In papillary thyroid cancer, Globo H expression is associated with invasiveness and BRAF mutation. Immunotherapy targeting Globo H may have potential applications in thyroid cancer. J. Surg. Oncol. 2016;114:853-858. © 2016 2016 Wiley Periodicals, Inc.

Interaction of Age at Diagnosis with Transcriptional Profiling in Papillary Thyroid Cancer.

BACKGROUND: Age is an important prognostic factor for papillary thyroid cancer (PTC). However, little is known about why advanced age is associated with poor prognosis. The study investigated the changes in transcriptional profiling related to age. METHODS: RNA sequencing data of PTC samples were retrieved from The Cancer Genome Atlas data portal. Spearman's correlation was used to test the association between age and gene expression. Correlation in the same direction to disease severity was considered functionally relevant. Functional enrichment analysis and pathway annotations were performed. RESULTS: There was no correlation between age and thyroid-specific genes, except for a weak, negative association between age and TSHR expression. Among 272 genes with a positive association between gene expression and age, the most prominent alteration was metabolic pathways, particularly glycolysis. Among 482 genes with a negative association between gene expression and age, the most enriched biological process was immune-related functions, particularly natural killer cell-mediated cytotoxicity. CONCLUSIONS: Our analysis characterized the age-associated molecular landscape in PTC. Metabolic alterations and immune dysregulation are probable mechanisms involving in worse prognosis in older patients with PTC.

Effect of perioperative dexamethasone on subjective voice quality after thyroidectomy: a meta-analysis and systematic review.

BACKGROUND: Prophylactic dexamethasone has been shown to reduce postoperative pain, nausea, and vomiting in patients undergoing thyroidectomy. However, its effects on postoperative voice outcomes remain uncertain. METHODS: A systematic review and meta-analysis of the literature was conducted. Cochrane database, MEDLINE, EMBASE, and CINAHL were thoroughly searched. Studies that compared intravenous dexamethasone administration with no dexamethasone in patients undergoing thyroidectomy were included. Main outcome measure was the difference in postoperative voice assessment between groups. Standardized mean difference (SMD) and 95 % confidence intervals (CIs) were estimated using fixed and random effects models. RESULTS: Four studies with a total of 313 patients met inclusion criteria. Significant heterogeneity of study results was noted. Using random effects models, pooled data showed no difference in subjective voice quality between groups preoperatively (SMD, 0.29; 95 % CI -0.37 to 0.96; P = 0.39), 24 h after thyroidectomy (SMD, -1.02; 95 % CI -2.36 to 0.31; P = 0.13), or at 48 h (SMD, -0.05; 95 % CI -0.30 to 0.21; P = 0.72). A sensitivity analysis excluding one observational study yielded similar results. CONCLUSION: There are insufficient data for definite conclusions to be drawn regarding the effectiveness of a single perioperative administration of dexamethasone to reduce short-term voice disturbances after thyroidectomy. Further prospective trials using objective voice analysis are warranted to evaluate the efficacy of dexamethasone.

Antiproliferative Activity of Hinokitiol, a Tropolone Derivative, Is Mediated via the Inductions of p-JNK and p-PLCγ1 Signaling in PDGF-BB-Stimulated Vascular Smooth Muscle Cells.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is important in the pathogenesis of vascular disorders such as atherosclerosis and restenosis. Hinokitiol, a tropolone derivative found in Chamacyparis taiwanensis, has been found to exhibit anticancer activity in a variety of cancers through inhibition of cell proliferation. In the present study, the possible anti-proliferative effect of hinokitiol was investigated on VSMCs. Our results showed that hinokitiol significantly attenuated the PDGF-BB-stimulated proliferation of VSMCs without cytotoxicity. Hinokitiol suppressed the expression of proliferating cell nuclear antigen (PCNA), a maker for cell cycle arrest, and caused G0/G1 phase arrest in cell cycle progression. To investigate the mechanism underlying the anti-proliferative effect of hinokitiol, we examined the effects of hinokitiol on phosphorylations of Akt, ERK1/2, p38 and JNK1/2. Phospholipase C (PLC)-γ1 phosphorylation, its phosphorylated substrates and p27kip1 expression was also analyzed. Pre-treatment of VSMCs with hinikitiol was found to significantly inhibit the PDGF-BB-induced phosphorylations of JNK1/2 and PLC-γ1, however no effects on Akt, ERK1/2, and p38. The up-regulation of p27kip1 was also observed in hinokitiol-treated VSMCs. Taken together, our results suggest that hinokitiol inhibits PDGF-BB-induced proliferation of VSMCs by inducing cell cycle arrest, suppressing JNK1/2 phosphorylation and PLC-γ1, and stimulating p27kip1 expression. These findings suggest that hinokitiol may be beneficial for the treatment of vascular-related disorders and diseases.