Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8+T-cell migration into tumor microenvironments. Here, we found that HIF-1α knockdown or overexpression ...resulted in increased or decreased CXCL9, −10, and −11 expression in vitro, respectively. Gene Set Variation Analysis revealed that elevated HIF-1α levels correlated with a poor prognosis, severe pathological stage, and an absence of CD8+ T cells in the tumor microenvironment in colorectal cancer (CRC) patients. HIF-1α was inversely associated with pathways beneficial to anti-tumor immunotherapy and cytokine/chemokine function. In vivo, inhibiting HIF-1α or its upstream regulator BIRC2 significantly suppressed tumor growth and promoted CD8+ T-cell infiltration. CXCR3 neutralizing antibodies reversed these effects, implicating the involvement of CXCL9, −10, and −11/CXCR3 axis. The presence of HIF-1α weakened the upregulation of CXCL9, −10, and −11 by bleomycin and doxorubicin. Combining HIF-1α inhibition with bleomycin promoted CD8+ T-cell infiltration and tumor suppression in vivo. Moreover, doxorubicin could upregulate CXCL9, −10 and −11 by suppressing HIF-1α. Our findings highlight the potential of HIF-1α inhibition to improve CRC microenvironments and increase chemotherapy sensitivity.
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•HIF-1α protein inhibits the expression of CXCL9, −10 and −11 in CRC.•BIRC2 promotes the expression of HIF-1α protein in CRC cell lines.•Knockdown of HIF-1α improves the anti-tumor impact of Bleomycin or Doxorubicin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In continuation of the series of perovskite oxides that includes 3d4 cubic BaFeO3 and 4d4 cubic BaRuO3, 5d4 cubic BaOsO3 was synthesized by a solid-state reaction at a pressure of 17 GPa, and its ...crystal structure was investigated by synchrotron powder X-ray diffraction measurements. In addition, its magnetic susceptibility, electrical resistivity, and specific heat were measured over temperatures ranging from 2 to 400 K. The results establish a series of d4 cubic perovskite oxides, which can help in the mapping of the itinerant ferromagnetism that is free from any complication from local lattice distortions for transitions from the 3d orbital to the 5d orbital. Such a perovskite series has never been synthesized at any d configuration to date. Although cubic BaOsO3 did not exhibit long-range ferromagnetic order unlike cubic BaFeO3 and BaRuO3, enhanced feature of paramagnetism was detected with weak temperature dependence. Orthorhombic CaOsO3 and SrOsO3 show similar magnetic behaviors. CaOsO3 is not as conducting as SrOsO3 and BaOsO3, presumably due to impact of tilting of octahedra on the width of the t 2g band. These results elucidate the evolution of the magnetism of perovskite oxides not only in the 5d system but also in group 8 of the periodic table.
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IJS, KILJ, NUK, PNG, UL, UM
The reliability of circuits is significantly affected by process variations in manufacturing and environmental variation during operation. Current yield optimization algorithms take process ...variations into consideration to improve circuit reliability. However, the influence of environmental variations (e.g., voltage and temperature variations) is often ignored in current methods because of the high computational cost. In this article, a novel and efficient approach named BNN-BYO is proposed to optimize the yield of analog circuits in multiple environmental corners. First, we use a Bayesian Neural Network (BNN) to simultaneously model the yields and performances of interest in multiple corners efficiently. Next, the multi-corner yield optimization can be performed by embedding BNN into a Bayesian optimization framework. Since the correlation among yields and performances of interest in different corners is implicitly encoded in the BNN model, it provides great modeling capabilities for yields and their uncertainties to improve the efficiency of yield optimization. Our experimental results demonstrate that the proposed method can save up to 45.3% of simulation cost compared to other baseline methods to achieve the same target yield. In addition, for the same simulation cost, our proposed method can find better design points with 3.2% yield improvement.
N‐Myc downstream‐regulated gene 2 (NDRG2), a new member of the N‐Myc downstream‐regulated gene family, has been found to be a differentially expressed gene involved in a variety of cancers. The ...present study aimed to investigate the expression of NDRG2 in esophageal squamous cell carcinoma (ESCC). Immunohistochemistry was performed in 154 samples from patients with ESCC to detect the expression level of NDRG2 and C‐MYC. Results indicated that the expression level of NDRG2 in the cancer samples was significantly lower than that in normal tissues; the trend of C‐MYC was the reverse. The Wilcoxon–Mann–Whitney test showed significant difference in the expression of NDRG2 in patients with different T stage, TNM stage, and differentiation degree of cancers (P = 0.036, 0.031, 0.001, respectively). Patients in stages I and II were followed up for 5 consecutive years and Kaplan–Meier survival analysis demonstrated that the survival time of ESCC patients with high expression of NDRG2 was longer than those with low expression during the 5‐year follow‐up period (P = 0.0018). Cox regression analysis indicated that low expression of NDRG2, cancer stage of pT1, and distant organ metastasis (pM1) were the independent poor prognostic factors of ESCC (P = 0.004, 0.019, 0.0013, respectively). Furthermore, up‐regulation of NDRG2 was introduced to ESCC cell lines (EC9706 and EC109) by plasmid transfection. In vivo and in vitro studies indicated that overexpression of NDRG2 markedly reduced proliferation and promoted the apoptosis of EC9706 and EC109 cells. In summary, our results demonstrated that NDRG2 played an important role in the proliferation of ESCC cells and the expression of NDRG2 in ESCC was closely related with the prognosis.
(Cancer Sci 2010; 101: 1292–1299)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Prunus armeniaca Lam. is the dominant species in the wild fruit forest in the Tianshan Mountains and has important values of ecology and resource. The altitude of wild fruit forest is closely linked ...to its distribution and growth. To clarify the changes of flowering phenological period and floral organs of P. armeniaca in different altitudes, the P. armeniaca forest in Tuergenxinghuagou, Xinyuan County, Xinjiang was selected as the research region from March to April 2021. In the mountainous area of 1000-1500 m with concentrated distribution of P. armeniaca, the sample plots were set up at the altitude gradient of I-V grade from low to high. We monitored the environmental conditions, and investigated the flowering phenological period and floral organ development characteristics of P. armeniaca population. The results showed that:（1） the flowering phenological period of P. armeniaca population lasted about 32 d, and the longest difference of each altitude gradient was 2 d. There was no significant difference in flowering phenological period between the grade I and grade Ⅱ, and there were significant differences between other altitude gradients. The last flowering grade V was 9 d later than the earliest flowering grade I, but the flowering phenological period of the P. armeniaca population was 4 d. The altitude was significantly positively correlated with the flowering phenological period, while temperature was significantly negatively correlated with flowering phenological period;（2） The sepalled length and width, ovary height and width of P. armeniaca were the largest at grade II; corolla diameter, petal longitudinal diameter and transverse diameter were the largest in grade I, while the anther length and width were the largest in grade IV; the style length was the largest in grade V. Altitude was significantly negatively correlated with the external organs and pistils of flowers, and positively correlated with the stamens. Light intensity was significantly negatively correlated with the external organs and pistils of flowers;（3） Climatic factors for the flowering period of P. armeniaca, with significant differences between grade IV, grade V and grade I. Altitude gradient and humidity, light intensity showed significantly positive correlation, altitude gradient and temperature showed significantly negative correlation. The flowering phenological period of P. armeniaca population in Xinjiang lasted about 32 d. As altitude rises, light intensity increases, temperature decreases and humidity increases in P. armeniaca woodlands. The flowering phenological period of P. armeniaca was delayed, and the flowering period increases in duration, with each 100m rise delaying flowering by about 1.8 d; the development of stamens gradually increased, and the development of external organs of pistils and flowers gradually decreased, which was the adaptability of P. armeniaca to altitude changes. The results can provide a theoretical basis for the study on the adaptability of P. armeniaca population distribution.
Pneumococcal polysaccharide-based vaccines are effective in preventing pneumococcus infection; however, some drawbacks preclude their widespread use in developing and undeveloped countries. Here, we ...evaluated the protective effects of ATP-dependent caseinolytic protease (ClpP), pneumolysin mutant (ΔA146 Ply), putative lipoate-protein ligase (Lpl), or combinations thereof against pneumococcal infections in mice. Vaccinated mice were intraperitoneally and/or intranasally challenged with different pneumococcal strains. In intraperitoneal challenge models with pneumococcal strain D39 (serotype 2), the most striking protection was obtained with the combination of the three antigens. Similarly, with the intranasal challenge models, (i) additive clearance of bacteria in lungs was observed for the combination of the three antigens and (ii) a combination vaccine conferred complete protection against intranasal infections of three of the four most common pneumococcal strains (serotypes 14, 19F, and 23F) and 80% protection for pneumococcal strain 6B. Even so, immunity to this combination could confer protection against pneumococcal infection with a mixture of four serotypes. Our results showed that the combination vaccine was as effective as the currently used vaccines (PCV7 and PPV23). These results indicate that system immunization with the combination of pneumococcal antigens could provide an additive and broad protection against Streptococcus pneumoniae in pneumonia and sepsis infection models.
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