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Study design:Case report.Setting:Tertiary referral center hospital in Taiwan.Objectives:To report a case of spinal Rosai-Dorfman disease (RDD) presenting with paraparesis and also preceding by relapsing uveitis for 6 months. A thoracic laminectomy was performed to remove the solid mass. The pathological diagnosis reveals infiltrating histiocytes, emperipolesis and positivity for S-100. There is no recurrence 1 year later with MR imaging.Conclusions:The relapsing idiopathic uveitis may be a prodrome for this unusual disease, because RDD is associated closely to defective immunogical response. Early and accurate diagnosis of CNS RDD may reverse the neurologic deficits by early decompression.Spinal Cord (2007) 45, 641-644; doi:10.1038/sj.sc.3102006; published online 16 January 2007. [ABSTRACT FROM AUTHOR]

This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) copy number and EGFR protein expression in oral cavity squamous cell carcinoma (OSCCs) in Taiwan. A total of 160 oral cavity squamous cell carcinomas were examined for EGFR protein overexpression using immunohistochemistry and for copy number using a fluorescence in situ hybridization (FISH) assay. Overexpression and increased gene copy numbers of EGFR were found in 75 (46.88%) and 50 (31.25%) cases, respectively. The concordance rate for EGFR gene amplification and protein overexpression was 100%. EGFR overexpression was associated with a poor prognosis both in terms of disease-free survival (DFS) and overall survival (OS). On the other hand, the association between an increase in EGFR gene copies and DFS or OS was insignificant. This was despite the observed significant associations between gene copy number and tumor stage, depth of tumor invasion, lymph node metastasis, bone invasion and perineural invasion. EGFR protein overexpression is closely related to EGFR copy number. Standard methodological and interpretation criteria need to be established that allows EGFR copy number combined with EGFR protein expression to be determined in a manner that allows individualized EGFR targeted therapy in OSCC patients. [ABSTRACT FROM AUTHOR]

Wnt-5a is a protein encoded by the WNT5A gene and is a ligand for the receptor tyrosine kinase-like orphan receptor 2 (ROR2). However, its biological impact on clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, the prognostic significance of concurrent WNT5A and ROR2 expression levels was observed to predict unfavorable overall survival and disease-specific survival. High Wnt-5a expression was detected in a ccRCC cell line panel but not in HK-2 cells, a normal proximal tubular cell line. Inhibition of DNA methyltransferase by 5-azacytidine in 786-O and Caki-2 cells resulted in Wnt-5a up-regulation, indicating potential epigenetic modification. Furthermore, there was a repression of cell movement in vitro and metastatic colonization in vivo on WNT5A and ROR2 knockdown. Suppressions of angiogenesis in vivo and tubular-like structure formation in endothelial cells in vitro were also observed after silencing WNT5A and ROR2 expression. In addition, alteration in the downstream gene signature of the Wnt-5a-ROR2 signaling was similar to that in metastasis-associated gene 1-β-catenin axis. Moreover, prunetin treatment reversed the gene signature derived from Wnt-5a-ROR2 signaling activation and to abolish ccRCC cell migration and proliferation. Overall, this study demonstrates the clinical and functional significance of the Wnt-5a-ROR2 axis and identifies prunetin as a potential precision medicine for patients with ccRCC harboring aberrant Wnt-5a-ROR2 signaling pathways., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Schwannomas are benign tumors derived from the sheath of Schwann cells. Though it is common to see schwannomas in the head and neck region, auricular schwannomas are rare and only few cases have been reported. There are no distinguishing clinical findings or images; therefore, the histopathological diagnosis is mandatory. We describe a case of auricular schwannoma with clinical pictures and discuss the differential diagnoses according to histopathologic findings., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(-) cyclin D1(+) SOX11(-), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We aimed to explore the clinical outcomes and prognostic factors for PTCL-NOS patients in the real world., Methods: Clinical data were retrospectively collected from adult patients with PTCL-NOS treated at a single center in Taiwan., Results: 104 PTCL-NOS patients with a median age of 53.0 years were enrolled. Patients with the International Prognostic Index (IPI) or prognostic index for peripheral T-cell lymphoma (PIT) scores of zero had a longer overall survival (OS) and progression free survival (PFS), while patients with IPI or PIT scores ≥1 did poorly. For patients who are eligible for transplantation, the use of pralatrexate as salvage chemotherapy has shown better OS (2-year OS 83.3% vs. 24.4%, P = 0.011) compared to patients who did not. By multivariate analysis, age >60 years, male, B symptoms, ECOG >1, lung involvement, and thrombocytopenia were independent adverse factors for OS. Incorporating factors in multivariate analysis, we established a novel predictive index for PTCL-NOS which efficiently stratifies patients into low (0-1 factor), intermediate-1 (2 factors), intermediate-2 (3 factors), and high risk (4-6 factors) groups with 2-year OS rates of 81.5%, 32.9%, 8.8%, and 0%, respectively (P < 0.001)., Conclusion: PTCL-NOS patients have a dismal prognosis in Taiwan. Novel agents may improve the outcomes of PTCL-NOS patients. The usefulness of the novel prognostic index for PTCL-NOS needs further validation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Pestalotiopsis sensu lato , commonly referred to as pestalotiopsis-like fungi, exhibit a broad distribution and are frequently found as endophytes, saprobes and pathogens across various plant hosts. The taxa within pestalotiopsis-like fungi are classified into three genera viz. Pestalotiopsis , Pseudopestalotiopsis and Neopestalotiopsis , based on the conidial colour of their median cells and multi-locus molecular phylogenies. In the course of a biodiversity investigation focusing on pestalotiopsis-like fungi, a total of 12 fungal strains were identified. These strains were found to be associated with stromata of Beauveria , Ophiocordyceps and Tolypocladium in various regions of Taiwan from 2018 to 2021. These strains were evaluated morphologically and multi-locus phylogenetic analyses of the ITS (internal transcribed spacer), tef1-α (translation elongation factor 1-α) and tub2 (beta-tubulin) gene regions were conducted for genotyping. The results revealed seven well-classified taxa and one tentative clade in Pestalotiopsis and Neopestalotiopsis . One novel species, Pestalotiopsismanyueyuanani and four new records, N.camelliae-oleiferae , N.haikouensis , P.chamaeropis and P.hispanica , were reported for the first time in Taiwan. In addition, P.formosana and an unclassified strain of Neopestalotiopsis were identified, based on similarities of phylogeny and morphology. However, the data obtained in the present study suggest that the currently recommended loci for species delimitation of pestalotiopsis-like fungi do not deliver reliable or adequate resolution of tree topologies. The in-vitro mycelial growth rates of selected strains from these taxa had an optimum temperature of 25 °C, but growth ceased at 5 °C and 35 °C, while all the strains grew faster under alkaline than acidic or neutral pH conditions. This study provides the first assessment of pestalotiopsis-like fungi, associated with entomopathogenic taxa., Competing Interests: The authors have declared that no competing interests exist., (Sheng-Yu Hsu, Yuan-Cheng Xu, Yu-Chen Lin, Wei-Yu Chuang, Shiou-Ruei Lin, Marc Stadler, Narumon Tangthirasunun, Ratchadawan Cheewangkoon, Hind A. AL-Shwaiman, Abdallah M. Elgorban, Hiran A. Ariyawansa.)

Plasmablastic lymphoma (PBL) is an aggressive large B-cell lymphoma with a terminal B-cell differentiation phenotype and is frequently associated with immunodeficiency. We aimed to investigate the clinicopathological and immunophenotypic features, genetic alterations, and mutational landscape of PBL in Taiwan. We retrospectively recruited 26 cases. Five (5/18; 28%) patients were HIV-positive and 21 (81%) presented extranodally. There were two morphological groups: one with purely monomorphic large cells (85%) and the other comprising large cells admixed with plasmacytic cells (15%). Phenotypically, the tumors expressed MYC (8/10; 80%), CD138 (20/26; 77%), and MUM1 (20/20; 100%), but not CD20 (n = 26; 0%). Fourteen (54%) cases were positive for EBV by in situ hybridization; the EBV-positive cases were more frequently HIV infected (p = 0.036), with extranodal presentation (p = 0.012) and CD79a expression (p = 0.012), but less frequent light chain restriction (p = 0.029). Using fluorescence in situ hybridization, we identified 13q14 deletion, MYC rearrangement, and CCND1 rearrangement in 74%, 30%, and 5% cases, respectively, without any cases having rearranged BCL6 or IGH::FGFR3 fusion. In the 15 cases with adequate tissue for whole exome sequencing, the most frequent recurrent mutations were STAT3 (40%), NRAS (27%), and KRAS (20%). In conclusion, most PBL cases in Taiwan were HIV-unrelated. Around half of the cases were positive for EBV, with distinct clinicopathological features. Deletion of chromosome 13q14 was frequent. The PBL cases in Taiwan showed recurrent mutations involving JAK-STAT, RAS-MAPK, epigenetic regulation, and NOTCH signaling pathways, findings similar to that from the West., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Liver fibrosis is reversible when treated in its early stages and when liver inflammatory factors are inhibited. Limited studies have investigated the therapeutic effects of corylin, a flavonoid extracted from Psoralea corylifolia L. (Fabaceae), on liver fibrosis. Therefore, we evaluated the anti-inflammatory activity of corylin and investigated its efficacy and mechanism of action in ameliorating liver fibrosis. Corylin significantly inhibited inflammatory responses by inhibiting the activation of mitogen-activated protein kinase signaling pathways and the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha in human THP-1 and mouse RAW264.7 macrophages. Furthermore, corylin inhibited the expression of growth arrest-specific gene 6 in human hepatic stellate cells (HSCs) and the activation of the downstream phosphoinositide 3-kinase/protein kinase B pathway. This inhibited the activation of HSCs and the expression of extracellular matrix proteins, including α-smooth muscle actin and type I collagen. Additionally, corylin induced caspase 9 and caspase 3 activation, which promoted apoptosis in HSCs. Moreover, in vivo experiments confirmed the regulatory effects of corylin on these proteins, and corylin alleviated the symptoms of carbon tetrachloride-induced liver fibrosis in mice. These findings revealed that corylin has anti-inflammatory activity and inhibits HSC activation; thus, it presents as a potential adjuvant in the treatment of liver fibrosis.

Objectives: The clinical presentations of essential thrombocythemia (ET) may be quite similar to early/prefibrotic primary myelofibrosis (pre-PMF), especially in pre-PMF presenting with thrombocytosis (pre-PMF-T), but may be associated with a different outcome. It is very important to distinguish these two entities. The aim of this study was to address the clinical and prognostic relevance of distinguishing pre-PMF-T from ET., Methods: All patients, including 258 with ET and 105 with pre-PMF-T, received JAK2V617F, MPL (exon 10), and CALR (exon 9) mutation analysis and allele burden measurement for JAK2V617F and CALR mutants., Results: Patients with pre-PMF-T had an older age and higher leukocyte and platelet counts but lower hemoglobin levels than patients with ET. Patients with pre-PMF-T had a shorter overall, leukemia-free, and thrombosis-free survival compared with patients with ET. Patients with ET had a higher rate of cerebral ischemic stroke, whereas patients with pre-PMF-T tended to have splanchnic vein thrombosis. The frequencies of JAK2V617F, CALR, and MPL mutations and CALR allele burden were no different, but JAK2V617F allele burden was significantly higher in pre-PMF-T. Patients with pre-PMF-T with the JAK2V617F mutation had an inferior overall survival and thrombosis-free survival, whereas the status of driver gene mutations did not influence the outcomes of patients with ET., Conclusions: ET and pre-PMF-T were two distinct disease entities and exhibited different clinical phenotype, genotype, and outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Vascularized bone marrow (VBM) is essential in tolerance induction through chimerism. We hypothesized that the inclusion of VBM contributes to the induction of mystacial pad allotransplantation tolerance., Method: In this study, 19 VBM, nine mystacial pad, and six sequential VBM and mystacial pad allografts were transplanted from Brown Norway (BN) rats to Lewis (LEW) rats to test our hypothesis. The VBM recipients were divided into antilymphocyte serum (ALS) monotherapy group (two doses of ALS on day 3 pretransplantation and day 1 posttransplantation), immunosuppressant group [a week of 2 mg/kg/day tacrolimus (Tac) and 3 weeks of 3 mg/kg/day rapamycin (RPM)], and combined therapy group. The mystacial pad recipients were divided into VBM and non-VBM transplantation groups, and both groups were treated with an immunosuppression regimen that consists of ALS, Tac, and RPM. For the recipients of sequential VBM and mystacial pad allotransplantations, additional Tac was given 1 week after mystacial pad transplantation. Allograft survival, donor-specific tolerance, and chimerism level were evaluated., Results: With the administration of ALS and short-term Tac and RPM treatments, VBM recipients demonstrated long-term graft survival (>120 days) with persistent chimerism for 30 days. CD3 + T cells from tolerant rats showed donor-specific hyporesponsiveness and tolerance to donor skin grafts but not to third-party counterparts. Furthermore, mystacial pad graft recipients with VBM transplantation exhibited a higher allograft survival rate than those without VBM transplantation [median survival time (MST) >90 days vs. 70 days, p < 0.05]., Conclusion: This study demonstrated that VBM transplantation is an efficient strategy to induce and maintain donor-specific tolerance for an osseous-free allograft., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Anggelia, Cheng, Hsieh, Chuang, Yang and Lin.)

Blastoid/pleomorphic morphology is associated with short survival in mantle cell lymphoma (MCL), but its prognostic value is overridden by Ki-67 in multivariate analysis. Herein, a nuclear segmentation model was developed using deep learning, and nuclei of tumor cells in 103 MCL cases were automatically delineated. Eight nuclear morphometric attributes were extracted from each nucleus. The mean, variance, skewness, and kurtosis of each attribute were calculated for each case, resulting in 32 morphometric parameters. Compared with those in classic MCL, 17 morphometric parameters were significantly different in blastoid/pleomorphic MCL. Using univariate analysis, 16 morphometric parameters (including 14 significantly different between classic and blastoid/pleomorphic MCL) emerged as significant prognostic factors. Using multivariate analysis, Biologic MCL International Prognostic Index (bMIPI) risk group (P = 0.025), low skewness of nuclear irregularity (P = 0.020), and high mean of nuclear irregularity (P = 0.047) emerged as independent adverse prognostic factors. Additionally, a morphometric score calculated from the skewness and mean of nuclear irregularity (P = 0.0038) was an independent prognostic factor in addition to bMIPI risk group (P = 0.025), and a summed morphometric bMIPI score was useful for risk stratification of patients with MCL (P = 0.000001). These results demonstrate, for the first time, that a nuclear morphometric score is an independent prognostic factor in MCL. It is more robust than blastoid/pleomorphic morphology and can be objectively measured., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Primary intestinal T-cell lymphomas (PITLs) comprise enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), extranodal NK/T-cell lymphoma (ENKTL), anaplastic large cell lymphoma (ALCL), and intestinal T cell lymphoma, NOS (ITCL-NOS). MEITL is composed of monomorphic medium cells expressing CD8 and CD56, with a cytotoxic phenotype. We retrospectively analyzed 77 cases of intestinal T-cell lymphomas, 71 primary and six secondary, at a tertiary center in Taiwan from 2001 to 2021. Perforation occurred in 57 (74%) patients, including 56 (73%) at presentation and one after chemotherapy. The primary cases included MEITL (68%), ENKTL (14%), ITCL-NOS (13%), ALCL (4%), and EATL (1%). The perforation rate was 90%, 70%, and 22% in MEITL, ENKTL, and ITCL-NOS cases, respectively (p < 0.0001, Fisher's exact test). Most (75%; n = 36) MEITL cases were typical; while seven (15%) had atypical morphology and five (10%) exhibited atypical immunophenotype. The tumor cells of ITCL-NOS were pleomorphic, with various expression of CD8 or CD56. All METIL, ITCL-NOS and ALCL cases were negative for EBER; while all ENKTL cases, either primary or secondary, were positive for cytotoxic granules and EBER. The prognosis of PITL was poor, with a medium survival of 7.0, 3.3, and 3.7 months among patients with MEITL, ENKTL, and ITCL-NOS, respectively. Of the six secondary cases, the primary tumors orginated from nasal ENKTL (n = 5) and cutaneous PTCL-NOS (n = 1). We showed a wide spectrum of intestinal T-cell lymphomas in Taiwan, with MEITL as the most common PITL, a high rate of perforation, and a wider morphological and immunophenotypic spectrum., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p = .001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ 2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Primary intestinal T-cell lymphoma (PITL) is highly aggressive and includes celiac disease-related enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), and primary intestinal peripheral T-cell lymphoma, not otherwise specified (ITCL-NOS). MEITL is the most common PITL in Asia, comprising of monomorphic medium-sized cells typically expressing CD8, CD56, and cytotoxic granules. Occasional cases with intermediate features between MEITL and ITCL-NOS are difficult to be classified and warrant further investigation. We collected 54 surgically resected PITLs from Taiwan, with 80% presenting with bowel perforation. The overall outcome was poor with a median survival of 7 months. Based on histopathology (monomorphic vs. pleomorphic) and immunophenotype, we classified these cases into 4 groups: MEITL with typical immunophenotype (n=34), MEITL with atypical immunophenotype (n=5), pleomorphic PITL with MEITL-like immunophenotype (n=6), and ITCL-NOS (n=9). There was no EATL in our cohort. Targeted next-generation sequencing of the first 3 groups showed highly prevalent loss-of-function mutations for SETD2 (85%, 80%, and 83%, respectively) and frequent activating mutations for STAT5B (64%, 60%, and 50%, respectively) and JAK3 (38%, 20%, and 50%, respectively). In contrast, ITCL-NOS cases had less frequent mutations of SETD2 (56%) and STAT5B (11%) and rare JAK3 mutations (11%). Our results suggest that there is a wider morphologic and immunophenotypic spectrum of MEITL as currently defined in the 2017 WHO classification. MEITL with atypical immunophenotype and PITL with MEITL-like immunophenotype shared clinicopathologic and molecular features similar to MEITL but distinct from ITCL-NOS, indicating that such cases may be considered as immunophenotypic or histopathologic variants of MEITL., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the Ministry of Science and Technology, Taiwan (107-2320-B-384-002). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Vascularized composite allotransplantation (VCA) allows functional and esthetic reconstruction for patients with complex anatomical defects. However, acute and chronic graft rejections are significant obstacles to VCA. Ultraviolet light is an oncogenic environmental hazard. However, ultraviolet B (UVB) has an immunomodulation effect. Therefore, this study aims to elucidate the impact of UVB irradiation on the VCA rat model., Methods: The rat vascularized bone marrow allotransplantation model was used. A vascularized bone marrow from a Brown Norway rat (RT1Ac) was transplanted into a Lewis rat (RT1Ab). The allograft and surrounding abdominal skin were exposed to narrow-band ultraviolet B (NB-UVB) (311 nm) radiation with an energy of 1350 mJ/cm2 3 times a week until the end of the study period. There were 5 study groups: syngeneic transplantation (group 1), allogeneic transplantation (group 2), allogenic transplantation-NB-UVB (group 3), allogenic transplantation-antilymphocyte serum (ALS)-tacrolimus (group 4), and allogenic transplantation-antilymphocyte serum-tacrolimus-NB-UVB (group 5)., Results: Group 5 had decreased graft survival compared with group 4. In the donor cell chimerism analysis, donor cell chimerism decreased significantly after UVB irradiation and was unresponsive to the administered immunosuppressants. After UVB irradiation, the CD8 T-cell ratio was increased, and the regulatory T-cell ratio was decreased., Conclusions: The preliminary data showed that NB-UVB irradiation of the VCA rat model may decrease graft survival. However, further studies are needed to elucidate the possible mechanisms of this phenomenon., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Detection of nodal micrometastasis (tumor size: 0.2-2.0 mm) is challenging for pathologists due to the small size of metastatic foci. Since lymph nodes with micrometastasis are counted as positive nodes, detecting micrometastasis is crucial for accurate pathologic staging of colorectal cancer. Previously, deep learning algorithms developed with manually annotated images performed well in identifying micrometastasis of breast cancer in sentinel lymph nodes. However, the process of manual annotation is labor intensive and time consuming. Multiple instance learning was later used to identify metastatic breast cancer without manual annotation, but its performance appears worse in detecting micrometastasis. Here, we developed a deep learning model using whole-slide images of regional lymph nodes of colorectal cancer with only a slide-level label (either a positive or negative slide). The training, validation, and testing sets included 1963, 219, and 1000 slides, respectively. A supercomputer TAIWANIA 2 was used to train a deep learning model to identify metastasis. At slide level, our algorithm performed well in identifying both macrometastasis (tumor size > 2.0 mm) and micrometastasis with an area under the receiver operating characteristics curve (AUC) of 0.9993 and 0.9956, respectively. Since most of our slides had more than one lymph node, we then tested the performance of our algorithm on 538 single-lymph node images randomly cropped from the testing set. At single-lymph node level, our algorithm maintained good performance in identifying macrometastasis and micrometastasis with an AUC of 0.9944 and 0.9476, respectively. Visualization using class activation mapping confirmed that our model identified nodal metastasis based on areas of tumor cells. Our results demonstrate for the first time that micrometastasis could be detected by deep learning on whole-slide images without manual annotation., (© 2021. The Author(s).)

Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

This study investigated the effects of using mushroom waste compost as the residue medium for Pleurotus eryngii planting, which was used as a feed replacement; its consequent influence on broiler chickens' intestinal microbiota, anti-inflammatory responses, and anti-oxidative status was likewise studied. A total of 240 male broilers were used and allocated to four treatment groups: the basal diet-control group (corn-soybean); 5% replacement of a soybean meal via PWMC ( Pennisetum purpureum Schum No. 2 waste mushroom compost); 5% replacement of a soybean meal via FPW ( Saccharomyces cerevisiae fermented PWMC); 5% replacement of a soybean meal via PP ( Pennisetum purpureum Schum No. 2). Each treatment had three replicates and 20 birds per pen. The levels of glutathione peroxidase and superoxide dismutase mRNA as well as protein increased in the liver and serum in chickens, respectively; mRNA levels of inflammation-related genes were also suppressed 2 to 10 times in all treatments as compared to those in the control group. The tight junction and mucin were enhanced 2 to 10 times in all treatment groups as compared to those in the control, especially in the PWMC group. Nevertheless, the appetite-related mRNA levels were increased in the PWMC and FPW groups by at least two times. In ileum and cecum, the Firmicutes/Bacteroidetes ratios in broilers were decreased in the PWMC, FPW, and PP groups. The Lactobacillaceae in the ileum were increased mainly in the PWMC and control groups. Overall, high-fiber feeds (PWMC, FPW, and PP) could enhance the broilers' health by improving their antioxidant capacities and decreasing their inflammatory response as compared to the control. Based on the results, a 5% replacement of the soybean meal via PWMC is recommended in the broiler chickens' diet.

Benign lesions, atypical adenomatous hyperplasia (AAH), and malignancies such as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA) may feature a pure ground-glass nodule (pGGN) on a thin-slide computed tomography (CT) image. According to the World Health Organization (WHO) classification for lung cancer, the prognosis of patients with IA is worse than those with AIS and MIA. It is relatively risky to perform a core needle biopsy of a pGGN less than 2 cm to obtain a reliable pathological diagnosis. The early and adequate management of patients with IA may provide a favorable prognosis. This study aimed to disclose suggestive signs of CT to accurately predict IA among the pGGNs. A total of 181 pGGNs of less than 2 cm, in 171 patients who had preoperative CT-guided localization for surgical excision of a lung nodule between December 2013 and August 2019, were enrolled. All had CT images of 0.625 mm slice thickness during CT-guided intervention to confirm that the nodules were purely ground glass. The clinical data, CT images, and pathological reports of those 171 patients were reviewed. The CT findings of pGGNs including the location, the maximal diameter in the long axis (size-L), the maximal short axis diameter perpendicular to the size-L (size-S), and the mean value of long and short axis diameters (size-M), internal content, shape, interface, margin, lobulation, spiculation, air cavity, vessel relationship, and pleural retraction were recorded and analyzed. The final pathological diagnoses of the 181 pGGNs comprised 29 benign nodules, 14 AAHs, 25 AISs, 55 MIAs, and 58 IAs. Statistical analysis showed that there were significant differences among the aforementioned five groups with respect to size-L, size-S, and size-M ( p = 0.029, 0.043, 0.025, respectively). In the univariate analysis, there were significant differences between the invasive adenocarcinomas and the non-invasive adenocarcinomas with respect to the size-L, size-S, size-M, lobulation, and air cavity ( p = 0.009, 0.016, 0.008, 0.031, 0.004, respectively) between the invasive adenocarcinomas and the non-invasive adenocarcinomas. The receiver operating characteristic (ROC) curve of size for discriminating invasive adenocarcinoma also revealed similar area under curve (AUC) values among size-L (0.620), size-S (0.614), and size-M (0.623). The cut-off value of 7 mm in size-M had a sensitivity of 50.0% and a specificity of 76.4% for detecting IAs. In the multivariate analysis, the presence of air cavity was a significant predictor of IA ( p = 0.042). In conclusion, the possibility of IA is higher in a pGGN when it is associated with a larger size, lobulation, and air cavity. The air cavity is the significant predictor of IA.

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma with uncommon clinical presentations and poor prognosis. The purpose of this study is to report the clinical features and outcome of IVLBCL in a single institution of Taiwan., Methods: Ten patients with IVLBCL diagnosed from June 2006 to January 2018 were retrospectively reviewed., Results: The median age was 61 (range 39-88) years. The most common presentation was fever (90%), cytopenia (90%), and confusion (50%). For all patients, the median progression free survival (PFS) and overall survival (OS) were 12.6 (95% confidence interval [CI] 0.0-76.1) and 18.8 (95% CI 0-59.3) months, respectively. Six patients received rituximab combined chemotherapy, and the other one patient was treated with chemotherapy alone. Six of seven (85.7%) patients achieved complete response after chemotherapy. The median PFS and OS for six patients who completed treatment were not reached. Three-year PFS and OS rates were 80% and 75%, respectively., Conclusion: Our study showed that patients might achieve durable remission after rituximab-based chemotherapy. The outcome of IVLBCL patients may further improve if early diagnosis and prompt treatment were made., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

In most patients, systemic anaplastic large cell lymphoma (sALCL) is an 18 F-FDG-avid tumor. Both ALK-positive and ALK-negative tumors can be evaluated by PET scans as both tumor types uptake 18 F-FDG in PET. The PET scan is also valuable in predicting prognosis during and after the treatment course. The evolution of 18 F-FDG uptake in patients with sALCL has not been reported. For tumors lacking 18 F-FDG uptake, there is a diagnostic pitfall of underestimating the cancer stage and misjudgment of metastases. In the present case, the PET scan results were negative at diagnosis but disseminated 18 F-FDG avid lesions were found at relapse. Biopsy of bone marrow and lymph nodes revealed the pathological features were identical to the original tumor at the time of diagnosis. In the wake of such evolutional change, physicians dealing with sALCL should be cautious in interpretation of PET/CT scans.

With the increase in world food demand, the output of agricultural by-products has also increased. Agricultural by-products not only contain more than 50% dietary fiber but are also rich in functional metabolites such as polyphenol (including flavonoids), that can promote animal health. The utilization of dietary fibers is closely related to their types and characteristics. Contrary to the traditional cognition that dietary fiber reduces animal growth, it can promote animal growth and maintain intestinal health, and even improve meat quality when added in moderate amounts. In addition, pre-fermenting fiber with probiotics or enzymes in a controlled environment can increase dietary fiber availability. Although the use of fiber has a positive effect on animal health, it is still necessary to pay attention to mycotoxin contamination. In summary, this report collates the fiber characteristics of agricultural by-products and their effects on animal health and evaluates the utilization value of agricultural by-products.

Objective: The aim of this study was to investigate the effects of different amounts of wheat bran (WB) inclusion and postbiotics form by Saccharomyces cerevisiae and phytase cofermented wheat bran (FWB) on the growth performance and health status of broilers., Methods: Study randomly allocated a total of 300 male broilers to a control and 4 treatment groups (5% WB, 5% FWB, 10% WB, and 10% FWB inclusion, respectively) with each pen having 20 broilers and 3 pens per treatment., Results: The WB does not contain enzymes, but there are 152.8, 549.2, 289.5, and 147.1 U/g dry matter xylanase, protease, cellulase and β-glucanase in FWB, respectively. Furthermore, FWB can decrease nitric oxide release of lipopolysaccharide stimulated chicken peripheral blood mononuclear cells by about two times. Results show that 10% FWB inclusion had significantly the highest weight gain (WG) at 1 to 21 d; 5% FWB had the lowest feed conversion rate at 22 to 35 d; 10% WB and 10% FWB inclusion have the highest villus height and Lactobacillus spp. number in caecum; and both 5% and 10% FWB can increase ash content in femurs. Compared to control group, all treatments increase mucin 2, and tight junction (TJ), such as occludin, claudin-1, zonula occludens-1, and mRNA expression in ileum by at least 5 folds. In chicken peripheral blood mononuclear cells, nicotinamide adenine dinucleotide phosphate-oxidase-1 mRNA expression decreases from 2 to 5 times, and glutamate-cysteine ligase catalytic subunit mRNA expression also increases in all treatment groups compared to control group. The mRNA expression of pro-inflammatory cytokines, including interleukin-6 (IL-6), nuclear factor-κB, and IL-1β, decreases in 5% and 10% FWB groups compared to control group., Conclusion: To summarize, both WB and FWB inclusion in broilers diets increase TJ mRNA expression and anti-oxidation and anti-inflammation, but up to 10% FWB groups have better WG in different stages of broiler development.

TAFRO syndrome is an extremely rare form of idiopathic MCD, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis on bone marrow biopsy, and organomegaly. Like idiopathic MCD, renal involvement is also a common presentation in patients with TAFRO syndrome. Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy. Several molecular mechanisms have been previously postulated in order to explain the TAFRO syndrome symptoms, including abnormal production of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), etc. The role of these cytokines in renal injury, however, is not well understood. The aim of this review article is to summarize the latest knowledge of molecular mechanisms behind the TAFRO syndrome and their potential role in renal damage.

Background: Recurrent laryngeal nerve (RLN) palsy is a common complication of upper mediastinal lymph node dissection (UMLND) in the context of oesophageal cancer surgery. In an effort to reduce its occurrence, we developed a standardised surgical procedure that allows flexible suspension of the left RLN during robotic McKeown oesophagectomy., Patients and Methods: Patients who received robotic McKeown oesophagectomy for cancer were divided into two groups (pre and poststandardisation). Perioperative outcomes were retrospectively compared., Results: The pre and poststandardisation groups consisted of 44 and 42 patients, respectively. There were no significant intergroup differences in terms of number of dissected lymph nodes. Compared with the prestandardisation group, patients treated after standardisation had a markedly lowered incidence of left RLN palsy (20.5% vs. 4.8%, respectively, p = 0.029) and a reduced mean thoracic operating time (161.05 vs. 131 min, respectively, p < 0.001)., Conclusion: Our standardised surgical approach is efficient and may increase the safety of UMLND., (© 2021 John Wiley & Sons Ltd.)

Background: The role of regulatory T cells (Treg) in tolerance induction of vascularized composite allotransplantation (VCA) remains unclear. This study was designed to examine characteristics of Treg after VCA and their capacity to rescue allografts from rejection., Methods: Osteomyocutaneous allografts were transplanted from Balb/c to C57BL/6 mice. All mice received costimulatory blockade and a short course of rapamycin. To elucidate the role of Treg for tolerance induction, Treg depletion was performed at postoperative day (POD) 0, 30, or 90. To assess capacity of Treg to rescue allografts from rejection, an injection of 2 × 106 Treg isolated from tolerant mice was applied., Results: Eighty percent of VCA recipient mice using costimulatory blockade and rapamycin regimen developed tolerance. The tolerant recipients had a higher ratio of circulating Treg to effector T cells and elevated interleukin-10 at POD 30. A significantly higher rejection rate was observed when Treg were depleted at POD 30. But Treg depletion at POD 90 had no effect on tolerance. Treg from tolerant recipients showed stronger suppressive potential and the ability to rescue allografts from rejection. Furthermore, transplanted Treg-containing skin grafts from tolerant mice delayed rejection elicited by adoptively transferred effector T cells to Rag2-/- mice., Conclusions: Circulating Treg are crucial for inducing VCA tolerance in the early posttransplant phase, and allograft-residing Treg may maintain tolerance. Treg may, therefore, serve as a potential cellular therapeutic to improve VCA outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Wheat bran (WB) was co-fermented with Aspergillus oryzae and phytase (Phy) to determine whether co-fermentation improve WB phosphorus and fiber utilization in Isa-brown layers., Methods: A total of 112 Isa brown layer were randomly divided into 7 treatments with 8 replicates per a treatment and 2 hens per a replicate. The treatments included basal diet (control), basal diet supplemented with 250 unit/kg Phy (control+Phy), diet with 10% WB (10% WB), diet with 5% WB and 250 unit/kg Phy (5% WB+Phy) diet with 10% WB and 250 unit/kg Phy (10% WB+Phy), diet with 5% fermented WB supplemented with molasses and phy (PCFWH) and 125 unit/kg Phy (5% PCFWH), and diet with 10% PCFWH (10% PCFWH). The intestinal microbial population, intestinal morphology, serum antioxidant enzyme activities, and excreta phosphorus content were assessed., Results: In PCFWH, spore counts, protease activity, xylanase activity, and ferulic acid were 8.50 log/g dry matter (DM), 190 unit/g DM, 120 unit/g DM, and 127 μg/g, respectively. Xylobiose and xylotriose were released in PCFWH, while they were not detectable in WB. Antioxidant capacity was also enhanced in PCFWH compared to WB. The 10% WB+Phy and 10% PCFWH groups produced higher egg mass, but hens fed 5% WB+Phy had the lowest amount of feed intake. Eggs from 10% PCFWH had better eggshell weight, eggshell strength, and eggshell thickness. Birds fed with 10% PCFWH also had higher serum superoxide dismutase and catalase activities. Compare to control, 10% PCFWH significantly reduced excreta phosphorus content., Conclusion: Diet inclusion of 10% PCFWH improved egg quality, antioxidant status, and excreta phosphorus content of laying hens.

Objective: This study compared the catechin composition of different tea byproducts and investigated the effects of dietary supplementation with green tea byproducts on the accumulation of abdominal fat, the modulation of lipid metabolism, and the inflammatory response in red feather native chickens., Methods: Bioactive compounds were detected, and in vitro anti-obesity capacity analyzed via 3T3-L1 preadipocytes. In animal experiments, 320 one-day-old red feather native chickens were divided into 4 treatment groups: control, basal diet supplemented with 0.5% Jinxuan byproduct (JBP), basal diet supplemented with 1% JBP, or basal diet supplemented with 5×106 colony-forming unit (CFU)/kg Bacillus amyloliquefaciens+5×106 CFU/kg Saccharomyces cerevisiae (BA+SC). Growth performance, serum characteristics, carcass characteristics, and the mRNA expression of selected genes were measured., Results: This study compared several cultivars of tea, but Jinxuan showed the highest levels of the anti-obesity compound epigallocatechin gallate. 3T3-L1 preadipocytes treated with Jinxuan extract significantly reduced lipid accumulation. There were no significant differences in growth performance, serum characteristics, or carcass characteristics among the groups. However, in the 0.5% JBP group, mRNA expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) were significantly decreased. In the 1% JBP group, FAS, ACC and peroxisome proliferator-activated receptor γ levels were significantly decreased. Moreover, inflammation-related mRNA expression levels were decreased by the addition of JBP., Conclusion: JBP contained abundant catechins and related bioactive compounds, which reduced lipid accumulation in 3T3-L1 preadipocytes, however there was no significant reduction in abdominal fat. This may be due to a lack of active anti-obesity compounds or because the major changes in fat metabolism were not in the abdomen. Nonetheless, lipogenesis-related and inflammation-related mRNA expression were reduced in the 1% JBP group. In addition, dietary supplementation with tea byproducts could reduce the massive amount of byproducts created during tea production and modulate lipid metabolism and the inflammatory response in chickens.

Objective: The study developed mushroom stalk residues as feed additives in the broiler diet for improving the growth performance and immunity of broilers as well as to increase the value of mushroom stalk residues., Methods: In total, 300 ROSS 308 broilers were randomly allocated into fifteen pens with five dietary treatments: i) control, basal diet; ii) CMWM, supplemented with 1% Cordyceps militaris waster medium (CM); iii) CMPE, supplemented with 0.5% CM+0.5% Pleurotus eryngii stalk residue (PE); iv) CMPS, supplemented with 0.5% CM+0.5% Pleurotus sajorcaju stalk residue (PS); v) CMFV, supplemented with 0.5% CM+0.5% Fammulina velutipes stalk residue (FV)., Results: The chemical analysis results showed that CM extracts, PE extracts, PS extracts, and FV extracts contain functional components such as polysaccharides and phenols and have both 2, 2-diphenyl-1-picryl-hydrazyl-hydrate scavenging and Ferrous scavenging capacities. The group CMWM saw increased body weight gain and feed conversion rate and the promotion of jejunum villus growth, but there is no significant difference in the intestinal bacteria phase. Antioxidant genes in the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)- antioxidant responsive element pathway among the groups are significantly higher than that of the control group, especially in group CMWM., Conclusion: The mushroom stalk residues have antioxidant functional components, can improve the intestinal health and body weight gain of chickens, and can activate the antioxidant pathway of Nrf2 to increase the heme oxygenase-1 expression. The treatment with 1% CM was the most promising as a feed additive.

The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood. In this study, vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation (CBMT) or vascularized bone marrow (VBM) transplantation from Balb/c (H2d) to C57BL/6 (H2b) mice were compared. Either high- or low-dose CBMT (1.5 × 10 8 or 3 × 10 7 bone marrow cells, respectively) was applied. In addition, recipients were treated with costimulation blockade (1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2, respectively) and short-term rapamycin (3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks). Similar to high-dose conventional bone marrow transplantation, 5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival (>120 days). In contrast, significantly shorter median survival was noted in the low-dose CBMT group (~64 days). Consistently high chimerism levels were observed in the VBM transplantation group. Notably, low levels of circulating CD4 + and CD8 + T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients (>30 days) but not in low-dose VBM transplant recipients. Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro. Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.

This retrospective study aimed to differentiate cyst-like musculoskeletal soft-tissue masses by using time-resolved magnetic resonance angiography (MRA). During May 2015 to November 2019, patients with cyst-like soft-tissue masses examined through contrast-enhanced MRI followed by histologic diagnosis were included. The masses were classified into vascular lesions, solid lesions, and true cysts. Size, T1 hyperintensity, T2 composition, perilesional edema, time-resolved MRA, and static internal enhancement were assessed. The time-resolved MRA manifestations were classified into vascular pooling, solid stain, and occult lesion. Imaging predictors for each type of mass were identified through logistic regression and were used to develop a diagnostic flowchart. A total of 80 patients (47 men; median age, 42 years) were included, with 22 vascular lesions, 38 solid lesions, and 20 true cysts. The T2 composition, time-resolved MRA, and static internal enhancement were significantly different among the masses. Vascular pooling on time-resolved MRA was the sole predictor of vascular lesions (odds ratio = 722.0, p < 0.001). Solid stain on time-resolved MRA was the sole predictor of solid lesions (odds ratio = 73.6, p < 0.001). Occult lesion on time-resolved MRA (odds ratio = 7.4, p = 0.001) and absence of static internal enhancement (odds ratio = 80.0, p < 0.001) both predicted true cysts, while the latter was the sole predictor of true cysts after multivariate analysis. A diagnostic flowchart based on time-resolved MRA correctly classified 89% of the masses. In conclusion, time-resolved MRA accurately differentiates cyst-like soft-tissue masses and provides guidance for management.

This study evaluated the antioxidant capacity of Ricinus communis L. (RC) leaves and powder when used as a feed additive for laying hens. Results showed that the total phenolic content of the aqueous leaf extract of Ricinus communis L. (RCE) was 48.39 mg gallic acid equivalent (GAE) per gram dry weight (DW). The flavonoid content was 9.76 mg quercetin dihydrate equivalent (QE)/g DW. Ferrous chelating activity was approximately 56.2% with an RCE concentration of 1 mg/mL; the highest chelating activity was 91.2% with 4 mg/mL extract. The reducing power of 1 mg/mL RC was 1.17 times better than 1 mg/mL butylated hydroxytoluene (BHT). The Trolox equivalent antioxidant capacity (TEAC) value of 12.5 mg/mL RCE was equivalent to 3.09 mg/mL Trolox. RCE (10 mg/mL) had a lipid oxidative inhibition capacity of 35.3%. A total of 80 ISA brown laying hens at twenty-nine weeks of age were randomly allocated into the control or 1 of 3 treatment groups; the latter received 0.5%, 1% or 2% of RC, respectively, for 12 weeks. Results showed that the RC supplementation improved the feed conversion rate and 0.5% RC generated the best results. Additionally, the egg yolk score was significantly increased in all RC-supplemented groups. Moreover, there was no significant difference in serum characteristics between the treatment groups. Serum antioxidant enzyme activity showed that superoxide dismutase (SOD) activity increased in the RC-supplemented groups relative to the control but was not significantly different. mRNA expression levels of the antioxidant regulatory genes GCLC , GST, HO-1, SOD1 , and SOD2 were significantly increased with 2% RC supplementation. In summary, RC is a suitable feed additive for laying hens and the addition of 0.5% RC leaf powder resulted in the greatest benefits., Competing Interests: No potential conflict of interest was reported by the authors., (2020, Japan Poultry Science Association.)

Acarbose (an α-glucosidase inhibitor) has been demonstrated to reduce the progression of atherosclerosis without affecting serum levels of glucose in rabbits fed a high cholesterol diet. The main focus of recent atherosclerosis studies has been microRNA targets. However, the mechanism by which acarbose targets miRNA-mediated atherosclerosis remains unclear. This study aimed to evaluate the effect of acarbose on microRNA-related regulation of rat aortic vascular smooth cell line (A7r5 cell) migration and proliferation induced by diabetic conditions. We reported that acabose exhibit significantly inhibits proliferative and cell migration abilities in A7r5 cells. The expression of protein and levels of mRNA were measured by Western blot analysis and real-time PCR. Acarbose inhibited the phosphorylation of focal adhesion kinase (FAK) and phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt), Ras signals, small GTPase proteins expression to attenuate cell migration and proliferation. Furthermore, acarbose upregulated the expression of miR-143, and transfected miR-143 mimic and its inhibitor to explore its mechanism. In conclusion, acarbose reduces VSMC migration and proliferation via upregulating miR-143 to inhibit Ras-related signaling, and potentially prevention of atherosclerosis.

Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, headache, diarrhea, and stroke. Magnolol is a phenolic compound extracted from M. officinalis , with proven antibacterial, antioxidant, anti-inflammatory, and anticancer activities. In this study, we modified magnolol to synthesize a methoxylated derivative, 2-O-methylmagnolol (MM1), and investigated the use of MM1, and magnolol in the treatment of liver cancer. We found that both magnolol and MM1 exhibited inhibitory effects on the growth, migration, and invasion of hepatocellular carcinoma (HCC) cell lines and halted the cell cycle at the G1 phase. MM1 also demonstrated a substantially better tumor-suppressive effect than magnolol. Further analysis suggested that by inhibiting class I histone deacetylase expression in HCC cell lines, magnolol and MM1 induced p21 expression and p53 activation, thereby causing cell cycle arrest and inhibiting HCC cell growth, migration, and invasion. Subsequently, we verified the significant tumor-suppressive effects of magnolol and MM1 in an animal model. Collectively, these findings demonstrate the anti-HCC activities of magnolol and MM1 and their potential for clinical use., (Copyright © 2020 Chen, Fang, Chen, Chuang, Leu, Ueng, Wei, Cheng, Hsueh and Wang.)

The purpose of this work was to evaluate the performance of an existing commercially available artificial intelligence (AI) software system in differentiating malignant and benign lung nodules. The AI tool consisted of a vessel-suppression function and a deep-learning-based computer-aided-detection (VS-CAD) analyzer. Fifty patients (32 females, mean age 52 years) with 75 lung nodules (47 malignant and 28 benign) underwent low-dose computed tomography (LDCT) followed by surgical excision and the pathological analysis of their 75 nodules within a 3 month time frame. All 50 cases were then processed by the AI software to generate corresponding VS images and CAD outcomes. All 75 pathologically proven lung nodules were well delineated by vessel-suppressed images. Three (6.4%) of the 47 lung cancer cases, and 11 (39.3%) of the 28 benign nodules were ignored and not detected by the AI without showing a CAD analysis summary. The AI system/radiologists produced a sensitivity and specificity (shown in %) of 93.6/89.4 and 39.3/82.1 in distinguishing malignant from benign nodules, respectively. AI sensitivity was higher than that of radiologists, though not statistically significant ( p = 0.712). Specificity obtained by the radiologists was significantly higher than that of the VS-CAD AI ( p = 0.003). There was no significant difference between the malignant and benign lesions with respect to age, gender, pure ground-glass pattern, the diameter and location of the nodules, or nodules <6 vs. ≥6 mm. However, more part-solid nodules were proven to be malignant than benign (90.9% vs. 9.1%), and more solid nodules were proven to be benign than malignant (86.7% vs. 13.3%) with statistical significance ( p = 0.001 and <0.001, respectively). A larger cohort and prospective study are required to validate the AI performance.

Pleosporales species are important plant pathogens, saprobes, and endophytes on a wide range of economically important plant hosts. The classification of Pleosporales has undergone various modifications in recent years due to the addition of many families described from multiple habitats with a high level of morphological deviation. Numerous asexual genera have been described in Pleosporales that can be either hyphomyceteous or coelomycetous. Phoma- or coniothyrium-like species are common and have been revealed as polyphyletic in the order Pleosporales and linked with several sexual genera. A total of 31 pleosporalean strains were isolated in different regions of Taiwan between 2017 and 2018 from the leaves of Camellia sinensis plants with symptoms of leaf spot disease. These strains were evaluated morphologically and genotypically using multi-locus sequence analyses of the ITS, LSU, SSU, rpb2, tef1 and tub2 genes. The results demonstrated the affiliation of these strains with the various families in Pleosporales and revealed the presence of one new genus (Neoshiraia) and eight new species (Alloconiothyrium camelliae, Amorocoelophoma camelliae, Leucaenicola camelliae, L. taiwanensis, Neoshiraia camelliae, N. taiwanensis, Paraconiothyrium camelliae and Paraphaeosphaeria camelliae). Furthermore, to the best of our understanding, Didymella segeticola, Ectophoma pomi and Roussoella mexican were reported for the first time from C. sinensis in Taiwan.

In addition to the influence of genes, the quality of poultry products is mainly controlled by the rearing environment or feed composition during rearing, and has to meet human use and economical needs. As the only source of energy for poultry, feed considerably affects the metabolic pattern of poultry and further affects the regulation of appetite-related endocrine secretion in poultry. Under normal circumstances, the accumulation of lipid in adipose reduces feed intake in poultry and increases the rate of adipose metabolism. When the adipose content in cells decreases, endocrines that promote food intake are secreted and increase nutrient concentrations in serum and cells. By regulating the balance between appetite and adipose metabolism, the poultry's growth and posture can maintain a balanced state. In addition, increasing fiber composition in feed can effectively increase poultry welfare, body weight, lean composition and antioxidant levels in poultry. According to this, the concept that proper fiber content should be added to feed should be considered for better economic benefits, poultry welfare and meat productivity., Competing Interests: The authors declare no conflict of interest.

Objectives: Peripheral arterial disease (PAD) is characterised by arterial occlusion and fibrosis in the lower extremities. Extracellular volume matrix fraction (ECV) is a biomarker of skeletal muscle fibrosis, but has not been applied to the lower extremities with PAD. This study investigated the clinical feasibility of using ECV for calf muscle fibrosis quantification by comparing normal controls (NC) and PAD patients., Methods: From October 2016 to December 2017, we recruited patients with PAD, and patients with head and neck cancer receiving fibular flap as NC group. All participants underwent magnetic resonance imaging (MRI) to determine the ECV of the calves and the differences between the NC and PAD groups. ECV was calculated from T1 values at steady-state equilibrium, defined as the point in time after contrast agent injection when the variance of T1 relaxation time in blood and muscle becomes less than 5%., Results: A total of 46 patients (18 in the NC group and 28 in the PAD group) were recruited. Steady-state equilibrium was reached at 11-12 min after contrast agent injection. The NC group had significantly lower mean ECV than the PAD group (12.71% vs. 31.92%, respectively, p < 0.001). In the PAD group, the mean ECV was slightly lower in patients with collateral vessels than in those without (26.58% vs. 34.88%, respectively, p = 0.047)., Conclusion: Evaluation of skeletal fibrosis in PAD using ECV is feasible. ECV can help identify PAD patients with collateral vessel formation and lay the foundation for future research in PAD management., Key Points: • Steady-state equilibrium for ECV measurement of the lower limbs can be reached at around 11-12 min. • Quantification of lower limb muscle fibrosis by measuring ECV is clinically feasible and can be used to differentiate between patients with PAD and histologically proven normal controls. • ECV can differentiate PAD patients with or without visible collateral vessels, further expanding its role in identifying the presence of collateral supply in clinical decision-making.

As probiotics, fungi enhance animal health and are suitable animal feed additives. In addition to brewing fungi, there are also edible and medicinal fungi. Common fungi utilized in feeding programs include Saccharomyces cerevisiae, Aspergillus oryzae , Pleurotus spp. , Antrodia cinnamomea , and Cordyceps militaris . These fungi are rich in glucans, polysaccharides, polyphenols, triterpenes, ergosterol, adenosine, and laccases. These functional components play important roles in antioxidant, anti-inflammatory, anti-obesity, and immune system regulation. As such, fungal feed additives could be of potential use when breeding livestock. In previous studies, fungal feed additives enhanced body weight and egg production in poultry and improved the feed conversion rate. Several mycotoxins can be produced by hazardous fungi but fortunately, the cell walls constituents and enzymes of fungal probiotics can also act to decrease the toxicity of mycotoxins. Overall, fungal feed additives are of value, but their safety and usage must be studied further, including cost-benefit economic analyses., Competing Interests: The authors declare no conflict of interest.

The aberrant subcellular translocation and distribution of epidermal growth factor receptor (EGFR) represent a major yet currently underappreciated cancer development mechanism in non-small cell lung cancer (NSCLC). In this study, we investigated the subcellular interactome of EGFR by using a spectral counting-based approach combined with liquid chromatography-tandem mass spectrometry to understand the associated protein networks involved in the tumorigenesis of NSCLC. A total of 54, 77, and 63 EGFR-interacting proteins were identified specifically in the cytosolic, mitochondrial, and nuclear fractions from a NSCLC cell line, respectively. Pathway analyses of these proteins using the KEGG database shown that the EGFR-interacting proteins of the cytosol and nucleus are involved in the ribosome and spliceosome pathways, respectively, while those of the mitochondria are involved in metabolizing propanoate, fatty acid, valine, leucine, and isoleucine. A selected nuclear EGFR-interacting protein, hnRNP A3, was found to modulate the accumulation of nuclear EGFR. Downregulation of hnRNP A3 reduced the nuclear accumulation of EGFR, and this was accompanied by reduced tumor growth ability in vitro and in vivo. These results indicate that variations in the subcellular translocation and distribution of EGFR within NSCLC cells could affect tumor progression.

Background: This study reviewed the clinical manifestations, pathological findings, and treatment outcomes of adenoid cystic carcinoma (ACC) in the external auditory canal (EAC)., Methods: This was a retrospective review of 12 patients with a diagnosis of ACC in the EAC seen in a single institution over a 30-year period. Data on the demographics, clinical presentation, treatment strategy, and outcome, as well as the pathological features of ACC, were reviewed and analyzed., Results: The male-to-female ratio was 1:3 and the mean patient age was 55.9 years. The most common clinical presentation was otalgia (75%). Ten patients underwent surgical interventions, including radical mastoidectomy in five patients, wide excision in three, and lateral temporal bone resection in two. Adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT) was performed in case of incomplete resection. Two patients underwent non-surgical treatments: radiotherapy in one and CCRT in the other. Microscopic perineural invasion was not associated with otalgia or histological subtype. The mean follow-up period was 84.6 months. Local recurrence occurred in 33% of patients. One-quarter of patients had distant metastasis, and all had lung metastasis. The 5-year overall survival rate for these patients was 82.5%., Conclusion: EAC ACC should be included in the differential diagnosis when a patient presents with otalgia and a mass in EAC for more than 6 months, particularly if the patient is a middle-aged female. Otalgia might not be associated with perineural invasion or histological subtype. The lung is the most common site of distant metastasis in patients with EAC ACC. Further studies should determine the optimal treatment protocol for this rare malignancy., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Pennisetum purpureum Schum No. 2 waste mushroom compost (PWMC) is the main byproduct when cultivating Pleurotus eryngii . Due to the high mycelium levels in PWMC, it may have potential as a feed supplement for broilers. This study investigated the effects of PWMC supplementation on antioxidant capacity and adipose metabolism in broilers. In the study, 240 broilers were randomly allocated to one of four treatment groups: basal diet (control), 0.5%, 1%, or 2% PWMC supplementation. Each treatment group had 60 broilers, divided into three replicates. The results showed that supplementation with 0.5% PWMC decreased the feed conversion rate (FCR) from 1.36 to 1.28, compared to the control. Supplementation with 0.5% or 2% PWMC decreased glucose and triglyceride levels, compared to the control ( p < 0.0001), the concentrations of adiponectin and oxytocin increased from 5948 to 5709, 11820, and 7938 ng/ mL; and 259 to 447, 873, and 963 pg/ mL, respectively. Toll-like receptor 4 was slightly increased in the 0.5% and 1% PWMC groups. Both interferon-γ (IFN-γ) and interleukin-1ß (IL-1ß) were significantly decreased, by about three to five times for IFN-γ ( p < 0.0001) and 1.1 to 1.6 times for IL-1ß ( p = 0.0002). All antioxidant-related mRNA, including nuclear factor erythroid 2-related factor 2 (Nrf-2) and superoxidase dismutase-1 (SOD-1), increased significantly following PWMC supplementation. Both claudin-1 and zonula occludens 1 increased, especially in the 2% PWMC group. Excitatory amino acid transporter 3 (EAAT3) significantly increased by about 5, 12, and 11 times in the 0.5%, 1%, and 2% PWMC groups. All adipolysis-related mRNA were induced in the PWMC treatment groups, further enhancing adipolysis. Overall, 0.5% PWMC supplementation was recommended due to its improving FCR, similar antioxidant capacity, and upregulated adipolysis.

Lymph node dissection (LND) along the left recurrent laryngeal nerve (RLN) is a technically challenging part of esophageal cancer surgery, especially after chemoradiotherapy (CRT). Robotic surgery holds promise to increase its safety and feasibility. The aim of this study was to describe a single thoracoscopic surgeon's experience related to the transition from video-assisted esophagectomy (VATE) to robotic esophagectomy (RE)-with a special focus on the safety of left RLN LND. Patients who underwent minimally invasive esophagectomy and RLN dissection following CRT were dichotomized according to the use of robotic surgery (robotic esophagectomy [RE] versus video-assisted thoracoscopic esophagectomy [VATE]). The following parameters were determined: (1) number of dissected nodes, (2) rates of RLN palsy, (3) rates of perioperative complications, and (4) learning curve. Learning curve analysis was performed using the 10-patient moving average (MA) for operation times and with the cumulative sum (CUSUM) method for left RLN LND (target failure rate: 15%). The RE and VATE groups consisted of 39 and 67 patients, respectively. The intraoperative identification of the left RLN was more common in the RE group (97.4%) than in the VATE group (68.7%; P < 0.001). Postoperative left RLN palsy was significantly more frequent in the VATE group (26.9%) than in the RE group (10.3%; P = 0.042), with a higher rate of pneumonia in the former (16.4% versus 2.6%; P = 0.03). The MA chart revealed a downward trend followed by a flattening of the RE operation time at operation number 17 and 29, respectively. CUSUM analysis showed that the left RLN palsy rate decreased to the target rate after 12 operations. We conclude that at least 12 cases are required for a surgeon with prior experience in VATE to safely accomplish left RLN LND through a robotic approach., (© The Author(s) 2019. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers., Experimental Design: We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo ., Results: Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R-STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice., Conclusions: Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the "TYRO3-STAT3-TYRO3" signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity., (©2019 American Association for Cancer Research.)

Abnormal histone deacetylase (HDAC) expression is closely related to cancer development and progression. Many HDAC inhibitors have been widely used in cancer treatment; however, severe side effects often limit their clinical application. In this study, we attempted to identify natural compounds with HDAC inhibitory activity and low physiological toxicity and explored their feasibility and mechanisms of action in liver cancer treatment. A yeast screening system was used to identify natural compounds with HDAC inhibitory activity. Further, western blotting was used to verify inhibitory effects on HDAC in human liver cancer cell lines. Cell functional analysis was used to explore the effects and mechanisms and the in vitro results were verified in BALB/c nude mice. We found that hydroxygenkwanin (HGK), an extract from Daphne genkwa, inhibited class I HDAC expression, and thereby induced expression of tumor suppressor p21 and promoted acetylation and activation of p53 and p65. This resulted in the inhibition of growth, migration, and invasion of liver cancer cells and promoted cell apoptosis. Animal models revealed that HGK inhibited tumor growth in a synergistic manner with sorafenib. HGK inhibited class I HDAC expression and had low physiological toxicity. It has great potential as an adjuvant for liver cancer treatment and may be used in combination with anticancer drugs like sorafenib to improve therapeutic efficacy., (Copyright © 2020 Chen, Chen, Chuang, Leu, Ueng, Hsueh, Yeh and Wang.)

Pathologic diagnosis of nasopharyngeal carcinoma (NPC) can be challenging since most cases are nonkeratinizing carcinoma with little differentiation and many admixed lymphocytes. Our aim was to evaluate the possibility to identify NPC in nasopharyngeal biopsies using deep learning. A total of 726 nasopharyngeal biopsies were included. Among them, 100 cases were randomly selected as the testing set, 20 cases as the validation set, and all other 606 cases as the training set. All three datasets had equal numbers of NPC cases and benign cases. Manual annotation was performed. Cropped square image patches of 256 × 256 pixels were used for patch-level training, validation, and testing. The final patch-level algorithm effectively identified NPC patches, with an area under the receiver operator characteristic curve (AUC) of 0.9900. Using gradient-weighted class activation mapping, we demonstrated that the identification of NPC patches was based on morphologic features of tumor cells. At the second stage, whole-slide images were sequentially cropped into patches, inferred with the patch-level algorithm, and reconstructed into images with a smaller size for training, validation, and testing. Finally, the AUC was 0.9848 for slide-level identification of NPC. Our result shows for the first time that deep learning algorithms can identify NPC.