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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. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

There is little research about the stress, quality of life (QOL) and gut microbiota in newly diagnosed breast cancer patients. We sought to determine the relationship of distress scale and FACT-B different domain and fecal microbial composition among newly diagnosed breast cancer patients. Total 82 newly diagnosed breast cancer patients were enrolled in this prospective, observational study. The mean score of the FACT-B was 104.5 (SD, 19.76). The mean DT score was 4.43, with 53.7% (44/82) of the patients reporting moderate to severe distress (score 5 or above). Several associations between distress, FACT-B different domain and microbial taxa were observed among this sample of breast cancer patients. Specifically, Alcaligenaceae and Sutterella were significantly more abundant in individuals with higher scores on the DT scale at the family and genus level, respectively (p = 0.017), while Streptococcaceae (p = 0.028) at the family level and Streptococcus (p = 0.023) at the genus level were significantly more abundant in individuals with lower scores on the DT scale. This study defines the relationships among stress, QOL and gut microbiota in newly diagnosed breast cancer patients and provides many useful information to find potential probiotics for decreasing stress and improving QOL in breast cancer patients.

Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity-associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K+ channel promoter, thereby causing K+ channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naive rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K+ channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K+ channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain.

Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are the important biomarkers in the prognosis of breast cancer, and their expression is used to categorize breast cancer into subtypes. We aimed to analyze the concordance among ER, PR, and HER2 expression levels and breast cancer subtyping results obtained by immunohistochemistry (IHC, for protein) and reverse transcriptase-polymerase chain reaction (RT-PCR, for mRNA) and to assess the recurrence-free survival (RFS) of the different subtypes as determined by the two methods. We compared biomarker expression by IHC and RT-PCR in 397 operable breast cancer patients and categorized all patients into luminal, HER2, and triple-negative (TN) subtypes. The concordance of biomarker expression between the two methods was 81.6% (κ = 0.4075) for ER, 87.2% (κ = 0.5647) for PR, and 79.1% (κ = 0.2767) for HER2. The κ-statistic was 0.3624 for the resulting luminal, HER2, and TN subtypes. The probability of 5-year RFS was 0.78 for the luminal subtype versus 0.77 for HER2 and 0.51 for TN, when determined by IHC (P=0.007); and 0.80, 0.71, and 0.61, respectively, when determined by the RT-PCR method (P=0.008). Based on the current evidence, subtyping by RT-PCR performs similar to conventional IHC with regard to the 5-year prognosis. The PCR method may thus provide a complementary means of subtyping when IHC results are ambiguous.

Introduction Motor neuron disease (MND) can be sporadic or familial, with approximately 10% of patients being familial. A number of genetic variants have been found in patients with or without family history. We present the results of genetic testing of a cohort of MND patients diagnosed at Royal Brisbane and Women’s Hospital (RBWH). Methods The criteria for genetic testing for our cohort were consenting MND patients with or without family history. Patients were tested for C9ORF72 repeat expansions and also with a panel of MND genes. The frequency of genetic variants and their clinical features were analysed and compared. Results There were 47 patients with a genetic variant. The most common variants were in C9ORF72 (27 patients; 57%), SOD1 (12 patients; 26%) and TARDBP (4 patients; 9%). Other genes with variants were TBK1, SPAST, NEK1 and HSPB1 (one patient for each gene). The median age of onset was 50, 49 and 58 years for C9ORF72, SOD1 and TARDBP, respectively. Survival was 813, 850 and 1889 days for C9ORF72, SOD1 and TARDBP, respectively. The frequency of bulbar onset was 26%; 8% and 50% for C9ORF72, SOD1 and TARDBP, respectively. A family history of MND was present in 63%, 83% and 50% of C9ORF72, SOD1 and TARDP patients, respectively. Conclusion The frequencies of genetic variants in our cohort are similar to what is described in European populations. Identification of genetic variants will aid the understanding of the associated phenotypes and identifying patients for possible therapy.

Introduction Voltage-gated calcium channel (VGCC) antibodies are considered specific for Lambert-Eaton myasthenic syndrome (LEMS). However, VGCC antibodies have been reported in other groups of patients without LEMS. Multiple acyl-CoA dehydrogenase deficiency (MADD) is a type of mitochondrial myopathy which can present with a late onset form. We report a case of a patient with positive VGCC antibodies concurrently with a diagnosis of possible late onset MADD. Methods Clinical information and results of investigations were obtained. Results A 75 year old woman presented with a gradual onset of proximal weakness associated with dyspnoea. There was no relevant past medical history and family history was unremarkable. Apart from mild proximal weakness, rest of the neurological examination was unremarkable. Deep tendon reflexes were normal. Acylcarnitine profile on multiple occasions showed a pattern consistent with MADD. Muscle biopsy showed mild mitochondrial changes. VGCC antibodies were detected on 2 separate occasions (86 and 100 pM; Ref Range The patient’s symptoms were thought to be secondary to MADD, therefore was treated with riboflavin, Q10 and carnitine and described significantly improved proximal strength and function. Conclusion It has been generally considered that the VGCC Ab has a high sensitivity and specificity for LEMS. However, in a study of 100 neuromuscular patients with elevated VGCC antibodies, only 6 patients were diagnosed with LEMS. This case illustrates the importance of applying appropriate clinical judgement with results of investigations.

Objective We report a favourable outcome following early treatment with rituximab in a patient with probable Susac’s syndrome (SuS). Background Delayed treatment of SuS leads to significant morbidity, however there is no consensus in its management. Results A 34-year-old man presented with severe headache, subacute confusion and blurred vision developing over 4 months. The MRI brain revealed multiple supratentorial and infratentorial FLAIR/T2 hyperintense lesions in white and gray matter, including characteristic corpus collosum ‘snow ball’ lesions. The fundus fluorescein angiography (FFA) showed typical branch retinal artery occlusion, consistent with his bilateral decrease in visual fields. CSF showed high protein (3000mg/L) and pleocytosis (18X106/L). Following diagnosis of probable SuS, he was treated with high-dose corticosteroids on day 3 of presentation, followed by IVIG, mycophenolate and rituximab. He had significant improvement within 1 week. By 3 months, he returned to his neuropsychological baseline in majority of cognitive domains from moderate-severe dysfunction, with concurrent MRI demonstrating resolving white matter lesions and FFA showing less evident vasculitis. The treatment response was maintained with tapering of steroids (25mg at 12 months). He was able to return to his previous occupation as a paramedic by 1 year. Conclusion SuS is a rare, immune-mediated microangiopathy in which early recognition with aggressive immunosuppression is required to achieve optimal outcome. No randomized controlled trial (RCT) exists for the management of this condition. In this report, early recognition through multidisciplinary input and aggressive immunotherapy with rituximab resulted in a favourable outcome. However, RCT evidence is needed to guide management.

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., Utilization of Oncotype DX is uncommon in Asia due to lack of clinical data. We compare a clinical-genomic model, developed from Taiwan, to Oncotype 21-gene panel in Chinese patients.

Bloodstream infections (BSI) are an important source of postoperative mortality in hepatobiliary–pancreatic surgery (HBPS) patients, and no prediction model has been analyzed before. 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. 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. 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.

Increased aerobic glycolysis portends an unfavorable prognosis in thyroid cancer. The metabolic reprogramming likely results from altered mitochondrial activity and may promote cancer progression. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) plays a pivotal role in mitochondrial biogenesis and function. In the present study, we aimed to evaluate the clinicopathological significance of PGC1α expression and the potential effects of PGC1α modulation. Firstly, the expression of PGC1α in thyroid cancer samples was evaluated using western blot analysis and immunohistochemical staining. Compared with normal thyroid tissue, PGC1α expression was downregulated in thyroid cancer. PGC1α-negative papillary cancer was associated with BRAF V600E mutation, large tumor size, extrathyroidal or lymphovascular invasion, lymph node metastasis, and advanced stage. The results were consistent with the analysis of The Cancer Genome Atlas data. PGC1α expression correlated with oxygen consumption in thyroid cancer cells and was inversely related to AKT activity. The biologic relevance of PGC1α was further investigated by gain- and loss-of-function experimental studies. PGC1α overexpression led to augmented oxidative metabolism and accelerated tumor growth, whereas PGC1α knockdown induced a glycolytic phenotype but reduced tumor growth in vivo. In conclusion, PGC1α downregulation is associated with glycolytic metabolism and advanced disease in thyroid cancer. Nonetheless, manipulating PGC1α expression and metabolic phenotype does not necessarily translate into beneficial effects. It suggests that the metabolic phenotype is likely the consequence rather than the cause of disease progression in thyroid cancer.

BackgroundNumerous prospective studies, predominantly in the Caucasian population, have proven the clinical utility of using multigene expression tests to prevent overtreatment in early-stage breast cancer patients with early-stage disease. In this study, we used an Asian population to validate a clinical-genomic assay (RecurIndex®) for estimating the risk of distant recurrence and relapse in early-stage breast cancer patients. MethodsA total of 298 patients with early-stage breast cancer, luminal-like subtype (85.6%) and HER2-enriched/ triple-negative subtype (14.4%), was enrolled in a retrospective study across five participating medical centers in Taiwan. The inclusion criteria were as follows: women (1) who underwent primary surgery without prior induction treatments, (2) with an early pathologic N stage and (3) who received either mastectomy or breast-conserving surgery. Kaplan Meier method and Cox proportional hazards model were used to, respectively, identify independent prognostic factors and calculate the 5- and 10-year survival rates of patients in the low- and high-risk groups assigned by the diagnostic test. A forest plot was produced to assess hazard ratios and 95% confidence intervals. The primary endpoint was distant recurrence-free survival (DRFS) and the secondary endpoint was relapse-free survival (RFS).ResultsThe 10-year DRFS rate was significantly higher in the good prognosis group than in the poor prognosis group (91.9% [95% CI, 86.1-98.1%] versus 62.9% [95% CI, 49.8-79.4%]). The overall hazard ratio for distant recurrence was 1.031 [95% CI, 1.017 - 1.046] per unit Recurrence index-distant recurrence (RI-DR) score increment. ConclusionsThe present study provides robust evidence of the clinical utility of using the RI-DR score to accurately predict clinical outcomes. RecurIndex® could be used to determine the utility of adjuvant chemotherapy in Asian patients, especially those having hormone-receptor positive tumors, leading to a meaningful reduction in adjuvant chemotherapy recommendations.

Originally characterized as an oncoprotein overexpressed in many forms of cancer that participates in numerous cellular pathways, DEK has since been well described regarding the regulation of epigenetic markers and transcription factors in neurons. However, its role in neuropathic allodynia processes remain elusive and intriguingly complex. Here, we show that DEK, which is induced in spinal dorsal horn neurons after spinal nerve ligation (SNL), is regulated by miR-489-3p. Moreover, SNL-induced decrease in miR-489-3p expression increased the expression of DEK, which recruited TET1 to the promoter fragments of the Bdnf, Grm5, and Stat3 genes, thereby enhancing their transcription in the dorsal horn. Remarkably, these effects were also induced by intrathecally administering naïve animals with miR-489-3p inhibitor, which could be inhibited by knockdown of TET1 siRNA or DEK siRNA. Conversely, delivery of intrathecal miR-489-3p-mimic into SNL rats attenuated allodynia behavior and reversed protein expression coupled to the promoter segments in the dorsal horn. Thus, a spinal miR-489-3p/DEK/TET1 transcriptional axis may contribute to neuropathic allodynia. These results may provide a new target for treating neuropathic allodynia.

Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity–associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K(+) channel promoter, thereby causing K(+) channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naïve rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K(+) channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K(+) channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00977-5.

Depression is a common mental disorder affecting more than 300 million people worldwide and is one of the leading causes of disability among all medical illnesses. The accumulation of preclinical data has fueled the revival of interest in targeting glutamatergic neurotransmission for the treatment of major depressive disorder. GLYX-13, a glutamatergic compound that acts as an N-methyl-d-aspartate (NMDA) modulator with glycine-site partial agonist properties, produces rapid and long-lasting antidepressant effects in both animal models and patients. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been fully characterized, especially in the midbrain ventrolateral periaqueductal gray (vlPAG), a brain stem area that controls stress-associated depression-like behavior. Here, we use a combination of electrophysiological recordings, behavioral tests, and pharmacological manipulations to study the antidepressant actions of GLYX-13 in the vlPAG. A single intravenous injection of a GLYX-13 rapidly mitigated footshock stress (FS)-induced depression-like behavior in rats. The FS-induced diminished glutamatergic transmission in the vlPAG was also reversed by a single GLYX-13 intravenous injection. Moreover, intra-vlPAG GLYX-13 microinjection produced a long-lasting antidepressant effect; however, this effect was prevented by the intra-vlPAG microinjection of tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, a selective mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, and CNQX, an AMPA receptor antagonist. Additionally, a bath application of GLYX-13 enhanced glutamatergic transmission in vlPAG neurons; however, this enhancement effect was blocked by the co-application of ANA-12 and rapamycin. These results demonstrate that BDNF-TrkB-mTORC1 signaling in the vlPAG is required for the sustained antidepressant effects of GLYX-13.

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.

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.

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.

Background Recurrence of papillary thyroid cancer is not uncommon, but incorporating clinicopathologic parameters to predict recurrence is suboptimal. The aim of this study was to identify systemically recurrence-associated genes using The Cancer Genome Atlas RNA sequencing database. Methods A total of 504 patients with transcriptome sequencing data of the primary neoplasm were included in this study. High and low levels of expression of each gene were defined by median splits. Differences in recurrence-free survival were compared using Kaplan-Meier curves and log-rank tests. Recurrence-associated genes were subjected to functional enrichment analyses with Kyoto Encyclopedia of Genes and Genomes annotation databases and Ingenuity Pathway Analysis. Results We found that 1,807 genes were associated with recurrence-free survival. There were 676 genes of which high expression was associated with a greater risk of recurrence. These genes were enriched in pathways involved in cell cycle regulation and DNA repair. Among 1,131 genes of which low expression was associated with recurrence, Kyoto Encyclopedia of Genes and Genomes–annotated functions were metabolism, calcium signaling, glycan biosynthesis, and the Notch signaling pathway. Canonical pathways identified by Ingenuity Pathway Analysis included RXR function, nitric oxide signaling, interleukin-8 signaling, and nutrient sensing. In addition, low expression of the majority of thyroid differentiation genes was associated with a significantly less recurrence-free survival. Conclusion Upregulation of cell cycle–regulating and DNA repair genes appears to have a negative impact on recurrence-free survival in patients with papillary thyroid cancer. Furthermore, recurrence is associated with thyroid dedifferentiation.

Objective: Extrathyroidal extension may not be accurately recognized during thyroidectomy and can increase the risk of positive margins and even recurrence. This study aimed to investigate the preoperative factors associated with extrathyroidal extension. Methods: We analyzed 887 patients with papillary thyroid cancer (PTC) who underwent surgery in the period of 2005–2017. Binary logistic regression analyses and generalized additive models were used to identify associations. Results: Minimal extrathyroidal extension was present in 233 (26%) patients and advanced extrathyroidal extension was found in 60 (7%) patients. Age, BMI, and tumor size were independent predictors of all or advanced extrathyroidal extension. Among the 493 patients whose BRAF mutation status was available, age (OR = 1.025), BMI (OR = 1.091), tumor size (OR = 1.544), and BRAF V600E mutation (OR = 2.311) were independently associated with extrathyroidal extension. Conclusions: Older age, a greater BMI, a larger tumor size, and presence of the BRAF mutation were predictive of extrathyroidal extension. These factors should be taken into consideration in decision-making before surgery is performed.

Mixed lineage leukemia 1 (MLL1)-mediated histone H3 lysine 4 trimethylation (H3K4me3) of a subset of genes has been linked to the transcriptional activation critical for synaptic plasticity, but its potential contribution to neuropathic allodynia development remains poorly explored. Here, we show that MLL1, which is induced in dorsal horn neuron after spinal nerve ligation (SNL), is responsible for mechanical allodynia and increased H3K4me3 at metabotropic glutamate receptor subtype 5 (mGluR5) promoter. Moreover, SNL induced WD (Trp-Asp) repeat domain 5 subunit (WDR5) expression as well as the MLL1-WDR5 interaction accompany with H3K4me3 enrichment and transcription of mGluR5 gene in the dorsal horn in neuropathic allodynia progression. Conversely, WDR5-0103, a novel inhibitor of the MLL1-WDR5 interaction, reversed SNL-induced allodynia and inhibited SNL-enhanced mGluR5 transcription/expression as well as MLL1, WDR5, and H3K4me3 at the mGluR5 promoter in the dorsal horn. Furthermore, disrupting the expression of MLL1 or WDR5 using small interfering RNA attenuated mechanical allodynia and reversed protein transcription/expression and complex localizing at mGluR5 promoter in the dorsal horn induced by SNL. This finding revealed that MLL1-WDR5 complex integrity regulates MLL1 and WDR5 recruitment to H3K4me3 enrichment at mGluR5 promoter in the dorsal horn underlying neuropathic allodynia. Collectively, our findings indicated that SNL enhances the MLL1-WDR5 complex, which facilitates MLL1 and WDR5 recruitment to H3K4me3 enrichment at mGluR5 promoter in spinal plasticity contributing to neuropathic allodynia pathogenesis.

The current guidelines recommend that potassium iodide be given in the immediate preoperative period for patients with Graves' disease who are undergoing thyroidectomy. Nonetheless, the evidence behind this recommendation is tenuous. The purpose of this study is to clarify the benefits of preoperative iodine administration from published comparative studies.We searched PubMed, Embase, Cochrane, and CINAHL from 1980 to June 2018.Studies were included that compared preoperative iodine administration and no premedication before thyroidectomy. For the meta-analysis, studies were pooled with the random-effects model.A total of 510 patients were divided into the iodine (n = 223) and control (n = 287) groups from 9 selected studies. Preoperative iodine administration was significantly associated with decreased thyroid vascularity and intraoperative blood loss. Significant heterogeneity was present among studies. We found no significant difference in thyroid volume or operative time. Furthermore, the meta-analysis showed no difference in the risk of postoperative complications, including vocal cord palsy, hypoparathyroidism/hypocalcemia, and hemorrhage or hematoma after thyroidectomy.Preoperative iodine administration decreases thyroid vascularity and intraoperative blood loss. Nonetheless, it does not translate to more clinically meaningful differences in terms of operative time and postoperative complications.

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 Wiley Periodicals, Inc.

// Shih-Hsin Tu 1, 2, 3 , Yin-Ching Lin 4 , Chi-Cheng Huang 1, 5, 6 , Po-Sheng Yang 7, 8 , Hui-Wen Chang 9 , Chien-Hsi Chang 9 , Chih-Hsiung Wu 1, 10 , Li-Ching Chen 2, 3, 11 , Yuan-Soon Ho 4, 9, 12, 13 1 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 2 Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan 3 Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan 4 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan 6 Breast Center, Cathay General Hospital, Taipei, Taiwan 7 Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan 8 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan 9 Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan 10 Department of Surgery, En Chu Kong Hospital, New Taipei City, Taiwan 11 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 12 Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan 13 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan Correspondence to: Li-Ching Chen, email: d117094003@tmu.edu.tw Yuan-Soon Ho, email: hoyuansn@tmu.edu.tw Keywords: protein phosphatase Mg 2+ /Mn 2+ dependent 1F, breast cancer, smoking, α9-nicotinic acetylcholine receptor, p53 Received: August 15, 2016 Accepted: October 04, 2016 Published: October 18, 2016 ABSTRACT We previously demonstrated that the activation of α9-nicotinic acetylcholine receptor (α9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in α9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg 2+ /Mn 2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F -knockdown and -overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro , nicotine induced PPM1F expression, whereas α9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of α9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited for cancer prevention and therapy.

Glucose transporters (GLUTs) are required for glucose uptake in malignant cells, and they can be used as molecular targets for cancer therapy. An RT-PCR analysis was performed to investigate the mRNA levels of 14 subtypes of GLUTs in human colorectal cancer (COLO 205 and HT-29) and normal (FHC) cells. RT-PCR (n = 27) was used to assess the differences in paired tissue samples (tumor vs normal) isolated from colorectal cancer patients. GLUT2 was detected in all tested cells. The average GLUT2 mRNA level in 12 of 27 (44.4%) cases was 2.4-fold higher in tumor compared to normal tissues (*, p = 0.027). Higher GLUT2 mRNA expression was preferentially detected in advanced-stage tumors (stage 0 vs 3 = 16.38-fold, 95% CI = 9.22-26.54-fold; *, p = 0.029). The apple polyphenol phloretin (Ph) and siRNA methods were used to inhibit GLUT2 protein expression. Ph (0-100 μM, for 24 h) induced COLO 205 cell growth cycle arrest in a p53-dependent manner, which was confirmed by pretreatment of the cells with a p53-specific dominant negative expression vector. Hepatocyte nuclear factor 6 (HNF6), which was previously reported to be a transcription factor that activates GLUT2 and p53, was also induced by Ph (0-100 μM, for 24 h). The antitumor effect of Ph (25 mg/kg or DMSO twice a week for 6 weeks) was demonstrated in vivo using BALB/c nude mice bearing COLO 205 tumor xenografts. In conclusion, targeting GLUT2 could potentially suppress colorectal tumor cell invasiveness.

The practice of mindfulness has not been well-developed for cancer survivors and their partners, and its effects on relational well-being and cortisol responses are unknown. This 14-month study aimed to examine the effects of the mindfulness-incorporated couples support group on psychological individual and relational well-being, and cortisol stress responses in breast cancer survivors and their partners. The participants were randomized into two groups: 21 couples in couples support group (CSG) and 19 couples in individual support program (ISP). Outcome measures for both survivors and their partners included Medical Outcomes Study Sleeping scale (MOS), Beck Depression Inventory (BDI-II), State-Trait Anxiety Inventory (STAI), Meaning of Life Questionnaire (MLQ), Short form-12 Health-related Quality of Life (SF-12 QOL), Experiences in close relationships-revision scale (ECR-R), and salivary cortisol. Among breast cancer survivors, the most significant effects of CSG were greater reductions of anxiety ECR-R compared with ISP. For partners, decreased levels of BDI-II, anxiety, and avoidant ECR-R, and increased levels of search and presence aspects of MLQ, physical, and mental QOL were identified in CSG compared with ISP. Moreover, CSG contributed to reduced cortisol levels at time of awakening and at 12:00 for both breast cancer survivors and their partners, cortisol levels at 30 min after awakening for survivors, and night cortisol levels at 21:00 for partners. In conclusion, mindfulness including individual and interactive breathing and meditation could guide clinical professionals to practice mindfulness themselves and become trainers to enhance the effective communication and relational well-being for cancer survivors and their partners.

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. 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. 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. 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.

3560 Background: Numerous prospective studies, predominantly in Caucasian population, have proven the clinical utility of using multigene expression tests to prevent overtreatment in early breast cancer (EBC) patients. Since racial and ethnic disparities exist in genetic and biological factors that could influence the disease, the primary purpose of this study is to access the clinical utility of RecurIndex, a recurrence risk test, that is based on a genomic profiling derived from Asian women. Methods: A total of 298 patients with EBC, luminal subtype (85.6%), HER2 subtype (7.7%) and triple-negative subtype (6.7%), were enrolled in a retrospective study across Taiwan medical centers. Kaplan Meier and Cox Proportional Hazards model were used to, respectively, identify independent prognostic factors and calculate the survival rates. The prediction model was then tested using the area under the receiver operating characteristic curve (AUC). The primary endpoint was distant recurrence-free survival (DRFS). Results: The 10-year DRFS was significantly higher in the good-prognosis group than the poor-prognosis group (92.0% [95% CI, 86.1-98.2] versus 63.0% [95% CI, 49.9-79.5]) (Table). The overall hazard ratio for distant recurrence was 1.031 (95% CI, 1.017±1.046) per RI score increment. In addition, in a subset of 179 cases (60.1%), the model yielded an 82.3% correct classification rate for predicting DR with a sensitivity of 87.0%, a specificity of 68.6% and negative predictive values of 97.3%. Conclusions: The present study provides robust evidence of the clinical utility of RI-DR to predict clinical outcomes. RecurIndex could be used to determine the utility of chemotherapy in Asian patients, especially in hormone-receptor positive and HER2 negative disease, leading to a meaningful reduction in adjuvant chemotherapy recommendations. [Table: see text]

Predicting a patient’s risk of recurrence after the resection of liver metastases from colorectal cancer is critical for evaluating and selecting therapeutic approaches. Clinical and pathologic parameters have shown limited accuracy thus far. Therefore, we combined the clinical status with a genomic approach to stratify relapse-free survival in colorectal cancer liver metastases patients. To identify new molecular and genetic signatures specific to colorectal cancer with liver metastasis (CRCLM) patients, we conducted DNA copy number profiling on a cohort of 21 Taiwanese CRCLM patients using a comparative genomic hybridization (CGH) array. We identified a three-gene signature based on differential copy number alteration between patients with different statuses of (1) recurrence and (2) synchronous metastasis. In relapse hotspot regions, only three genes (S100PBP, CSMD2, and TGFBI) were significantly associated with the synchronous liver metastasis factor. A final set of three genes—S100PBP, CSMD2, TGFBI—significantly predicted relapse-free survival in our cohort (p = 0.04) and another CRCLM cohort (p = 0.02). This three-gene signature is the first genomic signature validated for relapse-free survival in post-hepatectomy CRCLM patients. Our three-gene signature was developed using a whole-genome CGH array and has a good prognostic position for the relapse-free survival of CRCLM patients after hepatectomy.