Search

Abstract The route of oncolytic virotherapy is pivotal for immunotherapeutic efficacy in advanced cancers. In this preclinical study, an oncolytic reovirus (RC402) is orally administered to induce antitumor immunity. Oral reovirus treatment shows no gross toxicities and effectively suppresses multifocal tumor lesions. Orally administered reovirus interacts with the host immune system in the Peyer’s patch of the terminal ileum, increases IgA+ antibody-secreting cells in the lamina propria through MAdCAM-1+ blood vessels, and reshapes the gut microbiome. Oral reovirus promotes antigen presentation, type I/II interferons, and T cell activation within distant tumors, but does not reach or directly infect tumor cells beyond the gastrointestinal tract. In contrast to intratumoral reovirus injection, the presence of the gut microbiome, Batf3+ dendritic cells, type I interferons, and CD8+ T cells are indispensable for orally administered reovirus-induced antitumor immunity. Oral reovirus treatment is most effective when combined with αPD-1(L1) and/or αCTLA-4, leading to complete colon tumor regression and protective immune memory. Collectively, oral reovirus virotherapy is a feasible and effective immunotherapeutic strategy in preclinical studies.

This paper addresses the problem of computing the optimal stacking of two monotone polytopes P and Q in Rd. A monotone polytope in Rd is defined as a polytope whose intersection with any line parallel to the last coordinate axis xd is connected, and the stacking of P and Q is defined as a translation of Q, such that “Q touches P from above”. To evaluate the stack, we use three different scoring criteria: (1) the height of the stack, (2) the maximum pointwise distance along the xd-axis, and (3) the volume between P and Q. We propose exact algorithms to compute the optimal stacking for each scoring criterion.

ABSTRACTAntiangiogenic therapy is a recognized method for countering the immunosuppressive tumor microenvironment (TME) and improving anti-tumor immunity. PB101 is a glycosylated decoy receptor that binds to VEGF-A and PlGF with high affinity, based on the VEGFR1 backbone. Here, we elucidated PB101-induced remodeling of tumor angiogenesis and immunity, which enhances anti-PD-L1 immune checkpoint blockade. PB101 inhibited tumor growth by suppressing angiogenesis and enhancing CD8+ T cell infiltration into the tumors. PB101 induced robust reprogramming of antitumor immunity and activates intratumoral CD8+ T cells. Anti-tumor efficacy of PB101 is mostly dependent on CD8+ T cells and IFN-γ. PB101 reprograms tumor immunity in a manner distinct from that of the conventional VEGF decoy receptor, VEGF-trap. With its potent immune-modulating capability, PB101 synergizes with an anti-PD-L1, triggering strengthened antitumor immunity. Combining PB101 and anti-PD-L1 could establish durable protective immunity against tumor recurrence and metastasis. The findings of this study offer scientific rationales for further clinical development of PB101, particularly when used in combination with immune checkpoint inhibitors, as a potential treatment for advanced cancers.

Hybrid precoding has a great potential to achieve near-optimal performance with few radio-frequency (RF) chains in comparison to the number of antennas. This paper proposes a novel hybrid beamforming solution for sum rate maximization in a wideband multi-user multi-input multi-output (MU-MIMO) relay system. The problem at hand is non-convex and hence mathematically intractable due to the constant modulus constraints associated with the analog beamforming design at communicating nodes shared by all sub-carriers. Furthermore, relaying in MU-MIMO systems under frequency-selective channels is also a challenging task as it requires complicated signal processing. To address this problem, source analog beamformer, relay RF combiner and phase-only processing component at each destination are obtained by deriving the common RF processing matrix which enables beamforming gain over all sub-carriers. This process involves reconstruction loss minimization for designing the required analog beamforming vectors having ability to maximize end-to-end signal-to-interference plus noise ratio (SINR). The relay analog precoder is designed by maximizing the received power at each destination through gain maximization of the equivalent baseband channel over the allocated frequency spectrum. To reduce the computational complexity of the iterative approach used to find the relay RF precoding matrix, the closed form expression is derived for achieving the desired objective. Finally, digital baseband processing components are obtained from the equivalent baseband channels by suppressing the interference among transmitted signals indirectly. Simulation results for different system configurations reveal that the proposed algorithm can achieve near-optimal performance.

This paper proposes a novel remote monitoring system using a head mounted display (HMD). By using an HMD, a high degree of immersion and the sense of reality is provided to the user. Further, it becomes more convenient to move the camera position while controlling the robot arm on which the camera is mounted through the coordinates obtained from the HMD sensors. The proposed system performs two tasks. Initially, in order to render images in the HMD, the camera captures input images, and the PC connected to the robot arm sends the image to the PC connected to the HMD in real-time after which the image is rendered in the HMD. For the real-time monitoring, we increased the frame per second by reducing the data size. In order to reduce the data size, we define region of interest which is the region a user can see. Then, region of interest of the image is cropped and the resolution of entire image is degraded. Therefore, two images composed of cropped image and degraded image are transmitted and merged into an image. In this way, we can reduce the data size and provide the user with monitoring the image of the original quality. Next, using the inertial measurement unit sensor and base station sensors built into the HMD, the user controls the displacement of the camera during rotation and translation by controlling the robot arm by the user's own motion. The PC connected to the HMD transmits the motion coordinates of the HMD acquired from the sensor into the PC connected to the robot arm. To control the translation of the camera, we define a coordinate system that represents the y-axis as running from top to bottom, and the x-axis as running from the front to the back in three-dimensional space. Thus, each step motor along each axis, which controls the robot arm, has its movement controlled by supplying appropriate values of angular degrees. Through the above process, the proposed method implements a remote monitoring system with five degrees of freedom. In the experiment, we measured the data transmission delay time and the displacement error due to the robot arm's motion control to determine whether the system is suitable for a real-time remote monitoring system. Experimental results show that the proposed system can be optimally operated with a frame rate of 15 frames per second and a group of pixel resolutions of $640\times 640$ of the cropped image and $240\times 120$ of the degraded image. In addition, the average error rate of the robot arm's displacement was 6.45% when the camera position was controlled through the robot arm.

ObjectivesForeign patients are more likely to receive inappropriate health service in the emergency room. This study aimed to investigate whether there is health inequality between foreigners and natives who visited emergency rooms with injuries and to examine its causes. MethodsWe analyzed clinical data from the National Emergency Department Information System database associated with patients of all age groups visiting the emergency room from 2013 to 2015. We analyzed data regarding mortality, intensive care unit admission, emergency operation, severity, area, and transfer ratio.ResultsA total of 4,464,603 cases of injured patients were included, of whom 67,683 were foreign. Injury cases per 100,000 population per year were 2,960.5 for native patients and 1,659.8 for foreign patients. Foreigners were more likely to have no insurance (3.1% vs. 32.0%, p < 0.001). Serious outcomes (intensive care unit admission, emergency operation, or death) were more frequent among foreigners. In rural areas, the difference between serious outcomes for foreigners compared to natives was greater (3.7% for natives vs. 5.0% for foreigners, p < 0.001). The adjusted odds ratio for serious outcomes for foreign nationals was 1.412 (95% confidence interval [CI], 1.336–1.492), and that for lack of insurance was 1.354 (95% CI, 1.314–1.394).ConclusionsInjured foreigners might more frequently suffer serious outcomes, and health inequality was greater in rural areas than in urban areas. Foreign nationality itself and lack of insurance could adversely affect medical outcomes.

Background Peritoneal carcinomatosis is a fatal clinical presentation of colon cancer, characterized by unresponsiveness to conventional anticancer therapies, including immune checkpoint inhibitors. Here, we elucidated the immune-evasion mechanisms during the peritoneal carcinomatosis of colon cancer and developed a novel immunotherapy by activating the stimulator of interferon genes (STING) pathway.Methods We generated a syngeneic peritoneal carcinomatosis model of colon cancer. Mice were intraperitoneally treated with either STING agonist (MIW815, also known as ADU-S100) or PD-1 blockade or both. The tumor microenvironment was comprehensively analyzed using multiplexed immunofluorescence imaging, flow cytometry, and NanoString immune profiling.Results Intraperitoneal colon cancer cells induce a massive influx of immunosuppressive M2-like macrophages, upregulate immune checkpoints, and impair effector T cell functions during peritoneal dissemination; these collectively create a highly angiogenic and immunosuppressive milieu that is resistant to anti-PD-1 monotherapy. Intraperitoneal administration of a STING agonist suppressed aberrant angiogenesis, increased pericyte coverage, and normalized tumor vessels, thereby facilitating the infiltration of activated CD8+ T cells into peritoneal tumor nodules. Moreover, STING activation reprogramed tumor-associated macrophages toward the M1 phenotype. STING activation converted immunologically cold peritoneal tumors into T-cell-inflamed tumors in a type-I interferon-dependent manner. Lastly, the STING agonist synergistically cooperated with PD-1 and/or COX2 blockade to further suppress the peritoneal dissemination of colon cancer, resulting in complete eradication of tumor and ascites, and inducing durable antitumor immunity.Conclusions STING activation can normalize the peritoneal vascular and immune microenvironment, providing a rationale for a novel combination therapeutic strategy for peritoneal carcinomatosis in colon cancer.

Kynurenine (Kyn) is a key inducer of an immunosuppressive tumor microenvironment (TME). Although indoleamine 2,3-dioxygenase (IDO)-selective inhibitors have been developed to suppress the Kyn pathway, the results were not satisfactory due to the presence of various opposing mechanisms. Here, we employed an orally administered novel Kyn pathway regulator to overcome the limitation of anti-tumor immune response. We identified a novel core structure that inhibited both IDO and TDO. An orally available lead compound, STB-C017 (designated hereafter as STB), effectively inhibited the enzymatic and cellular activity of IDO and TDO in vitro. Moreover, it potently suppressed Kyn levels in both the plasma and tumor in vivo. STB monotherapy increased the infiltration of CD8+ T cells into TME. In addition, STB reprogrammed the TME with widespread changes in immune-mediated gene signatures. Notably, STB-based combination immunotherapy elicited the most potent anti-tumor efficacy through concurrent treatment with immune checkpoint inhibitors, leading to complete tumor regression and long-term overall survival. Our study demonstrated that a novel Kyn pathway regulator derived using deep learning technology can activate T cell immunity and potentiate immune checkpoint blockade by overcoming an immunosuppressive TME.

Summary: Stress-driven ribosome dysfunction triggers an eIF2α-mediated integrated stress response to maintain cellular homeostasis. Among four key eIF2α kinases, protein kinase R (PKR) expression positively associates with poor prognoses for colorectal cancer (CRC) patients. We identified PKR-linked Wnt signaling networks that facilitate early inflammatory niche and epithelial-mesenchymal transitions of tumor tissues in response to ribosomal insults. However, the downstream Wnt signaling target fibrogenic connective tissue growth factor (CTGF/CCN2) regulates the nuclear translocation of β-catenin in a negative feedback manner. Moreover, dwindling expression of the Wnt/β-catenin pathway-regulator CTGF triggers noncanonical Wnt pathway-mediated exacerbation of intestinal cancer progression such as an increase in cancer stemness and acquisition of chemoresistance in the presence of ribosomal insults. The Wnt-CTGF-circuit-associated landscape of oncogenic signaling events was verified with clinical genomic profiling. This ribosome-associated wave of crosstalk between stress and oncogenes provides valuable insight into potential molecular interventions against intestinal malignancies.

G3BP1 is RasGAP SH3 domain binding protein 1 that interacts with 48S pre-initiation complex when translation is stalled. Here, Twiss and colleagues show that neuronal G3BP1 can negatively regulate axonal mRNA translation, and inhibit axonal regeneration after injury.

Various types of ginsenosides are present in ginseng and have been recognized for their health-promoting effects. Compound K (CK) is a metabolite of ginsenoside Rb1 and reportedly exerts chemotherapeutic effects against several types of cancers. However, the anti-cancer effect and the molecular mechanism of CK against hormone-independent breast cancer is unknown. Through a direct comparison, it was discovered that CK elicits the strongest anti-cancer effect against breast cancer cells when compared to other ginsenosides. CK treatment suppresses the growth of hormone-independent human breast cancer cells and induces G1 phase cell cycle arrest. CK also markedly suppresses tumor growth in a mouse xenograft model, concomitant with the suppression of cyclin D1 via protein degradation. These findings suggest that CK can be used to target hormone-independent breast cancers by inducing degradation of cyclin D1.

Purpose We aimed to investigate the triage results and the degree of agreement between prehospital and hospital stages of pediatric patients who visited the emergency department (ED) via emergency medical service providers (EMSP) in comparison with adult patients. Methods We retrospectively reviewed 8,152 pediatric patients who visited a regional emergency medical center ED via EMSP from January 2015 to December 2015. Pediatric patients were defined as younger than 15 years according to the Korean Triage and Acuity Scale (KTAS). Given the difference of the triage tools of the prehospital (EMSP) and hospital (KTAS) stages, we performed the re-triage into “critical” and “non-critical”. Comparisons of characteristics between pediatric and adult patients were made using chi-square tests. The degree of agreement between the tools was analyzed using κanalysis. Results Of 8,152 patients, 654 (8.0%) were pediatric patients. Direct medical control was more frequently performed to adult patients (P < 0.001). Critical patients were more common among adults (12.2% by KTAS, 24.8% by EMSP) than children (3.5% by KTAS, 14.1% by EMSP). The κ value of pediatric patients was lower than that of adult patients (0.09 [poor]; 95% confidence interval [CI], 0.01-0.18 vs. 0.38 [fair]; 95% CI, 0.35-0.40). Conclusion Pediatric patients transferred by EMSP showed lower severity and degree of agreements of the triage results between prehospital and hospital stages than adult patients. It is necessary to pay particular attention to pediatric triage in a pre-hospital setting.

Objective We investigated the association between lactate clearance or serum lactate levels and neurologic outcomes or in-hospital mortality in cardiac arrest survivors who were treated with targeted temperature management (TTM). Methods A retrospective analysis of data from cardiac arrest survivors treated with TTM between 2012 and 2015 was conducted. Serum lactate levels were measured on admission and at 12, 24, and 48 hours following admission. Lactate clearance at 12, 24, and 48 hours was also calculated. The primary outcome was neurologic outcome at discharge. The secondary outcome was in-hospital mortality. Results The study included 282 patients; 184 (65.2%) were discharged with a poor neurologic outcome, and 62 (22.0%) died. Higher serum lactate levels at 12 hours (odds ratio [OR], 1.157; 95% confidence interval [CI], 1.006 to 1.331), 24 hours (OR, 1.320; 95% CI, 1.084 to 1.607), and 48 hours (OR, 2.474; 95% CI, 1.459 to 4.195) after admission were associated with a poor neurologic outcome. Furthermore, a higher serum lactate level at 48 hours (OR, 1.459; 95% CI, 1.181 to 1.803) following admission was associated with in-hospital mortality. Lactate clearance was not associated with neurologic outcome or in-hospital mortality at any time point after adjusting for confounders. Conclusion Increased serum lactate levels after admission are associated with a poor neurologic outcome at discharge and in-hospital mortality in cardiac arrest survivors treated with TTM. Conversely, lactate clearance is not a robust surrogate marker of neurologic outcome or in-hospital mortality.

Microchips are widely used to separate circulating tumor cells (CTCs) from whole blood by virtues of sophisticated manipulation for microparticles. Here, we present a chip with an 8 μm high and 27.9 mm wide slit to capture cancer cells bound to 3 μm beads. Apart from a higher purity and recovery rate, the slit design allows for simplified fabrication, easy cell imaging, less clogging, lower chamber pressure and, therefore, higher throughput. The beads were conjugated with anti-epithelial cell adhesion molecules (anti-EpCAM) to selectively bind to breast cancer cells (MCF-7) used to spike the whole blood. The diameter of the cell-bead construct was in average 23.1 μm, making them separable from other cells in the blood. As a result, the cancer cells were separated from 5 mL of whole blood with a purity of 52.0% and a recovery rate of 91.1%, and also we confirmed that the device can be applicable to clinical samples of human breast cancer patients. The simple design with microslit, by eliminating any high-aspect ratio features, is expected to reduce possible defects on the chip and, therefore, more suitable for mass production without false separation outputs.

Proper development of the CNS axon-glia unit requires bi-directional communication between axons and oligodendrocytes (OLs). We show that the signaling lipid phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] is required in neurons and in OLs for normal CNS myelination. In mice, mutations of Fig4, Pikfyve or Vac14, encoding key components of the PI(3,5)P2 biosynthetic complex, each lead to impaired OL maturation, severe CNS hypomyelination and delayed propagation of compound action potentials. Primary OLs deficient in Fig4 accumulate large LAMP1+ and Rab7+ vesicular structures and exhibit reduced membrane sheet expansion. PI(3,5)P2 deficiency leads to accumulation of myelin-associated glycoprotein (MAG) in LAMP1+perinuclear vesicles that fail to migrate to the nascent myelin sheet. Live-cell imaging of OLs after genetic or pharmacological inhibition of PI(3,5)P2 synthesis revealed impaired trafficking of plasma membrane-derived MAG through the endolysosomal system in primary cells and brain tissue. Collectively, our studies identify PI(3,5)P2 as a key regulator of myelin membrane trafficking and myelinogenesis.

Recently, the range of available Radio Frequency Identification (RFID) tags has been widened to include smart RFID tags which can monitor their varying surroundings. One of the most important factors for better performance of smart RFID system is accurate measurement from various sensors. In the multi-sensing environment, some noisy signals are obtained because of the changing surroundings. We propose in this paper an improved Kalman filter method to reduce noise and obtain correct data. Performance of Kalman filter is determined by a measurement and system noise covariance which are usually called the R and Q variables in the Kalman filter algorithm. Choosing a correct R and Q variable is one of the most important design factors for better performance of the Kalman filter. For this reason, we proposed an improved Kalman filter to advance an ability of noise reduction of the Kalman filter. The measurement noise covariance was only considered because the system architecture is simple and can be adjusted by the neural network. With this method, more accurate data can be obtained with smart RFID tags. In a simulation the proposed improved Kalman filter has 40.1%, 60.4% and 87.5% less Mean Squared Error (MSE) than the conventional Kalman filter method for a temperature sensor, humidity sensor and oxygen sensor, respectively. The performance of the proposed method was also verified with some experiments.

This paper proposes an efficient management system utilizing a Radio Frequency Identification (RFID) antenna control unit which is moving along with the path of boxes of materials on the conveyor belt by manipulating a motor. The proposed antenna control unit, which is driven by a motor and is located on top of the gate, has an array structure of two antennas with parallel connection. The array structure helps improve the directivity of antenna beam pattern and the readable RFID distance due to its configuration. In the experiments, as the control unit follows moving materials, the reading time has been improved by almost three-fold compared to an RFID system employing conventional fixed antennas. The proposed system also has a recognition rate of over 99% without additional antennas for detecting the sides of a box of materials. The recognition rate meets the conditions recommended by the Electronic Product Code glbal network (EPC)global for commercializing the system, with three antennas at a 20 dBm power of reader and a conveyor belt speed of 3.17 m/s. This will enable a host of new RFID conveyor belt gate systems with increased performance.

Although real-time monitoring of bladder volume together with intravesical pressure can provide more information for understanding the functional changes of the urinary bladder, it still entails difficulties in the accurate prediction of real-time bladder volume in urodynamic studies with small animal models. We studied a new implantable bladder volume monitoring device with eight rats. During cystometry, microelectrodes prepared by the microelectromechanical systems process were placed symmetrically on both lateral walls of the bladder, and the expanded bladder volume was calculated. Immunohistological study was done after 1 week and after 4 weeks to evaluate the biocompatibility of the microelectrode. From the point that infused saline volume into the bladder was higher than 0.6 mL, estimated bladder volume was statistically correlated with the volume of saline injected (p

Medulloblastoma, the most common pediatric brain tumor, is thought to arise from deregulated proliferation of cerebellar granule precursor (CGP) cells. Sonic hedgehog (Shh) is the primary mitogen that regulates proliferation of CGP cells during the early stages of postnatal cerebellum development. Aberrant activation of Shh signaling during this time has been associated with hyperplasia of CGP cells and eventually may lead to the development of medulloblastoma. The molecular targets of Shh signaling involved in medulloblastoma formation are still not well-understood. Here, we show that Shh regulates sustained activation of histone deacetylases (HDACs) and that this activity is required for continued proliferation of CGP cells. Suppression of HDAC activity not only blocked the Shh-induced CGP proliferation in primary cell cultures, but also ameliorated aberrant CGP proliferation at the external germinal layer (EGL) in a medulloblastoma mouse model. Increased levels of mRNA and protein of several HDAC family members were found in medulloblastoma compared to wild type cerebellum suggesting that HDAC activity is required for the survival/progression of tumor cells. The identification of a role of HDACs in the early steps of medulloblastoma formation suggests there may be a therapeutic potential for HDAC inhibitors in this disease.