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Purpose: To quantitatively analyze choroidal and retinal vascular changes in HLA-B27-associated anterior uveitis. Study Design: A retrospective study. Methods: Medical records of 51 eyes with unilateral HLA-B27-associated anterior uveitis, their fellow eyes and 47 sex and age-matched healthy eyes were retrospectively reviewed. Their choroidal and retinal vasculature were analyzed using swept-source (SS) optical coherence tomography (OCT) and OCT angiography (OCTA) scans. Results: Deep capillary plexus (DCP) vessel density (VD) (p < 0.001), choroidal vascularity index (CVI) (p = 0.012), and choriocapillary flow deficit (CCFD) (p < 0.001) of uveitic and fellow eye group were significantly higher than those of control group. On the contrary, superficial capillary plexus (SCP) VD (p < 0.001) of uveitic and fellow eye group were significantly lower than of control group. The vascular parameters of uveitis and fellow eye group showed no significant difference between uveitic and resolution period. Conclusion: Certain choroidal and retinal vascular parameters were significantly changed in both HLA-B27-associated anterior uveitis without posterior segment involvement and the quiet fellow eyes, suggesting their possible effects as a systemic inflammatory disorder. [ABSTRACT FROM AUTHOR]

Purpose: This single center retrospective study aimed to investigate the factors associated with central nervous system (CNS) involvement of primary vitreoretinal lymphoma (PVRL). Methods: Clinical features of patients with PVRL (Group 1), those diagnosed with vitreoretinal lymphoma (VRL) after primary CNS lymphoma diagnosis (Group 2), and those concurrently diagnosed with CNS lymphoma and VRL (Group 3), were compared. The main outcomes included sex, age, types of treatment, survival, visual acuity, diagnostic methods, VRL recurrence, ocular manifestations, and interleukin levels in the aqueous humor. Results: Groups 1, 2, and 3 included 66 eyes in 38 patients, 29 eyes in 18 patients, and 14 eyes in 8 patients, respectively. Group 3 had shorter overall survival (OS) than Groups 1 and 2 (P = 0.042 and P = 0.009, respectively). The three groups did not differ in progression-free survival (P = 0.060). The 5-year survival rates of Groups 1, 2, and 3 were 56.5%, 44.0%, and 25.0%, respectively (P = 0.001). Patients with CNS involvement in Group 1 exhibited VRL recurrence (P < 0.001), high interleukin-10 (P = 0.024), and sub-retinal pigment epithelium (RPE) infiltration (P = 0.009). Patients experiencing VRL recurrence in Group 1 tended to show CNS involvement (P < 0.001). Conclusion: Patients concurrently diagnosed with CNS lymphoma and VRL had a shorter OS and a lower 5-year survival rate. In patients with PVRL, the recurrence of VRL, high interleukin-10, and sub-RPE infiltration were associated with CNS involvement. [ABSTRACT FROM AUTHOR]

Purpose: To determine the cut-off points of minimum linear diameter (MLD) and base diameter (BD) at which the progression rate of idiopathic full-thickness macular holes (MHs) decreases before vitrectomy. Study design: A retrospective study. Methods: We investigated the differences in MLD and BD between baseline and operation days in patients with stages 2, 3, and 4 MHs using optical coherence tomography (OCT). Each difference in OCT parameters was divided by the time interval to calculate the MH progression rates and the cut-off points of MLD and BD. Results: Overall, 269 patients (282 eyes) were included. It took an average of 36.02 ± 24.69 (7–197) days from baseline to operation. MLD and BD progressed faster in stages 2 and 3 without posterior vitreous detachment (PVD) than in stage 4 with PVD (MLD: p < 0.001 and p = 0.007; BD: p < 0.001 and p = 0.019, respectively). Simple linear regression showed the relationship between baseline MLD and BD, and the progression rate; the progression rate decreased as baseline MLD (p = 0.004) and BD increased (p < 0.001). For baseline MLD and BD, the cut-off points where the progression rate decreased were 306.0 and 470.0 μm, respectively. Conclusion: The group without PVD progressed faster than the group with PVD. Moreover, the progression rates were faster in MHs with MLD < 306.0 μm and BD < 470.0 μm. In these patients, vitrectomy without delay is expected to improve the visual prognosis. [ABSTRACT FROM AUTHOR]

Somatostatin analogues have recently been used as therapeutic targets for metastatic or surgically unresectable gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), and associated somatostatin receptor (SSTR) expression has been well demonstrated in most GEP NETs, with the exception of rectal NETs. SSTR2 immunohistochemical expressions were evaluated in 350 surgically or endoscopically resected rectal NETs and compared to clinicopathologic factors. SSTR2 expression was observed in 234 (66.9%) rectal NET cases and associated tumors with smaller size (p = 0.001), low pT classification (p = 0.030), low AJCC tumor stage (p = 0.012), and absence of chromogranin expression (p = 0.009). Patients with rectal NET and SSTR2 expression had significantly better overall survival than those without SSTR2 expression both by univariable (p = 0.006) and multivariable (p = 0.014) analyses. In summary, approximately two-thirds of rectal NETs expressed SSTR2. SSTR2 expression was significantly associated with favorable behavior and good overall survival in patients with rectal NETs. Furthermore, SSTR2 expression can be used as prognostic factors. When metastatic disease occurs, SSTR2 expression can be used a possible target for somatostatin analogues. [ABSTRACT FROM AUTHOR]

Polygraphs are used in criminal interrogations to detect deception. However, polygraphs can be difficult to administer under circumstances that prevent the use of biosensors. To address the shortcomings of the biosensors, deception-detection technology without biosensors is needed. We propose a deception-detection method, FacialCueNet, which is a multi-modal network that utilizes both facial images and facial cues based on deep-learning technology. FacialCueNet incorporates facial cues that indicate deception, such as action-unit frequency, symmetry, gaze pattern, and micro-expressions extracted from videos. Additionally, the spatial-temporal attention module, based on convolutional neural network and convolutional long short-term memory, is applied to FacialCueNet to provide interpretable information from interrogations. Because our goal was developing an algorithm applicable to criminal interrogations, we trained and evaluated FacialCueNet using the DDCIT dataset, which was collected using a data acquisition protocol similar to those used in actual investigations. To compare deception-detection performance with state-of-the-art works, a public dataset was also used. As a result, the mean deception-detection F1 score using the DDCIT dataset was 81.22%, with an accuracy of 70.79%, recall of 0.9476, and precision of 0.7107. When evaluating against the public database, our method demonstrated an evaluation accuracy of 88.45% and achieved an AUC of 0.9541, indicating a improvement of 1.25% compared to the previous results. We also present interpretive results of deception detection by analyzing the influence of spatial and temporal factors. These results show that FacialCueNet has the potential to detect deception using only facial videos. By providing interpretation of predictions, our system could be useful tool for criminal interrogation. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate perivascular reflectivity in patients with branched retinal vascular obstruction (BRVO) using en-face optical coherence tomography (OCT). The study retrospectively analyzed 45 patients with recurrent BRVO, 30 with indolent BRVO, and 45 age- and sex-matched controls. Using a 3.0 × 3.0-mm deep capillary plexus slab on macular scans, OCT angiography (OCTA) and structural en-face OCT scans were divided into four quadrants. Obstructive quadrants of OCTA scans were binarized using a threshold value of mean + 2 standard deviation. The selected area of high signal strength (HSS) was applied to the structural en-face OCT scans, and the corrected mean perivascular reflectivity was calculated as the mean reflectivity on the HSS area/overall en-face OCT mean reflectivity. The same procedure was performed in the quadrants of the matched controls. Regression analysis was conducted on several factors possibly associated with corrected perivascular reflectivity. The perivascular reflectivity in the obstructive BRVO quadrant was significantly higher than in the indolent BRVO and control quadrants (P = 0.009, P = 0.003). Both univariate and multivariate regression analyses showed a significant correlation between the average number of intravitreal injections (anti-vascular endothelial growth factor or dexamethasone implant) per year and refractive errors and image binarization threshold and perivascular reflectivity (P = 0.011, 0.013, < 0.001/univariate; 0.007, 0.041, 0.005/multivariate, respectively). En-face OCT scans of the deep capillary plexus slab revealed higher perivascular reflectivity in recurrent BRVO eyes than in indolent BRVO and control eyes. The results also indicate a remarkable correlation between perivascular reflectivity and the average number of intravitreal injections, suggesting a link to recurrence rates. [ABSTRACT FROM AUTHOR]

Background: TBC1 domain-containing kinase (TBCK) protein functions as a growth suppressor in certain cell types and as a tumor promoter in others. Although TBCK knockdown increases the responsiveness of cancer cells to anticancer drugs, the detailed mechanisms by which TBCK knockdown increases susceptibility to anticancer drugs remain unknown. Objective: This study analyzed the role of TBCK in sensitivities to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and doxorubicin in human renal cancer cells. Methods: Flow cytometry was employed to evaluate the extent of apoptosis. Western blotting, transient transfection, and lentiviral infection techniques were conducted to investigate the impact of TBCK on apoptosis-related protein expression and mitogen-activated protein kinase (MAPK). Results: TBCK knockdown in renal cancer cells inhibits ERK and Akt signaling pathways and increases TRAIL and doxorubicin sensitivity. In TBCK-knockdown Caki-1 cells, ERK and Akt phosphorylation was suppressed compared to control cell lines, and TRAIL and doxorubicin sensitivities were increased in these cells. In addition, the phosphorylation of PDK1 was suppressed in TBCK-suppressed cells, indicating that TBCK may be involved in the PDK1 and Akt signaling pathways. The introduction of dominantly active Akt into TBCK-suppressed cells restored their sensitivity to TRAIL. In addition, TBCK downregulation enhanced TRAIL sensitivity in different renal cancer cell lines. Conclusions: These data suggest that TBCK could potentially have a crucial function in influencing the effects of anti-cancer drugs including TRAIL by modulating the signaling pathway involving Akt and PDK1 in human renal cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze characteristics, treatment, long-term outcomes, and prognostic factors for children, adolescents and young adults with rhabdomysosarcoma (RMS). Methods: This retrospective historical study included 75 patients with RMS treated between 2002 and 2019. Clinical data and follow-up results were collected including all diagnosis, treatment and prognosis information. Results: Patients median-age-at-diagnosis was 6 years. Embryonal and alveolar histology occurred in 51 (68.0%) and 21 (28.0%) patients, respectively. The tumors most frequently originated from parameningeal site (28.0%). Of 74 evaluable patients for treatment outcome, 60 (81.1%) achieved complete response for first-line treatment, of whom, 34 (56.6%) maintained complete response, 26 (43.3%; 23/26, local relapse) showed relapse. Of 40 patients with treatment failure, 16 and 6 occurred in parameningeal area and retroperitoneum/perineum, respectively. The 5-year progression-free survival (PFS) and overall survival (OS) were 45.0% and 64.5%, respectively. In multivariate analyses, parameningeal site (p = 0.027), no gross total resection (p = 0.047), and no radiation therapy (RT) (p < 0.001) for PFS; and parameningeal site (p < 0.001) and no RT (p = 0.010) for worse OS, were significant. The median PFS and OS from treatment failure date in 40 patients with primary treatment failure were 1.3 and 4.1 years, respectively. Of 26 patients with relapse, interval to relapse < 7 months, retroperitoneum/perineum site, TNM stages III/IIV, and no salvage RT were independently associated with OS. Conclusion: The importance of adequate local therapy was highlighted in RMS treatment. Treatment failure was largely a local failure. Whether as a component of initial or salvage treatment, RT could improve patients' survival. [ABSTRACT FROM AUTHOR]

To investigate the preoperative morphology of the foveal avascular zone (FAZ) for prediction of the postoperative visual acuity in advanced idiopathic epiretinal membrane (ERM). 28 patients (28 eyes) with unilateral idiopathic ERM who underwent pars plana vitrectomy with internal limiting membrane peeling were included. Superficial FAZ was measured preoperatively in both eyes using optical coherence tomography angiography. Area, perimeter, and circularity of FAZ were achieved, and the differences between the ERM eyes and the contralateral eyes were evaluated to analyze the degree of FAZ distortion in diseased eyes. The best-corrected visual acuity (BCVA) and central foveal thickness (CFT) were measured at baseline and more than 6 months after surgery. The correlations of the preoperative FAZ with BCVA and CFT were assessed. The FAZ in the eyes with ERM was significantly reduced, and the BCVA was significantly correlated with the FAZ area (FAZa) (P = 0.001) and the FAZ perimeter (FAZp) (P < 0.001) before surgery. LogMAR BCVA and CFT were significantly improved from 0.550 ± 0.221 to 0.354 ± 0.229 (P = 0.008), and from 524.393 ± 93.575 µm to 400.071 ± 75.979 µm (P < 0.001) after surgery. The preoperative FAZa and FAZp were significantly associated with letter score gain (P < 0.001, P < 0.001) and the postoperative final BCVA (P = 0.026, P = 0.006). The preoperative FAZp had correlation with ratio of postoperative to preoperative CFT (P = 0.016). The preoperative FAZp is a predictor of visual acuity and morphological prognosis after surgery in advanced idiopathic ERM. [ABSTRACT FROM AUTHOR]

Obinutuzumab is a therapeutic antibody for B cell non-Hodgkin's Lymphoma (BNHL), which is a glyco-engineered anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and causes binding-induced direct cell death (DCD) through lysosome membrane permeabilization (LMP). Tumour necrosis factor receptor 1 (TNFR1), a pro-inflammatory death receptor, also evokes cell death, partly through lysosomal rupture. As both obinutuzumab- and TNFR1-induced cell deaths are mediated by LMP and combining TNFR1 and obinutuzumab can amplify LMP-mediated cell death, we made dual-targeting antibody for CD20 and TNFR1 to enhance DCD of obinutuzumab. Obinutuzumab treatment-induced CD20 and TNFR1 colocalisation, and TNFR1-overexpressing cells showed increased obinutuzumab-induced DCD. Two targeting modes, anti-CD20/TNFR1 bispecific antibodies (bsAbs), and obinutuzumab-TNFα fusion proteins (OBI-TNFαWT and OBI-TNFαMUT), were designed to cluster CD20 and TNFR1 on the plasma membrane. OBI-TNFαWT and OBI-TNFαMUT showed significantly enhanced LMP, DCD, and ADCC compared with that induced by obinutuzumab. TNFR1 expression is upregulated in many BNHL subtypes compared to that in normal B cells; OBI-TNFαMUT specifically increased DCD and ADCC in a B cell lymphoma cell line overexpressing TNFR1. Further, OBI-TNFαMUT blocked NF-κB activation in the presence of TNF-α, implying that it can antagonise the proliferative role of TNF-α in cancers. Our study suggests that dual targeting of CD20 and TNFR1 can be a new therapeutic strategy for improving BNHL treatment. The OBI-TNFαMUT fusion protein enhances DCD and ADCC and prevents the proliferating effect of TNFα signalling; therefore, it may provide precision treatment for patients with BNHL, especially those with upregulated TNFR1 expression. [ABSTRACT FROM AUTHOR]

The purpose of this study is to evaluate choroidal hyperreflective foci (HRF) changes in central serous chorioretinopathy (CSC) on en-face optical coherence tomography (OCT). Retrospective analysis of 42 patients with unilateral CSC (84 eyes, including fellow eyes for controls) and 42 age- and sex-matched controls. With 4.5 × 4.5 mm macular scans, structural en-face OCT choriocapillaris (CC) slabs were used to calculate the density and number of HRF in acute CSC eyes with serous retinal detachment (SRD), resolved CSC eyes without SRD, unaffected fellow eyes, control eyes, and 1-year follow-up eyes. Based on the 2-disc diameter (3000 μm), the en-face OCT scan was divided into foveal and perifoveal lesion and analyzed to consider the impact of SRF in HRF measurement. Regression analyses were performed on the several factors with HRF number and density in the acute and resolved CSC eyes. The perifoveal density and number of CC HRF was significantly lower in the resolved CSC eyes when compared to the acute CSC eyes (P = 0.002, both), fellow eyes (P = 0.042/density, 0.028/number), and controls (P = 0.021/density, P = 0.003/number). There was no significant difference between the acute CSC eyes, fellow eyes, controls, and 1-year follow-up eyes. As subfoveal choroidal thickness decreased and choroidal vascularity (CVI) increased, the perifoveal density and number of HRF was measured higher with a significant correlation in univariate regression analysis of the acute and resolved CSC eyes (all, P < 0.05). The authors hypothesized that stromal edema induced by choroidal congestion and hyperpermeability has the greatest influence on HRF measurement, possibly affected by inflammatory cells and materials extravasation. [ABSTRACT FROM AUTHOR]

Cancer therapy using immune checkpoint inhibitor antibodies has markedly shifted the paradigm of cancer treatment. However, methods completely eliminating the effector function of these signal-regulating antibodies is urgently required. The heterogeneity of glycan chains in antibodies limits their use as therapeutic agents due to their variability; thus, the development of uniform glycan chains is necessary. Here, we subjected the anti-programmed cell death protein (PD)-1 antibody nivolumab, a representative immune checkpoint inhibitor, to GlycoDelete (GD) engineering to remove the antibody-dependent cellular cytotoxicity (ADCC) of the antibody, leaving only one glycan in the Fc. Glyco-engineered CHO cells were prepared by overexpressing endo-β-N-acetyl-glucosaminidase (Endo T) in CHO cells, in which N-acetyl-glucosaminyl-transferase I was knocked out using Cas9. GD IgG1 nivolumab and GD IgG4 nivolumab were produced using GD CHO cells, and glycan removal was confirmed using mass spectrometry. Target binding and PD-1 inhibition was not altered; however, ADCC decreased. Furthermore, the IgG4 form, determined to be the most suitable form of GD nivolumab, was produced in a plant GD system. The plant GD nivolumab also reduced ADCC without affecting PD-1 inhibitory function. Thus, CHO and plant GD platforms can be used to improve signal-regulating antibodies by reducing their effector function. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the choriocapillaris (CC) flow in central serous chorioretinopathy (CSC) and determine the relationship between CC flow void with the choroidal thickness (CT) and choroidal vascularity index (CVI). Methods: Retrospective analysis of 20 patients with CSC (40 eyes, including unaffected fellow eyes) and 20 age- and sex-matched controls. After compensation with optical coherence tomography (OCT) en-face structural image, the CC flow void (%) was measured using the phansalkar threshold with a window radius of 3 and 15 pixels. The mean CC flow voids of acute CSC, recovered-acute CSC, unaffected fellow, and control eyes were compared by matched data analysis. A regression analysis was performed on the choroidal parameters (CT and CVI) and CC flow voids. Results: The CC flow void had an increasing tendency in the following order: control, fellow, recovered-acute CSC, and acute CSC eyes. Acute/recovered comparison showed a significant P value (0.008) in the foveal lesion. Recovered/fellow and fellow/control presented significant P values regardless of location to fovea (all <0.05). There were significant positive correlations between CT and CC flow void (P < 0.05) in the acute CSC, recovered-acute CSC eyes. Conclusion: The CC flow on OCT angiography decreased in acute CSC eyes, especially in the foveal lesion, with a published compensation method. The findings suggest that unmodulated choroidal blood flow contributed to partially reversible diminished CC flow. [ABSTRACT FROM AUTHOR]

Although autophagy is critical for pancreatic β-cell function, the role and mechanism of mitophagy in β-cells are unclear. We studied the role of lysosomal Ca2+ in TFEB activation by mitochondrial or metabolic stress and that of TFEB-mediated mitophagy in β-cell function. Mitochondrial or metabolic stress induced mitophagy through lysosomal Ca2+ release, increased cytosolic Ca2+ and TFEB activation. Lysosomal Ca2+ replenishment by ER- > lysosome Ca2+ refilling was essential for mitophagy. β-cell-specific Tfeb knockout (TfebΔβ-cell) abrogated high-fat diet (HFD)-induced mitophagy, accompanied by increased ROS and reduced mitochondrial cytochrome c oxidase activity or O2 consumption. TfebΔβ-cell mice showed aggravation of HFD-induced glucose intolerance and impaired insulin release. Metabolic or mitochondrial stress induced TFEB-dependent expression of mitophagy receptors including Ndp52 and Optn, contributing to the increased mitophagy. These results suggest crucial roles of lysosomal Ca2+ release coupled with ER- > lysosome Ca2+ refilling and TFEB activation in mitophagy and maintenance of pancreatic β-cell function during metabolic stress. Autophagy is important for pancreatic β-cell function, however, the role of mitophagy and mechanism for mitophagy in β-cells are unclear. Here the authors report that in stressed β-cells, lysosomal Ca2+ release promotes mitophagy via activation of the transcription factor EB (TFEB) and loss of β-cell TFEB aggravates glucose intolerance during high-fat diet. [ABSTRACT FROM AUTHOR]

Background: Neferine is the major alkaloid extracted from a seed embryo of Nelumbo nucifera and shows cytotoxic effects in various human cancer cells. However, no detailed studies have been reported on its antitumor efficacy of a combinational treatment in human renal cancer cells. Objective: This study evaluated the antitumor effects of a combination therapy of neferine and various drugs on renal cancer Caki-1 cells. Methods: Flow cytometry analysis was performed to evaluate the cell cycle analysis and apoptosis, respectively. Western blotting and reverse transcription polymerase chain reaction were performed to analyze the effect of neferine on the expression of apoptosis-related genes in Caki-1 cells. In addition, reactive oxygen species (ROS) generation was evaluated using flow cytometry. Results: Treatment with neferine dose-dependently induces apoptosis and Bcl-2 downregulation in Caki-1 cells. In addition, neferine triggers cell cycle arrest at the G2/M phase in Caki-1 cells. The neferine-induced apoptosis was mediated by ROS generation, and neferine-facilitated Bcl-2 downregulation was regulated at the transcriptional level through the suppression of p65 expression, resulting in inactivation of the NF-κB pathway in Caki-1 cells. The ROS scavenger, N-acetyl-l-cysteine (NAC), intensely reversed the effects of neferine on apoptosis and Bcl-2 downregulation. We determined that neferine markedly potentiates the antitumor effects of multiple anticancer drugs (cisplatin, silybin, and thapsigargin), and those effects can be reversed by Bcl-2 overexpression or NAC pretreatment in Caki-1 cells. Conclusion: These results suggest that neferine can increase chemosensitivities to anticancer drugs via downregulation of Bcl-2 expression through ROS-dependent suppression of the NF-κB signaling pathway in human renal cancer cells. [ABSTRACT FROM AUTHOR]

This retrospective study aimed to evaluate the factors affecting recurrence and visual prognosis in patients with treatment-naïve subfoveal polypoidal choroidal vasculopathy (PCV). Patients who had received three consecutive intravitreal injections of ranibizumab or aflibercept and had reached remission were enrolled. They were divided into a group without recurrence (group 1, 26 eyes) and a group with recurrence (group 2, 121 eyes) and followed up for at least 5 years. Patients in group 2 received additional treatment for worsening. Logistic regression analysis revealed that a young age of onset (P = 0.001), high choroidal vascularity index (CVI; P = 0.019), and presence of choroidal vascular hyperpermeability (CVH; P = 0.037) were associated with a low risk of recurrence. Multiple regression analysis revealed that recurrence (P = 0.001), greatest linear dimension (P = 0.003), and polyp configuration (single or cluster; P = 0.043) were associated with final visual acuity. Patients without recurrence had a lower age of onset and higher CVI than those with recurrence, and they tended to have CVH. In addition, patients with recurrence, large lesion, and cluster polyps had worse final visual acuity than those without these factors. CVI and CVH may be used to predict recurrence of PCV. [ABSTRACT FROM AUTHOR]

Plants are promising drug-production platforms with high economic efficiency, stability, and convenience in mass production. However, studies comparing the equivalency between the original antibodies and those produced in plants are limited. Amino acid sequences that constitute the Fab region of an antibody are diverse, and the post-transcriptional modifications that occur according to these sequences in animals and plants are also highly variable. In this study, rituximab, a blockbuster antibody drug used in the treatment of non-Hodgkin's lymphoma, was produced in Nicotiana benthamiana leaves and Arabidopsis thaliana callus, and was compared to the original rituximab produced in CHO cells. Interestingly, the epitope recognition and antigen-binding abilities of rituximab from N. benthamiana leaves were almost lost. In the case of rituximab produced in A. thaliana callus, the specific binding ability and CD20 capping activity were maintained, but the binding affinity was less than 50% of that of original rituximab from CHO cells. These results suggest that different plant species exhibit different binding affinities. Accordingly, in addition to the differences in PTMs between mammals and plants, the differences between the species must also be considered in the process of producing antibodies in plants. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of cataract surgery combined with pars plana vitrectomy (ppV) on choroidal vascularity index (CVI) in eyes with epiretinal membrane (ERM) and full thickness macular hole (FTMH). Medical records of 132 eyes with ERM or FTMH were retrospectively reviewed and classified into a ppV group and a ppV combined with cataract surgery group (phaco + ppV group). The CVI were measured at baseline, 1, 3 and 6 months after the surgery, using the selected swept-source (SS) optical coherence tomography (OCT) scan passing through the central fovea, which was then segmented into luminal and stromal area by image binarization. The mean CVI of phaco + ppV group were 61.25 ± 1.97%, 61.66 ± 1.81%, and 62.30 ± 1.92% at baseline, 1 and 3 months, respectively (p < 0.001). The mean CVI of ppV group were 62.69 ± 1.92%, 62.03 ± 1.51%, and 61.45 ± 1.71% at baseline, 1 and 3 months, respectively (p < 0.001). The final CVI were measured at 6 months and compared with the baseline CVI. The mean CVI of phaco + ppV group were 61.21 ± 1.99% at baseline and 60.68 ± 2.02% at 6 months (p < 0.001). The mean CVI of ppV group were 62.93 ± 1.70% at baseline and 61.77 ± 1.74% at 6 months (p < 0.001). Vitrectomy significantly decreases CVI in vitreomacular diseases possibly due to the removal of vitreomacular traction or postoperative oxygenation change in the eye. On the contrary, combined surgery of vitrectomy and cataract surgery significantly increases CVI in the early stage of postoperative period, which suggests choroidal vascular dilatation or congestion due to postoperative inflammation. Although the CVI were measured lower than the baseline in the end, more thorough inflammation control may be essential after combined surgery. [ABSTRACT FROM AUTHOR]

Background: Lactucin, a naturally occurring active sesquiterpene lactone, is abundantly found in chicory and romaine lettuce. A recent study reported that lactucin could induce apoptosis in leukemia cells. However, its cytotoxicity and potential molecular mechanisms underlying cancer cell death remain unclear. Objective: Therefore, in this study, we aimed to investigate the direct effect and underlying mechanism of action of lactucin on renal cancer cells. Methods: MTT assay and flow cytometry were performed to evaluate the rate of cell proliferation and apoptosis, respectively. Western blotting, reverse transcription polymerase chain reaction, and protein stability analyses were performed to analyze the effect of lactucin on the expression of apoptosis-related proteins such as B-cell lymphoma 2 (BCL-2) and CFLAR (CASP8 and FADD like apoptosis regulator) long isoform (CFLARL) in Caki-1 human renal cancer cells. In addition, reactive oxygen species (ROS) generation was evaluated using flow cytometry. Results: Lactucin treatment induced apoptosis in Caki-1 cells in a dose-dependent manner via activation of the caspase pathway. It downregulated BCL-2 and CFLARL expression levels by suppressing BCL-2 transcription and CFLARL protein stability, respectively. Pretreatment with N-acetyl-1-cysteine, a ROS scavenger, attenuated the lactucin-induced apoptosis and restored the BCL-2 and CFLARL expression to basal levels. Lactucin-facilitated BCL-2 downregulation was regulated at the transcriptional level through the inactivation of the NF-κB pathway. Conclusions: Our study is the first to demonstrate that lactucin-induced apoptosis is mediated by ROS production, which in turn activates the caspase-dependent apoptotic pathway by inhibiting BCL-2 and CFLARL expression in Caki-1 cells. [ABSTRACT FROM AUTHOR]

Screening tests in which 30 species of succulent plants were inoculated with A136 or C58 strains of Agrobacterium tumefaciens led to selecting genus Kalanchoe for further study of Agrobacterium-mediated transformation. Regeneration studies showed that 4.55 µM Thidiazuron (TDZ) combined with 2.15 µM α-naphtaleneacetic acid (NAA) significantly proliferated callus development from Kalanchoe pinnata leaf explants in Murashige and Skoog (MS) medium. Subsequently, 4.55 µM TDZ significantly enhanced shoot formation from the green and compact callus. NAA (5.37 µM) accelerated root growth leading to establishment of transgenic plants in soil. A gene encoding the fluorescent protein, ZsGreen1, was cloned into a plasmid vector harboring a constitutive figwort mosaic virus (FMV) 35S promoter, a kanamycin resistance gene, and a NOS-terminator. The plasmids were delivered into the genome of K. pinnata by A. tumefaciens strain C58 (ABI). The ZsGreen1-transgenic plants exhibited very strong, green fluorescence from the callus, leaves, stems, roots, and flowers visible through a green emission filter (GFP, 480/510 nm, excitation/emission) under excitation by ultra-violet light. Transcription analysis by sqRT-PCR and qPCR confirmed the stable integration of the ZsGreen1 in the genome of K. pinnata. The FMV 35S promoter conferred uniform expression throughout whole plant organ. ZsGreen1 was proven to be a stable marker for gene expression in genetic transformation of K. pinnata. Key message: The ZsGreen1-transgenic Kalanchoe pinnata mediated by Agrobacterium tumefaciens exhibited strong, green fluorescence from the callus, leaves, stems, roots and flowers under the control of the figwort mosaic virus (FMV) 35S promoter. [ABSTRACT FROM AUTHOR]

Occupation ratio and fatty infiltration are important parameters for evaluating patients with rotator cuff tears. We analyzed the occupation ratio using a deep-learning framework and studied the fatty infiltration of the supraspinatus muscle using an automated region-based Otsu thresholding technique. To calculate the amount of fatty infiltration of the supraspinatus muscle using an automated region-based Otsu thresholding technique. The mean Dice similarity coefficient, accuracy, sensitivity, specificity, and relative area difference for the segmented lesion, measuring the similarity of clinician assessment and that of a deep neural network, were 0.97, 99.84, 96.89, 99.92, and 0.07, respectively, for the supraspinatus fossa and 0.94, 99.89, 93.34, 99.95, and 2.03, respectively, for the supraspinatus muscle. The fatty infiltration measure using the Otsu thresholding method significantly differed among the Goutallier grades (Grade 0; 0.06, Grade 1; 4.68, Grade 2; 20.10, Grade 3; 42.86, Grade 4; 55.79, p < 0.0001). The occupation ratio and fatty infiltration using Otsu thresholding demonstrated a moderate negative correlation (ρ = − 0.75, p < 0.0001). This study included 240 randomly selected patients who underwent shoulder magnetic resonance imaging (MRI) from January 2015 to December 2016. We used a fully convolutional deep-learning algorithm to quantitatively detect the fossa and muscle regions by measuring the occupation ratio of the supraspinatus muscle. Fatty infiltration was objectively evaluated using the Otsu thresholding method. The proposed convolutional neural network exhibited fast and accurate segmentation of the supraspinatus muscle and fossa from shoulder MRI, allowing automatic calculation of the occupation ratio. Quantitative evaluation using a modified Otsu thresholding method can be used to calculate the proportion of fatty infiltration in the supraspinatus muscle. We expect that this will improve the efficiency and objectivity of diagnoses by quantifying the index used for shoulder MRI. [ABSTRACT FROM AUTHOR]

Adaptive radiation is a phenomenon in which various organs are diversified morphologically or functionally as animals adapt to environmental inputs. Leeches exhibit a variety of ingestion behaviors and morphologically diverse ingestion organs. In this study, we investigated the correlation between behavioral pattern and feeding organ structure of leech species. Among them, we found that Alboglossiphonia sp. swallows prey whole using its proboscis, whereas other leeches exhibit typical fluid-sucking behavior. To address whether the different feeding behaviors are intrinsic, we investigated the behavioral patterns and muscle arrangements in the earlier developmental stage of glossiphoniid leeches. Juvenile Glossiphoniidae including the Alboglossiphonia sp. exhibit the fluid ingestion behavior and have the proboscis with the compartmentalized muscle layers. This study provides the characteristics of leeches with specific ingestion behaviors, and a comparison of structural differences that serves as the first evidence of the proboscis diversification. [ABSTRACT FROM AUTHOR]

Biliary intraepithelial neoplasia (BilIN) is a noninvasive precursor lesion which progresses to cholangiocarcinoma (CC). BilIN is often found synchronously adjacent to the tumor or at the surgical resection margin of resection CC. However, irrespective of its location, its prognostic significance on outcome after CC resection is unknown. The aim of this study was to elucidate the prevalence of BilIN in CC and to determine if the presence of BilIN has a prognostic or predictive effect on survival after resection for CC with curative intent. We retrospectively analyzed the database of patients with CC who underwent curative surgery performed at our institution from 2010 to 2017. There were 142 patients who underwent curative surgery for CC. BilIN was detected in 42 patients (29.5%) and showed a significantly higher prevalence in extrahepatic CC (90.5%) than in intrahepatic CC (9.5%; p = 0.003). On univariate analysis, extrahepatic hepatic CC patients with BilIN lesions significantly showed better disease-free survival (p = 0.05). Also, although not statistically significant, extrahepatic CC patients with BilIN lesions revealed better overall survival (p = 0.09). On multivariate analysis, presence of BilIN lesion, irrespective of location, was significantly associated with better disease-free (HR = 1.959, 95% CI 1.026–3.743, p = 0.042) and overall survival (HR = 2.140, 95% CI 1.006–4.552, p = 0.048) in extrahepatic CC patients. In conclusion, the presence of BilIN lesions was not uncommon in CC patients and was significantly associated with better disease-free and overall survival in extrahepatic CC patients. However, larger studies with longer follow-up are needed to accurately determine its clinical significance. [ABSTRACT FROM AUTHOR]

O-Glycosylation occurs in recombinant proteins produced by CHO cells, but this phenomenon has not been studied extensively. Here, we report that rituximab is an O-linked N-acetyl-glucosaminylated (O-GlcNAcylated) protein and the production of rituximab is increased by thiamet G, an inhibitor of O-GlcNAcase. The production of rituximab doubled with OGA inhibition and decreased with O-GlcNAc transferase inhibition. O-GlcNAc-specific antibody and metabolic labelling with azidO-GlcNAc confirmed the increased O-GlcNAcylation with thiamet G. Protein mass analysis revealed that serine 7, 12, and 14 of the rituximab light chain were O-GlcNAcylated. S12A mutation of the light chain decreased rituximab stability and failed to increase the production with thiamet G without any significant changes of mRNA level. Cytotoxicity and thermal stability assays confirmed that there were no differences in the biological and physical properties of rituximab produced by thiamet G treatment. Therefore, thiamet G treatment improves the production of rituximab without significantly altering its function. [ABSTRACT FROM AUTHOR]

“With no lysine” (WNK) kinases have been shown to regulate various ion transporters in various tissues, but studies on the function of WNK kinases in the brain have been limited. In this study, we discovered that WNK1 and WNK4 in POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice (WNK1 TG) decrease appetite via degradation of Kir6.2. Weight gain after 20 weeks of age was delayed in WNK1 TG mice as a result of reduced food intake. Expression of WNK1 and proopiomelanocortin (POMC) was higher in POMC-expressing neurons in the hypothalamus of WNK1 TG mice than in WT mice. Immunostaining of serial sections of the hypothalamus revealed that POMC-expressing neurons were smaller in WNK1 TG mice than in WT mice. In addition, expression of Kir6.2 was significantly reduced in WNK1 TG mice. Overexpression and knockdown of WNK4 demonstrated that WNK4 regulates protein expression of Kir6.2 via protein-protein interaction. Accordingly, reduced age-dependent weight gain of WNK1 TG mice seems to be related with the decreased Kir6.2 expression via WNK1- and WNK4-regulated protein stability of Kir6.2. [ABSTRACT FROM AUTHOR]

The movement of microglia is regulated mainly by P1 and P2 purinergic receptors, which are activated by various nucleotides and their metabolites. Recently, such purinergic signalling has been spotlighted because of potential roles in the pathophysiologies of neurodegenerative and neuropsychiatric disorders. To understand the characteristics of microglia in relation of P1 and P2 signalling, we investigated the ectoenzymes expressed in microglia. At first, we profiled the expression of all known ectoenzymes in cultured microglia. We found that, like NTPDase1 (ectonucleoside triphosphate diphosphohydrolase 1, CD39), NPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1, PC-1) is also highly expressed in primary cultured murine microglia. Knockdown of NPP1 significantly reduced ATP hydrolysis and Pi production in cultured microglia. In addition, the knockdown of NPP1 enhanced basal nucleotide-stimulating responses of cultured microglia, such as phagocytosis and cell migration, and these results were very similar to NTPDase1 knockdown results. Moreover, inhibition of the adenosine receptors by caffeine treatment reduced phagocytosis of NPP1 knock downed-cultured microglia. In conclusion, we suggest that these potent ectoenzymes of primary cultured murine microglia, NPP1 together with CD73 (ecto-5′-nucleotidase) maintain the adenosine levels for triggering nucleotide-stimulating responses. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the incidence of colon cancer as a second primary cancer (CCSPC) and the survival outcomes of women with and without CCSPC after the diagnosis of endometrial cancer (EC).Methods: The standardized incidence ratio (SIR) of CCSPC and survival outcomes of EC survivors with and without CCSPC were analyzed using data from January 1 1993 to December 31 2011, obtained from the Korea Central Cancer Registry.Results: Of 14,797 EC survivors, 147 (0.99%) developed CCSPC after an average interval of 5.5 years. The SIR of CCSPC among EC survivors was 2.56, higher than that of colon cancer in the general population. The SIR of CCSPC was highest for the ascending (3.77), followed by the transverse (3.45), descending colon (2.06), and rectum (1.99). The risk of a proximal site of CCSPC was high, especially within 5 years after the diagnosis of EC in the ascending (SIR, 4.37) and transverse (4.91) colon, and in young survivors (< 60 years) in the ascending (5.19) and transverse (3.82) colon. The 5- and 10-year overall survival rates were 84.8 and 80.4% among survivors with EC only and 89.2 and 76.3% for survivors with CCSPC, respectively.Conclusions: The risk of CCSPC among EC survivors increases especially in the proximal colon in young survivors. These results could be used for surveillance and counseling of EC survivors. [ABSTRACT FROM AUTHOR]

Well-differentiated pancreatic neuroendocrine neoplasms/tumors (PanNETs) are rare neoplasms with diverse clinical behavior. Biomarker discovery is important for predicting clinical course and prognosis of PanNET patients. Carbonic anhydrase 9 (CA9) and vimentin are hypoxia and epithelial-mesenchymal transition-related proteins of which expression in many carcinomas has been associated with poor prognosis, but their significance in PanNET has yet to be determined. We assessed CA9 and vimentin expression in 164 PanNETs and compared this with clinicopathologic characteristics. CA9 expression was observed in normal islets, while neuroendocrine microadenomas and small (< 1 cm) PanNETs showed loss of CA9 expression. CA9 and vimentin expression was observed in 38 (23%) and 36 (22%) of PanNETs, respectively. CA9 expression was associated with larger size (p = 0.001), higher grade (p < 0.001), higher pT category (p < 0.001), lymph node (p = 0.003) and distant (p = 0.047) metastases, higher AJCC stage (p < 0.001), and lymphovascular (p < 0.001) and perineural (p = 0.002) invasion. PanNET patients with CA9 expression had a shorter recurrence-free survival (5-year survival rate 47%) than those without CA9 expression (76%) by univariate (p = 0.001) but not multivariate analysis. Vimentin expression correlated with CA9 expression (p < 0.001) but not with other clinicopathologic factors. In conclusion, CA9 expression was observed in normal islets, while neuroendocrine microadenomas and small (< 1 cm) PanNETs showed CA9 expression loss. CA9 expression gradually reappeared in larger PanNETs, and this was associated with clinical progression and decreased patient survival by univariate but not multivariate analysis. [ABSTRACT FROM AUTHOR]

Blood stain evidence obtained from a violent crime scene provides decisive clues that can enable a case to be solved through forensic analyses such as genetic identification. However, collected samples usually contain a mixture of biological material from different sources, making genetic identification difficult. To address this issue, we developed an activatable aptamer sensor targeting 17β-estradiol for detection of female-specific blood in mixed samples. With the sensor, we were able to detect blood originating from females using a variable light source (495 nm). The sensor was especially sensitive to blood from young females (10-40 years) but not to blood from older females (≥ 50 years). Genomic DNA was extracted from the female blood specimens identified by this method and used for quantification and short tandem repeat genotyping. We confirmed that there was no fluorescence interference from the aptamer sensor. These results indicate that this novel aptamer sensor can be used to analyze evidentiary blood samples and thereby facilitate subsequent genetic identification. [ABSTRACT FROM AUTHOR]

Glutamine metabolism is emerging as one aspect of dysregulated metabolism of tumors. Triple-negative breast cancer (TNBC) cells are glutamine dependent, whereas luminal-type cells tend to be glutamine independent. Therefore, TNBC patients might benefit from therapies targeting glutamine metabolism. To investigate the clinical significance of glutamine metabolism, we examined expression and prognostic significance of glutaminase in tumor cells and tumor-infiltrating lymphocytes (TILs) in TNBC. We retrieved 658 surgically resected TNBCs and analyzed glutaminase expression in tumor cells and TILs by immunohistochemical staining. Glutaminase expression was observed in 237 cases (36.0%) in tumor cells and 104 cases (15.5%) in TILs. Although glutaminase expression in tumor cells was significantly associated with a low level of TILs (p = 0.018), glutaminase expression in TILs was significantly higher in cases with a high level of TILs (p = 0.031). Glutaminase expression in tumor cells was significantly associated with poor disease-free survival in patients with lymph node metastasis and high levels of TILs (p = 0.020). In addition, it was an independent poor prognostic factor (hazard ratio = 10.643, 95% confidence interval = 1.999-56.668; p = 0.006). Glutaminase expression in tumor cells was observed in a subset of TNBC patients. It was significantly associated with a low level of TILs and poor disease-free survival in TNBCs presenting with lymph node metastasis and high levels of TILs. [ABSTRACT FROM AUTHOR]

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: The goal of this study was to investigate clinical manifestations of lower extremity edema (LEE) after lymph node dissection in patients with primary endometrial cancer. Methods: Women with primary endometrial cancer who underwent staging surgery between November 2001 and March 2011 were included in the study. Medical records and/or responses to the Gynecologic Cancer Lymphedema Questionnaire (GCLQ) were used for LEE evaluation. Results: All 154 patients underwent pelvic lymph node dissection, and 126 patients (81.8 %) underwent paraaortic LN dissection. The median age of the patients was 52 years, the majority had stage I cancer (78.6 %), and most had endometrioid histology (90.9 %). The most frequent GCLQ responses were 'experienced swelling' (35.7 %), 'experienced numbness' (30.5 %), 'experienced heaviness' (29.9 %), and 'experienced aching' (29.9 %). Sixty-four patients (41.6 %) had previous (9/64, 14.1 %) and/or current (55/64, 85.9 %) patient-reported LEE. Most patients developed LEE within 12 months after surgery (39/56, 69.6 %), and LEE lasted for more than 12 months in most patients (45/56, 80.4 %). Three patients reported recurrent LEE after recovery. Multivariate logistic regression identified the number of dissected pelvic lymph node (≥21) as a risk factor for LEE [odds ratio (OR) 3.28; 95 % confidence interval (CI) 1.058-10.136] and postoperative radiotherapy (OR 3.81, 95 % CI 1.67-8.69). Conclusions: LEE developed in more than one-third of patients with endometrial cancer after surgery, and LEE lasted for more than 12 months in most patients. A high number of dissected pelvic lymph nodes and postoperative radiotherapy is associated with LEE. [ABSTRACT FROM AUTHOR]

Background: This study investigated the clinical manifestations of lower extremity edema (LEE) in locally advanced cervical cancer patients treated with two different strategies. Methods: In total, 79 cervical cancer survivors with International Federation of Gynecology and Obstetrics stage IB2-IIB were included. Six survivors with stage IB1 and who had been suspicious for lymph node metastasis on pretreatment image also were included. Forty-two patients received radiotherapy after pretreatment laparoscopic surgical staging (Group 1), and 43 patients received primary radiotherapy (Group 2). The patients' medical records and survey results of the Korean version of the Gynecologic Cancer Lymphedema Questionnaire (GCLQ-K) were analyzed. Results: The incidence of LEE was higher in Group 1 than in Group 2 (69.0 vs. 11.6 %; P < 0.001). The duration of LEE was longer in Group 1 (mean 77.3 vs. 9.4 months). At the time of survey, 47.6 % of the patients in Group 1 were clinically diagnosed with lymphedema compared with no patients in Group 2. In GCLQ-K, the mean symptom cluster scores for general swelling (0.74 vs. 0.09; P < 0.001), limb swelling (0.22 vs. 0.00; P = 0.006), and heaviness (0.45 vs. 0.23; P = 0.033) were significantly higher in Group 1. One patient in Group 1 developed lymphedema-related angiosarcoma that was diagnosed at 7.8 years after surgery. Conclusions: Patients with cervical cancer who underwent radiotherapy after laparoscopic surgical staging more commonly experienced LEE and related symptoms than patients who underwent primary radiotherapy. As LEE decreases patients' quality of life, it should be considered during patient consultation and surveillance. [ABSTRACT FROM AUTHOR]

Although the prognostic and predictive significance of tumor-infiltrating lymphocytes (TILs) in HER2-positive breast cancers has been established, the drivers of TIL influx remain unclear. We tested whether potential triggers for this response could include high mobility group B1 and N1 (HMGB1 and HMGN1) proteins, which are immunogenic damage-associated molecular pattern molecules. We evaluated TILs and the immunohistochemical expression of HMGB1 and HMGN1 in 447 HER2-positive breast cancer tissues. Normal luminal cells exhibited nuclear expression of HMGB1 and HMBN1. The nuclear and cytoplasmic expression levels of HMG proteins showed a significant inverse correlation (rho = -0.150, p = 0.001 for HMGB1; rho = -0.247, p < 0.001 for HMGN1). Low levels of HMGB1 and HMGN1 nuclear expression were identified in 185 (41.4 %) and 208 (46.5 %) cases, respectively. High levels of cytoplasmic HMGB1 and HMGN1 expression were identified in 107 (23.9 %) and 49 (11.0 %) cases, respectively. High cytoplasmic expression of HMG proteins was significantly associated with a high histological grade, high levels of TILs, peritumoral lymphocytic infiltration, and tertiary lymphoid structures in HER2-positive breast cancer tissues. Tumors with low levels of cytoplasmic HMGB1 and HMGN1 showed significantly lower levels of TILs than those with high levels of each or both HMG proteins. However, the nuclear or cytoplasmic expression of either HMG protein was not found to be significantly associated with survival. High levels of cytoplasmic HMGB1 and HMGN1 protein expression correlated with high levels of TILs in HER2-positive breast cancers. The manipulation of HMGB1 and HMGN1 could represent an immunotherapeutic approach to promote TIL influx into a tumor. [ABSTRACT FROM AUTHOR]

Purpose: We retrospectively compared the treatment outcomes of localized prostate cancer between radical prostatectomy (RP) and external beam radiotherapy (EBRT).Materials and Methods: We retrospectively analyzed 738 patients with localized prostate cancer who underwent either RP (n = 549) or EBRT (n = 189) with curative intent at our institution between March 2001 and December 2011. Biochemical failure was defined as a prostate-specific antigen (PSA)  level of ≥ 0.2 ng/ml in the RP group and the nadir of + ≥ 2 ng/ml in the EBRT group.Results: The median (range) follow-up duration was 48.8 months (0.7-133.2 months) and 48.7 months (1.0-134.8 months) and the median age was 66 years (45-89 years) and 71 years (51-84 years; p < 0.001) in the RP and EBRT groups, respectively. Overall, 21, 42, and 36 % of patients in the RP group, and 15, 27, and 58 % of patients in the EBRT group were classified as low, intermediate, and high risk, respectively (p < 0.001). Androgen-deprivation therapy was more common in the EBRT group (59 vs. 27 %, respectively; p < 0.001). The 8-year biochemical failure-free survival rates were 44 and 72 % (p < 0.001) and the disease-specific survival rates were 98 % and 97 % (p = 0.543) in the RP and EBRT groups, respectively.Conclusions: Although the EBRT group included more high-risk patients than did the RP group, the outcomes of EBRT were not inferior to those of RP. Our data suggest that EBRT is a viable alternative to RP for treating localized prostate cancer. [ABSTRACT FROM AUTHOR]

Dioscin, a saponin extracted from the roots of Polygonatum zanlanscianense, shows several bioactivities such as antitumor, antifungal, and antiviral properties. Although, dioscin is already known to induce cell death in variety cancer cells, the molecular basis for dioscin-induced cell death was not definitely known in cancer cells. In this study, we found that dioscin treatment induced cell death in dose-dependent manner in breast cancer cells such as MDA-MB-231, MDA-MB-453, and T47D cells. Dioscin decreased expressions of Bcl-2 and cIAP-1 proteins, which were down-regulated at the transcriptional level. Conversely, Mcl-1 protein level was down-regulated by facilitating ubiquitin/proteasome-mediated Mcl-1 degradation in dioscin-treated cells. Pretreatment with z-VAD fails to attenuate dioscin-induced cell death as well as caspase-mediated events such as cleavages of procaspase-3 and PARP. In addition, dioscin treatment increased the population of annexin V positive cells and induced DNA fragmentation in a dose-dependent manner in MDA-MB-231 cells. Furthermore, apoptosis inducing factor (AIF) was released from the mitochondria and translocated to the nucleus. Suppression in AIF expression by siRNA reduced dioscin-induced apoptosis in MDA-MB-231 cells. Taken together, our results demonstrate that dioscin-induced cell death was mediated via AIF-facilitating caspase-independent pathway as well as down-regulating anti-apoptotic proteins such as Bcl-2, cIAP-1, and Mcl-1 in breast cancer cells. [ABSTRACT FROM AUTHOR]

We analyzed the treatment outcomes of intracranial ependymomas in Korean children aged <18 years. Data for 96 patients were collected from five hospitals. Survival rates were calculated using the Kaplan-Meier method. Log-rank tests for univariate analyses and Cox regression model for multivariate analysis were conducted to identify prognostic factors for survival. The median age of the patients was 4 years (range, 0.3-17.9 years). The median follow-up was 55 months (range, 2-343 months). Age <3 years was an important factor for selecting adjuvant therapy after surgery. Among children aged <3 and ≥3 years, adjuvant radiotherapy (RT) was applied to 55 and 84 %, respectively, and adjuvant chemotherapy to 52 and 10 %, respectively. The 5 year local progression-free survival (LPFS), disease-free survival (DFS), and overall survival (OS) rates were 54, 52, and 79 %, respectively. Gross total resection was the most significant prognostic factor for all survival endpoints. Age ≥3 years and RT were significant prognostic factors for superior LPFS and DFS. However, the significance of age was lost in multivariate analysis for DFS. LPFS, DFS, and OS were superior in patients who started RT within 44 days after surgery (the median time) than in patients who started RT later in the patients aged ≥3 years. Postoperative RT was a strong prognostic factor for intracranial ependymomas. Our results suggest that early use of RT is an essential component of treatment, and should be considered in young children. [ABSTRACT FROM AUTHOR]

Objective: The prognosis of stage IVB cervical cancer is generally poor. In the current study, treatment outcomes were evaluated in patients with International Federation of Gynecologic Oncology stage IVB cervical cancer treated with radiotherapy and chemotherapy for progression-free survival (PFS) and treated-related toxicities. Study Design: The medical records of the patients with stage IVB cervical cancer who were treated at the National Cancer Center, South Korea were reviewed retrospectively. From February 2002 to February 2010, 45 patients were diagnosed with FIGO stage IVB cervical cancer. Survival and toxicities were compared between the 13 patients with concomitant chemoradiotherapy (CCRT) with weekly cisplatin versus 20 patients with CCRT with 5-fluorouracil/cisplatin. Results: Initial treatment included weekly cisplatin-CCRT, 5-fluorouracil/cisplatin-CCRT, neoadjuvant chemotherapy, and radiotherapy with subsequent combination chemotherapy in 13, 20, 4, and 5 patients, respectively. Overall survival (OS) and PFS were 26.2 and 6.7 months, respectively. There was no statistical difference in OS ( p = 0.47) and PFS ( p = 0.64) between the weekly cisplatin-CCRT and 5-fluorouracil/cisplatin-CCRT groups; however, the incidence of anemia >grade 3 as an acute toxicity was higher in the 5-fluorouracil/cisplatin-CCRT chemotherapy regimen group than the weekly cisplatin-CCRT group ( p = 0.03). Acute toxicity >grade 2 showed a tendency to be higher in the 5-fluorouracil/cisplatin-CCRT group. Based on multivariate analysis, poor performance status was the only independent prognostic factor of OS ( p = 0.03, 9.77; 95% CI 1.3-73.3) and PFS ( p = 0.04, 9.58; 95% CI 1.14-81.26). Conclusions: CCRT using combination chemotherapeutic agents may not have survival advantage over single agent cisplatin-based CCRT. Further improvement in treatment is needed to increase survival outcomes and to decrease treatment-related toxicities in patients with stage IVB cervical cancer. [ABSTRACT FROM AUTHOR]

Coxsackievirus B3 (CVB3) is an RNA virus that mainly causes myocarditis. We have reported previously that immunoreceptor tyrosine-based activation motif (ITAM)-like sequences are contained in the capsid protein VP2 of CVB3. The substitution of two tyrosines for phenylalanines in the ITAM-like region causes attenuation of CVB3, possibly via defective viral assembly. In this study, we found that Syk, a downstream molecule of ITAM, interacts with the wild-type (WT) CVB3 VP0 protein, but not with the mutant CVB3 VP0 (called YYFF), and that an inhibitor of Syk reduced the growth of CVB3. The WT CVB3 activated nuclear factor kappa B (NF-κB), a protein activated by ITAM, and eventually induced the production of interleukin-6 (IL-6)-one of the proinflammatory cytokines induced by NF-κB-in macrophages. However, the YYFF form did not. In addition, viral VP2 protein may be dependent on the phosphorylation of an ITAM-like region that affected the activation of NF-κB. Taken together, these results suggest that the ITAM-like sequences in CVB3 VP2 can not only affect viral structure but also act as signals in pathogenesis. [ABSTRACT FROM AUTHOR]

Receptor-evoked Ca2+ signalling involves Ca2+ release from the endoplasmic reticulum, followed by Ca2+ influx across the plasma membrane. Ca2+ influx is essential for many cellular functions, from secretion to transcription, and is mediated by Ca2+-release activated Ca2+ (Icrac) channels and store-operated calcium entry (SOC) channels. Although the molecular identity and regulation of Icrac and SOC channels have not been precisely determined, notable recent findings are the identification of STIM1, which has been indicated to regulate SOC and Icrac channels by functioning as an endoplasmic reticulum Ca2+ sensor, and ORAI1 (ref. 7) or CRACM1 (ref. 8) — both of which may function as Icrac channels or as an Icrac subunit. How STIM1 activates the Ca2+ influx channels and whether STIM1 contributes to the channel pore remains unknown. Here, we identify the structural features that are essential for STIM1-dependent activation of SOC and Icrac channels, and demonstrate that they are identical to those involved in the binding and activation of TRPC1. Notably, the cytosolic carboxyl terminus of STIM1 is sufficient to activate SOC, Icrac and TRPC1 channels even when native STIM1 is depleted by small interfering RNA. Activity of STIM1 requires an ERM domain, which mediates the selective binding of STIM1 to TRPC1, 2 and 4, but not to TRPC3, 6 or 7, and a cationic lysine-rich region, which is essential for gating of TRPC1. Deletion of either region in the constitutively active STIM1D76A yields dominant-negative mutants that block native SOC channels, expressed TRPC1 in HEK293 cells and Icrac in Jurkat cells. These observations implicate STIM1 as a key regulator of activity rather than a channel component, and reveal similar regulation of SOC, Icrac and TRPC channel activation by STIM1. [ABSTRACT FROM AUTHOR]

Purpose: Carbonic anhydrase IX (CA9) has emerged as an important surrogate marker for hypoxia in solid tumors. CA12 shares a role with CA9 in acidification of micromilieu but it is less strictly regulated by hypoxia than CA9. In this study, we investigated expression of CA9 and CA12 mRNA in primary cervical cancer. We also examined whether CA9 expression can be an indicator of reoxygenation of tumor by measuring its mRNA expression during fractionated radiotherapy. Methods: Tumor tissues were obtained from 59 patients with uterine cervical cancer who underwent radiotherapy, and a second biopsy was taken after patients had received either 10 or 20 Gy of radiation. The follow-up period ranged from 2.4 to 75 months (median=23 months). The ratio of CA9 and β-actin mRNA expression was determined both pre- and during radiation treatment by RT-PCR. Results: CA9 and CA12 mRNA expression was detected in 62.7 and 88.1% of tumors (i.e. patients), respectively, and co-expression was observed in 61% of patients. Multivariate analysis revealed that CA9 expression was the most significant factor associated with metastasis-free survival ( P=0.008, hazard ratio 34.8), whereas CA12 mRNA expression was linked to a lower risk of metastasis ( P=0.007, hazard ratio of 0.07). Tumor CA9 expression was not altered following either 10 or 20 Gy of radiotherapy. Conclusion: The strong correlation between CA9 expression and metastasis suggests that CA9 expression might be an important indicator for identifying patients who require more aggressive systemic therapy. [ABSTRACT FROM AUTHOR]

The present study investigated the association between single nucleotide polymorphisms (SNPs) in immune- or DNA repair-related genes and the integration pattern of human papillomavirus (HPV), a promising prognostic marker in cervical cancer. The HPV integration patterns of cervical cancer patients were determined by polymerase chain reaction and in situ hybridization, and categorized as episomal (group A), single-copy or multi-copy tandem repetition integrated (group B), and undetectable HPV types (group C). After sample and SNP quality control, 166,505 SNPs in 161 samples (38, 111, and 12 patients in groups A, B, and C, respectively) were examined. None of the SNPs reached genome-wide significance, and several candidate SNPs for future study were selected, including rs10999435 on chromosome 10q22, rs1322054 on chromosome 9q32-33, and rs10902171 on chromosome 11p15. Luciferase assay identified rs1322054 as the primary functional variant to regulate gene expression in immune cell. Further studies are needed to determine the genetic background of different integration patterns of HPV in cervical cancer patients. [ABSTRACT FROM AUTHOR]

This retrospective study was to compare the efficacy of intravitreal injection of ranibizumab and aflibercept for patients with pachychoroid neovasculopathy. 54 eyes were initially treated with 3 monthly loading injections of ranibizumab or aflibercept. Treatment switching from ranibizumab to aflibercept, and aflibercept to photodynamic therapy was done at 3 months in case of incomplete fluid absorption. At 3 months, the rate of complete fluid absorption was significantly higher in the aflibercept-treated group than in the ranibizumab-treated group (82.6% vs 51.6%, p = 0.018). The mean reduction of subfoveal choroidal thickness was significantly greater in the aflibercept group than in the ranibizumab group (−35 µm vs −9 µm, p = 0.013). There was no significant difference between the two groups in terms of visual improvement or decrease in central macular thickness. Complete fluid absorption was achieved after switching from ranibizumab to aflibercept in 13 of 15 eyes (86.7%). Adjunctive photodynamic therapy was required in 6 eyes. In conclusion, treatment mainly with anti-vascular endothelial growth factor effectively improved visual acuity within 12 months (from 20/56 to 20/44 at 3 months and to 20/36 at 12 months). Aflibercept was superior to ranibizumab in achieving dry macula and reducing choroidal thickness at 3 months. [ABSTRACT FROM AUTHOR]

This study was conducted to assess whether systemic arterial stiffness, indicated by cardio-ankle vascular index (CAVI), is related to changes in the microvasculature of the retina and choroid in diabetes mellitus (DM). This study included 113 patients with a confirmed diagnosis of type-2 DM. Among them, 18 patients did not have diabetic retinopathy (DR), 71 had non-proliferative DR (NPDR), and 24 had proliferative DR (PDR). The mean CAVI was 7.58 ± 1.41 in no DR, 8.72 ± 1.47 in NPDR, and 8.43 ± 1.25 in PDR group. Of the 113 eyes, 42 (37.2%) were classified as abnormal CAVI group (CAVI ≥ 9). This group had significantly higher cardiac autonomic neuropathy risk index score, decreased central choroidal thickness, and decreased choroidal vascularity index (CVI). Deep foveal avascular zone area was higher in the abnormal CAVI group. After adjustment for possible confounding factors, CAVI showed negative correlation with the CVI (r = −0.247, P = 0.013). In conclusion, there was a significant correlation between arteriosclerosis and choroidal vascular changes in DR. We suggest prompt ophthalmic evaluation in patients with systemic arteriosclerosis. If the ophthalmologist notes advanced DR, the patient should be referred to a cardiovascular clinic for detailed evaluation of systemic arteriosclerosis. [ABSTRACT FROM AUTHOR]

CFTR is a transmembrane protein that reaches the cell surface via the conventional Golgi mediated secretion pathway. Interestingly, ER-to-Golgi blockade or ER stress induces alternative GRASP-mediated, Golgi-bypassing unconventional trafficking of wild-type CFTR and the disease-causing ΔF508-CFTR, which has folding and trafficking defects. Here, we show that Sec16A, the key regulator of conventional ER-to-Golgi transport, plays a critical role in the ER exit of protein cargos during unconventional secretion. In an initial gene silencing screen, Sec16A knockdown abolished the unconventional secretion of wild-type and ΔF508-CFTR induced by ER-to-Golgi blockade, whereas the knockdown of other COPII-related components did not. Notably, during unconventional secretion, Sec16A was redistributed to cell periphery and associated with GRASP55 in mammalian cells. Molecular and morphological analyses revealed that IRE1α-mediated signaling is an upstream regulator of Sec16A during ER-to-Golgi blockade or ER stress associated unconventional secretion. These findings highlight a novel function of Sec16A as an essential mediator of ER stress-associated unconventional secretion. [ABSTRACT FROM AUTHOR]

The Lophophora genus of the Cactaceae family includes Lophophora diffusa and Lophophora williamsii, which has traditionally been used as a natural analgesic; however, its use is now under strict regulation worldwide as it contains mescaline, a unique psychotropic agent. Recently, non-medical and illegal distribution and abuse of L. williamsii have increased worldwide; thus, effective species identification methods are urgently needed. Here, we identified a new variable number tandem repeat (VNTR) marker in the trnL intron region to identify and characterize species in forensic analyses. The VNTR marker has a unique structure of tandem repeats, each with 13 nucleotides; one repeat unit was found in L. williamsii and two in L. diffusa. Phylogenetic and length polymorphism analyses confirmed that this novel VNTR marker could distinguish between Lophophora species. Furthermore, our newly developed TaqMan genotyping assay utilizes two probes; the color and position of dots on the discrimination plot differ according to the tandem repeat count within the VNTR marker. The limits of detection of the assay were 0.000063 ng (LW-VNTR probe-1) and 0.000066 ng (LW-VNTR probe-2), indicating high sensitivity. Moreover, when crime scene samples of 16 presumed L. williamsii species were analyzed, the results coincided with those of gas chromatography–mass spectrometry, confirming the applicability of our marker for Lophophora species identification. Thus, the tandem repeats within the trnL intron region can be exploited as a VNTR marker to identify L. williamsii and L. diffusa. Our dual TaqMan genotyping assay based on a novel marker demonstrates potential for forensic applications. [ABSTRACT FROM AUTHOR]