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Background: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL., Methods: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL., Findings: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10 -16 ; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10 -26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants., Interpretation: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention., Funding: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pleomorphic mantle cell lymphoma (PMCL) can closely mimic diffuse large B-cell lymphoma (DLBCL) morphologically, and expression of CD5 and cyclin D1 is helpful for differential diagnosis. To date, no cases of CD5/cyclin D1 double-negative PMCL have been reported. Four cases of B-cell lymphoma with an immunophenotype of CD5(-) cyclin D1(-) SOX11(+) and morphologic features compatible with DLBCL were included. Two were previously identified, and the other 2 were screened from 500 cases of B-cell lymphoma. We analyzed their clinicopathologic, immunophenotypic, genetic, and gene expression features. Cases of cyclin D1-positive PMCL, cyclin D1-negative PMCL, germinal center B-cell (GCB) DLBCL, and activated B cell (ABC) DLBCL were also studied for comparison. Similar to other PMCL cases, these 4 patients were mainly elderly male individuals with an aggressive clinical course. None of these tumors had detectable translocations involving CCND1, CCND2, CCND3, CCNE1, CCNE2, MYC, BCL2, or BCL6. The genome-wide copy number profile of these 4 cases was similar to that of cyclin D1-negative PMCL. None of these tumors had high expression of cyclin D1, cyclin D2, or cyclin D3. Similar to cyclin D1-negative PMCL, these cases had higher expression of cyclin E1 and cyclin E2 compared with cyclin D1-positive PMCL. The gene expression pattern of these tumors was also similar to that of cyclin D1-negative PMCL. Here we report for the first time 4 cases of CD5/cyclin D1 double-negative PMCL. SOX11 positivity is useful to identify these rare tumors, and further genetic and gene expression analysis can be used to confirm the diagnosis.

We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1β. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their ASC speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients, better local recurrence-free survival was significantly associated with high-level expression of NDUFB8 ( p = 0.037) and ATP5B ( p = 0.029), as examined using immunohistochemistry. However, there were no significant associations between the expression of NDUFB8 and ATP5B with overall survival of NPC patients. Together, our results demonstrate that up-regulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be markers for local recurrence and/or promising therapeutic targets in patients with NPC., (© 2020 Chung et al.)

Fatigue is one problem with driving as it can lead to difficulties with sustaining attention, behavioral lapses, and a tendency to ignore vital information or operations. In this research, we explore multimodal physiological phenomena in response to driving fatigue through simultaneous functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) recordings with the aim of investigating the relationships between hemodynamic and electrical features and driving performance. Sixteen subjects participated in an event-related lane-deviation driving task while measuring their brain dynamics through fNIRS and EEGs. Three performance groups, classified as Optimal, Suboptimal, and Poor, were defined for comparison. From our analysis, we find that tonic variations occur before a deviation, and phasic variations occur afterward. The tonic results show an increased concentration of oxygenated hemoglobin (HbO 2 ) and power changes in the EEG theta, alpha, and beta bands. Both dynamics are significantly correlated with deteriorated driving performance. The phasic EEG results demonstrate event-related desynchronization associated with the onset of steering vehicle in all power bands. The concentration of phasic HbO 2 decreased as performance worsened. Further, the negative correlations between tonic EEG delta and alpha power and HbO 2 oscillations suggest that activations in HbO 2 are related to mental fatigue. In summary, combined hemodynamic and electrodynamic activities can provide complete knowledge of the brain's responses as evidence of state changes during fatigue driving.

Saccharomyces cerevisiae and Aspergillus oryzae are both ancient probiotic species traditionally used as microbes for brewing beer and soy sauce, respectively. This study investigated the effect of adding these two probiotics with phytase fermentation products to the broilers diet. Fermented products possess protease and cellulase, and the activities were 777.1 and 189.5 U/g dry matter (DM) on S. cerevisiae fermented products (SCFP) and 190 and 213.4 U/g DM on A. oryzae fermented products (AOFP), respectively. Liposaccharides stimulated PBMCs to produce nitric oxide to 120 μmol. Both SCFP and AOFP reduced lipopolysaccharides stimulated peripheral blood mononuclear cells (PBMCs) nitric oxide release to 40 and 60 μmol, respectively. Nevertheless, in an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, SCFP and AOFP also increased the survival rate of lipopolysaccharides stimulated PBMCs by almost two-fold compared to the negative control. A total of 240 broilers were divided into four groups as Control, SCFP 0.1% (SCFP), SCFP 0.05% + AOFP 0.05% (SAFP), and AOFP 0.1% (AOFP) groups, respectively. Each group had 20 broilers, and three replicate pens. The results showed that the addition of SCFP, SAFP, and AOFP groups did not affect the growth performances, but increased the jejunum value of villus height and villus: crypt ratio on SAFP and AOFP groups compared to the control and SCFP groups. Furthermore, adding SCFP, SAFP, and AOFP significantly reduced the number of Clostridium perfringens in ileum chyme. SCFP, SAFP, and AOFP significantly reduced the amount of interleukin-1β, inducible nitric oxide synthases, interferon-γ, and nuclear factor kappa B mRNA expression in PBMCs, especially in the AOFP group. In summary, all the SCFP, SAFP, and AOFP groups can be suggested as a functional feed additive since they enhanced villus: crypt ratio and decreased inflammation-related mRNA expression, especially for AOFP group in broilers.

Fine needle aspiration cytology (FNAC) is the final diagnosis of thyroid nodules before surgery. It is important to further improve the indeterminate FNAC diagnosis results using computerized cytological features. This retrospective cross-sectional study included 240 cases, of whom 110 had histologic diagnosis of papillary thyroid cancers (PTC), 100 had nodular/adenomatous goiters/hyperplasia (benign goiters), 10 had follicular/Hurthle cell carcinomas, and 20 had follicular adenomas. Morphological and chromatic features of FNAC were quantified and analyzed. The result showed that six quantified cytological features were found significantly different between patients with a histologic diagnosis of PTC and patients with histologic diagnosis of benign goiters in multivariate analysis. These cytological features were used to estimate the malignancy risk in nodules with indeterminate FNAC results. The Area Under the Receiver Operating Characteristics (AUROC) of the diagnostic accuracy with a benign or malignant nature was 81.3% ( p < 0.001), 78.7% ( p = 0.014), and 56.8% ( p = 0.52) for nodules with FNAC results of atypia, which is suspicious for malignancy and follicular neoplasm, respectively. In conclusion, quantification of cytological features could be used to develop a computer-aided tool for diagnosing PTC in thyroid nodules with indeterminate FNAC results.

Positive proximal resection margins are strongly associated with anastomotic recurrence in esophageal cancer. However, the prognostic significance of dysplastic proximal resection margins remains unclear. The aim of this study is to investigate whether the dysplastic proximal resection margin can predict anastomotic recurrence and overall survival in patients with esophageal squamous cell carcinoma. Between 2000 and 2014, patients with esophageal squamous cell carcinoma who received a nonpalliative resection and survived the perioperative period were included. Two expert pathologists independently reviewed the proximal resection margin status, which was classified as negative, dysplastic, or positive. The kappa statistic was used to test interobserver reliability. Anastomotic recurrence and overall survival served as the main outcome measures. The study cohort consisted of 469 patients (445 males and 27 females). There was an excellent interobserver agreement for negative (kappa = 0.88), dysplastic (kappa = 0.88), and positive (kappa = 1) proximal resection margins-which were identified in 418 (89.1%), 37 (7.9%), and 14 (3.0%) patients, respectively. After a median follow-up of 21.6 months, 30 (6.4%) patients developed an anastomotic recurrence. Compared with patients with negative proximal resection margins (24/418, 5.7%), the occurrence of anastomotic recurrence was more commonly observed in those with positive proximal resection margins (3/14, 21.4%, P = 0.017) but not in those with dysplastic proximal resection margins (3/37, 8.1%, P = 0.56). Multivariable Cox regression analysis identified positive proximal resection margins (hazard ratio: 5.93, P = 0.010) and advanced clinical stage (hazard ratio: 12.04, P = 0.023) as independent risk factors for anastomotic recurrence. Dysplastic proximal resection margins were not retained in the model as an independent predictor (hazard ratio: 1.38, P = 0.602). The 5-year overall survival rates of patients with negative (38.2%) and dysplastic margins (27.0%) were similar (P = 0.814), and significantly higher than that observed in those with positive proximal resection margins (9.5%, P = 0.015). In conclusion, dysplastic proximal resection margins can be identified in at least 7.9% of patients with esophageal squamous cell carcinoma, but neither they are associated with an increased risk of anastomotic recurrence nor they portend a poor overall survival., (© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Background & Aims : Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths worldwide. Many studies indicate that disruption of cellular thyroid hormone signaling promotes HCC progression. However, the mechanisms underlying the regulation of genes downstream of thyroid hormone actions in HCC have remained elusive. In the current study, we identified NUPR1 (nuclear protein-1), a stress-induced protein that overexpresses in various neoplasia, is upregulated by triiodothyronine/thyroid hormone receptor (T 3 /TR) signaling and aimed to elucidate its role in angiogenesis in cancer progression. Methods : Quantitative reverse transcription-PCR, luciferase promoter and chromatin immunoprecipitation assays were performed to identify the NUPR1 regulatory mechanism by T 3 /TR. In vitro and In vivo vascular formations were performed to detect the angiogenic function of NUPR1. Human angiogenesis arrays were performed to identify the downstream angiogenic pathway. The sorafenib resistant ability of TR/NUPR1 was further examined in vitro and in vivo . Clinical relevance of TR, NUPR1 and platelet-derived growth factor A (PDGFA) were investigate in HCC samples using qRT-PCR and western blot. Results : Our experiments disclosed positive regulation of NUPR1 expression by T 3 /TR through direct binding to the -2066 to -1910 region of the NUPR1 promoter. Elevated NUPR1 and TR expression link to poor survival in clinical HCC specimens. An analysis of clinicopathological parameters showed that expression of NUPR1 is associated with vascular invasion and pathology stage. Functional studies revealed that NUPR1 induced endothelial cell angiogenesis in vitro and in vivo . Using a human angiogenesis array, we identified PDGFA as a target of NUPR1 in the downstream angiogenic pathway. NUPR1 induced transcription of PDGFA through direct binding to the corresponding promoter region, and inhibition of the PDGFA signaling pathway impaired angiogenesis in human umbilical vein endothelial cells (HUVECs). Notably, the angiogenic effects of NUPR1/PDGFA were mediated by the MEK/ERK signaling pathway. TR/NUPR1 expression increased cell viability and resistance to sorafenib treatment. Moreover NUPR1 expression was positively correlated with TRα, TRβ, and PDGFA expression. Conclusions : We propose that the T 3 /TR/NUPR1/PDGFA/MEK/ERK axis has a vital role in hepatocarcinogenesis and suggest NUPR1 as a potential therapeutic target in HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The association between houseplants and indoor air quality improvement has been reported in previous studies. However, the effect of houseplant-emitted isoprene on the association between ozone (O 3 ) formation and respiratory health remains unclear. We recruited 60 adult subjects from 60 houses with or without houseplants (1:1) in Taipei; twelve house visits were conducted in each home throughout 2014. The indoor air pollutants that were measured consisted of particulate matter less than or equal to 2.5 μm in diameter (PM 2.5 ), O 3 and isoprene. Peak expiratory flow rate (PEFR) was measured in each study subject during each house visit. Household information was collected by a questionnaire. Mixed-effects models were used to explore the association between indoor air pollution levels and PEFR. We found that the concentrations of O 3 and isoprene in houses with houseplants were higher than those in houses without houseplants. In contrast, PM 2.5 levels and % predicted PEFR were higher in houses without houseplants than in those with houseplants. Moreover, increased levels of O 3 and PM 2.5 in houses with houseplants were associated with a decreased % predicted PEFR, especially in the summer. We concluded that increased levels of indoor O 3 and PM 2.5 were associated with decreased PEFR. The presence of houseplants was associated with indoor O 3 , isoprene and PEFR variations in the summer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Thyroid hormone (T3) and its receptor (TR) are involved in cancer progression. While deregulation of long non-coding RNA (lncRNA) expression has been detected in many tumor types, the mechanisms underlying specific involvement of lncRNAs in tumorigenicity remain unclear. Experiments from the current study revealed negative regulation of BC200 expression by T3/TR. BC200 was highly expressed in hepatocellular carcinoma (HCC) and effective as an independent prognostic marker. BC200 promoted cell growth and tumor sphere formation, which was mediated via regulation of cell cycle-related genes and stemness markers. Moreover, BC200 protected cyclin E2 mRNA from degradation. Cell growth ability was repressed by T3, but partially enhanced upon BC200 overexpression. Mechanistically, BC200 directly interacted with cyclin E2 and promoted CDK2-cyclin E2 complex formation. Upregulation of cell cycle-related genes in hepatoma samples was positively correlated with BC200 expression. Our collective findings support the utility of a potential therapeutic strategy involving targeting of BC200 for the treatment of HCC.

Objective: Several surgical techniques and modifications have been described to reduce the high recurrence rate after excision of preauricular sinus (PAS). This study was designed to evaluate the surgical outcomes of PAS excision using a new modified supra-auricular approach (SAA) and to assess the predisposing factors for recurrence., Methods: A total of 175 (158 patients) PAS excision procedures were performed from 2007 to 2016 in a single institute using this modified SAA with helix cartilage suture to obliterate the dead space. The specimens were assessed to measure the closest distance between the squamous tract and the excised auricular cartilage (sinocartilaginous distance). We also evaluated the surgical outcomes and investigated the predisposing factors for recurrence, including gender, lesion laterality, etiology (primary or revised), anesthesia methods (general or local), history of infection, and history of incision and drainage (I&D) for abscess., Results: Patients were followed up for a median duration of 45 months (range from 6 months to 10 years). There was a 2.3% (4 ears) recurrence rate and a 1.7% (3 ears) complication rate in our series. The average sinocartilaginous distance was 0.44 mm (median distance, 0.3 mm) and this value was less than 0.5 mm in 66% of cases. Recurrence was not significantly affected by gender, lesion laterality, etiology of surgery, anesthesia method, or a history of infection or preoperative I&D for abscess., Conclusions: Surgical PAS excision using the modified SAA with cartilage suture of dead space yielded low overall recurrence and complication rates in this series. Cosmesis was maintained due to a smaller incision. No significant predisposing factors for recurrence were identified. Thus, the modified technique described in the present study can be regarded as a simple, effective and reproducible surgical treatment for PAS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The prognostic value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal carcinoma (NPC) is controversial, with previous studies showing conflicting results. Most NPCs in endemic areas are Epstein-Barr virus (EBV)-positive. Our aim was to evaluate the clinical significance of PD-L1 expression in EBV-positive NPC. We retrospectively analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs) by immunohistochemistry in 208 EBV-positive NPC patients who underwent radiotherapy (203 with concurrent chemotherapy). The percentages of TCs and ICs expressing PD-L1 were evaluated respectively. There was a strong correlation between local recurrence and low PD-L1 expression on ICs ( p = 0.0012), TCs ( p = 0.013) or both ( p = 0.000044), whereas all clinical parameters had no influence on local recurrence. Using multivariate analysis, low PD-L1 expression on ICs was an independent adverse prognostic factor ( p = 0.0080; HR = 1.88; 95% CI = 1.18⁻3.00) for disease-free survival. High PD-L1 expression on both ICs and TCs was an independent favorable prognostic factor ( p = 0.022; HR = 0.46; 95% CI = 0.24⁻0.89) for overall survival. We show for the first time that low PD-L1 expression on ICs and TCs strongly correlates with local recurrence in EBV-positive NPC patients after radiation-based therapy. A simple immunohistochemical study for PD-L1 can identify patients prone to local recurrence, and such patients might benefit from more aggressive treatment in future clinical trials., Competing Interests: The authors declare no conflict of interest.

DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC.

Objectives: We aimed to define the clinical features, outcome, and prognostic factors for extranodal NK/T-cell lymphoma (ENKTL) patients in Taiwan., Methods: We retrospectively reviewed 101 ENKTL patients diagnosed between February 1998 and October 2015., Results: The median age of 101 patients was 52 years old (range 22-85); 76.2% of patients were Ann Arbor stage I/II disease. The 5-year progression-free survival (PFS) and overall survival (OS) were 49.9% and 54.8%, respectively. Patients with log[EBV-DNA] ≥ 3.8 and bone marrow hemophagocytosis at diagnosis had inferior PFS and OS. Most stage I/II patients received combined chemoradiotherapy with anthracycline-containing regimen, with overall response rate of 96.7%, complete response rate 86.9%, 5-year PFS 65%, and OS 72%. The relapse rate was 29.3% with a short median disease-free survival of 6.2 months. In advanced stage patients, overall response rate was only 13.6%, with median PFS 2.3 months, and OS 4.8 months. Age ≥ 60 (HR 3.773, 95% CI 1.733-8.215, P = 0.001) and stage III/IV (HR 7.785, 95% CI 2.312-26.213, P = 0.001) were unfavorable prognostic factors for PFS and OS by multivariate analyses., Conclusions: Age ≥ 60 and stage III/IV are independent poor prognostic factors for PFS and OS. Early-stage ENKTL patients had good response to combined chemoradiotherapy with anthracycline-containing regimen but with a high relapse rate and short disease-free survival. Anthracycline-containing regimen in advanced stage had poor response and dismal outcome., (© 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Raoultella planticola is an emerging zoonotic pathogen that is associated with rare but life-threatening cases of bacteremia, biliary tract infections, and urinary tract infections. Moreover, increasing antimicrobial resistance in the organism poses a potential threat to public health. In spite of its importance as a human pathogen, the genome of R. planticola remains largely unexplored and little is known about its virulence factors. Although lipopolysaccharides has been detected in R. planticola and implicated in the virulence in earlier studies, the genetic background is unknown. Here, we report the complete genome and comparative analysis of the multidrug-resistant clinical isolate R. planticola GODA. The complete genome sequence of R. planticola GODA was sequenced using single-molecule real-time DNA sequencing. Comparative genomic analysis reveals distinct capsular polysaccharide synthesis gene clusters in R. planticola GODA. In addition, we found bla TEM-57 and multiple transporters related to multidrug resistance. The availability of genomic data in open databases of this emerging zoonotic pathogen, in tandem with our comparative study, provides better understanding of R. planticola and the basis for future work.

The order Pleosporales comprises a miscellaneous group of fungi and is considered to be the largest order of the class Dothideomycetes. The circumscription of Pleosporales has undergone numerous changes in recent years due to the addition of large numbers of families reported from various habitats and with a large amount of morphological variation. Many asexual genera have been reported in Pleosporales and can be either hyphomycetes or coelomycetes. Phoma -like taxa are common and have been shown to be polyphyletic within the order and allied with several sexual genera. During the exploration of biodiversity of pleosporalean fungi in Taiwan, a fungal strain was isolated from mycelium growing on the fruiting body of an Ophiocordyceps species. Fruiting structures that developed on PDA were morphologically similar to Phoma and its relatives in having pycnidial conidiomata with hyaline conidia. The fungus is characterised by holoblastic, cylindrical, aseptate conidiogenous cells and cylindrical, hyaline, aseptate, guttulated, thin-walled conidia. Phylogenetic analysis based on six genes, ITS, LSU, rpb2 , SSU, tef1 and tub2 , produced a phylogenetic tree with the newly generated sequences grouping in a distinct clade separate from all of the known families. Therefore, a new pleosporalean family Tzeananiaceae is established to accommodate the monotypic genus Tzeanania and the species T.taiwanensis in Pleosporales, Dothideomycetes. The Ophiocordyceps species was identified as O.macroacicularis and this is a new record in Taiwan.

Aim: To determine the prevalence and clinical consequences of cytomegalovirus (CMV) DNA in the aqueous and corneal tissues obtained at the time of corneal transplantation to evaluate the diagnostic value of PCR analysis in identifying patients at risk of postkeratoplasty CMV endotheliitis., Methods: Thirty patients who underwent corneal transplantation were included in 2011. The aqueous, excised recipient corneas and donor corneoscleral rims were analysed by PCR for the presence of CMV DNA. The medical records of the patients were retrospectively reviewed and linked with PCR results., Results: CMV DNA was detected in three (10%) aqueous, eight (26.7%) recipient corneas and six (20.0%) donor corneas obtained during keratoplasty from the 30 patients. Postoperatively, four patients, who had CMV DNA in either aqueous (3) or recipient cornea (1), were diagnosed with CMV endotheliitis based on clinical features and repeat aqueous tapping for real-time PCR analysis. At the median 60.5 months follow-up, 8 (72.7%), including 4 with postkeratoplasty CMV endotheliitis, of the 11 patients with CMV positivity in any one sample had graft failure, while 9 (47.3%) of the 19 patients without evidence of CMV DNA experienced graft failure., Conclusions: We found a relatively high prevalence of CMV DNA in the aqueous and corneas obtained during keratoplasty. All the patients who had CMV positivity in aqueous developed CMV endotheliitis postoperatively and experienced graft failure eventually. Aqueous tapping at the time of corneal transplantation for PCR analysis may help to improve the diagnosis and follow-up management of postkeratoplasty CMV endotheliitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: The rare morphological variant of anaplastic large cell lymphoma (ALCL) may pose a challenge in diagnosis, especially when presentation primarily involves skin lesions., Patient Concerns: Here we describe a rare case of small cell variant of ALCL in an 11-year-old girl., Diagnosis: We performed clinical, morphological, and immunohistochemical analyses of developed cutaneous nodules., Interventions: Pathologists should consider this small cell variant in ALCL differential diagnosis, as early and correct diagnosis has important clinical implications., Outcomes: Allogeneic hematopoietic stem cell transplantation appears to be a promising treatment option for small cell variant of ALCL., Lessons: Histological diagnosis of small cell variant of ALCL is challenging among pediatricians because of its low incidence and atypical presentation. We provide a short review of the small cell variant of ALCL to facilitate the diagnosis of this difficult-to-recognize entity.

Objectives: Recent advances in neoadjuvant chemoradiotherapy (nCRT) have significantly increased the rates of pathological complete response achieved by patients with oesophageal cancer. Consequently, a watchful waiting strategy based on 'active endoscopic surveillance and surgery as needed' has been proposed for cases without clinical evidence of disease after neoadjuvant chemoradiotherapy. Here, we investigated whether endoscopic surveillance is a reliable tool for the detection of the initially unidentified residual cancer in this patient group., Methods: We performed a careful pathological re-review of all cases with oesophageal squamous cell carcinoma, who attained a clinical complete response, despite showing a pathological non-complete response. The detailed anatomical locations of such unidentified malignancies were investigated in each patient to determine the prevalence of cancer involvement for each oesophageal layer., Results: Among the 73 patients with clinical complete response, 46 (63%) patients were found to have pathological non-complete response. The majority (89.1%; n = 41) of patients had evidence of residual cancer in the oesophagus, whereas only 5 (10.9%) patients had T0N+ disease. However, a high percentage (39.1%; n = 16) of patients had no detectable cancer in the mucosa and 9 of them also had no detectable cancer in sub-mucosal layer, ultimately hampering their detection via endoscopic biopsy., Conclusions: Nearly 40% of patients with oesophageal squamous cell carcinoma who attained clinical complete response but showed a pathological non-complete response had residual cancer hidden underneath a cancer-free mucosa layer., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Nasopharyngeal cancer (NPC) with mastoid recurrence is extraordinarily rare, and its development is thought to involve the Eustachian tube. We herein report a case of NPC with mastoid recurrence masquerading as acute otomastoiditis with facial paralysis in a 60-year-old man 44 months after concurrent chemoradiotherapy. The diagnosis was confirmed by exploratory tympanomastoidectomy with biopsy and Epstein-Barr-encoding region (EBER) in situ hybridization. Distant liver metastasis was detected simultaneously, and the patient underwent salvage treatment. He died 15 months later. Despite the rarity of mastoid recurrence, clinicians should be vigilant in the differential diagnosis of mastoiditis in patients with NPC after radiotherapy. Tumor biopsy and EBER in situ hybridization can aid in the accurate diagnosis of this uncommon condition., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Repetitive transcranial magnetic stimulation (rTMS), including theta burst stimulation (TBS), is considered helpful for functional recovery in post-stroke patients. However, the safety is a common concern forusingr TMS for neuro-rehabilitation and research in patients with stents., Method: Prolonged continuous theta burst stimulation (cTBS) with 1200 pulses at 50% of maximum output of Magstim Super Rapid2 was delivered in three different angles to a carotid stent placed in an isolated fresh swine carotid artery or on a table at a distance of 5cm. The possible migration and temperature change of the stent caused by cTBS was monitored by video recording and a digital thermometer, respectively. Histopathological study with hematoxylin and eosin stain were done on the vessel wall to identify possible micro thermal injury., Results: Stents in vessels did not cause any significant morphology change, such as thermal damage, after cTBS was given at three different angles. Neither visible migration nor significant temperature elevation was induced by cTBS., Conclusion: There was no temperature change, thermal injury or migration after prolonged TBS at a high intensity, suggesting TBS is safe for clinical neuro-rehabilitation and physiological assessments in stroke patients with vascular stents., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Infection by hepatitis B virus (HBV) accounts for 50-80% of hepatocellular carcinoma (HCC) development worldwide, in which the HBV-encoded X protein (HBx) has critical role in the induction of carcinogenesis. Several studies have shown that thyroid hormone (TH) suppresses HCC development and protects hepatocytes from HBx-induced damage, thus it is of interest to examine whether TH can protect hepatocytes from HBx-induced carcinogenesis. By treating HBx- transgenic mice with or without TH, we confirmed the protective effects of TH on HBx-induced hepatocarcinogenesis, which was achieved via reduction of reactive oxygen species (ROS) inflicted DNA damage. We further found that TH induced biogenesis of mitochondria (MITO) and autophagy of HBx-targeted MITO simultaneously, consequently leading to suppression of HBx-promoted ROS and carcinogenesis. Using microarray data analysis, this protective effect of TH was found to be mediated via activation of PTEN-induced kinase 1 (PINK1) in hepatocytes. PINK1, in turn, activated and recruited Parkin, an E3 ligase, to ubiquitinate MITO-associated HBx protein and trigger selective mitophagy. The pathological significance of the TH/PINK1 pathway in liver protection was confirmed by the concomitant decrease in expression of both TR and PINK1 in matched HCC tumor tissues and negatively correlated with aggressive progression of cancer and poor prognosis. Our data indicate that TH/PINK1/Parkin pathway has a critical role in protecting hepatocytes from HBx-induced carcinogenesis. Notably, several liver-targeting therapeutic derivatives of TH facilitating prevention or therapy of steatosis have been identified. Furthermore, our proof-of-concept experiments suggest that application of T 3 constitutes an effective novel therapeutic or preventive option for HCC. Thus, the utilization of the agonists of TRs could be the meaningful strategy in liver relative diseases, ranging from simple hepatic steatosis to HCC.

Background: The EGFR and downstream signaling pathways play an important role in tumorigenesis in oral squamous cell carcinoma (OSCC). Gene copy number alteration is one mechanism for overexpressing the EGFR protein and was also demonstrated to be related to lymph node metastasis, tumor invasiveness and perineural invasion. Therefore, we hypothesized that EGFR gene copy number alteration in the primary tumor could predict amplification in recurrent tumors, lymph node metastatic foci or secondary primary tumors., Methods: We recruited a group of newly diagnosed OSCC patients (n = 170) between Mar 1997 and Jul 2004. Metastatic lymph nodes were identified from neck dissection specimens (n = 57). During follow-up, recurrent lesions (n = 41) and secondary primary tumors (SPTs, n = 17) were identified and biopsied. The EGFR gene amplifications were evaluated by fluorescence in situ hybridization (FISH) assay in primary tumors, metastatic lymph nodes, recurrences and SPTs., Results: Of the 170 primary OSCCs, FISH showed low EGFR amplification/polysomy in 19 (11.4%) patients and amplification in 33 (19.8%) patients. EGFR gene amplification was related to lymph node metastasis (χ2 trend test: p = 0.018). Of 57 metastatic lymph nodes, nine (15.8%) had EGFR polysomy and 14 (24.6%) had EGFR gene amplification. The concordance rate of EGFR gene copy number in primary tumors and lymph node metastasis was 68.4% (McNemar test: p = 0.389). Of 41 recurrent tumors, five (12.2%) had EGFR polysomy and five (12.2%) had gene amplification. The concordance rate of EGFR gene copy number between primary tumors and recurring tumors was 65.9% (McNemar test: p = 0.510). The concordance rate between primary tumors and SPTs was 70.6%. EGFR amplification in either primary tumors, metastatic lymph nodes or recurrent tumors had no influence on patient survival., Conclusion: We can predict two-thirds of the EGFR gene copy number alterations in lymph node metastasis or recurrent tumors from the analysis of primary tumors. For OSCC patients who are unable to provide lymph node or recurrent tumor samples for EGFR gene copy number analysis, examining primary tumors could provide EGFR clonal information in metastatic, recurrent or SPT lesions.

Well-prepared and preserved freshly frozen specimens are indispensable materials for clinical studies. To manage specimen quality and to understand the factors potentially affecting specimen quality during preservation processes, we analyzed the quality of RNA and genomic DNA of various tissues collected between 2002 and 2011 in Linkou Chang Gung Memorial Hospital, Taiwan. During this period, a total of 1059 freshly frozen specimens from eight major cancer categories were examined. It was found that preservation duration, organ origin, and tissue type could all influence the quality of RNA samples. The increased preservation period correlated with decreased RNA quality; the brain, breast, and stomach RNA specimens displayed faster degradation rates than those of other organs, and RNA specimens isolated from tumor tissues were apparently more stable than those of other tissues. These factors could all be used as quality predictors of RNA quality. In contrast, almost all analyses revealed that the genomic DNA samples had good quality, which was not influenced by the aforementioned factors. The results assisted us in determining preservation factors that affect specimen quality, which could provide evidence for improving processes of sample collection and preservation. Furthermore, the results are also useful for researchers to adopt as the evaluation criteria for choosing specimen collection and preservation strategies.

This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) CA repeats polymorphism and protein expression in oral cavity squamous cell carcinoma (OSCC). A total of 194 OSCCs were examined for EGFR protein overexpression, gene copy number and the length of their CA repeats. The length of the EGFR CA repeats was found not to be associated with EGFR gene copy number or with protein overexpression. To exclude the effect of EGFR gene copy number on protein overexpression, only those OSCC tumors with disomy of the EGFR gene were included in further analysis. In this subgroup, EGFR protein overexpression was significantly associated with poor differentiation of the tumor cells and lymph node metastasis, especially extra-capsular spread. However, EGFR CA repeats were not related to any clinicopathological factor. Interestingly, patients genetically found to have the EGFR CA repeats SS genotype and having tumors with EGFR protein overexpression were found to have a worst prognosis in terms of disease-free survival (DFS) (HR = 2.68; 95% CI, 1.03-6.98) after multivariate adjustment. The present study demonstrates that concurrent overexpression of EGFR protein in the presence genetically of the SS form CA repeats acts as a predictor for poor DFS.

Aims: To characterize the clinicopathological and genetic features of pleomorphic mantle cell lymphoma (PMCL), which morphologically mimics diffuse large B cell lymphoma (DLBCL)., Methods and Results: We screened systematically 500 B cell lymphomas morphologically compatible with DLBCL using an immunohistochemical algorithm of three markers (CD5, cyclin D1 and SOX11). Ten cases of PMCL were identified for further study and, surprisingly, four (40%) of them were cyclin D1-negative. These 10 patients were mainly elderly males with advanced disease, and their median survival was only 11 months. All cyclin D1-positive PMCLs tested showed an IGH-CCND1 translocation, whereas one of the four cyclin D1-negative PMCLs had a translocation involving CCND2 and a high CCND2 mRNA level (P < 0.000001). The genomewide copy number profiles of both cyclin D1-positive and cyclin D1-negative PMCLs were similar to those of classical mantle cell lymphoma (MCL) reported previously, confirming the diagnosis. Secondary genetic alterations involved in oncogenic pathways of MCL were observed more frequently in these PMCLs, possibly decreasing the dependence on the driving CCND1 translocation and accounting for the common cyclin D1 negativity. Copy number gains of PIK3CA and CCDC50 were detected in all cyclin D1-negative PMCLs but in only 40% of the cyclin D1-positive PMCLs. These additional oncogenic signals may compensate for the common absence of CCND2 translocation in cyclin D1-negative PMCL., Conclusion: We demonstrate for the first time that cyclin D1 negativity is surprisingly common in PMCL morphologically mimicking DLBCL, and the use of a simple immunohistochemical algorithm can prevent misclassification and inappropriate treatment., (© 2016 John Wiley & Sons Ltd.)

Background/objective: To investigate the influence of serum anti-thyroglobulin antibody (TgAb) on the prognosis in papillary thyroid cancer (PTC) patients., Methods: In this retrospective study, the participants were enrolled from 1206 PTC patients (927 women, 279 men; mean age, 42.2 years) with T2 and higher, or N1 or M1 classifications in tumor-node-metastasis staging after total thyroidectomy. We recorded the final serum TgAb data (on thyroxin therapy) at the end of follow-up in 2012. Patients were classified as negative TgAb or positive TgAb groups on the basis of their serum TgAb levels (< 70 IU/mL or ≥ 70 IU/mL)., Results: Among the 1206 patients, after mean follow-up for 11.6 ± 6.1 years (range, 2.0-29.2 years), there were 75 with positive TgAb and 1131 with negative TgAb. Patient categorization depending on the follow-up time (2-5 years after surgery, 5-10 years after surgery, and 10-30 years after surgery) was performed. In comparison to traditional risk factors, such as age, tumor size, and sex, which were important prognostic factors for cancer recurrence and mortality in PTC patients, there was no significant difference in the prognosis between positive TgAb patients and negative TgAb patients by the multivariate analyses (cancer recurrence, p = 0.164, p = 0.112, p = 0.202, respectively; cancer mortality, p = 0.181, p = 0.646, p = 0.656, respectively) based on the different follow-up times., Conclusion: Positive serum TgAb was not a risk factor, and was not associated with the prognosis of PTC patients., (Copyright © 2017. Published by Elsevier Taiwan.)

A self-sustained multi-sensor platform for indoor environmental monitoring is proposed in this paper. To reduce the cost and power consumption of the sensing platform, in the developed platform, organic materials of PEDOT:PSS and PEDOT:PSS/EB-PANI are used as the sensing films for humidity and CO₂ detection, respectively. Different from traditional gas sensors, these organic sensing films can operate at room temperature without heating processes or infrared transceivers so that the power consumption of the developed humidity and the CO₂ sensors can be as low as 10 μW and 5 μW, respectively. To cooperate with these low-power sensors, a Complementary Metal-Oxide-Semiconductor (CMOS) system-on-chip (SoC) is designed to amplify and to read out multiple sensor signals with low power consumption. The developed SoC includes an analog-front-end interface circuit (AFE), an analog-to-digital convertor (ADC), a digital controller and a power management unit (PMU). Scheduled by the digital controller, the sensing circuits are power gated with a small duty-cycle to reduce the average power consumption to 3.2 μW. The designed PMU converts the power scavenged from a dye sensitized solar cell (DSSC) module into required supply voltages for SoC circuits operation under typical indoor illuminance conditions. To our knowledge, this is the first multiple environmental parameters (Temperature/CO₂/Humidity) sensing platform that demonstrates a true self-powering functionality for long-term operations.

Background: The purpose of this study was to investigate the prognosis and its predictors in patients with esophageal squamous cell carcinoma (ESCC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT)., Methods: We examined a total of 187 ESCC patients who achieved MaHR following nCRT and survived the perioperative period. MaHR was defined as either absence or <10% vital residual tumor cells (VRTC) in the resected esophagus without nodal involvement. Univariate and multivariate analyses were used to identify factors significantly associated with overall survival (OS)., Results: At the time of analysis, 113 patients (60.4%) were dead (5-year OS = 48%; median survival time = 54.8 months). The amount of VRTC (1-10% versus 0% VRTC; hazard ratio [HR] = 1.9, P < 0.001) and the thoroughness of histopathological examination (standard [≤ 4 tumor blocks] versus thorough [> 4 tumor blocks], HR = 1.57; P = 0.013) were independent predictors of OS in multivariate analysis. A stepwise increase in OS was observed in the following groups: patients with 1-10% VRTC identified by the standard protocol, patients with 1-10% VRTC identified by the thorough protocol, patients with 0% VRTC identified by the standard protocol, and patients with 0% VRTC identified by the thorough protocol (5-year OS rates = 20%, 40%, 50%, and 62%, respectively, P < 0.001)., Conclusions: In ESCC patients who achieve MaHR after nCRT, the presence of microscopical residual disease and the thoroughness of histopathological examination are associated with survival., (Copyright © 2016 Elsevier Ltd, BASO ~ the Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Recent studies have demonstrated a critical association between disruption of cellular thyroid hormone (TH) signaling and the incidence of hepatocellular carcinoma (HCC), but the underlying mechanisms remain largely elusive. Here, we showed that disruption of TH production results in a marked increase in progression of diethylnitrosamine (DEN)-induced HCC in a murine model, and conversely, TH administration suppresses the carcinogenic process via activation of autophagy. Inhibition of autophagy via treatment with chloroquine (CQ) or knockdown of ATG7 (autophagy-related 7) via adeno-associated virus (AAV) vectors, suppressed the protective effects of TH against DEN-induced hepatic damage and development of HCC. The involvement of autophagy in TH-mediated protection was further supported by data showing transcriptional activation of DAPK2 (death-associated protein kinase 2; a serine/threonine protein kinase), which enhanced the phosphorylation of SQSTM1/p62 (sequestosome 1) to promote selective autophagic clearance of protein aggregates. Ectopic expression of DAPK2 further attenuated DEN-induced hepatoxicity and DNA damage though enhanced autophagy, whereas, knockdown of DAPK2 displayed the opposite effect. The pathological significance of the TH-mediated hepatoprotective effect by DAPK2 was confirmed by the concomitant decrease in the expression of THRs and DAPK2 in matched HCC tumor tissues. Taken together, these findings indicate that TH promotes selective autophagy via induction of DAPK2-SQSTM1 cascade, which in turn protects hepatocytes from DEN-induced hepatotoxicity or carcinogenesis.

Background: A 'surgery as needed' strategy has been proposed for patients with oesophageal cancer who truly achieve a pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT). However, the ability to detect residual disease remains problematic. This study investigated the anatomical locations and pathological characteristics of residual cancer in patients with oesophageal squamous cell carcinoma (SCC) who achieved a near pCR following nCRT., Methods: Patients with oesophageal SCC who achieved a near pCR after nCRT were eligible. Near pCR was defined as residual cancer in the resection specimen representing less than 10 per cent of the apparent original tumour area., Results: Detailed histopathological reassessment of 76 consecutive patients (mean age 54·4 years) with a near pCR was undertaken. Some 32 patients (42 per cent) with a near pCR had no detectable mucosal lesions. Residual tumour was identified most frequently in the submucosal layer (54, 71 per cent), followed by the mucosa (44, 58 per cent), muscle layer (36, 47 per cent) and adventitia (22, 29 per cent) (P < 0·001). Among patients without ypT1a disease, increasing depth of tumour invasion correlated negatively with the likelihood of mucosal involvement. Of patients with ypT3 disease, 16 of 22 had no detectable cancer located in the mucosa, compared with six of 29 with ypT1b disease (P < 0·001)., Conclusion: Better tools for predicting pCR are required before considering a 'surgery as needed' approach in the management of oesophageal cancer., (© 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Amplification of 11q13.3 is a frequent event in human cancers, including head and neck squamous cell carcinoma. This chromosome region contains several genes that are potentially cancer drivers, including FADD (Fas associated via death domain), an apoptotic effector that was previously identified as a novel oncogene in laryngeal/pharyngeal cancer. This study was designed to explore the role of FADD in oral squamous cell carcinomas (OSCCs) samples from Taiwanese patients, by assessing copy number variations (CNVs) and protein expression and the clinical implications of these factors in 339 male OSCCs. The intensity of FADD protein expression, as determined by immunohistochemistry, was strongly correlated with gene copy number amplification, as analyzed using a TaqMan CNV assay. Both FADD gene copy number amplification and high protein expression were significantly associated with lymph node metastasis (P < 0.001). Patients with both FADD copy number amplification and high protein expression had the shortest disease-free survival (DFS; P = 0.074 and P = 0.002) and overall survival (OS; P = 0.011 and P = 0.027). After adjusting for primary tumor status, tumor differentiation, lymph node metastasis and age at diagnosis, DFS was still significantly lower in patients with either copy number amplification or high protein expression (hazard ratio [H.R.] = 1.483; 95% confidence interval [C.I.], 1.044-2.106). In conclusion, our data reveal that FADD gene copy number and protein expression can be considered potential prognostic markers and are closely associated with lymph node metastasis in patients with OSCC in Taiwan., Competing Interests: The authors have declared that no competing interests exist.

Background: To characterize the potential function and clinical significance of Transketolase (TKT) in esophageal cancer. Methods: High invasive esophageal squamous cell carcinoma (ESCC) cell line CE48T/VGH was used. Cellular functions in response to TKT modulation were examined, including cell growth, migration and invasion. The underlying molecules involved in the TKT regulatory mechanism were determined by western blot and confocal microscopic analysis. Clinically, TKT expressions in 76 ESCC patients were assessed by immunohistochemical (IHC) method, and the association with treatment outcome was determined. Results: TKT silencing inhibited cell migration and invasion but had a minimal effect on cell growth. This TKT silencing also induced the reversion of epithelial-mesenchymal transition (EMT), as evidenced by the spindle to cuboidal morphological change, increased the expression of epithelial markers (γ-catenin), and decreased the levels of mesenchymal markers (fibronectin and N-cadherin). Mechanically, TKT was shown to modulate the EMT through the pERK-Slug/Snail-associated signaling pathway. Clinically, a high level of TKT in the cancer tissues of patients with esophageal squamous cell carcinoma was associated with poor survival ( P = 0.042). In the multivariate analysis, a high TKT level was also shown to be an independent unfavorable prognostic factor (Odds ratio: 1.827, 95% confidence interval: 1.045-3.196, P = 0.035). Conclusions: TKT contributes to esophageal cancer by promoting cell invasion via meditating EMT process. Clinically, the over-expression of TKT in ESCC patients predicts poorer survival. TKT inhibition may be a useful strategy to intervene in cancer cell invasion and metastasis, which may lead to better prognosis for ESCC patients., Competing Interests: The authors have declared that no competing interest exists.

There is a significant learning curve for endoscopic submucosal dissection of esophageal neoplasms that has not been fully characterized. This retrospective study included 33 consecutive superficial esophageal neoplasms for analysis of the learning curve for esophageal endoscopic submucosal dissection based on a single, novice endoscopist's experience. The study was divided into three periods (T1, T2, and T3) of 10 endoscopic submucosal dissection procedures in chronological order, with 13 procedures in the last period. Patient factors (age, sex, coexistent esophageal varices, or submucosal fibrosis) and tumor factors (location at upper esophagus, involving >3/4 esophageal circumference) for endoscopic submucosal dissection were not statistically different between the periods. The mean procedure time was 74.6 min/cm(2) , 23.4 min/cm(2) , and 10.5 min/cm(2) for T1, T2, and T3, respectively. The procedure time decreased over time (P = 0.02) and post hoc test revealed significant difference was only between T3 and T1 (P = 0.019). The en bloc resection rate was 50%, 100%, and 92.3% for T1, T2, and T3, respectively (P for trend = 0.015). R0 resection rate was 40%, 100%, and 84.6% for T1, T2, and T3, respectively (P for trend = 0.023). Two patients had complications: each one patient in T1 and T3 period experienced major bleeding during the procedure (P for trend = 0.875). None of the patients had esophageal perforation. The results of the study concluded that at least 30 cases of endoscopic submucosal dissection of esophageal neoplasms are needed for a novice endoscopist to gain early proficiency in this technique., (© 2015 International Society for Diseases of the Esophagus.)

Tolerance induction by means of costimulation blockade has been successfully applied in solid organ transplantation; however, its efficacy in vascularized composite allotransplantation, containing a vascularized bone marrow component and thus a constant source of donor-derived stem cells, remains poorly explored. In this study, osteomyocutaneous allografts (alloOMCs) from Balb/c (H2(d) ) mice were transplanted into C57BL/6 (H2(b) ) recipients. Immunosuppression consisted of 1 mg anti-CD154 on day 0, 0.5 mg CTLA4Ig on day 2 and rapamycin (RPM; 3 mg/kg per day from days 0-7, then every other day for 3 weeks). Long-term allograft survival, donor-specific tolerance and donor-recipient cell trafficking were evaluated. Treatment with costimulation blockade plus RPM resulted in long-term graft survival (>120 days) of alloOMC in 12 of 15 recipients compared with untreated controls (median survival time [MST] ≈10.2 ± 0.8 days), RPM alone (MST ≈33 ± 5.5 days) and costimulation blockade alone (MST ≈45.8 ± 7.1 days). Donor-specific hyporesponsiveness in recipients with viable grafts was demonstrated in vitro. Evidence of donor-specific tolerance was further assessed in vivo by secondary donor-specific skin graft survival and third-party graft rejection. A significant increase of Foxp3(+) regulatory T cells was evident in tolerant animals. Donor cells populated peripheral blood, thymus, and both donor and recipient bone marrow. Consequently, combined anti-CD154/CTLA4Ig costimulation blockade-based therapy induces donor-specific tolerance in a stringent murine alloOMC transplant model., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Despite increasing application of the pre-grafting expansion during autologous fat transplantation in breast reconstruction, little is known about its mechanism of action. To address that, ventral skins of miniature pigs were treated over a 10-day or 21-day period, with continuous suction at -50 mm Hg via a 7-cm diameter rubber-lined suction-cup device. Soft tissue thickness increased immediately after this external volume expansion (EVE) treatment, such increase completely disappeared by the next day. In the dermis and subcutaneous fat, the EVE treated groups showed significant increases in blood vessel density evident by CD31 staining as well as in vascular networks layered with smooth muscle cells when compared with the control group. This finding was corroborated by the increased percentage of endothelial cells present in the treatment groups. There was no significant difference in the percentages of proliferating basal keratinocytes or adipocytes, nor in epidermal thickness. Moreover, the EVE had no effect on proliferation or differentiation potential of adipose stem cells. Taken together, the major effects of EVE appeared to be vascular remodeling and maturation of functional blood vessels. This understanding may help clinicians optimize the vascularity of the recipient bed to further improve fat graft survival.

Overexpression of receptor tyrosine kinase-like orphan receptor (ROR1) in a variety of human malignancies is associated with aggressive behaviour. Therapeutic agents targeting ROR1 have shown promising results in vivo and in vitro studies. In breast cancer, high-level expression of ROR1 mRNA is associated with high-grade tumours and metastasis. We investigated the prevalence and prognostic significance of ROR1 expression in triple negative breast cancer (TNBC). ROR1 was immunohistochemically stained on full-face sections of 210 TNBC patient samples. Forty-seven TNBC cases (22.4 %) showed strong ROR1 expression, which was associated with shorter disease-free survival (DFS; P = 0.00015), distant metastasis-free survival (DMFS; P = 0.00013) and overall survival (OS; P = 0.026) in univariate analyses. Results were confirmed by multivariate analysis. Seventy TNBC cases (33.3 %) with medullary features showed longer OS (P = 0.00013). We divided the whole series into two subgroups based on the presence or absence of medullary features. Strong ROR1 expression retained a predictive value of shorter DFS and DMFS in both subgroups. Our study suggests that strong ROR1 expression might be an independent adverse prognostic factor in TNBC patients and may serve as a potential marker for patient selection in ROR1-targeted therapy. More large-scale studies are needed to clarify its potential usefulness.

We report 4 pediatric cases of biopsy-proven posttransplant lymphoproliferative disorder (PTLD) in the context of allogeneic hematopoietic stem cell transplantation (HSCT). All cases showed diffuse staining with latent membrane protein-1 in immunohistochemistry. The median age at transplant of 4 patients with PTLD was 10.1 years (range, 2.2 to 13.2 y). The median interval between HSCT and the diagnosis of PTLD was 5.5 months (range, 4 to 8 mo). All patients were treated with rituximab at dosage of 375 mg/m at weekly intervals. Reduction of immunosuppression was warranted in all cases. All patients survived with median follow-up duration of 27 months. Although PTLD has been rare following allogeneic HSCT, reduction of immunosuppression combined with rituximab yielded significant response rates in patients with this infrequent but potentially lethal complication. The preliminary finding of this study demonstrated that severe aplastic anemia is closely associated with the development of PTLD in children.

The coexistence of hepatocellular carcinoma (HCC) and non-Hodgkin's lymphoma (NHL) in the liver is rare. Reports show that these patients have cirrhotic livers or hepatitis virus infections before they develop HCC and NHL. We present a patient with hepatitis B virus infection who was transferred to our hospital with a newly detected liver mass; abdominal computed tomography examination showed one hypodense mass of 7 cm in diameter and multiple mesenteric and mediastinal lymph nodes. A liver tumor biopsy showed a hepatoma, and the pathologic findings from an inguinal lymph node excision showed mantle cell lymphoma. An immunohistochemical stain confirmed that the atypical lymphoid cells within the HCC were positive for the CD20, CD5 and cyclin D1 antigens. Taking these findings into account, the hepatic tumor was determined to be a HCC infiltrated by mantle cell lymphoma.

Object: Deep brain stimulation (DBS) surgery under general anesthesia is an alternative option for patients with Parkinson's disease (PD). However, few studies are available that report whether neuronal firing can be accurately recorded during this condition. In this study the authors attempted to characterize the neuronal activity of the subthalamic nucleus (STN) and elucidate the influence of general anesthetics on neurons during DBS surgery in patients with PD. The benefit of median nerve stimulation (MNS) for localization of the dorsolateral subterritory of the STN, which is involved in sensorimotor function, was explored., Methods: Eight patients with PD were anesthetized with desflurane and underwent contralateral MNS at the wrist during microelectrode recording of the STN. The authors analyzed the spiking patterns and power spectral density (PSD) of the background activity along each penetration track and determined the spatial correlation to the target location, estimated mated using standard neurophysiological procedures., Results: The dorsolateral STN spiking pattern showed a more prominent bursting pattern without MNS and more oscillation with MNS. In terms of the neural oscillation of the background activity, beta-band oscillation dominated within the sensorimotor STN and showed significantly more PSD during MNS (p < 0.05)., Conclusions: Neuronal firing within the STN could be accurately identified and differentiated when patients with PD received general anesthetics. Median nerve stimulation can enhance the neural activity in beta-band oscillations, which can be used as an index to ensure optimal electrode placement via successfully tracked dorsolateral STN topography.

This work demonstrates a printable blending material, i.e., reduced graphene oxide (RGO) mixed with poly(methyl methacrylate) (PMMA), for formaldehyde sensing. Based on experimental results, 2% RGO/10% PMMA is an optimal ratio for formaldehyde detection, which produced a 30.5% resistance variation in response to 1000 ppm formaldehyde and high selectivity compared to different volatile organic compounds (VOCs), humidity, CO, and NO. The demonstrated detection limit is 100 ppm with 1.51% resistance variation. Characterization of the developed formaldehyde sensing material was performed by Fourier-transform infrared (FTIR) spectrometry, scanning electron microscopy (SEM), and Raman spectroscopy. Based on Raman spectroscopy, the basic sensing mechanism is the band distortion of RGO due to blending with PMMA and the adsorption of formaldehyde. This work establishes insights into the formaldehyde sensing mechanism and explores a potential printable sensing material for diverse applications.

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Age over 60 years is one of the five parameters of the International Prognostic Index (IPI), which is the most important clinical prognostic predictor in DLBCL. A previous study on German DLBCL patients over 60 years of age showed that immunoblastic morphology, but not germinal center B cell-like (GCB)/non-GCB subtype, correlated with short survival. We collected 174 DLBCL cases over 60 years of age in Taiwan and performed immunophenotyping and detection of Epstein-Barr virus (EBV)-encoded RNA (EBER) by in situ hybridization. Of the cases, 5.2 % were positive for CD5 and 5.7 % positive for EBER. Neither immunoblastic morphology nor GCB/non-GCB subtype correlated with survival. In univariate analysis, adverse prognostic factors included IPI ≥ 3 (P < 0.000001), B symptoms (P = 0.000075), bone marrow/peripheral blood involvement (P = 0.017), EBER positivity (P = 0.0013), and CD5 positivity (P = 0.016). In multivariate analysis, CD5 positivity was the only independent adverse prognostic factor (HR = 3.16; 95 % CI = 1.34-7.47; P = 0.0087) in addition to IPI ≥ 3 (HR = 3.07; 95 % CI = 1.84-5.11; P = 0.000018). Surprisingly, despite an overall 5.2 % incidence of central nervous system (CNS) relapse in our patients, none of the CD5+ cases experienced CNS relapse (P = 1.00). This is in stark contrast to the more frequent CNS relapse in Japanese CD5+ DLBCL patients. EBER positivity was associated with IPI ≥ 3 (P = 0.010), stage III-IV (P = 0.0082), and B symptoms (P = 0.011). In multivariate analysis, EBER positivity was not an independent adverse prognostic factor (P = 0.81), its effect being due likely to accompanying adverse clinical parameters.

Mechanistic (or mammalian) target of rapamycin (mTOR) plays important roles in cell growth and proliferation. In esophageal squamous cell carcinoma (SCC), high expression of phosphorylated (activated) mTOR (p-mTOR) has been reported as an adverse prognostic factor in some but not all studies. The signals of mTOR pathway and mitogen-activated protein kinase (MAPK) pathway converge on 4E-binding protein 1 (4EBP1), which drives the downstream proliferative signals. We previously found that high expression of phosphorylated 4EBP1 (p-4EBP1) is an adverse prognostic factor in esophageal SCC. Podoplanin is a type-1 transmembrane glycoprotein expressed in various normal human tissues, including lymphatic endothelium. Our previous study showed that high podoplanin expression correlates with clinical nodal metastasis, which is associated with short survival in esophageal SCC. In current study, we investigated p-mTOR expression by immunohistochemistry in 75 cases of surgically resected esophageal SCC. The result was correlated with p-4EBP1 expression, podoplanin expression, clinicopathologic features and patient survival. We found that high p-mTOR expression was significantly associated with high podoplanin expression (P = 0.0030) and high tumor grade (P = 0.0014). No correlation with p-4EBP1 expression, patient survival or other clinicopathologic features was found. Recently, podoplanin expression in astrocytic brain tumors was found to be regulated by the phosphatidylinositol 3-kinase (PI3K)/AKT/activator protein-1 (AP-1) pathway. Similarly, mTOR is activated by a PI3K/AKT/mTOR pathway. The association of p-mTOR and podoplanin expression in our study could be due to a common upstream pathway. Since both mTOR and podoplanin are potential therapeutic targets, the possible benefit of combined targeted therapy warrants further investigation.

The aim of this study was 2-fold: first, to assess the prognostic significance on overall survival (OS) of the 3-point tumor regression grade (TRG) in patients with esophageal squamous cell carcinoma (ESCC) who received neoadjuvant chemoradiotherapy (nCRT); second, to investigate the associations of TRG with the clinicopathological characteristics of the study patients.A total of 357 ESCC patients were retrospectively enrolled. The 3-point TRG was determined by assessing the percentage of viable residual tumor cells (VRTC) in the resected specimens as follows: TRG 1, 0% VRTC; TRG 2, 1% to 50% VRTC; and TRG 3, >50% VRTC.A TRG of 1, 2, and 3 was found in 32.2%, 38.9%, and 28.9% of the specimens, respectively. High TRG values were significantly associated with advanced pretreatment clinical stage, longer tumor length, and higher posttreatment tumor depth of invasion (yT), the presence of lymph node metastases (LNM), and lymphovascular invasion. We observed a stepwise decrease in 5-year OS rates with increasing TRG, as follows: 51% for patients with a TRG of 1, 28% for patients with a TRG of 2, and 22% for patients with a TRG of 3 (P < 0.001). TRG and LNM were independent predictors of OS in multivariate analysis. Notably, the prognostic impact of TRG on OS was greater in patients without LNM (P < 0.001) and ypT3 disease (P = 0.021).TRG is independently associated with OS in ESCC patients treated with nCRT. The interrelationships between TRG, LNM, and depth of tumor invasion may improve the prognostic stratification in esophageal cancer.

Sex determining region Y-box 2 (SOX2) is a transcription factor involved in self-renewal and pluripotency. Dysregulation of SOX2 expression has been found in squamous cell carcinoma (SCC), including esophageal SCC. Recently, high SOX2 expression was found to be a negative predictor of occult lymph node metastasis in early oral SCC, but the clinical significance of SOX2 expression in esophageal SCC remains controversial. Here we investigated SOX2 expression by immunohistochemistry in 75 cases of surgically resected esophageal SCC. Similar to oral SCC, we found for the first time that high SOX2 expression correlates with absence of clinical nodal metastasis (P = 0.011). Podoplanin is a glycoprotein which is variably expressed by esophageal SCC. Since we previously found that podoplanin expression correlates with nodal metastasis in esophageal SCC, we also assessed podoplanin expression in these cases. Interestingly, SOX2 expression correlates negatively with podoplanin expression (P = 0.018). It is in contrast with a recent finding that SOX2 can up-regulate podoplanin expression in SCC of the skin. Our result suggests that SOX2 might suppress nodal metastasis through down-regulation of podoplanin in esophageal SCC. Further studies are needed to clarify the exact mechanism of regulation.

Background: The combination of fat grafting and negative pressure (VAC) therapy represents a synergistic interaction of all essential components for wound healing. The aim of this experimental study was to determine whether it could promote healing of wounds with exposed bone., Methods: Full-thickness wounds with denuded bone in Sprague-Dawley rats were treated with either polyurethane foam dressing, fat grafting alone, polyurethane foam dressing with VAC, or polyurethane foam dressing with VAC combined with a single, or two administrations of fat graft. Wound healing kinetics, tissue growth, cell proliferation (Ki-67) and angiogenesis (platelet endothelial cell adhesion molecule 1 and α-smooth muscle actin) were investigated. Messenger RNA levels related to angiogenesis (vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF)), profibrosis (platelet-derived growth factor A and transforming growth factor β), adipocyte expression (fatty acid-binding protein (FABP) 4 and peroxisome proliferator activated receptor γ), and extracellular matrix remodelling (collagen I) were measured in wound tissues., Results: Wounds treated by VAC combined with fat grafting were characterized by cell proliferation, neoangiogenesis and maturation of functional blood vessels; they showed accelerated granulation tissue growth over the denuded bone compared with VAC- or foam dressing-treated wounds. Fat grafting alone over denuded bone resulted in complete necrosis. Expression of angiogenesis markers (VEGF and b-FGF) and adipocyte expression factors (FABP-4) was upregulated in wounds treated with VAC combined with fat grafting., Conclusion: Fat grafting with VAC therapy may represent a simple but effective clinical solution for a number of complex tissue defects, and warrants testing in clinical models., Surgical Relevance: The combination of fat grafting and vacuum therapy represents a synergistic interaction of regenerative cells, hospitable wound matrix and stimulating micromechanical forces. It could accelerate complex wound healing through cell proliferation, neoangiogenesis and maturation of functional blood vessels. The efficacy of a multimodal wound healing approach is established in this experimental model; it could easily be translated into clinical trials of treatment for difficult wounds., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)