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Background: CD4+ T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4+ T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4+ T cells in the tumor microenvironment. Methods: TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4+ T cells to examine the function and mechanism of TRAPs in CD4+ T cell differentiation and function. TRAPs-elicited CD4+ T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model. Results: Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4+ T cell production of IL-6 via a TLR2–MyD88–NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4+ T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4+ T cells inhibited CD4+ and CD8+ effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4+ T cells markedly retarded tumor growth. Furthermore, B cell or CD4+ T cell depletion impeded tumor growth by increasing effector T cell function. Conclusions: HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4+ T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Wilson's disease (WD) is an autosomal recessive disease of impaired copper metabolism. Previous study demonstrated that WD with corpus callosum abnormalities (WD-CCA) was limited to the posterior part (splenium). This study aimed to compare clinical features between WD-CCA and WD without corpus callosum abnormalities (WD-no-CCA).Methods: Forty-one WD patients who had markedly neurological dysfunctions were included in this study. We retrospectively reviewed clinical, biochemical characteristics and MRI findings in the 41 WD patients. All patients were assessed using the Unified Wilson's Disease Rating Scale.Results: Nine patients had corpus callosum abnormalities, 4 of 9 patients had abnormal signal in the genu and splenium, 5 of 9 patients had abnormal signal only in the splenium. WD-CCA had longer course (9.9 ± 4.0 years vs. 3.4 ± 3.6 years, p<0.01), more severe neurological dysfunctions (37.6 vs. 65.9, p<0.01) and higher psychiatric symptoms scores (11.2 vs. 22.5, p<0.01) than WD-no-CCA. The MRI findings indicated that WD-CCA had higher ratio than WD-no-CCA in globus pallidus (88.9% vs. 43.8%, p = 0.024) and thalamus (100% vs. 59.4%, p = 0.038). The index of liver function and copper metabolism had no significant in WD-CCA and WD-no-CCA patients.Conclusion: Our findings indicate Wilson's disease can involve the posterior as well as the anterior part of CC and patients with CC involvement had more extensive brain lesions, more severe neurological dysfunctions and psychiatric symptoms. [ABSTRACT FROM AUTHOR]

Topological Dirac semimetals (DSMs) present a kind of topologically nontrivial quantum state of matter, which has massless Dirac fermions in the bulk and topologically protected states on certain surfaces. In superconducting DSMs, the effects of their nontrivial topology on superconducting pairing could realize topological superconductivity in the bulk or on the surface. As superconducting pairing takes place at the Fermi level EF, to make the effects possible, the Dirac points should lie in the vicinity of EF so that the topological electronic states can participate in the superconducting paring. Here, we show using angle-resolved photoelectron spectroscopy that in a series of (Ir1−xPtx)Te2 compounds, the type-II Dirac points reside around EF in the superconducting region, in which the bulk superconductivity has a maximum Tc of ∼ 3 K. The realization of the coexistence of bulk superconductivity and low-energy Dirac fermions in (Ir1−xPtx)Te2 paves the way for studying the effects of the nontrivial topology in DSMs on the superconducting state. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) facilitate tumor progression via establishment of an immunosuppressive tumor microenvironment (TME). However, it is poorly understood how tumor cells could functionally modulate TAMs. Our previous work indicated that tumor cell-released autophagosomes (TRAPs), a type of LC3-II+ double-membrane extracellular vesicles (EVs) was sufficient to suppress anti-tumor immune responses by inducing IL-10-producing B cells and immune suppressive neutrophils. Here, we hypothesized that TRAPs may participate in regulating macrophage polarization. Methods: TRAPs isolated from multiple murine tumor cell lines and pleural effusions or ascites of cancer patients were incubated with bone marrow-derived macrophages (BMDMs) and monocytes, respectively. Cellular phenotypes were examined by flow cytometry, ELISA and quantitative PCR. TRAPs treated BMDMs were tested for the ability to suppress T-cell proliferation in vitro, and for promotion of tumor growth in vivo. Transwell chamber and neutralization antibodies were added to ascertain the inhibitory molecules expressed on BMDMs exposed to TRAPs. Knockout mice were used to identify the receptors responsible for TRAPs-induced BMDMs polarization and the signaling mechanism was examined by western blot. Autophagy-deficient tumors were profiled for phenotypic changes of TAMs and IFN-γ secretion of T cells by flow cytometry. The phenotype of monocytes from pleural effusions or ascites of cancer patients was assessed by flow cytometry. Results: TRAPs converted macrophages into an immunosuppressive M2-like phenotype characterized by the expression of PD-L1 and IL-10. These macrophages inhibited the proliferation of both CD4+ and CD8+ T cells in vitro, and promoted tumor growth mainly through PD-L1 in vivo. TRAPs-induced macrophage polarization was dependent on TLR4-mediated MyD88-p38-STAT3 signaling. In vivo studies indicated that disruption of autophagosome formation in B16F10 cells by silencing the autophagy gene Beclin1 resulted in a remarkable delay in tumor growth, which was associated with reduced autophagosome secretion, TAMs reprogramming and enhanced T cell activation. Moreover, the levels of LC3B+ EVs appeared to correlate significantly with up-regulation of PD-L1 and IL-10 in matched monocytes from effusions or ascites of cancer patients, and TRAPs isolated from these samples could also polarize monocytes to an M2-like phenotype with increased expression of PD-L1, CD163 and IL-10, decreased expression of HLA-DR, and T cell-suppressive function. Conclusions: These findings suggest the TRAPs-PD-L1 axis as a major driver of immunosuppression in the TME by eliciting macrophage polarization towards an M2-like phenotype, and highlight the potential novel therapeutic approach of simultaneously targeting autophagy and PD-L1. [ABSTRACT FROM AUTHOR]

Rainfall during typhoons is one of the most important water resources in Taiwan, but heavy typhoon rainfall often leads to serious disasters and consequently results in loss of lives and property. Hence, accurate forecasts of typhoon rainfall are always required as important information for water resources management and rainfall-induced disaster warning system. In this study, a methodology is proposed for providing quantitative forecasts of 24 h cumulative rainfall during typhoons. Firstly, ensemble forecasts of typhoon rainfall are obtained from an ensemble numerical weather prediction (NWP) system. Then, an evolutionary algorithm, i.e., genetic algorithm (GA), is adopted to real-time decide the weights for optimally combining these ensemble forecasts. That is, the novelty of this proposed methodology is the effective integration of the NWP-based ensemble forecasts through an evolutionary algorithm-based strategy. An actual application is conducted to verify the forecasts resulting from the proposed methodology, namely NWP-based ensemble forecasts with a GA-based integration strategy. The results confirm that the forecasts from the proposed methodology are in good agreement with observations. Besides, the results from the GA-based strategy are more accurate as compared to those by simply averaging all ensemble forecasts. On average, the root mean square error decreases about 7%. In conclusion, more accurate typhoon rainfall forecasts are obtained by the proposed methodology, and they are expected to be useful for disaster warning system and water resources management during typhoons. [ABSTRACT FROM AUTHOR]

In this study, the complete mitogenome sequence of two moray eels ofGymnothorax formosusandScuticaria tigrina(Anguilliformes: Muraenidae) has been sequenced by the next-generation sequencing method. The assembled mitogenome, with the length of 16,558 bp forG. formosusand 16,521 bp forS. tigrina, shows 78% identity to each other. Both mitogenomes follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, two ribosomal RNAs genes, and a non-coding control region of D-loop. The length of D-loop is 927 bp (G. formosus) and 850 bp (S. tigrina), which is located between tRNA-Pro and tRNA-Phe. The overall GC content is 45.5% forG. formosusand 47.9% forS. tigrina. Complete mitogenomes ofG. formosusandS. tigrinaprovide essential and important DNA molecular data for further phylogenetic and evolutionary analysis for moray eel. [ABSTRACT FROM AUTHOR]

Our previous studies have confirmed that tumor cell-released autophagosomes (TRAP) could induce the differentiation of B cells into IL-10+ regulatory B cells (Bregs) with suppressive activities on T lymphocytes. However, the mechanism of TRAP-mediated immune suppression is still largely unclear. Herein, we sought to assess the immunomodulatory effect of TRAPs on human neutrophils, a major immune cell type that infiltrates human tumor tissues. We found that TRAPs enriched from malignant effusions or ascites of cancer patients and tumor cell lines were rapidly and effectively phagocytized by neutrophils through macropinocytosis and promoted neutrophil apoptosis via reactive oxygen species (ROS) generation and caspase-3 activation. Moreover, the apoptotic neutrophils that have phagocytized TRAPs inhibited the proliferation and activation of CD4+ T and CD8+ T cells in a cell contact- and ROS-dependent manner. These findings define a novel TRAP-mediated mechanism in neutrophils that potentially suppresses the anti-tumor T cell immunity and highlight TRAPs as an important target for future tumor immunotherapy. [ABSTRACT FROM AUTHOR]

We report the anisotropic magnetotransport measurement on a noncompound band semiconductor black phosphorus (BP) with magnetic field B up to 16 Tesla applied in both perpendicular and parallel to electric current I under hydrostatic pressures. The BP undergoes a topological Lifshitz transition from band semiconductor to a zero-gap Dirac semimetal state at a critical pressure Pc, characterized by a weak localization-weak antilocalization transition at low magnetic fields and the emergence of a nontrivial Berry phase of p detected by SdH magneto-oscillations in magnetoresistance curves. In the transition region, we observe a pressure-dependent negative MR only in the B||I configuration. This negative longitudinal MR is attributed to the Adler-Bell-Jackiw anomaly (topological E·B term) in the presence of weak antilocalization corrections. [ABSTRACT FROM AUTHOR]

There is a long-standing confusion concerning the physical origin of the anomalous resistivity peak in transition metal pentatelluride HfTe5. Several mechanisms, such as the formation of charge density wave or polaron, have been proposed, but so far no conclusive evidence has been presented. In this work, we investigate the unusual temperature dependence of magneto-transport properties in HfTe5. It is found that a three-dimensional topological Dirac semimetal state emerges only at around Tp (at which the resistivity shows a pronounced peak), as manifested by a large negative magnetoresistance. This accidental Dirac semimetal state mediates the topological quantum phase transition between the two distinct weak and strong topological insulator phases in HfTe5. Our work not only provides the first evidence of a temperature-induced critical topological phase transition in HfTe5 but also gives a reasonable explanation on the long-lasting question. [ABSTRACT FROM AUTHOR]

Although pressure therapy (PT) represents the standard care for prevention and treatment of hypertrophic scar (HS) from burns, its practice is largely based on empirical evidence and its effectiveness remains controversial. To clarify the effect of PT (15-25 mmHg) for HS, we performed the systematic review and meta-analysis. Several electronic databases were screened to identify related randomized controlled trials (RCTs). 12 RCTs involving 710 patients with 761 HS resulting from burn injuries were included. Compared with non/low-PT, cases treated with PT (15-25 mmHg) showed significant differences in Vancouver Scar Scale score (MD = −0.58, 95% CI = −0.78-−0.37), thickness (SMD = −0.25, 95% CI = −0.40-−0.11), brightness (MD = 2.00, 95% CI = 0.59-3.42), redness (MD = −0.79, 95% CI = −1.52-−0.07), pigmentation (MD = −0.16, 95% CI = −0.32-−0.00) and hardness (SMD = −0.65, 95% CI = −1.07-−0.23). However, there was no difference in vascularity (MD = 0.03, 95% CI = −0.43-0.48). Our analysis indicated that patients with HS who were managed with PT (15-25 mmHg) showed significant improvements. Due to limitations, more large and well-designed studies are needed to confirm our findings and the side-effects of the PT may also need to be evaluated. [ABSTRACT FROM AUTHOR]

It is well-known that vaccines comprising of irradiated whole tumor cells or tumor-derived heat shock proteins can generate tumor-specific immune responses. In contrast, we showed recently that vaccines composed of autophagosomes (DRibbles) derived from syngeneic sarcomas could induce cross-reactive T-cell responses and cross-protection against the tumor. This unusual property of DRibbles was related to the selective recruitment of defective ribosomal products (DRiPs) and other short-lived proteins (SLiPs) into autophagosomes via sequestosome (SQSTM1, p62) mediated association of ubiquitinated SLiPs to the autophagy gene product LC3. Here, we extend our observations to mammary carcinomas from mice of different genetic background. We demonstrated that combined of intranodal administration of autologous or allogeneic DRibbles together with anti-OX40 antibody led to robust proliferation, expansion, and differentiation of memory and effector T cells. We also showed that SLiPs is an excellent source of antigen for cross-priming of CD8+ T-cells that recognize shared tumor antigens in the context of host MHC class I molecules. Thus, our results provide a strong basis for novel clinical trials that combine allogeneic 'off-the-shelf' DRibble vaccines together with antibodies against co-stimulatory molecules. [ABSTRACT FROM AUTHOR]

Recent studies have shown that tumor cells can release autophagosomes, which transport a broad array of biologically active molecules with potential modulatory effects on immune cell functions. In this study, we aimed to investigate the role of tumor cells-released autophagosomes (i.e. TRAP) in regulating B cell differentiation and function. TRAPs from murine tumor cell lines were found to induce splenic B cells to differentiate into IL-10-producing regulatory B cells (Bregs) with a distinct phenotype of CD1d+CD5+, which could potently inhibit CD8+and CD4+T cell responses in IL-10-depedent manner bothin vitroandin vivo. Notably, adoptive transfer of TRAP-induced Bregs abrogated the immune response and antitumor effect induced by OVA-loaded DC vaccinations in E.G7-OVA-bearing mouse model. Mechanistic studies revealed that membrane-bound high-mobility group B1 (HMGB1) on the intact TRAPs was crucial for inducing Breg differentiation via the activation of TLR2-MyD88-NF-κB signal pathway in B cells. Moreover, TRAPs enriched from malignant effusions of cancer patients could induce human B cells to differentiate into IL-10-producing B cells with immunoregulatory functions, the frequency of which were positively correlated with the HMGB1 levels on TRAPs. Together, our findings have demonstrated that TRAPs promote the generation of IL-10+Bregs, which may contribute to the suppression of antitumor immunity. [ABSTRACT FROM AUTHOR]

High-resolution angle-resolved photoemission measurements are carried out on transition metal dichalcogenide PdTe2 that is a superconductor with a Tc at 1.7 K. Combined with theoretical calculations, we discover for the first time the existence of topologically nontrivial surface state with Dirac cone in PbTe2 superconductor. It is located at the Brillouin zone center and possesses helical spin texture. Distinct from the usual three-dimensional topological insulators where the Dirac cone of the surface state lies at the Fermi level, the Dirac point of the surface state in PdTe2 lies deeply below the Fermi level at ∼1.75 eV binding energy and is well separated from the bulk states. The identification of topological surface state in PdTe2 superconductor deeply below the Fermi level provides a unique system to explore new phenomena and properties and opens a door for finding new topological materials in transition metal chalcogenides. [ABSTRACT FROM AUTHOR]

Patients with developmental dysplasia of the hip (DDH) generally undergo multiple x-ray examinations of both hip joints. During these examinations, the gonads are completely exposed to radiation, unless shielded. Although many types and sizes of gonad shields exist, they often do not provide adequate protection because of size and placement issues; additionally, these shields are frequently omitted for female patients. Our aim was to assess gonad protection during x-ray examination that is provided by gonad shields designed for individual female patients with DDH.We retrospectively retrieved data from the Picture Archiving and Communication System database; pelvic plain x-ray films from 766 females, 18 years old or younger, were included in our analysis. Based on x-ray measurements of the anterior superior iliac spine, we developed a system of gonad shield design that depended on the distance between anterior superior iliac spine markers. We custom-made shields and then examined shielding rates and shielding accuracy before and after these new shields became available. Standard (general-purpose) shields were used before our custom design project was implemented. The shielding rate and shielding accuracy were, respectively, 14.5% and 8.4% before the project was implemented and 72.7% and 32.2% after it was implemented. A shield that is more anatomically correct and available in several different sizes may increase the likelihood of gonad protection during pelvic x-ray examinations. [ABSTRACT FROM AUTHOR]

Background: Autophagy regulates innate and adaptive immune responses to pathogens and tumors. We have reported that autophagosomes derived from tumor cells after proteasome inhibition, DRibbles (Defective ribosomal products in blebs), were excellent sources of antigens for efficient cross priming of tumor-specific CD8⁺ T cells, which mediated regression of established tumors in mice. But the activity of DRibbles in human has not been reported.Methods: DRibbles or cell lysates derived from HEK293T or UbiLT3 cell lines expressing cytomegalovirus (CMV) pp65 protein or transfected with a plasmid encoding dominant HLA-A2 restricted CMV, Epstein-Barr virus (EBV), and Influenza (Flu) epitopes (CEF) were loaded onto human monocytes or PBMCs and the response of human CMV pp65 or CEF antigen-specific CD4⁺ and CD8⁺ memory T cells was detected by intracellular staining. The effect of cytokines (GM-CSF, IL-4, IL-12, TNF-α, IFN-α and IFN-γ) TLR agonists (Lipopolysaccharide, Polyinosinic-polycytidylic acid (poly(I:C), M52-CpG, R848, TLR2 ligand) and CD40 ligand on the cross-presentation of antigens contained in DRibbles or cell lysates was explored.Results: In this study we showed that purified monocytes, or human PBMCs, loaded with DRibbles isolated from cells expressing CMV or CEF epitopes, could activate CMV- or CEF-specific memory T cells. DRibbles were significantly more efficient at stimulating CD8⁺ memory T cells compared to cell lysates expressing the same antigenic epitopes. We optimized the conditions for T-cell activation and IFN-γ production following direct loading of DRibbles onto PBMCs. We found that the addition of Poly(I:C), CD40 ligand, and GM-CSF to the PBMCs together with DRibbles significantly increased the level of CD8⁺ T cell responses.Conclusions: DRibbles containing specific viral antigens are an efficient ex vivo activator of human antigen-specific memory T cells specific for those antigens. This function could be enhanced by combining with Poly(I:C), CD40 ligand, and GM-CSF. This study provides proof-of-concept for applying this strategy to activate memory T cells against other antigens, including tumor-specific T cells ex vivo for immunological monitoring and adoptive immunotherapy, and in vivo as vaccines for patients with cancer. [ABSTRACT FROM AUTHOR]

Background: To clarify the feasibility and efficacy of chemoradiotherapy (CRT) in elderly (age≥65 years) patients with locoregionally advanced nasopharyngeal carcinoma (NPC).Methods: From January 2000 to December 2006, 101 newly diagnosed elderly non-metastatic NPC patients (age≥65 years) who received cisplatin 3-weekly or weekly concurrent CRT with/without sequential chemotherapy were recruited. Each patient from the CRT group was matched to another patient treated with radiotherapy (RT) alone based on age, gender, pathological type, performance status, overall stage, stage method, Adult Comorbidity Evaluation-27 (ACE-27) score and RT technique, from the same institute and time period. We also recruited 101 young patients (age<65 years) as the referent group, which had been matched to the CRT group based on patient characteristics and treatment parameters. Treatment tolerability and toxicity were clarified, and treatment outcomes were calculated and compared among groups.Results: CRT was feasible in elderly NPC patients, while a concurrent regimen of weekly cisplatin was more tolerable. Grade≥3 acute toxicity in CRT group was similar with referent group, although it was significantly higher than the RT alone group (65.3% vs. 43.6%, P=0.002). Furthermore, patients with ACE-27 score≥2 in the CRT group had significantly higher severe acute toxicity and dose reduction. Survival was poorer in elderly patients than the referent group. Compared to RT alone, CRT significantly improved the 5-year overall survival (OS: 54.6% vs. 39.3%, P=0.009), cancer-specific survival (CSS: 56.6% vs. 42.7%, P=0.022), disease-free survival (DFS: 51.6% vs. 30.2%, P=0.028) and locoregional relapse-free survival (LRRFS: 78.4% vs. 52.2%, P=0.003), but not distant metastasis-free survival (DMFS: 69.6% vs. 63.6%, P=0.669). However, CRT did not significantly improve 5-year OS (43.6% vs. 27.3%, P=0.893) or CSS (43.6% vs. 34.1%, P=0.971) in elderly NPC patients with ACE-27 score≥2.Conclusions: CRT is feasible and effective in elderly patients with locoregionally advanced NPC without severe comorbidities. CRT should be used under serious consideration and be further tested in elderly patients with severe comorbidities. As such, it is essential to perform a comprehensive evaluation of pretreatment comorbidity status for all elderly NPC patients. [ABSTRACT FROM AUTHOR]

Abstract: Sonographic texture analysis can reflect histopathological components and their arrangement in metastatic and common benign lymph nodes. It is helpful in differentiation between metastatic and benign lymph node lesions for target selection during biopsy of multiple lymph nodes and the strategy of the management. Two ultrasound systems, 107 sonographic regions of interest (ROIs) of metastases and 174 sonographic ROIs of common benign lymph nodes, were recruited in the study. Thirteen texture features derived from co-occurrence matrix were used in characterization of above ROI ultrasound images. Support vector machine (SVM) was used as a classifier and a feature selector. The experimental results show that the entropy gains the best cross-validation accuracy of 94.66% and 87.73% in both ultrasound systems 1 and 2 for the classification of metastatic and benign lymph nodes disease. The accuracy can be further increased to 97.86% and 100% by the combination of the sum average in the study. There are significantly higher entropy and sum average values of the metastatic lymph nodes than of the benign lymph nodes, which are due to the heterogeneous compositions and arrangement of larger cancer cells, lymphocytes, and stroma in metastatic lymph nodes that contrast with simple inflammatory cells infiltration in common benign lymph nodes. [Copyright &y& Elsevier]

Abstract: This study aims to measure the two-dimensional (2D) neutron spatial distribution inside a cubic and a head PMMA phantom for the purpose of further comparison with the treatment planning. The measurements were made by using the indirect neutron radiography (INR), which utilized a thin copper foil and the imaging plate. The developed image provides satisfactory spatial resolution and very low statistical error (< 1%). As to the time cost, the whole procedure normally takes less than 3h. The result shows that the indirect neutron radiography can be a quick and reliable method to provide a 2D neutron spatial distribution inside a phantom. [Copyright &y& Elsevier]

Abstract: This paper aims to measure the spectra of HB11 (high flux reactor, HFR) and the Tsing Hua open-pool reactor (THOR) boron neutron capture therapy (BNCT) beams by multiple activation foils. The self-shielding corrections were made with the aid of MCNP calculations. The initial spectra were adjusted by a sophisticated process named coarse-scaling adjustment using SAND-EX, which can adjust a given coarse-group spectrum into a fine-group structure, i.e. 640 groups, with excellent continuity. The epithermal neutron flux of the THOR beam is about three times of HB11. The thermal neutron flux, boron and gold reaction rates along the central axis of a PMMA phantom are calculated for both adjusted spectra for comparison. [Copyright &y& Elsevier]