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Background and purpose Delineating organs at risk (OARs) on computed tomography (CT) images is an essential step in radiation therapy; however, it is notoriously time-consuming and prone to inter-observer variation. Herein, we report a deep learning-based automatic segmentation (AS) algorithm (WBNet) that can accurately and efficiently delineate all major OARs in the entire body directly on CT scans. Materials and methods We collected 755 CT scans of the head and neck, thorax, abdomen, and pelvis and manually delineated 50 OARs on the CT images. The CT images with contours were split into training and test sets consisting of 505 and 250 cases, respectively, to develop and validate WBNet. The volumetric Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (95% HD) were calculated to evaluate delineation quality for each OAR. We compared the performance of WBNet with three AS algorithms: one commercial multi-atlas-based automatic segmentation (ABAS) software, and two deep learning-based AS algorithms, namely, AnatomyNet and nnU-Net. We have also evaluated the time saving and dose accuracy of WBNet. Results WBNet achieved average DSCs of 0.84 and 0.81 on in-house and public datasets, respectively, which outperformed ABAS, AnatomyNet, and nnU-Net. WBNet could reduce the delineation time significantly and perform well in treatment planning, with clinically acceptable dose differences compared with those in manual delineation. Conclusion This study shows the feasibility and benefits of using WBNet in clinical practice.

Background To validate tumor volume-based imaging markers for predicting local recurrence-free survival (LRFS) in locoregionally advanced nasopharyngeal carcinoma patients, who underwent induction chemotherapy followed by definitive intensity-modulated radiotherapy. Methods We enrolled 145 patients with stage III–IVA nasopharyngeal carcinoma in this retrospective study. Pre-treatment tumor volume (Vpre) and late-course volume (LCV) were measured based on the MRIs scanned before treatment and during the first 3 days in the sixth week of radiotherapy, respectively. The volume regression rate (VRR) was calculated according to Vpre and LCV. Receiver operating characteristic (ROC) curves were used to identify the cut-off best separating patient subgroups in assessing the prognostic value of Vpre, LCV and VRR. The Kaplan–Meier method was used for survival analysis. Prognostic analyses were performed using univariate and multivariate COX proportional hazard models. Results The LCV was 5.3 ± 0.5 (range 0–42.1) cm3; The VRR was 60.4 ± 2.2% (range 2.9–100.0). The median follow-up period was 36 months (range 6–98 months). The cut-off value of LCV determined by the ROC was 6.8 cm3 for LRFS prediction (sensitivity 68.8%; specificity 79.8%). The combination of LCV and VRR for LRFS prediction (AUC = 0.79, P P = 0.002, 95% CI 0.60–0.88) and Vpre (AUC = 0.71, P = 0.007, 95% CI 0.56–0.85) are better than T category (AUC = 0.64, P = 0.062, 95% CI 0.50–0.79) alone. Patients with LCV ≤ 6.8 cm3 had significantly longer LRFS (P P P = 0.005) than those with LCV > 6.8 cm3. Multivariate Cox regression showed LCV was the only independent prognostic factor for local control (HR = 7.80, 95% CI 2.69–22.6, P Conclusions LCV is a promising prognostic factor for local control and chemoradiosensitivity in patients with locoregionally advanced NPC. The LCV, and the combination of LCV with VRR are more robust predictors for patient survival than T category.

Current chemotherapy for lung cancer achieved limited efficacy due to poor tumor targeting and tissue penetration. Another obstacle in the therapy is activated nuclear factor-κB (NF-κB) in tumor cells, which plays a crucial role in promotion of antiapoptosis and drug resistance. In this study, we utilized a multifunctional liposome loaded with irinotecan and surface modified with a cell-permeable NF-κB inhibitor (CB5005), for treatment of non-small-cell lung carcinoma. CB5005 downregulated the level of NF-κB-related protein in the nuclei of A549 cells, and increased cellular uptake of the modified liposomes. In vivo antitumor activity in mice bearing A549 xenografts revealed that modification with CB5005 significantly improved the tumor inhibition rate of irinotecan. Immunohistochemical assays showed that the tumors treated with CB5005-modified liposomes possessed the most apoptotic cells and the lowest level of p50 in the cell nuclei. These results strongly suggest that antitumor efficacy of the irinotecan liposomes can be enhanced by tumor-penetrating and NF-κB-inhibiting functions of CB5005. Consequently, CB5005-modified liposomes provide a possible synergistic therapy for lung cancer, and would also be appropriate for other types of tumors associated with elevated NF-κB activity.

In glioblastoma with typical immunosuppressive characteristics, immune checkpoint inhibitors treatment showed unsatisfactory clinical effects, attributable to the exclusion of antibodies by blood-brain barrier (BBB) to a large extent. Herein, a conjugate of anti-programmed death ligand 1 antibody (αPDL1) and the targeting moiety p-hydroxybenzoic acid (pHA) was designed to realize crossing BBB of antibody based on the dopamine receptor mediated transcytosis. Conjugation with pHA did not influence the binding affinity of αPDL1 with PD-L1 protein, thus maintaining the capability of PD pathway blockade. Importantly, pHA-αPDL1 crossed BBB, demonstrated by the increased distribution in both the brain and the glioma after intravenous administration of pHA-αPDL1. Compared with the unmodified αPDL1, pHA-αPDL1 prolonged the survival time and suppressed tumor growth more effectively in an orthotopic glioblastoma model by activating glioma-infiltrating T cells. Our results suggested the potential of the antibody-pHA conjugate to improve efficacy for cerebral diseases by providing a potential platform for macromolecules to play therapeutics role in the brain.

Theranostics 12(7), 3420-3437 (2022). doi:10.7150/thno.70346, Published by Ivyspring, Wyoming, NSW

Retinoblastoma is the most common primary intraocular malignancy in infancy with a metastases-related death risk. However, a safe and convenient treatment without enucleation is still an unmet clinical need. In this work, a cell-penetrating peptide, 89WP, was conjugated with melphalan (89WP-Mel), which achieved comparable tumor inhibition effects to intravitreally injected melphalan via topical instillation for the first time. Notably, the “outside-in” diffusion of instilled 89WP-Mel created a protective shield surrounding the eye, efficiently preventing tumor metastases. In contrast, the mice treated with intravitreally injected melphalan suffered more brain metastases related death, probably due to the “inside-out” diffusion of injected melphalan expelling the tumor outside the eye. The ocular absorption of 89WP-conjugated melphalan and other small molecules, both hydrophobic and hydrophilic, occurred via non-corneal pathway with high safety and a prolonged residence duration in retina up to 24 h. The present work paves a new avenue for simultaneous intraocular tumor inhibition and extraocular metastases prevention in a safe and convenient way via topical instillation.

Developing an ultra-thin polyamide selective layer with sufficient mechanical robustness on a highly porous ceramic substrate is challenging for removing heavy metal ions from wastewater. We synthesized a reliable ceramic-polyamide membrane by assembling nanocomposite interlayers of alumina and carbon black on the kaolin substrate. The surface morphology, pore size distribution, and roughness of ceramic substrates were improved by introducing the nanocomposite interlayer. The corresponding optimized water flux, Pb(II), and Cd(II) removal efficiency are 2.75 L m

Gene therapy is promising for chronic posterior ocular diseases, which are causal factors for severe vision impairment and even blindness worldwide. However, the inherent absorption barriers of the eye restrict intraocular delivery of therapeutic nucleic acids via topical instillation. Safe and efficient nonviral vectors for ocular gene therapy are still unmet clinical desires. Herein, an octopus-like flexible multivalent penetratin (MVP) was designed to facilitate condensation and delivery of therapeutic nucleic acids using multiarm polyethylene glycol (PEG) as a core and conjugating penetratin at each end of the PEG arms as outspread tentacles. Among the MVPs, 8-valent penetratin (8VP) stably compacted nucleic acids into positively charged polyplexes smaller than 100 nm, promoting cellular uptake efficiency (approaching 100%) and transfection rate (over 75%). After being instilled into the conjunctival sac, 8VP enabled rapid (10 min) and prolonged (6 h) distribution of nucleic acids in the retina via a noncorneal pathway. In a retinoblastoma-bearing mice model, topical instillation of 8VP/siRNA efficiently inhibited the protein expression of intraocular tumor without toxicity. MVP is advantageous over the commercial transfection reagent in safety and efficiency, and therefore provides a promising vector for noninvasive intraocular gene delivery.

Radiation-induced rectal injury is one of the common side effects of pelvic radiation therapy. This study aimed to explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in this process. In vivo, knockout (KO) of Nrf2 led to aggravated radiation-induced histological changes in the rectums. In vitro, interference or overexpression of Nrf2 resulted in enhanced or reduced radiosensitivity in human intestinal epithelial crypts (HIEC) cells, respectively. A potential relationship between Nrf2 and necroptosis was identified using RNA sequencing (RNA-seq) and western blotting (WB), which showed that necroptosis-related proteins were negatively correlated with Nrf2. Upon treatment with necrostatin-1 (Nec-1), the increased radiosensitivity, decreased cell viability, increased γH2AX foci formation, and decreased mitochondrial membrane potential (MMP) in Nrf2-interfered HIEC cells were alleviated. A significant recovery in morphological alterations was also observed in Nrf2 KO mice administered with Nec-1. Taken together, our results highlight the important protective effect of Nrf2 in radiation-induced rectal injury through the inhibition of necroptosis, and the physiological significance of necroptosis in radiation-induced rectal injury.

Glioblastoma is the most common and aggressive primary brain tumor, whose malignancy is closely correlated with elevated proto-oncogene c-myc. Intranasal administration emerges as a potential approach to deliver gene into the brain and interfere c-Myc expression. However, powerful permeability in nasal mucosa, selective delivery to glioma and avoidance of premature release during remote transport are imperative to ensure the therapeutic effectiveness. To address the above concerns, herein we constructed a lipoplex based on pre-compression of c-Myc-targeting siRNA (sic-Myc) by octaarginine and subsequent encapsulation by liposome modified with a selected peptide derived from penetratin, named 89WP. It was found that the lipoplex exhibited a stable core-shell structure and could be preferentially internalized along with cell debris by glioma cells via active macropinocytosis. Through this cellular uptake pathway, the lipoplex avoided being entrapped by lysosome and released siRNA in cytoplasm within 4 h, inducing substantial downregulation of c-Myc mRNA and protein expression of glioma cells. Furthermore, due to significantly enhanced permeability in tumor spheroids and nasal mucosa, the lipoplex was competent to deliver more siRNA to orthotopic glioma after intranasal administration, and therefore prolonged the survival time of glioma-bearing mice by inducing apoptosis. Statement of significance In the present work, a lipoplex was designed to address the unmet demands on intranasal siRNA delivery to the brain for treatment of glioma. First, a powerful peptide was selected to enable the lipoplex to penetrate nasal mucosa. Second, we found the lipoplex could be selectively internalized along with cell debris by glioma cells via active macropinocytosis, and recorded the entire process. This cellular uptake pathway not only prevented the lipoplex being entrapped by lysosome, but also increased distribution of the lipoplex in orthotopic glioma. Third, this lipoplex provided additional protection for siRNA to avoid premature release during transport from nasal to brain. Overall, this lipoplex improved the gene delivery efficiency of intranasal administration and was promising in the perspective of selectively silencing disease-related genes in intracranial tumor.

It is widely known that the printing quality of fused filament fabrication (FFF) is heavily affected by environmental temperature and humidity, taking the form of warping and porosity. However, there is little understanding about the quantitative relations between environmental conditions, geometry, and the mechanical properties of printed parts. In this study, we systematically investigated those relations using bisphenol A polycarbonate as a model material system. For the environmental temperature, an in-situ infrared imaging analysis revealed the presence of an up to 5.4 &deg, C/mm thermal gradient when printing using an open-chamber printer and a heated build plate. For the environmental humidity, an analysis of X-ray micro-computed tomography (micro-CT) scans showed an up to 11.7% porosity that was brought by polymer water content absorbed from environmental moisture. Meanwhile, tensile tests showed a mechanical performance loss associated with those defects, but, surprisingly, the transverse direction ductility had the potential to increase at a higher porosity. Furthermore, the experimental results were combined with analytical and parametrical studies to elucidate quantitative relations between environmental conditions and printing quality. Based on the results, quantitative guidelines for the estimation of printing quality based on environmental conditions are provided that would also help users to obtain desired printing results with a better understanding of the effects of environmental conditions.

AL3810, a molecular dual inhibitor of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), has earned the permission of phase II clinical trial for tumor treatment by China FDA. As a reversible ATP-competitive inhibitor, AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR, whereas, AL3810 lacking interplay with extracellular region of receptors rendered deficient blood–brain tumor barrier (BBTB) recognition, poor brain penetration and unsatisfactory anti-glioma efficacy. Integrin αvβ3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma. The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia, activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3b and C5b-9, and experienced complement-dependent opsonization. We newly proposed a pentapeptide mn with superb αvβ3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation, targeting ability, and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly. Stemming from attenuated immunogenicity, peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents., Graphical abstract Compared with c(RGDyK)-liposome, αvβ3-targeted mn-liposome abated the opsonic effect as lower anti-liposome IgG and IgM antibody titer, less complements activation and subsequently less phagocytosis by macrophages. Stemming from attenuated immunogenicity, mn-liposome successfully realized AL3810 delivery for glioma-targeted therapy.Image 1

The Intergroup 0116 study has demonstrated a significant survival benefit for completely resected (R0) gastric cancer patients treated with a fluorouracil/leucovorin chemoradiotherapy regimen. However, this regimen is also toxic and less effective in terms of distant disease control. Therefore, a more efficacious and safer regimen is urgently needed. Patients with R0 resected gastric carcinoma received up to two 21-day cycles of postoperative adjuvant preradiation and postradiation DCF chemotherapy (docetaxel 37.5 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1 to 3, and a continuous infusion of fluorouracil 750 mg/m2 on days 1 to 5), respectively. Chemoradiotherapy between preradiation and postradiation chemotherapy was initiated on day 43 and consisted of intensity-modulated radiotherapy (45 Gy) plus concurrent docetaxel 20 mg/m2 weekly for 5 weeks. A total of 55 patients were evaluated and 76% (42) of patients completed the prescribed therapy. With a median follow-up of 61 months, the 3- and 5-year progression-free survival rates were 67% (95% confidence interval [CI], 54%-80%) and 59% (95% CI, 46%-72%), respectively; and the 3- and 5-year overall survival rates were 72% (95% CI, 60%-84%) and 61% (95% CI, 48%-74%), respectively. The most common grade 3 or greater toxicity, during the chemotherapy phase, was neutropenia (24%). Common grade 3/4 toxicities during concurrent chemoradiotherapy were nausea (32%), vomiting (26%), fatigue (15%), and anorexia (19%). These results demonstrate that this adjuvant regimen is active with an acceptable toxicity profile. A randomized phase 3 trial comparing the Intergroup 0116 chemoradiotherapy regimen with this regimen is underway. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

The receptor associated protein (RAP) is a 39 kDa chaperone protein, binding tightly to low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed in glioma, tumor neovasculature, vasculogenic mimicry (VM), the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB). Herein, we miniaturized the RAP protein into a short peptide RAP12 (EAKIEKHNHYQK) aiding by computer-aided peptide design technique. RAP12 contained the essential lysines at the positions 253 and 256. The binding affinity of RAP12 to LRP1 was theoretically and experimentally evaluated. In cellular level, RAP12 could effectively internalize into U87, HUVEC and bEnd.3 cells. When modified on the surface of PEG–PLA micelles (RAP12-PEG–PLA), RAP12 could effectively facilitate the penetration of micelles through the BBB/BBTB in vitro/vivo. Paclitaxel-loaded RAP12-PEG–PLA could remarkably inhibit the growth of glioma cells and the formation of tumor neovasculature and VM, significantly prolong the median survival time of nude mice bearing intracranial glioma in comparison to model mice treated with plain micelles or Taxol. These results suggested that the RAP12 held the potential for multifunctional glioma-targeted drug delivery.

Aims Many studies have demonstrated that circRNAs are closely associated with human diseases. Nonetheless, the potential mechanism by which circRNAs impacts spinal cord injury (SCI) is not fully understood. The aim of this study was to explore the regulatory roles of circRNAs in SCI. Main methods The sequencing data of circRNA, miRNA and mRNA were obtained from Gene Expression Omnibus (GEO) datasets. Candidates were identified to construct a circRNA-miRNA-mRNA network based on circRNA-miRNA interactions and miRNA-mRNA interactions. Protein-protein interactions (PPI) analysis was performed to determine hub genes, and a connectivity map (CMap) analysis was applied to determine potential therapeutic targets for SCI. Key findings A total of 1656 differentially expressed circRNAs (DEcircRNAs), 71 differentially expressed miRNAs (DEmiRNAs) and 2782 differentially expressed mRNAs (DEmRNAs) were identified. We integrated four overlapped circRNAs, six miRNAs and 101 target mRNAs into a circRNA–miRNA–mRNA network. We next identified two hub genes (DDIT4, EZR) based on the PPI network and identified five circRNA-miRNA-hub gene regulatory axes. In addition, we discovered three chemicals (tanespimycin, fulvestrant, carbamazepine) as potential treatment options for SCI. Significance Our study suggests a regulatory role for circRNAs in the pathogenesis and treatment of SCI from the view of a competitive endogenous RNA (ceRNA) network.

In many i-vector based speaker recognition frameworks, the key challenge is to develop effective channel compensation methods for enlarging inter-class differences while reducing intra-class variations. This challenge is handled with a discriminatively learned network (DLN), which uses both speaker classification and verification signals as supervision. The speaker classification task forces the embeddings (vectors mapped from i-vectors) of different identities drawing apart to increase the inter-class variation, while the verification task pulls the embeddings of the same identity together to reduce the intra-class variation. DLN projects i-vectors to a more discriminative embedding space. However, the verification scores are cosine similarities between these embeddings. The learned DLN can be well generalised to new speakers unseen in the training data. On the text-dependent challenging Robust Speaker Recognition (RSR2015) database, the performance is significantly improved when compared with the linear discriminant analysis (LDA) and Gaussian probabilistic LDAmethods.

Purpose Local persistence and relapse of disease in the gross tumor volume (GTV) account for the majority of treatment failures after standard chemoradiation therapy. The primary objective of this phase 1 trial was to define the maximum tolerated dose (MTD) of a hyperfractionated radiation therapy (HFRT) boost to the GTV with concurrent weekly paclitaxel and carboplatin after standard-dose chemoradiation therapy, using image guided intensity modulated radiation therapy techniques. Methods and Materials Eligible patients were given weekly doses of paclitaxel (45 mg/m2) and carboplatin (area under the curve 1.5) for 5 weeks with concurrent radiation therapy (50 Gy), immediately followed by an HFRT boost to the GTV with the same chemotherapy regimen. The boost doses were escalated in increments of 7.2 Gy delivered in 6 twice-daily fractions of 1.2 Gy using a modified Fibonacci design. Once the MTD was established, additional patients were treated at that dose to determine the safety. Results Thirty-one patients fulfilled the inclusion criteria. The incidence of dose-limiting toxicity was 0 of 3, 0 of 3, 0 of 3, 1 of 6 (grade 4 esophagitis), 0 of 3, and 2 of 3 (1 case each of grade 5 esophageal fistula and grade 3 pneumotitis) at 7.2, 14.4, 21.6, 28.8, 36, and 43.2 Gy, respectively, indicating an MTD of 36 Gy. Ten patients treated with this MTD showed no dose-limiting toxicities. The most common acute grade 3 or greater toxicities were esophagitis (26%) and neutropenia (19%). Late toxicity of grade 2 esophageal stricture occurred in 4 patients. The overall response rate was 84% (95% confidence interval, 42%-93%) in the entire cohort. The 1-year local control rate was 100% among those receiving a cumulative dose of the MTD or greater. Conclusions The MTD of the HFRT boost after standard chemoradiation therapy in the setting of concurrent chemotherapy was 36 Gy, resulting in the cumulative tumor dose of 86 Gy in patients primarily with advanced intrathoracic/cervical esophageal squamous cell carcinomas and not adenocarcinomas of the gastroesophageal junction. A phase 2 study to further evaluate this regimen is underway.

Purpose: This article compares the dosimetric differences between jaw tracking and no jaw tracking technique in static intensity-modulated radiation therapy plans of large and small tumors. Methods: Eight plans with large tumor (nasopharyngeal carcinoma, volume range: 510.9 to 768.0 cm3) and 8 plans with small tumor (single brain metastasis, volume range: 5.3 to 9.9 cm3) treated with jaw tracking on Varian EDGE LINAC were chosen and recalculated with no jaw tracking to study the dosimetric differences. We compared the differences of organ-at-risk doses (Dmax, Dmean), monitor units, and γ passing rate of plan verification (3mm/3%, threshold 10%; 2mm/2%, threshold 10%) between the 2 techniques. Results: The organ-at-risk doses of nasopharyngeal carcinoma cases having jaw tracking are all less than those with no jaw tracking. The Dmax and Dmean of organ-at-risks reduced 0.61% to 17.65% and 2.17% to 19.32%, P < .05, respectively. In cases with single brain metastasis, the organ-at-risk doses with jaw tracking were also lower than no jaw tracking. The Dmax and Dmean of organ-at-risk doses reduced 0.84% to 1.52% and 0.90% to 1.86%, P < .05, respectively. The monitor units for the large tumor and small tumor were increased by 2.41% and 1.1%, respectively. The γ passing rates (3mm/3%, th10%; 2mm/2%, th10%) of nasopharyngeal carcinoma plans are 99.89% ± 0.06% (jaw tracking) versus 99.56% ± 0.19% (no jaw tracking; P = .127); 97.15% ± 0.98% (jaw tracking) versus 91.90% ± 1.40% (no jaw tracking; P = .000), and the γ passing rates (3mm/3%, th10%; 2mm/2%, th10%) of brain metastasis plans are 99.97% ± 0.05% (jaw tracking) versus 99.44% ± 1.24% (no jaw tracking; P = .251), 98.65% ± 1.27% (jaw tracking) versus 93.35% ± 2.72% (no jaw tracking; P = .000). Conclusion: Jaw tracking can reduce the dose of organ-at-risks compared to no jaw tracking, and the effect is more significant for plans with large tumor. The γ passing rate of plans with jaw tracking is also higher than the plans with no jaw tracking. Although the monitor units in plans of jaw tracking will increase slightly, it is recommended to use jaw tracking in static intensity-modulated radiation therapy both in large and in small tumors.

The RAP12 peptide derived from miniaturization of receptor-associated protein (RAP) holds binding affinity with low-density lipoprotein receptor-related protein-1 (LRP1). However, RAP12 exhibited weak α-helical segments when taken out of the stabilizing protein context. Considering that the α-helix is a common structural motif of the peptide to mediate ligand-receptor interactions, we utilized the peptide stapling technique to generate RAP12 with all-hydrocarbon tethers, named stapled RAP12 (ST-RAP12). This optimized ST-RAP12 was verified to obtain an increased α-helical content, binding affinity with LRP1 and serum stability compared to RAP12. In addition, ST-RAP12 exhibited enhanced cellular internalization of bEnd.3 cell, U87 glioma cells and HUVEC. Furthermore, the ability of ST-RAP12 to overcome in vitro BBB/BBTB was also potentiated. Next, ST-RAP12 peptide was further applied to modify polymeric materials to construct ST-RAP12-micelles. It is verified that the ST-RAP12-micelles effectively penetrated BBB/BBTB and targeted glioma in vitro/vivo, and immunofluorescence studies demonstrated its targeting ability to tumor angiogenesis and LRP1. Moreover, ST-RAP12-micelles efficiently delivered paclitaxel (PTX) to glioma, prolonged the survival time of glioma-bearing mice, inhibited tumor angiogenesis and induced glioma apoptosis, which displayed obvious anti-glioma efficacy. Overall, ST-RAP12 is anticipated to be a widely used LRP1-targeted peptide and could be translated as a multifunctional ligand for glioma-targeted drug delivery.

As the separated modeling methods are widely used in text-dependent speaker verification task. The reason why they are so effective is discussed in this paper. A word-based scoring method is then proposed based on our discussion. Specifically, a segmentation algorithm is firstly used for segmenting the enrollment and test utterances into words, automatically. Then every segment of the enrollment utterance is used to enroll a word based speaker model. Scoring is done with each testing segment and a corresponding word-based speaker model of the same word. The experiments are camed out on a short duration text-dependent speaker verification database in Chinese spoken language. Our examples show that, systems based on word-based scoring method are superior to the relevance MAP GMM-UBM system and achieve significant performance improvement.

Although the state-of-the-art i-vector-based probabilistic linear discriminant analysis systems resulted in promising performances in the National Institute of Standards and Technology speaker recognition evaluations, the impact of domain mismatch when the system development data and the evaluation data are collected from different sources remains a challenging problem. This issue was a focus of the Johns Hopkins University 2013 speaker recognition workshop where a domain adaptation challenge (DAC13) corpus was created to address it. The cross-domain variation compensation (CDVC) approach has been recently proposed to address it when in-domain development data are available. The work reported by the present authors addresses this issue when in-domain development data are unavailable using a library of CDVC transforms. This approach is evaluated on the DAC13 corpus and is shown to be more powerful than nuisance attribute projection-based inter-dataset variability compensation and the whitening library.

Purpose To assess the efficacy and feasibility of concurrent chemoradiation therapy (CCRT) plus preradiation and postradiation chemotherapy for patients with nonmetastatic gastric carcinoma who do not undergo surgery. Methods and Materials Patients with inoperable (due to medical comorbid conditions or patient's refusal to undergo surgery) or unresectable gastric cancer received up to 2 21-day cycles of preradiation and postradiation chemotherapy (docetaxel 37.5 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and a continuous infusion of fluorouracil [FU] 750 mg/m2 on days 1-5), respectively. CCRT between preradiation and postradiation chemotherapy was initiated on day 43 and consisted of intensity modulated radiation therapy (50.4 Gy) plus concurrent docetaxel 20 mg/m2 weekly for 6 weeks. Results 36 patients were evaluable; 21 patients with comorbid conditions were unsuitable for surgery (group 1), 8 had unresectable disease (group 2), and 7 refused surgery (group 3). The clinical complete response (cCR) rate for the 36 evaluable patients was 36% (95% confidence interval [CI], 19%-53%) and the overall response rate was 83% (95% CI, 75%-97%). The median survival time and estimated 2-year survival rate were 25.8 months (95% CI, 7.1-44.5 months) and 52% (95% CI, 38%-67%), respectively. The estimated median OS and 2-year OS rates for groups 1, 2, and 3 were 37.0 months (95% CI, 7.9-66.1 months) and 52% (95% CI, 31%-73%), 17.7 months (95% CI, 7.8-27.6 months) and 20% (95% CI, 0%-49%), and 38.9 months (95% CI, 16.6-58.3 months) and 67% (95% CI, 30%-100%), respectively. Achieving a cCR was associated with significantly better overall survival (P=.004) and progression-free survival (P=.003). The most common grade 3 or greater toxicity during the chemotherapy phase was neutropenia. Common grade 3/4 toxicities during CCRT were nausea and vomiting. Conclusions This regimen is tolerable and shows promising efficacy in inoperable or medically unresectable GC.

Axonal transport of mitochondria is critical for neuronal survival and function. Automatically quantifying and analyzing mitochondrial movement in a large quantity remain challenging. Here, we report an efficient method for imaging and quantifying axonal mitochondrial transport using microfluidic-chamber-cultured neurons together with a newly developed analysis package named “MitoQuant”. This tool-kit consists of an automated program for tracking mitochondrial movement inside live neuronal axons and a transient-velocity analysis program for analyzing dynamic movement patterns of mitochondria. Using this method, we examined axonal mitochondrial movement both in cultured mammalian neurons and in motor neuron axons of Drosophila in vivo. In 3 different paradigms (temperature changes, drug treatment and genetic manipulation) that affect mitochondria, we have shown that this new method is highly efficient and sensitive for detecting changes in mitochondrial movement. The method significantly enhanced our ability to quantitatively analyze axonal mitochondrial movement and allowed us to detect dynamic changes in axonal mitochondrial transport that were not detected by traditional kymographic analyses. Electronic supplementary material The online version of this article (doi:10.1007/s13238-016-0268-3) contains supplementary material, which is available to authorized users.

A new type of water phantom which would be specialised for the absorbed dose measurement in total body irradiation (TBI) treatment is developed. Ten millimetres of thick Plexiglas plates were arranged to form a square cube with 300 mm of edge length. An appropriate sleeve-type piston was installed on the side wall, and a tabular Plexiglas piston was positioned inside the sleeve. By pushing and pulling the piston, the length of the self-made water phantom could be varied to meet the required patients' physical sizes. To compare the international standard water phantom with the length-adjustable and the Plexiglas phantoms, absorbed dose for 6-MV X ray was measured by an ionisation chamber at different depths in three kinds of phantoms. In 70 cases with TBI, midplane doses were metered using the length-adjustable and the Plexiglas phantoms for simulating human dimensions, and dose validation was synchronously carried out. There were no significant statistical differences, p > 0.05, through statistical processing of data from the international standard water phantom and the self-designed one. There were significant statistical differences, p < 0.05, between the two sets of data from the standard and the Plexiglas one. In addition, the absolute difference had a positive correlation with the varied depth of the detector in the Plexiglas phantom. Comparing the data of clinical treatment, the differences were all