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Abstract Vaccines are an important tool in the rapidly evolving repertoire of immunotherapies in oncology. Although cancer vaccines have been investigated for over 30 years, very few have achieved meaningful clinical success. However, recent advances in areas such antigen identification, formulation development and manufacturing, combination therapy regimens, and indication and patient selection hold promise to reinvigorate the field. Here, we provide a timely update on the clinical status of cancer vaccines. We identify and critically analyze 360 active trials of cancer vaccines according to delivery vehicle, antigen type, indication, and other metrics, as well as highlight eight globally approved products. Finally, we discuss current limitations and future applications for clinical translation of cancer vaccines.

Abstract Monoclonal antibodies that target SARS-CoV-2 with high affinity are valuable for a wide range of biomedical applications involving novel coronavirus disease (COVID-19) diagnosis, treatment, and prophylactic intervention. Strategies for the rapid and reliable isolation of these antibodies, especially potent neutralizing antibodies, are critical toward improved COVID-19 response and informed future response to emergent infectious diseases. In this study, single B cell screening was used to interrogate antibody repertoires of immunized mice and isolate antigen-specific IgG1+ memory B cells. Using these methods, high-affinity, potent neutralizing antibodies were identified that target the receptor-binding domain of SARS-CoV-2. Further engineering of the identified molecules to increase valency resulted in enhanced neutralizing activity. Mechanistic investigation revealed that these antibodies compete with ACE2 for binding to the receptor-binding domain of SARS-CoV-2. These antibodies may warrant further development for urgent COVID-19 applications. Overall, these results highlight the potential of single B cell screening for the rapid and reliable identification of high-affinity, potent neutralizing antibodies for infectious disease applications.

Abstract Nanoparticles (NPs) can serve as a promising vaccine delivery platform for improving pharmacological property and codelivery of antigens and adjuvants. However, NP‐based vaccines are generally associated with complex synthesis and postmodification procedures, which pose technical and manufacturing challenges for tailor‐made vaccine production. Here, modularly programmed, polyethyleneimine (PEI)‐based NP vaccines are reported for simple production of personalized cancer vaccines. Briefly, PEI is conjugated with neoantigens by facile coupling chemistry, followed by electrostatic assembly with CpG adjuvants, leading to the self‐assembly of nontoxic, sub‐50 nm PEI NPs. Importantly, PEI NPs promote activation and antigen cross‐presentation of antigen‐presenting cells and cross‐priming of neoantigen‐specific CD8+ T cells. Surprisingly, after only a single intratumoral injection, PEI NPs with optimal PEGylation elicit as high as ≈30% neoantigen‐specific CD8+ T cell response in the systemic circulation and sustain elevated CD8+ T cell response over 3 weeks. PEI‐based nanovaccines exert potent antitumor efficacy against pre‐established local tumors as well as highly aggressive metastatic tumors. PEI engineering for modular incorporation of neoantigens and adjuvants offers a promising strategy for rapid and facile production of personalized cancer vaccines.

BackgroundRecent studies have shown the importance of postprandial glucose (PPG) in the development of diabetes complications. This study was conducted in order to survey the perceptions of clinicians and diabetic patients with respect to PPG management and the current status of diabetes education.MethodsThis was a cross-sectional study involving face-to-face interviews and an open questionnaire survey conducted in Korea. A total of 300 patients and 130 clinicians completed questionnaires, which included current education status, self monitoring of blood glucose (SMBG), criteria of diagnosis and management, and perceptions relating to PPG management.ResultsWhile there was a significantly higher perceived need for diabetes education, the sufficiency of the current education was considered to be severely lacking. Fasting plasma glucose (FPG), PPG, and glycosylated hemoglobin (HbA1c) were all important considerations for clinicians when making a diagnosis of diabetes, although PPG was considered less important than FPG or HbA1c in the treatment of diabetes. Most clinicians and patients were aware of the importance of PPG, but actual education on the importance of PPG was not actively being delivered.ConclusionOur study showed that the current status of diabetes education is insufficient to meet the needs of the Korean population. A considerable gap was found to exist between awareness and what was actually taught in the current education program in regard to the importance of PPG. These results suggest that clinicians need to be more active in patient education, especially in regard to the importance of PPG.

Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant myeloid function is often observed in MS plaques in the central nervous system (CNS), the role of myeloid cells in therapeutic intervention is currently overlooked. Here, we developed a myeloid cell-based strategy to reduce the disease burden in experimental autoimmune encephalomyelitis (EAE), a mouse model of progressive MS. We developed monocyte-adhered microparticles ("backpacks") for activating myeloid cell phenotype to an anti-inflammatory state through localized interleukin-4 and dexamethasone signals. We demonstrate that backpack-laden monocytes infiltrated into the inflamed CNS and modulated both the local and systemic immune responses. Within the CNS, backpack-carrying monocytes regulated both the infiltrating and tissue-resident myeloid cell compartments in the spinal cord for functions related to antigen presentation and reactive species production. Treatment with backpack-monocytes also decreased the level of systemic pro-inflammatory cytokines. Additionally, backpack-laden monocytes induced modulatory effects on TH1 and TH17 populations in the spinal cord and blood, demonstrating cross talk between the myeloid and lymphoid arms of disease. Backpack-carrying monocytes conferred therapeutic benefit in EAE mice, as quantified by improved motor function. The use of backpack-laden monocytes offers an antigen-free, biomaterial-based approach to precisely tune cell phenotype in vivo, demonstrating the utility of myeloid cells as a therapeutic modality and target. [ABSTRACT FROM AUTHOR]

A kinetic equation for the solid-solution formation is established for CdSe/ZnSe and the solid-solution formation mechanism is elucidated as [Zn.sup.2+] ion diffusion in [Cd.sup.2+]-[Se.sup.2-] matrices. The kinetic analysis approach is applied to the derivation of kinetic equations for other solid-solution formation reactions of semiconductor nanocrystals and supplies a key not to estimate and control the wavelength of possible light emission from each solid solution nanocrystal.

We demonstrate a new design of Ge-based electrodes comprising three-dimensional (3-D) spherical microflowers containing crystalline nanorod networks on sturdy 1-D nanostems directly grown on a metallic current collector by facile thermal evaporation. The Ge nanorod networks were observed to self-replicate their tetrahedron structures and form a diamond cubic lattice-like inner network. After etching and subsequent carbon coating, the treated Ge nanostructures provide good electrical conductivity and are resistant to gradual deterioration, resulting in superior electrochemical performance as anode materials for LIBs, with a charge capacity retention of 96% after 100 cycles and a high specific capacity of 1360 mA h g-1 at 1 C and a high-rate capability with reversible capacities of 1080 and 850 mA h g-1 at the rates of 5 and 10 C, respectively. The improved electrochemical performance can be attributed to the fast electron transport and good strain accommodation of the carbon-filled Ge microflower-on-nanostem hybrid electrode. [ABSTRACT FROM AUTHOR]

Differentiation of B cells into Ab-secreting cells induces changes in gene transcription, IgH RNA processing, the unfolded protein response (UPR), and cell architecture. The transcription elongation factor eleven nineteen lysine-rich leukemia gene (ELL2) stimulates the processing of the secreted form of the IgH mRNA from the H chain gene. Mice (mus musculus) with the ELL2 gene floxed in either exon 1 or exon 3 were constructed and crossed to CD19-driven cre/CD19+. The B cell-specific ELL2 conditional knockouts (cKOs; ell2loxp/loxp CD19cre/+) exhibit curtailed humoral responses both in 4-hydroxy-3-nitrophenyl acetyl-Ficoll and in 4-hydroxy-3-nitrophenyl acetyl-keyhole limpet hemocyanin immunized animals; recall responses were also diminished. The number of immature and recirculating B cells in the bone marrow is increased in the cKOs, whereas plasma cells in spleen are reduced relative to control animals. There are fewer IgG1 Ab-producing cells in the bone marrow of cKOs. LPS ex vivo-stimulated B220loCD138+ cells from ELL2-deficient mouse spleens are 4-fold less abundant than from control splenic B cells; have a paucity of secreted IgH; and have distended, abnormal-appearing endoplasmic reticulum. IRE1a is efficiently phosphorylated, but the amounts of Ig κ, ATF6, BiP, Cyclin B2, OcaB (BOB1, Pou2af1), and XBP1 mRNAs, unspliced and spliced, are severely reduced in ELL2-deficient cells. ELL2 enhances the expression of BCMA (also known as Tnfrsf17), which is important for long-term survival. Transcription yields from the cyclin B2 and the canonical UPR promoter elements are upregulated by ELL2 cDNA. Thus, ELL2 is important for many aspects of Ab secretion, XBP1 expression, and the UPR. [ABSTRACT FROM AUTHOR]

High-quality single-crystalline Sn-doped In2O3 (ITO) nanowires (NWs) with diameters of about 60-80 nm and lengths of several tens of micrometers were produced using a simple thermal co-evaporation method at a substrate temperature of ~540 °C. The electrical conductivity of as-synthesized ITO NW was ~115.9 S/cm at room temperature. Photocurrent generation devices were prepared by self-assembling di(3-aminopropyl)viologen and Ru(2,2'-bipyridine-4,4'-dicarboxylic acid)2(NCS)2 on the surface of ITO NWs. The maximum photocurrent density of the device with an ITO NW electrode under illumination of 100 mW/cm² was 11.05 µA/cm², which is about three orders of magnitude larger than that of the device with a bare ITO thin film electrode. The high photocurrent density could be attributed to the large surface area, high crystallinity, and electrical conductivity of the ITO NW electrode. [ABSTRACT FROM AUTHOR]

Monodispersed core/shell spinel ferrite/carbon nanoparticles are formed by thermolysis of metal (Fe3+, Co2+) oleates followed by carbon coating. The phase and morphology of nanoparticles are characterized by x-ray diffraction and transmission electron microscopy. Pure Fe3O4 and CoFe2O4 nanoparticles are initially prepared through thermal decomposition of metal-oleate precursors at 310 °C and they are found to exhibit poor electrochemical performance because of the easy aggregation of nanoparticles and the resulting increase in the interparticle contact resistance. In contrast, uniform carbon coating of Fe3O4 and CoFe2O4 nanoparticles by low-temperature (180 °C) decomposition of malic acid allowed each nanoparticle to be electrically wired to a current collector through a conducting percolative path. Core/shell Fe3O4/C and CoFe2O4/C nanocomposite electrodes show a high specific capacity that can exceed 700 mAh g-1 after 200 cycles, along with enhanced cycling stability. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to identify prognostic factors for overall survival (OS) in patients with small cell lung cancer (SCLC) and to construct a prognostic index on the basis of their expected OS. Long-term survivors were also given special attention. Methods: We retrospectively analyzed 295 patients diagnosed with SCLC from January 2002 to September 2007 at the Severance Hospital, Seoul, Republic of Korea. Patient history was reviewed regarding both clinical and tumor-related markers, and treatment-related factors were also evaluated. Results: There were 131 (44.4%) patients with limited disease (LD) and 164 (55.6%) with extensive disease (ED). Median follow-up lasted 9.4 months. Objective response to chemotherapy was 66.8%. The median survival time (MST) was 11.2 months in all patients, 20.4 months in LD patients, and 7.7 months in ED patients. The median progression-free survival was 9.4 months. Independent prognostic factors for overall survival (OS) were extent of disease, performance status, and CYFRA 21-1 level. We classified all patients into four groups based on the results of multivariate analysis using classification and regression tree analysis. Median survival times were 22.7, 13.7, 8.5, and 3.2 months, respectively. A total of 51 (17.3%) patients from the entire study population were evaluated for long-term survival, which was defined as survival >2 years. Their MST was 43.1 months, and extent of disease, performance status, and CYFRA 21-1 were independent prognostic factors for long-term survival. Conclusions: We confirmed the well-known prognosticators, disease extent and performance status, in our patients, but further identified CYFRA 21-1 as independent prognostic factor. A prognostic index was constructed to create four classifications of SCLC considering these variables. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The human inducible NOS (iNOS) promoter transcriptionally regulated by 5′ flanking region extending 16 kb upstream that contains cytokine-responsive DNA motifs. In this study, we further identified a classic inducible enhancer located between --5 and --6 kb in the hiNOS upstream promoter. This 1 kb promoter sequence functions as a cytokine-inducible enhancer in an orientation- and position-independent manner in human lung A549 and liver AKN1 cells. This DNA enhancer also confers cytokine inducibility to the heterologous thymidine kinase (TK) promoter. Chromatin immunoprecipitation (ChIP) analysis was applied, and confirmed cytokine-inducible in vivo DNA-protein interactions within this enhancer region. In vivo functional binding of both NF-κB (p65/p50) and Stat-lα at the --5.8 kb human iNOS promoter site was significantly increased in A549 cells after cytokine stimulation, while only Stat-1α bound at the --5.2 kb site. These results identify the --5 to --6 kb promoter region as a classic transcriptional enhancer for the human iNOS gene and provide definitive in vivo evidence of specific NF-κB and Stat-1 nuclear protein binding that mediates transcription of the hiNOS gene under cytokine stimulation. [ABSTRACT FROM AUTHOR]

Doping and hybridization with other semiconductors are highly effective ways to address the limitations, including their weak response to visible light and significant recombination of photogenerated carriers. In addition, the assisted carbon on the catalyst surface and the structural design have the advantage of being catalytically active. Herein, visible-light-active N-doped C/Na2Ti6O13/TiO2 hollow spheres (denoted as N–C/NTO/TiO2 HS) were successfully prepared using a facile two-step method and evaluated for methylene blue (MB) aqueous solution degradation under visible-light irradiation.The as-obtained N–C/NTO/TiO2 HS demonstrated improved photocatalytic efficiency (94 %) and pseudo-first-order kinetic degradation rate (0.023 min−1). Moreover, after three cycles of testing, N–C/NTO/TiO2 HS showed a 91 % degradation rate in its photostability. The enhanced photocatalytic performance was attributed to the combined effects of N-doping, carbon species on the surface, and the coupling of TiO2 and Na2Ti6O13 using morphology engineering. Finally, based on the experimental results, a possible photocatalytic mechanism was proposed. This study provides a rational approach toward the development of high-performance titanate-based photocatalysts for solar energy-assisted wastewater treatment.

A measure of insulin resistance is routinely evaluated as the rate constant for plasma glucose disappearance. The purpose of this study was to develop a mixed effect model approach to estimate insulin resistance that can be applied to sparsely-sampled plasma glucose data. Data were taken from 1516 subjects who took an insulin tolerance test. Blood samples were collected at 3, 6, 9, 12, 15 min after intravenous injection of insulin with a dose of 0.1U/kg. Plasma glucose concentrations were analyzed by the glucose oxidase method. A one-compartment pharmacokinetic model consisting of the plasma glucose disappearance rate constant (K) and the baseline plasma glucose concentration (CO) was used incorporating clinical covariates to describe the time course of glucose, within the context of mixed effect model framework. Validity of the model was tested by internal validation. Based on the model so derived, a set of sparse sample times that best describes the original glucose kinetics was determined from the combinations of the 5 sample times. Estimated population means for K and C0 were 0.0362min[sup -1] and 4.8769mmol/L with interindividual variability of 41.71% and 4.83% in CV, respectively. Important covariates found were age, sex and clinical status for K, while C0 dependent only on clinical status. The weighted residuals (WRES) obtained from NONMEM lied approximately within -3 and 3 with a mean of about zero, indicating no bias for the model. For a sparse sample design, a set of samples at 3, 6, and 15 min allowed best prediction of plasma glucose concentration, with no noticeable deviation in the estimate of K. This work suggests the feasibility of applying a sparse-sample design approach to assessing insulin resistance. The classical approach such as the glucose clamp test may be necessary to further validate the accuracy of the model suggested. [ABSTRACT FROM AUTHOR]

Served as one of general transcription coactivators, p300 plays an important role in mediating gene transcriptional activation. Our previous work demonstrated that human iNOS expression can be highly induced with the cytokine mixture (CM) of TNFα + IL-1β + IFNγ. In this study, we explored the potential function of p300 in the regulation of human iNOS gene expression. Our initial results showed that overexpression of p300 by transient transfection in human A549 lung cells significantly increased the basal and cytokine induced human iNOS promoter activities. Interestingly, p300 activated cytokine induced human iNOS transcription which was completely abrogated by the deletion of an enhancer region between -5 kb and -6 kb in the hiNOS upstream promoter. However, the enhanced basal promoter activity by p300 overexpression still remained high even with the enhancer deletion. Our data suggest that coactivator p300 is capable of up-regulating human iNOS transcription. The transcription machinery responsible for p300 interaction with necessary transcription factors is being further investigated. [ABSTRACT FROM AUTHOR]

Transcriptional regulation of hiNOS gene is highly complex and tightly controlled. It requires an orchestrated flow of positive and negative transcription factors that bind to specific cis-acting upstream response elements. The hiNOS promoter is known to be one of the largest promoters with inducible elements extending up to -16 kb. Oct-1 protein belongs to the POU domain transcription factor family and is constitutively expressed in all dividing cells. Therefore, it's essential for proliferation, differentiation and other key cell processes. Oct-1 binding to DNA may either stimulate or inhibit transcription of the target gene. In this work, the octamer sequence ATGCAAAT at -10.2 kb of the hiNOS promoter was identified as high-affinity Oct-1 binding by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (CHIP) assay. Cytokine-induced hiNOS promoter activity was significantly reduced by Oct-1 siRNA targeting. Mutation of the Oct-1 motif decreased cytokine-induced hiNOS promoter activity by 40 % and Oct-1 silencing also reduced the promoter activity of mutant hiNOS at -10.2 Oct-1. Taken together, we found a functional Oct-1 motif regulating hiNOS gene expression at -10.2 kb in the hiNOS promoter. [ABSTRACT FROM AUTHOR]

Inspired by the relatively simple morphological blueprint provided by batoid fish such as stingrays and skates, we created a biohybrid system that enables an artificial animal—a tissue-engineered ray—to swim and phototactically follow a light cue. By patterning dissociated rat cardiomyocytes on an elastomeric body enclosing a microfabricated gold skeleton, we replicated fish morphology at 1/10 scale and captured basic fin deflection patterns of batoid fish. Optogenetics allows for phototactic guidance, steering, and turning maneuvers. Optical stimulation induced sequential muscle activation via serpentinepatterned muscle circuits, leading to coordinated undulatory swimming. The speed and direction of the ray was controlled by modulating light frequency and by independently eliciting right and left fins, allowing the biohybrid machine to maneuver through an obstacle course [ABSTRACT FROM AUTHOR]

Abstract Background Nanoparticles have been used for biomedical applications, including drug delivery, diagnosis, and imaging based on their unique properties derived from small size and large surface-to-volume ratio. However, concerns regarding unexpected toxicity due to the localization of nanoparticles in the cells are growing. Herein, we quantified the number of cell-internalized nanoparticles and monitored their cellular localization, which are critical factors for biomedical applications of nanoparticles. Methods This study investigates the intracellular trafficking of silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate dye [MNPs@SiO2(RITC)] in various live single cells, such as HEK293, NIH3T3, and RAW 264.7 cells, using site-specific direct stochastic optical reconstruction microscopy (dSTORM). The time-dependent subdiffraction-limit spatial resolution of the dSTORM method allowed intracellular site-specific quantification and tracking of MNPs@SiO2(RITC). Results The MNPs@SiO2(RITC) were observed to be highly internalized in RAW 264.7 cells, compared to the HEK293 and NIH3T3 cells undergoing single-particle analysis. In addition, MNPs@SiO2(RITC) were internalized within the nuclei of RAW 264.7 and HEK293 cells but were not detected in the nuclei of NIH3T3 cells. Moreover, because of the treatment of the MNPs@SiO2(RITC), more micronuclei were detected in RAW 264.7 cells than in other cells. Conclusion The sensitive and quantitative evaluations of MNPs@SiO2(RITC) at specific sites in three different cells using a combination of dSTORM, transcriptomics, and molecular biology were performed. These findings highlight the quantitative differences in the uptake efficiency of MNPs@SiO2(RITC) and ultra-sensitivity, varying according to the cell types as ascertained by subdiffraction-limit super-resolution microscopy. Graphical Abstract

While primaquine has long been used for malaria treatment, treatment failure is common. This study aims to develop a population pharmacokinetic model of primaquine and its metabolite, carboxyprimaquine, and examine factors influencing pharmacokinetic variability. The data was obtained from a clinical study in 24 Korean subjects randomly assigned to normal and obese groups. The participants received primaquine 15 mg daily for 4 days and blood samples were collected at day 4. Pharmacokinetic modeling was performed with NONMEM and using simulations; the influences of doses and covariates on drug exposure were examined. A minimal physiology-based pharmacokinetic model connected with a liver compartment comprehensively described the data, with CYP450 mediated clearance being positively correlated with the body weight and CYP2D6 activity score (p < 0.05). In the simulation, while the weight-normalized area under drug concentration for primaquine in the obese group decreased by 29% at the current recommended dose of 15 mg, it became similar to the normal weight group at a weight-normalized dose of 3.5 mg/kg. This study has demonstrated that the body weight and CYP2D6 activity score significantly influence the pharmacokinetics of primaquine. The developed model is expected to be used as a basis for optimal malaria treatment in Korean patients.

The article presents the kinetic analysis for formation of cadmium1-xzincxselenide solid-solution nanocrystals. The photoluminescence (PL) results exhibited that the partially solid-solution-treated nanocystals had higher PL emission intensity than almost totally solid-solution-treated nanocyrstals. The energy band gap of zinc selenide is larger than that of cadmium1-xzincxselenide.