Machine Learning-Directed Conversion of Glioblastoma Cells to Dendritic Cell-like Antigen-Presenting Cells as Cancer Immunotherapy.

Immunotherapy has limited efficacy in glioblastoma (GBM) due to the blood-brain barrier and the immunosuppressed or "cold" tumor microenvironment (TME) of GBM, which is dominated by immune-inhibitory cells and depleted of cytotoxic T lymphocytes (CTL) and dendritic cells (DC). Here, we report the development and application of a machine-learning precision method to identify cell fate determinants (CFD) that specifically reprogram GBM into induced antigen-presenting cells with DC-like functions (iDC-APC). In murine GBM models, iDC-APCs acquired DC-like morphology, regulatory gene expression profile, and functions comparable to natural DCs. Among these acquired functions were phagocytosis, direct presentation of endogenous antigens, and cross presentation of exogenous antigens. The latter endowed the iDC-APCs with the ability to prime naïve CD8+ CTLs, a hallmark DC function critical for antitumor immunity. Intratumor iDC-APCs reduced tumor growth and improved survival only in immunocompetent animals, which coincided with extensive infiltration of CD4+ T cells and activated CD8+ CTLs in the TME. The reactivated TME synergized with an intratumor soluble PD-1 decoy immunotherapy and a DC-based GBM vaccine, resulting in robust killing of highly resistant GBM cells by tumor-specific CD8+ CTLs and significantly extended survival. Lastly, we defined a unique CFD combination specifically for the human GBM to iDC-APC conversion of both glioma stem-like cells (GSC) and non-GSC GBM cells, confirming the clinical utility of a computationally directed, tumor-specific conversion immunotherapy for GBM and potentially other solid tumors.

Poor Health Behaviors among Housebound Japanese Community-Dwelling Older Adults Due to Prolonged Self-Restraint during the First COVID-19 Pandemic: A Cross-Sectional Survey.

BACKGROUND: Prolonged self-restraining behaviors induced by the coronavirus disease 2019 (COVID-19) pandemic's containment measures can limit various positive health behaviors. OBJECTIVE: We examined the decline in going-out and certain other positive health behaviors and investigated the relationship between excessive decreases in going-out frequency and declining engagement in positive health behaviors among community-dwelling older adults during the self-restraint period. DESIGN: This study employed a cross-sectional survey design. SETTING: This study was conducted in Nishi Tokyo City, Tokyo, Japan. PARTICIPANTS: The participants were 294 respondents (150 women) aged 50 years and older who lived in public housing that were permitted to be surveyed during the self-restraint period. MEASUREMENTS: Their pre-pandemic going-out frequency around February 2020 and going-out frequency during the self-restraint period starting in April 2020 were reported. We mainly assessed the existence of home health behaviors (i.e., exercise, in-person and phone conversations, and healthy diet). A self-report questionnaire was used to obtain data. RESULTS: Going-out frequency decreased in 41.2% of the 294 respondents owing to the government's request for self-restraint. In total, 13 individuals had been going out less than one time per week (housebound) before the request. Of the 281 people who were not housebound before the government's self-restraint request, 13.9% were newly housebound. Newly housebound individuals were 5.3 times less likely to exercise, had 2.1 times fewer social contacts, and 2.6 times less balanced or healthy diets than those who maintained their frequency of going out. CONCLUSIONS: Prolonged self-restraint due to the COVID-19 pandemic may lead to housebound status and poor health behaviors. Public health intervention is needed to prevent excessive self-restraint, along with new measures integrating information and communication technologies to enable older adults to live active lives.

Social Detachment Influenced Muscle Mass and Strength during the COVID-19 Pandemic in Japanese Community-Dwelling Older Women.

Social detachment due to coronavirus disease (COVID-19) has caused a decline in physical activity, leading to sarcopenia and frailty in older adults. This study aimed to compare muscle mass, strength, and function values in older women before and after the first wave of the COVID-19 pandemic (April-May 2020). Furthermore, changes in muscle measures across women who experienced different levels of impact on their social participation due to the COVID-19 pandemic were examined. Muscle mass (total, trunk, and appendicular muscle), grip strength, oral motor skills, social interactions (social network and participation), and social support were assessed in 46 Japanese community-dwelling older women (mean, 77.5 y; range 66-93 y) before and after the first wave of the COVID-19 pandemic. Trunk muscle mass significantly decreased after the first wave of the pandemic. When comparing changed values between the enhanced/maintained and reduced group during the pandemic, significant group difference was observed in trunk muscular mass, grip strength, and oral motor skills. Intriguingly, those who enhanced social participation had a positive change of grip strength values, showing that social participation might influence muscle function during the COVID-19 pandemic.

Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma.

Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors - cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) - and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Dynamic and subtype-specific interactions between tumour burden and prognosis in breast cancer.

We investigated the relationship between the prognostic importance of anatomic tumour burden and subtypes of breast cancer using data from the Korean Breast Cancer Registry Database. In HR+/HER2+ and HR-/HER2-tumours, an increase in T stage profoundly increased the hazard of death, while the presence of lymph node metastasis was more important in HR+/HER2+ and HR-/HER2+ tumours among 131,178 patients with stage I-III breast cancer. The patterns of increasing mortality risk and tumour growth (per centimetre) and metastatic nodes (per node) were examined in 67,038 patients with a tumour diameter ≤ 7 cm and < 8 metastatic nodes. HR+/HER2- and HR-/HER2- tumours showed a persistent increase in mortality risk with an increase in tumour diameter, while the effect was modest in HER2+ tumours. Conversely, an increased number of metastatic nodes was accompanied by a persistently increased risk in HR-/HER2+ tumours, while the effect was minimal for HR-/HER2- tumours with > 3 or 4 nodes. The interactions between the prognostic significance of anatomic tumour burden and subtypes were significant. The prognostic relevance of the anatomic tumour burden was non-linear and highly dependent on the subtypes of breast cancer.

Differential Stability of miR-9-5p and miR-9-3p in the Brain Is Determined by Their Unique Cis- and Trans-Acting Elements.

microRNAs (miRs) are fundamental regulators of protein coding genes. In the CNS, miR-9 is highly enriched and critical for neuronal development and function. Mature miRs are derived from a duplex precursor, and the -5p strand ("guide") is preferentially incorporated into an RNA-induced silencing complex (RISC) to exert its regulatory functions, while the complementary -3p strand ("passenger") is thought to be rapidly degraded. By contrast, both strands of the miR-9 duplex have unique functions critical for neuronal physiology, yet their respective degradation rates and mechanisms governing degradation are not well understood. Therefore, we determined the degradation kinetics of miR-9-5p and miR-9-3p and investigated the cis and trans elements that affected their stability in the brain. Using a combination of homogeneous neuronal/astrocyte cell models and heterogeneous brain tissue lysate, we demonstrate the novel finding that miR-9-3p was more stable than the miR-9-5p guide strand in all models tested. Moreover, the degradation kinetics of both miR-9-5p and miR-9-3p were brain-region specific, suggesting that each brain region was differentially enriched for specific degradation factors. We also determined that the 3' nucleotides harbor important cis elements required to not only maintain stability, but also to recruit potential protein degradation factors. We used mass spectrometry to assess the miR-9 interacting proteins and found that the -5p and -3p strands were associated with functionally distinct proteins. Overall, these studies revealed unique miR-9-5p and miR-9-3p degradation kinetics in the brain and proposed critical nucleotide sequences and protein partners that could contribute to this differential stability.

Electron beam induced removal of PMMA layer used for graphene transfer.

We demonstrate the development of an effective technique to remove the poly methyl methacrylate (PMMA) layer used for transferring graphene synthesized by a chemical vapor deposition (CVD). This was achieved utilizing electron-beam bombardment and following developing processes, prior to the use of conventional organic solvents. Field-effect transistors were fabricated on the transferred graphene in order to explore their Dirac points and carrier motilities in the ambient condition - the results were then compared with those from the conventional wet chemical treatment. It was found that the Dirac points were located close to the zero gate bias when compared to those from the acetone and the acetic acid treatments. Most significantly, the field-effect mobility reached as high as 6770 cm2/Vs and 7350 cm2/Vs on average for holes and electrons, respectively, which is more than seven times improvement in comparison to conventional acetone treatments for CVD-grown graphene devices.

Long-term Survival Outcomes of Primary Breast Cancer in Women With or Without Preoperative Magnetic Resonance Imaging: A Matched Cohort Study.

AIMS: To investigate whether preoperative magnetic resonance imaging (MRI) in patients with primary breast cancer is predictive of disease-free (DFS) and overall survival and to determine the prognostic factors indicating survival. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. From 2009 to 2010, 828 women with primary breast cancer and preoperative MRI were matched with 1613 women without such imaging. Patients were matched with regards to 25 patient and tumour-related covariates. A Cox proportional hazards model was used to investigate the time to recurrence and to estimate the hazard ratio for preoperative MRI. Log-rank tests and Cox proportional hazards survival analysis were carried out on total recurrence DFS and overall survival in the unmatched datasets. RESULTS: In total, 799 matched pairs were available for survival analysis. The MRI group showed a tendency towards better survival outcome; however, there were no significant differences in DFS and overall survival. Age at diagnosis (DFS hazard ratio = 0.98; overall survival hazard ratio = 1.04), larger tumour size (DFS hazard ratio = 1.01; overall survival hazard ratio = 1.02), triple negative breast cancer (DFS hazard ratio = 2.64; overall survival hazard ratio = 3.44) and the presence of lymphovascular invasion (DFS hazard ratio = 2.12; overall survival hazard ratio = 2.70) were independent significant variables for worse DFS and overall survival. CONCLUSION: Preoperative MRI did not result in an improvement in a patient's outcome. Age at diagnosis, tumour size, molecular subtype and lymphovascular invasion were significant independent factors affecting both DFS and overall survival.

TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation.

Non-small cell lung cancer (NSCLC) remains one of the leading causes of death worldwide, and thus new molecular targets need to be identified to improve treatment efficacy. Although epidermal growth factor receptor (EGFR)/KRAS mutation-driven lung tumorigenesis is well understood, the mechanism of EGFR/KRAS-independent signal activation remains elusive. Enhanced TFAP2C (transcription factor activating enhancer-binding protein 2C) expression is associated with poor prognosis in some types of cancer patients, but little is known of its relation with the pathogenesis of lung cancer. In the present study, we found that TFAP2C overexpression was associated with cell cycle activation and NSCLC cell tumorigenesis. Interestingly, TFAP2C blocked AKAP12-mediated cyclin D1 inhibition by inducing the overexpression of oncogenic microRNA (miRNA)-183 and simultaneously activated cyclin-dependent kinase 6-mediated cell cycle progression by downregulating tumor-suppressive miRNA-33a. In a mouse xenograft model, TFAP2C promoted lung tumorigenesis and disease aggressiveness via the miR-183 and miR-33a pathways. The study provides a mechanism of mitogenic and oncogenic signaling via two functionally opposed miRNAs and suggests that TFAP2C-induced cell cycle hyperactivation contributes to lung tumorigenesis.

[Increasing resistance against hazardous effects of metals-containing nanoparticles as a prospective approach to health risks management].

Extremely high toxicity of metal-containing nanoparticles necessitates search of methods to increase body resistance against its harmful effects. The authors' experiments summarized in the article demonstrated that some combinations of certain biologically active substances selected according to sound theoretic background and prescribed in harmless doses can significantly decrease integral and specific manifestations of organ and system toxicity and even genotoxicity of such nanoparticles. Further development of this research direction should be recommended for practical implementation.

Suspended single-walled carbon nanotube fluidic sensors.

In this paper, we demonstrate the fabrication of liquid flow sensors employing partially suspended single-walled carbon nanotubes (SWNTs). We have found that the sign of the conductance change in SWNT flow sensors is not influenced by the direction of water flow for both supported and suspended devices. Therefore, the streaming potential is not the principal mechanism of the SWNT sensor response. Instead, the conductance change is more likely due to a reduction in the cation density in the electrical double layer, whose equilibrium conditions are determined by the liquid flow rate. More importantly, we have found that the sensitivity of suspended SWNT devices is more than 10 times greater than that of supported SWNT devices. A reduced screening effect and an increase in effective sensing volume are responsible for the enhanced sensitivity, which is consistent with the ion depletion model. We also have measured conductance as a function of gate bias at different flow rates and have determined the flow-rate dependent effective charge density, which influences the electrostatic configuration around SWNT devices.

Sensitive detection of yeast using terahertz slot antennas.

We demonstrated sensitive detection of individual yeast cells and yeast films by using slot antenna arrays operating in the terahertz frequency range. Microorganisms located at the slot area cause a shift in the resonant frequency of the THz transmission. The shift was investigated as a function of the surface number density for a set of devices fabricated on different substrates. In particular, sensors fabricated on a substrate with relatively low permittivity demonstrate higher sensitivity. The frequency shift decreases with increasing slot antenna width for a fixed coverage of yeast film, indicating a field enhancement effect. Furthermore, the vertical range of the effective sensing volume has been studied by varying the thickness of the yeast film. The resonant frequency shift saturates at 3.5 µm for a slot width of 2 µm. In addition, the results of finite-difference time-domain simulations are in good agreement with our experimental data.

Terahertz conductivity of reduced graphene oxide films.

We performed time-domain terahertz (THz) spectroscopy on reduced graphene oxide (rGO) network films coated on quartz substrates from dispersion solutions by spraying method. The rGO network films demonstrate high conductivity of about 900 S/cm in the THz frequency range after a high temperature reduction process. The frequency-dependent conductivities and the refractive indexes of the rGO films have been obtained and analyzed with respect to the Drude free-electron model, which is characterized by large scattering rate. Finally, we demonstrate that the THz conductivities can be manipulated by controlling the reduction process, which correlates well with the DC conductivity above the percolation limit.

Bilateral persistent primitive trigeminal arteries associated with trigeminal neuralgia.

Persistent carotid-vertebrobasilar anastomoses (PCVBA) include the primitive trigeminal artery (PTA), the primitive otic artery (POA), the primitive hypoglossal artery and proatlantal arteries (ProAs). The PTA is the most commonly seen of these accounting for approximately 80-85% of PCVBAs. The PTA which connects the internal carotid artery (ICA) to the basilar artery (BA) may occasionally connect to the superior or posterior inferior cerebellar arteries without interposition to the BA. It is then referred to as a persistent trigeminal artery variant (PTAV), an anomalous carotid-cerebellar anastomosis. Bilateral occurrence of PTA is extremely rare. During vertebral artery (VA) development the anterior radicular artery of segment C1 from the proatlantal artery of Padget evolves into the intradural component of the VA (V4 segment) plus a short extradural segment (distal V3 segment). Agenesis of a single anterior radicular artery of ProA results in the absence of one distal VA associated with an unremarkable contralateral VA and the BA. Absence or hypoplasia of the terminal portion of one VA is a commonly observed anatomic variant. However, absence of the terminal portions of both VAs is exceptional. A rare case of bilateral PTAs is presented with unilateral PTA and a contralateral PTAV causing trigeminal neuralgia. Furthermore, the bilateral PTAs were associated with the absence of the proximal portion of the BA in addition to the bilateral lack of a distal VA. This finding comes as a logical consequence of the developmental anatomy of the vertebrobasilar junction and is consistent with the assumed congenital nature of the anatomic variant.

Mechanistic insights into the role of river sediment in the attenuation of the herbicide isoproturon.

Mechanistic insights into the relative contribution of sorption and biodegradation on the removal of the herbicide isoproturon (IPU) are reported. (14)C-radiorespirometry indicated very low levels of catabolic activity in IPU-undosed and IPU-dosed (0.1, 1, 100 µg L(-1)) river water (RW) and groundwater (GW) (mineralisation: <2%). In contrast, levels of catabolic activity in IPU-undosed and IPU-dosed river sediment (RS) were significantly higher (mineralisation: 14.5-36.9%). Levels of IPU catabolic competence showed a positive log-linear relationship (r(2) = 0.768) with IPU concentration present. A threshold IPU concentration of between 0.1 µg L(-1) and 1 µg L(-1) was required to significantly (p < 0.05) increase levels of catabolic activity. Given the EU Drinking Water Directive limit for a single pesticide in drinking water of <0.1 µg L(-1) this result suggests that riverbed sediment infiltration is potentially an appropriate 'natural' means of improving water quality in terms of pesticide levels at concentrations that are in keeping with regulatory limits.

[Comparative experimental assessment of the impact of gold and silver nanoparticles on the phagocyting cells of the lower airways].

Judging by the cytological characteristics of the free cell population of the lower airways obtained with assistance of the bronchoalveolar lavage in 24 hours after the intratracheal instillation of equal doses of equidimensional gold or silver nanoparticles, both metals result in active recruitment of phagocytes with domination of neutrophile leukocytes, especially marked after the instillation of the nanosilver. The higher ratio of these cells count to that of alveolar macrophages gives evidence for the significantly higher cytotoxicity of the nanosilver comparing with both nanogold and even the smallest silver particles in the micrometric range. Transmission electron microscopy demonstrates similar pictures of intracellular distribution and ultra-structural damages caused by internalized nanoparticles in both types of phagocytes, while there are significant differences between cells under impact of nanosilver vs. those under impact of nanogold. The highest importance is higher propensity of the nanosilver particles to aggregation and to ingression into mitochondria with damaging these organelles.

Diffusion Length in Nanoporous Photoelectrodes of Dye-Sensitized Solar Cells under Operating Conditions Measured by Photocurrent Microscopy.

We determined the carrier diffusion lengths in nanoporous layers of dye-sensitized solar cells by using scanning photocurrent microscopy. The diffusion lengths were found to be 60-100 µm for the conventional cells. In addition, we found a correlation between the carrier diffusion lengths and the cell efficiency, which proved that improvement in the diffusion length is one of the crucial factors for optimizing device performance. The diffusion length was measured for various operating conditions by varying parameters such as solar light intensity and applied electrical voltage. In particular, we observed electric-field-driven, carrier transport phenomena (i.e., drift current) in modified cells. Fitting with the drift-diffusion model enabled us to extract the electric field strengths present in the TiO2 nanoporous layer.

Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis.

BACKGROUND: Interleukin (IL)-33 is involved in the Th2 immune response and could play an essential role in nasal allergy. Therefore, we aimed to investigate the therapeutic potential of anti-IL-33 for allergic rhinitis (AR). METHODS: Twenty-four BALB/c mice were used. In group A (control group, n = 6), mice were sensitized and challenged with saline. Group B [ovalbumin (OVA) group, n = 6] mice received intraperitoneal and intranasal OVA challenge. In group C (control IgG group, n = 6), mice were injected intraperitoneally with rabbit control IgG before OVA challenge. In group D (anti-IL-33 group, n = 6), anti-IL-33 was injected before challenge. We evaluated the number of nose-scratching events and external morphology; serum total and OVA-specific IgE; number of eosinophils, neutrophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid; histopathologic examination of nasal cavity; and IL-4, IL-5, and IL-13 in BAL fluid. RESULTS: Anti-IL-33 treatment significantly reduced the nose-scratching events and ameliorated skin denudation. Serum total and OVA-specific IgE was significantly decreased in group D. The number of eosinophils in BAL fluid was also significantly decreased. Eosinophilic infiltration in the nasal cavity was significantly decreased in group D. IL-4, IL-5, and IL-13 in BAL fluid were also significantly decreased after treatment. CONCLUSIONS: Anti-IL-33 antibody has a therapeutic potential for experimental AR.