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ABSTRACTNon-small-cell lung cancer (NSCLC) has a terrible consequence called leptomeningeal metastases (LM). It is crucial to look for novel biomarkers because none of the known biomarkers could effectively reflect the oncogenesis, progression and therapeutic responses of LM. Exosomal miRNAs from plasma have a critical function in lung cancer, according to growing data. However, unique biomarkers of cerebrospinal fluid (CSF) are more representative for patients with LM, which have not been reported. Here, we explore the possibility of using CSF-derived exosomal microRNAs as potential biomarkers for NSCLC-LM. Nine NSCLC-LM patients who received regular intrathecal chemotherapy with permetexed were divided into a partial response (PR) group and a progressive disease (PD) group. CSF samples were taken from all patients before and after intrathecal treatment and five non-cancerous controls. Using the size exclusion chromatography (SEC) method, the exosome microRNAs were isolated and profiled. Between LM patients and controls, 56 differentially expressed genes (DEGs) were found, of which three highly elevated diagnostic biomarkers (hsa-miR-183-5p, hsa-miR-96-5p and hsa-miR-182-5p) were ruled out. The two most significant DEGs between the untreated PR group and the PD group were determined to be upregulated hsa-miR-509-3p and downregulated hsa-miR-449a, and they may serve as potential indicators of intrathecal anti-pemetrexed treatment. Hsa-miR-1-3p increased gradually with the intrathecal chemotherapy in the PR group, which might offer a new approach to screen optimal patients and estimate the efficacy. This study revealed specific CSF exosomal miRNAs profile and dynamic changes of patients with NSCLC-LM for the first time and identified several potential exosomal miRNA biomarkers in diagnosis, drug resistance and prognosis.

In this paper, the manufacturability of 3D topologically optimized (TO) heat sinks for forced-air cooling is studied for both additive manufacturing and subtractive numerical control machining. To mitigate the manufacturing difficulties which are frequently encountered when fabricating TO designs, we adopt two approaches. First, a constraint on the projected undercut perimeter is added to the standard optimization formulation to limit the number and severity of costly non-self supporting features in additive manufacturing. Second, a multi-axis machining (MAM) constraint is adopted to serve as the basis for enforcing manufacturability in a TO design for an alternative, highly-popular manufacturing modality. Locally refined nonuniform unstructured meshing and unit-cell assembly techniques for increasing the mesh and design resolution were pursued during optimization. Post-analyses were conducted in OpenFOAM for all TO and corresponding parallel-fin designs. Simulation results showed that topologically optimized heat sinks offer a 35–40% advantage in temperature performance over conventional parallel fins. A limited or non-existent compromising of thermal-hydraulic performance was necessary to enforce manufacturability. Finally, to prove the practical efficacy of the overhang angle control constraint, the AM-constrained heat sinks designs were fabricated through direct metal laser sintering in both aluminum and stainless steel.

The inherent uncertainties, particularly material uncertainties, significantly impact the buildability of 3D concrete-printed curved walls, leading to substantial variations that complicate quality control. To address this, a data-driven stochastic analysis framework is proposed for reliability-oriented buildability evaluation. Material uncertainties are quantified using a maximum likelihood-based stochastic parameter estimation method and considered as the uncertainty sources. Subsequently, a data-driven model, namely sparse Gaussian process regression (SGPR) model, is trained and combined with Monte Carlo simulation to assess the stochastic behavior of curved wall buildability. The influences of print speed, layer height, and horizontal curvature on buildability are analyzed under varying reliability levels. Additionally, an empirical model is proposed for the rapid evaluation of maximum buildability at specified horizontal curvature and reliability levels, providing significant practical value for 3D concrete printing designers. The impact of other uncertainty sources including the model error on reliability-oriented buildability is also discussed. These sources exhibit negligible influence when their intensities are less than 30 % of that caused by material uncertainty. Furthermore, the feasibility of the data-driven reliability-oriented buildability analysis for more complex geometry is also demonstrated.

Neoantigen-based tumor vaccines have been applied in patient-specific melanoma-derived immunogenic mutated epitopes (neoantigens), with potential antineoplastic and immunomodulating effects. Yet, their use is limited by different physicochemical properties and poor pharmacokinetics. Herein, we constructed a human serum albumin-based dual adjuvant neoantigen nanovaccine loaded with imiquimod and magnesium. Magnesium, in coordination with imiquimod, could greatly activate dendritic and T cells. After subcutaneous injection, the nanovaccine effectively targeted tumor-draining lymph nodes (LNs) and promoted the presentation of neoantigens, thus generating a large number of effector T cells. In the B16F10 mouse melanoma prevention model, the nanovaccine effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. To sum up, this new neoantigen nanovaccine could be used as a new method for targeting melanoma and may be potentially applied in clinical work.

One fifth of idiopathic clubfoot deformities cannot be fully corrected by Serial Ponseti casting and deformity recurs in 20%–30% of cases. To avoid x-ray exposure, the joints with largely unossified bones are diagnosed with magnetic resonance images (MRI). Typically, geometric measurements are made in the MRI planes; however, this method is inaccurate compared to measurements on three-dimensional (3D) models of the joint. More accurate measurements using the 3D bone shapes may be better at identifying differences between groups; and therefore, improve diagnosis. The entire set of shape features from MRI can be analysed simultaneously through statistical shape modelling (SSM) which assesses bone morphology of clubfoot in a more sensitive way. A method for SSM of the talus is developed in this study and the shape of the normal talus is compared with the one in clubfeet with residual deformity through both geometric measurements and SSM. Significant differences between two groups were found by both methods; and therefore, might contribute to improve diagnosis of clubfoot.

Objective: To explore the targeting effect of PLGA-NP and iRGD co-administration with PTXPLGA NP (PTX-PLGA + iRGD) on colorectal cancer. Methods: Whether PLGA-NP co-administration with iRGD peptide could show effective tumor-targeting ability in contrast to with PLGA-NP in colorectal cancer mice models was evaluated. Moreover, the chemotherapeutics Paclitaxel (PTX) was loaded into the PLGA-NP to impart anti-tumor efficiency to the PTX-PLGA. Whether iRGD co-administration with PTX-PLGA NP (PTX-PLGA + iRGD) in colorectal cancer models enabled PTX to achieve better anti-tumor efficiency and biocompatibility was further assessed. Results: The targeting ability of PLGA-NP was enhanced in cell experiment and colorectal cancer mice models by co-administration of iRGD. As a result, PTX-PLGA + iRGD achieved better anti-tumor efficacy than PTX and PTX-PLGA. Conlusion: The nanocarrier based on PLGA with specific targeting ability could promote the clinical application of various chemotherapeutics similar to PTX. The combination of drug-loaded nanoparticles and iRGD could develop into a promising drug delivery system.

ABSTRACTLong noncoding RNAs (lncRNAs) have been shown to play important roles in various tumors including colorectal cancer (CRC). Here, we obtained data from RNA-sequencing analysis using 3 paired of CRC tissues and corresponding normal tissues. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the biological functions of these dysregulated genes were identified. Moreover, we analyzed the expression levels of lncRNA PGM5-AS1 and B3GALT5-AS1 by quantitative real-time PCR (qRT-PCR) assay. To evaluate the accuracy of the lncRNA-mRNA co-expression network we built, we also detected PGM5 expression and analyzed the relationship between PGM5-AS1 and PGM5 in CRC. In addition, we explored the potential function of PGM5-AS1 in vitro and in vivo. In conclusion, we identified dysregulated lncRNAs and constructed the lncRNA-mRNA co-expression network in CRC. Then, we showed that the expression levels of PGM5-AS1, B3GALT5-AS1 and PGM5 were significantly downregulated in CRC tissues compared with corresponding normal tissues. Besides, PGM5-AS1 expression was positively associated with PGM5 expression. These findings were consistent with our RNA-sequencing data. Functionally, overexpression of PGM5-AS1 could induce cell apoptosis and cell cycle arrest in CRC. Animal study indicated that PGM5-AS1 overexpression inhibited CRC growth in vivo. This work provides dysregulated lncRNAs as candidates for further study in CRC. The lncRNA-mRNA co-expression network brings novel insights into further function research. More importantly, PGM5-AS1 is a critical tumor suppressor in CRC.

It is important for antitumor drugs to accumulate at the tumor site and penetrate deeply to play a role in treatment. However, it is difficult for the drugs to reach the destination on account of the complex tumor microenvironment such as elevated tumor interstitial fluid pressure (IFP) and solid stress. Here, we report a type of nanocarrier composed entirely of Camellia oleiferaprotein (COP), which could lower tumor IFP and solid stress. Its physicochemical properties, cellular uptake, in vitrocytotoxicity and tumor perfusion, biodistribution, and in vivoantitumor efficiency were evaluated. It was found that COP NPs had good cellular uptake ability and cytocompatibility. When loading doxorubicin, COP NPs showed an in vitroconcentration-dependent cytotoxicity. Importantly, the tumor IFP and solid stress were greatly reduced after injecting COP NPs into tumor-bearing mice, leading to more drug accumulating in the tumor and a longer survival time for tumor-bearing mice. Therefore, our study provided a new strategy to improve the tumor microenvironment and to achieve better antitumor efficiency.

ABSTRACTPancreatic cancer is among the most lethal malignant neoplasms, and few patients with pancreatic cancer benefit from immunotherapy. We retrospectively analyzed advanced pancreatic cancer patients who received PD-1 inhibitor-based combination therapies during 2019–2021 in our institution. The clinical characteristics and peripheral blood inflammatory markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and lactate dehydrogenase [LDH]) were collected at baseline. Chi-squared and Fisher’s exact tests were used to evaluate relationships between the above parameters and tumor response. Cox regression analyses were employed to assess the effects of baseline factors on patients’ survival and immune-related adverse events (irAEs). Overall, 67 patients who received at least two cycles of PD-1 inhibitor were considered evaluable. A lower NLR was independent predictor for objective response rate (38.1% vs. 15.2%, P = .037) and disease control rate (81.0% vs. 52.2%, P = .032). In our study population, patients with lower LDH had superior progression-free survival (PFS) and overall survival(OS) (mPFS, 5.4 vs. 2.8 months, P < .001; mOS, 13.3 vs. 3.6 months, P < .001). Liver metastasis was verified to be a negative prognostic factor for PFS (2.4 vs. 7.8 months, P < .001) and OS (5.7 vs. 18.0 months, P < .001). The most common irAEs were hypothyroidism (13.4%) and rash (10.5%). Our study demonstrated that the pretreatment inflammatory markers were independent predictors for tumor response, and the baseline LDH level and liver metastasis were potential prognostic markers of survival in patients with pancreatic cancer treated with PD-1 inhibitors.

In this paper, we have applied topology optimization (TO) to the latent heat based thermal energy storage (LHTES) device design. The high conductivity materials (HCM) are added to the phase change materials (PCM) to increase the overall thermal conductivity. Distribution of HCM in PCM is optimized by the TO method to maximize the charging speed of the LHTES device at the different charging periods. The time-dependent Navier–Stokes (NS) equations, involving natural convection and PCM phase change, are chosen as the governing equations of fluid motion. The energy equation including latent heat is strongly coupled with the NS equation. The adjoint method is utilized to derive and calculate the sensitivity. Several 2D numerical examples with different charging periods and different HCM volume fractions have been studied with this TO method. The charging period showed a huge influence on the optimized TO structures. The short charging period designs exhibit more conductive structures while the long charging period designs show convective structures. A pareto front of the topologically optimized designs has been constructed, which shows up to 110.7% of improvement in the charging speed over the parallel-fin design with the same root fin width.

ABSTRACTLong noncoding RNAs are widely acknowledged as a group of regulatory factors in various diseases, especially in cancers. KCNQ1 overlapping transcript 1 (KCNQ1OT1) has been reported as oncogene in human cancers. However, the role of KCNQ1OT1 in colorectal cancer (CRC) has not been fully explained. Based on the database analysis, KCNQ1OT1 was highly expressed in CRC samples and predicted the poor prognosis for CRC patients. Functional experiments revealed that KCNQ1OT1 knockdown negatively affected the proliferation, migration and epithelial-mesenchymal transition (EMT) in CRC cells. Moreover, we identified the cytoplasmic localization of KCNQ1OT1 in CRC cells, indicating the post-transcriptional regulation of KCNQ1OT1 on gene expression. Mechanism experiments including RNA Immunoprecipitation (RIP) assay and dual luciferase reporter assays verified that KCNQ1OT1 acted as a competing endogenous RNA (ceRNA) in CRC by sponging microRNA-217 (miR-217) to up-regulate the expression of zinc finger E-box binding homeobox 1 (ZEB1). Further mechanism investigation revealed that ZEB1 enhanced the transcription activity of KCNQ1OT1 by acting as a transcription activator. Finally, rescue assays were designed to demonstrate the effect of KCNQ1OT1-miR-217-ZEB1 feedback loop on proliferation, migration, and EMT of CRC cells. In brief, our research findings revealed that ZEB1-induced upregulation of KCNQ1OT1 improved the proliferation, migration and EMT formation of CRC cells via regulation of miR-217/ZEB1 axis.

In this paper, we formulate the generation of support structures for additive manufacturing as a topology optimization problem. Compared with usual geometric considerations based support structure design, this formulation affords mechanistic meaning to the computed support structures. Moreover, our study reveals that the topology optimization formulation generally leads to self-supporting designs without extraneous self-supporting constraints. We show the generality of the procedure by computing supports for a variety of parts in both two and three dimensions, including a complex model of the mascot of the University of Wisconsin-Madison. The resulting support structures have been 3D printed, demonstrating that the computed designs can successfully be used as supports.

BACKGROUND:Most tumor cell lines exhibited low-dose hyperradiosensitivity (LDHRS) to radiation doses lower than 0.3 Gy. Pulsed low–dose rate radiotherapy (PLDR) took advantage of LDHRS and maximized the tumor control process. In this study, we retrospectively analyzed patients receiving PLDR for refractory malignancies. PATIENTS AND METHODS:In total, 22 patients were included in our study: 9 females and 13 males. The median age was 61 years old. All the patients previously received multiline treatments and failed with an estimated survival less than 6 months. Thus, palliative PLDR was given. The PLDR was delivered using 10 fractions of 2 Gy/day, with an interval of 3 minutes, for 5 days per week. The dose rate was 6.67 cGy/min. The median follow-up was 1 year (range 8-30 months). Nine patients underwent PLDR for reirradiation due to locally recurrent diseases. The time interval from last irradiation was 11 to 168 months. Ten patients received PLDR due to poor performance status. Three patients were given PLDR for bulky tumor. The irradiated sites included primary disease (seven patients), locally recurrent disease (nine patients), and retroperitoneal adenopathy (six patients). RESULTS:Five patients developed grade 3 or 4 toxicities. No grade 5 toxicities occurred. All the toxicities recovered after treatments. In general, the 1-year local-regional control rate was approximately 40%, and almost all the patients developed progression at the second year after PLDR. The 6-month survival rate was 76%, and the 1-year survival rate was 69%. For the three patients given PLDR for bulky tumor, all of them achieved partial remission 1 month after the PLDR, and one patient achieved complete response at the fourth month. CONCLUSION:PLDR is an effective and safe option not only for reirradiation but also for patients with poor performance status or bulky tumors. A prospective clinical trial (NCT03061162) is ongoing to validate our results.

DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

Supramolecular polymer micelles composed of seven-armed poly(2-methy-2-oxazoline) as the coating and linear poly(dl-lactide) as the core were prepared through synthesizing β-cyclodextrin-terminated poly(2-methy-2-oxazoline) and adamantine-terminated linear poly(dl-lactide), followed by host–guest interaction between β-cyclodextrin and adamantine groups in two polymers and self-assembly in aqueous solution. Dynamic light-scattering measurement showed that the micelles based on supramolecular amphiphilic polymers have the size of 119 nm and were highly stable in salt solution. When the micelles were used as the carrier of cabazitaxel, an antitumor agent for drug-resistant cancers, satisfactory drug loading content and encapsulation efficacy were obtained. In vitro cellular cytotoxicity assays found that cabazitaxel-loaded micelles presented obvious cytotoxicity against taxane-sensitive and -resistant cancer cells. Further in vivo antitumor activity evaluation showed that cabazitaxel-loaded micelles have significantly superior efficacy in inhibiting tumor growth and prolonging survival in tumor-bearing mice compared to that of free paclitaxel and free cabazitaxel.

•SLAMF8 is a potential new immune checkpoint molecule.•High SLAMF8 expression is associated with poor prognosis of colorectal cancer.•The expression of SLAMF8 corelates with the expression of classical immune checkpoint molecules.•Prediction of the potential function of SLAMF8 in the tumor microenvironment in CRC.

This is a phase II study of PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC, respectively). Twenty-nine patients are enrolled in the study. The objective response rate (ORR) is 60%, and the R0 resection rate is 90% (9/10). The 12-month progression-free survival (PFS) rate and 12-month overall survival (OS) rate are 64% and 72%, respectively. Grade 3 or higher adverse events are anemia (8%), thrombocytopenia (8%), and jaundice (8%). Circulating tumor DNA analysis reveals that patients with a >50% decline in maximal somatic variant allelic frequency (maxVAF) between the first clinical evaluation and baseline have a longer survival outcome and a higher response rate and surgical rate than those who are not. PD-1 blockade plus chemoradiotherapy as preoperative therapy displays promising antitumor activity, and multiomics potential predictive biomarkers are identified and warrant further verification.

Conventional in vitrocirculating tumor cell (CTC) detection methods are always limited by blood sample volume because of the requirement of a large amount of blood. The aim of this study was to overcome the limitation by designing and making an in vivoCTC capture device. In this study, we designed and prepared a kind of proper material to serve the purpose of intervention. A method employing 3-aminopropyltriethoxysilane (γ-APS) as the coupling reagent to graft carboxybetaine methacrylate (CBMA) and to immobilize an anti-epithelial cell adhesion molecular (EpCAM) antibody on Nylon was developed. The results of X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy proved the successful graft of γ-APS and CBMA to Nylon. Furthermore, the predicted improvement in the biocompatibilities of our modified Nylon was confirmed by water contact angle measurement, bovine serum albumin adhesion, platelet adhesion, plasma recalcification time determination, and cytotoxicity tests. The tumor cells adhesion experiment revealed that Nylon with the antibody immobilized on it had an affinity for EpCAM positive tumor cells higher than that of pristine Nylon. Additionally, the capture ability of the CTCs was demonstrated in a nude mouse tumor model using the interventional device made of the modified Nylon wire. The positive results suggest that CBMA-grafted and anti-EpCAM antibody-immobilized Nylon is a promising new material for in vivoCTC capture devices.

Non-toxic, safe materials and preparation methods are among the most important factors when designing nanoparticles (NPs) for future clinical application. Here we report a novel and facile method encapsulating anticancer drug paclitaxel (PTX) into silk fibroin (SF), a biocompatible and biodegradable natural polymer, without adding any toxic organic solvents, surfactants or other toxic agents. The paclitaxel loaded silk fibroin nanoparticles (PTX-SF-NPs) with a diameter of 130 nm were formed in an aqueous solution at room temperature by self-assembling of SF protein, which demonstrated mainly silk I conformation in the NPs. In cellular uptake experiments, coumarin-6 loaded SF NPs were taken up efficiently by two human gastric cancer cell lines BGC-823 and SGC-7901. In vitro cytotoxicity studies demonstrated that PTX kept its pharmacological activity when incorporating into PTX-SF-NPs, while SF showed no cytotoxicity to cells. The in vivo antitumor effects of PTX-SF-NPs were evaluated on gastric cancer nude mice exnograft model. We found that locoregional delivery of PTX-SF-NPs demonstrated superior antitumor efficacy by delaying tumor growth and reducing tumor weights compared with systemic administration. Furthermore, the organs of mice in NP treated groups didn’t show obvious toxicity, indicating the in vivo safety of SF NPs. These results suggest that SF NPs are promising drug delivery carriers, and locoregional delivery of SF NPs could be a potential future clinical cancer treatment regimen.

Novel pemetrexed-loaded gelatinase-responsive nanoparticles were prepared as a targeted delivery system to determine its potential for clinical therapy of malignant melanoma. The pemetrexed-loaded poly(ethylene glycol)(PEG)–peptide–poly(-caprolactone) (PCL) nanoparticles included a gelatinase-cleavage peptide and a PEG–PCL-based structure. The pemetrexed-loaded PEG–peptide–PCL nanoparticles have shown the best antimetastatic effect in experimental lung metastasis models. The expressions of CD133 and thymidylate synthetase of metastatic tumors were also evaluated in our studies. Our results showed that pemetrexed-loaded gelatinase-responsive nanoparticles may represent a potent drug delivery system for inhibiting pulmonary metastasis and our preclinical results can provide new avenues for clinical therapy of malignant melanoma.

Paclitaxel (Ptx) has demonstrated encouraging activity in the treatment of gastric cancer. Development of drug-containing biodegradable polymeric nanoparticles (np) becomes one of the solutions to relieve side effects of Ptx. However, Ptx-loaded nanoparticles prepared by the nanoprecipitation method are unstable in the aqueous phase. Here we report that tetrandrine (Tet) effectively increases the stability of Ptx-loaded nanoparticles when Tet is coencapsulated with Ptx into mPEG-PCL nanoparticles. The current study demonstrates the synergistic antitumor effect of Tet and Ptx against gastric cancer cells, which provides the basis of coadministration of Tet and Ptx by nanoparticles. It is reported that the cellular chemoresistance to Ptx correlates with intracellular antioxidant capacity and the depletion of cellular antioxidant capacity could enhance the cytotoxicity of Ptx. Tet effectively induces intracellular ROS production. Therefore, the present study provides a promising novel therapeutic strategy basing on “oxidation therapy” that it could amplify the antitumor effect of paclitaxel by employing Tet as a pro-oxidant. More intracellular Tet accumulation by endocytosis of Ptx/Tet-np than equivalent doses of free drug leads to more intracellular ROS induction, which could efficiently enhance the cytotoxicity of Ptx by sequential inhibition of ROS-dependent Akt pathway and activation of apoptotic pathways, all of which would mediate the superior cytotoxicity of Ptx/Tet-np over free drug. The present results suggest that the codelivery of Ptx and Tet by nanoparticles provides a novel therapeutic strategy basing on “oxidation therapy” against gastric cancer.

The power conversion efficiency of polymer solar cells today has passed 10%, the commonly acceptable value for commercial usage. However, in general labs, the power conversion efficiency routinely achievable is only at 3–5% because of the lack of effective tools to optimize the device design and the fabrication process. Instead of using trial-and-error experiments to improve the power efficiency, modeling and simulation provides an alternative, effective, and economical way to optimize the design of polymer solar cells for best device performance. This review gives a literature survey, including some of our own studies, on modeling and simulation of polymer solar cells. First, the fundamentals of polymer solar cells are briefly explained. Then, the optical and electrical modeling and simulation are discussed in detail, followed by a discussion on optimization of polymer solar cells via modeling and simulation. This review ends with an outlook for the future study on modeling, simulation, and optimization of polymer solar cells.

Neoantigen vaccines have opened a new paradigm for cancer immunotherapy. Here, we constructed a neoantigen nanovaccine-HemoMap, with the ability to target lymph nodes and activate immune cells. We propose a HemoMap nanovaccine consisting of the mouse melanoma highly expressed antigenic peptide Tyrp1 and a magnesium nanoadjuvant-HemoM. By immunofluorescence labeling of the nanovaccine, the lymph node targeting of the vaccine was observed and verified by a mouse near-infrared imaging system. About two-fold higher effective retention of HemoMap induces the internalization of Tyrp1 in DCs than that of free Tyrp1 in draining lymph nodes (DLNs) for 48 h. A mouse melanoma subcutaneous model was established to evaluate neoantigen-specific antitumor immune responses. In comparison to the control group, the tumor growth rate was dramatically slowed down by HemoMap treatment, and the median survival time was extended by 7 days. We discovered that effective co-delivery of Tyrp1 antigen and magnesium (Mg2+) to lymph nodes (LNs) boosted cellular internalization and activated immune cells, such as CD11c+DCs and CD8+T lymphocytes. Spleen lymphocytes from the HemoMap group displayed much more antitumor activity than those from the other groups. Our findings highlight that HemoMap is promising to trigger T cell responses and to provide novel nanoadjuvants strategies for cancer immunotherapy.

Optical metrology has been widely used in quality inspection. However, the sensor setup during part inspection is often done in an ad hocway. This leads to unnecessarily high signal dynamic range. Consequently, optical sensors do not have sufficient light dynamic range capabilities especially for shiny surface measurement. We present a computational approach for optimal sensor setup that takes into account the sensor/part interaction to decrease signal dynamic range and to increase model coverage for structured light or similar optical inspection systems. First, we transform the signal dynamic range issue into a distance problem in a spherical map. We then present novel algorithms on the spherical map to search a near-optimal sensor orientation. Based on this near-optimal orientation, we use a gradient method to obtain the free-optimal solution that gives the lowest possible dynamic range. Experimental results demonstrated that under the optimal orientation, there is lower signal dynamic range and better model coverage. Future work on extending this method to multiple sensor planning, sensor design, and stage design for large part inspection is also discussed. © 2003 Society of Photo-Optical Instrumentation Engineers.

Most biological composites including bones, teeth and nacres have superior fracture resistance properties than that of their constituents. Their complex mixing of stiff and soft constituents enables energy dissipation ahead of the crack tip and contributes to enhance the fracture performance. In this study, phase-field based modeling is used to understand the fracture resistance of bio-inspired designs. Phase-field based topology optimization is then proposed to further improve the fracture resistance of these composite structures. The fracture process from damage to multiple crack propagation and ultimately to failure is fully studied. Numerical experiments show that significant enhancement of the fracture toughness, failure strain and overall strength can be achieved over the homogeneous constitutive stiff material.

The paper presents a method to optimize build orientation and topological layout simultaneously in density-based topology optimization for additive manufacturing. Support structures are required in additive manufacturing of parts of complex shape. To eliminate or reduce support structures during the additive processes, we constrain the lower bound of the overhang angle of the optimized design. In this method, the build orientation and the density field used to represent the part are simultaneously optimized to satisfy the overhang angle constraints for part self-support. While these angle constraints are locally defined on every material point over the design domain, they are transformed into two global constraints through the Heaviside projection-based aggregations. The first directional gradient based global constraint controls the overhang angle of the solid/void interface inside the design domain to eliminate the internal supports. The second density-based global constraint controls the angle of the design domain boundary to reduce the external supports. Numerical examples on both 2D and 3D linear elastic problems are presented to demonstrate the validity and efficiency of the proposed formulations in the build orientation optimization and in the overhang angle control.

In the initial published version of this article, there was a mistake in the Pvalue for the correlation between gene-expression changes and 5 hmC changes in tumors. The correct Pvalue should be same as the Pvalue shown in Fig. S6A: 9.8?×?10-6(mistakenly shown as “9.8?×?106” in the main text). This correction does not affect the description of results or the conclusions of this study, since the range of Pvalue is between 0 and 1.