Objective This study aimed to compare the causal effect of overall obesity and abdominal obesity on type 2 diabetes among Chinese Han individuals. Methods The causal relationship of BMI and waist‐to‐hip ratio (WHR) with the risk of glucose deterioration and glycemic traits was compared using two different genetic instruments based on 30 BMI loci and 6 WHR loci with Mendelian randomization (MR) in three prospective cohorts ( n = 6,476). Results Each 1‐SD genetically instrumented higher WHR was associated with a 65.7% higher risk of glucose deterioration (95% CI = 1.069‐2.569, P = 0.024), whereas no significant association of BMI with glucose deterioration was observed. Furthermore, a causal relationship was found only between BMI and homeostatic model assessment β‐cell function (HOMA‐B) (β = 0.143, P = 0.001), and there was a nominal association with Stumvoll second‐phase insulin secretion traits (β = 0.074, P = 0.022). The significance level did not persist in sensitivity analyses, except in the causal estimate of WHR on the Gutt index in MR‐Egger (β = −0.379, P = 0.022) and the causal estimate of BMI on homeostatic model assessment β‐cell function in weighted median MR (β = 0.128, P = 0.017). Conclusions The data from this study support the potential causal relationship between abdominal obesity and hyperglycemia, which may be driven by aggravated insulin resistance, in contrast with the potential causal relationship between overall obesity and insulin secretion.
Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care.
The type VI secretion system (T6SS) has recently been demonstrated to mediate interbacterial competition and to discriminate between self and nonself. T6SS(+) bacteria employ toxic effectors to inhibit rival cells and concurrently use effector cognate immunity proteins to protect their sibling cells. The effector and immunity pairs (E-I pairs) endow the bacteria with a great advantage in niche competition. Tle4-Tli4 (PA1510-PA1509) is a newly identified E-I pair that is controlled by H2-T6SS in Pseudomonas aeruginosa. Tle4 exhibits phospholipase activity, which destroys the cell membrane of rival cells, and the periplasm-located Tli4 in donor cells eliminates this toxic effect of Tle4. In this paper, the structure of the Tle4-Tli4 complex is reported at 1.75 Å resolution. Tle4 consists of two domains: a conserved α/β-hydrolase domain and an unusual cap domain in which two lid regions (lid1 and lid2) display a closed conformation that buries the catalytic triad in a deep funnel. Tli4 also displays a two-domain structure, in which a large lobe and a small lobe form a crab claw-like conformation. Tli4 uses this crab claw to grasp the cap domain of Tle4, especially the lid2 region, which prevents the interfacial activation of Tle4 and thus causes enzymatic dysfunction of Tle4 in sister cells.
Quantifying the effect of maize tassel on canopy reflectance is essential for creating a tasseling progress monitoring index, aiding precision agriculture monitoring, and understanding vegetation canopy radiative transfer. Traditional field measurements often struggle to detect the subtle reflectance differences caused by tassels due to complex environmental factors and challenges in controlling variables. The three-dimensional (3D) radiative transfer model offers a reliable method to study this relationship by accurately simulating interactions between solar radiation and canopy structure. This study used the LESS (large-scale remote sensing data and image simulation framework) model to analyze the impact of maize tassels on visible and near-infrared reflectance in heterogeneous 3D scenes by modifying the structural and optical properties of canopy components. We also examined the anisotropic characteristics of tassel effects on canopy reflectance and explored the mechanisms behind these effects based on the quantified contributions of the optical properties of canopy components. The results showed that (1) the effect of tassels under different planting densities mainly manifests in the near-infrared band of the canopy spectrum, with a variation magnitude of ±0.04. In contrast, the impact of tassels on different leaf area index (LAI) shows a smaller response difference, with a magnitude of ±0.01. As tassels change from green to gray during growth, their effect on reducing canopy reflectance increases. (2) The effect of maize tassel on canopy reflectance varied with spectral bands and showed an obvious directional effect. In the red band at the same sun position, the difference in tassel effect caused by the observed zenith angle on canopy reflectance reaches 200%, while in the near-infrared band, the difference is as high as 400%. The hotspot effect of the canopy has a significant weakening effect on the shadow effect of the tassel. (3) The non-transmittance optical properties of maize tassels reduce canopy reflectance, while their high reflectance increases it. Thus, the dual effects of tassels create a game in canopy reflectance, with the final outcome mainly depending on the sensitivity of the canopy spectrum to transmittance. This study demonstrates the potential of using 3D radiative transfer models to quantify the effects of crop fine structure on canopy reflectance and provides some insights for optimizing crop structure and implementing precision agriculture management (such as selective breeding of crop optimal plant type).
The effectiveness of combination therapy using a suicide gene and cytokine genes for the treatment of metastatic colon carcinoma in the mouse liver was investigated. Pre-established hepatic tumors treated with a recombinant adenoviral vector containing the herpes simplex virus thymidine kinase gene(tk) exhibited substantial regression, although all treated animals suffered from subsequent relapses. Although cotreatment with a mouse interleukin 2 (mIL-2)-containing adenoviral vector induced an effective antitumor immune response, the immunity waned with time, and the treated animals eventually succumbed to hepatic tumor relapse or distant metastases. In this study, mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) gene was tested for its ability to further enhance and prolong the antitumoral cellular immunity. A fraction of the animals treated with tk + mIL-2 + mGM-CSF developed long-term antitumor immunity and survived for more than 4 months without recurrence. This long-term antitumor immunity could be enhanced further by subsequent "vaccination" with mIL-2-expressing parental tumor cells. The results indicate that local expression of GM-CSF in the hepatic tumors and prolonged mIL-2 expression are necessary to generate persistent antitumor immunity that is essential for the prevention of tumor recurrence and long-term animal survival.
// Ning Liu 1, 2, * , Rebecca J. Boohaker 1, * , Chunling Jiang 3, 4, * , James R. Boohaker 5 , Bo Xu 1, 6 1 Department of Oncology, Southern Research Institute, Birmingham, AL 35205, USA 2 Department of Gastric Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China 3 Nanchang University Graduate School, Nanchang 330047, China 4 Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang 330029, China 5 Department of Economics, American University, Washington, DC 20016, USA 6 Cancer Cell Biology Program, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35205, USA * These authors have contributed equally to this work Correspondence to: Bo Xu, e-mail: xu@sri.org , e-mail: bxu@uab.edu Keywords: miRNA, radiosensitivity, ATM Received: January 29, 2015 Accepted: September 24, 2015 Published: October 06, 2015 ABSTRACT MicroRNA, a class of small non-coding RNAs, play critical roles in the cellular response to DNA damage induced by ionizing irradiation (IR). Growing evidence shows alteration of miRNAs, in response to radiation, controls cellular radiosensitivity in DNA damage response pathways. However, it is less clear about the clinical relevance of miRNA regulation in radiosensitivity. Using an in vitro system, we conducted microarray to identify a miRNA signature to assess radiosensitivity. The data were validated by analyzing available Head and Neck Squamous Cell Carcinoma (HNSCC) samples in the cancer genome atlas (TCGA) database. A total of 27 miRNAs showed differential alteration in response to IR in an Ataxia-Telangiectasia Mutated (ATM) kinase-dependent manner. We validated the list and identified a five miRNA signature that can predict radiation responsiveness in HNSCC. Furthermore, we found that the expression level of ATM in these patients was correlated with the radiation responsiveness. Together, we demonstrate the feasibility of using a miRNA signature to predict the clinical responsiveness of HNSCC radiotherapy.
Resistance to radiation and chemotherapy in colorectal cancer (CRC) patients contribute significantly to refractory disease and disease progression. Herein, we provide mechanistic rationale for acquired or inherent chemotherapeutic resistance to the anti-tumor effects of 5-fluorouracil (5-FU) that is linked to oncogenic GLI1 transcription activity and NBS1 overexpression. Patients with high levels of GLI1 also expressed high levels of NBS1. Non-canonical activation of GLI1 is driven through oncogenic pathways in CRC, like the BRAFV600E mutation. GLI1 was identified as a novel regulator of NBS1 and discovered that by knocking down GLI1 levels in vitro, diminished NBS1 expression, increased DNA damage/apoptosis, and re-sensitization of 5-FU resistant cancer to treatment was observed. Furthermore, a novel GLI1 inhibitor, SRI-38832, which exhibited pharmacokinetic properties suitable for in vivo testing, was identified. GLI1 inhibition in a murine BRAFV600E variant xenograft model of CRC resulted in the same down-regulation of NBS1 observed in vitro as well as significant reduction of tumor growth/burden. GLI1 inhibition could therefore be a therapeutic option for 5-FU resistant and BRAFV600E variant CRC patients
It has become important to accurately evaluate the status of HER-2/neu in invasive breast cancer, especially when one is considering the use of anti-HER-2 monoclonal antibody therapy (Trastuzumab). Almost one third of invasive breast carcinomas overexpress the HER-2/neu protein, so the use of the anti-HER-2/neu monoclonal antibody Herceptin (trastuzumab) to block the protein has become important in the management of and in prolonging the survival for patients with metastatic breast cancer. The effectiveness of this therapy is dependent on accurately evaluating the HER-2 status in these tumors, which can be done either by studying the expression of HER-2 protein by immunohistochemistry (IHC) or by evaluating HER-2 gene amplification by fluorescent in situ hybridization (FISH). Since interobserver variability may occur in manually grading HER-2 protein expression by IHC, the aim of this study was to compare the HER-2/neu expression by IHC using a computer-based image analysis system with that of the gene amplification by FISH. Formalin-fixed paraffin-embedded archival tissue from 108 primary infiltrating ductal carcinomas were immunostained using the HercepTest (DAKO). To reduce interobserver variability, membrane staining was evaluated using the Automated Cellular Imaging System (ACIS) by ChromaVision, and the cases were divided into four groups: group 1 (n=23) with HER-2/neu expression ACIS score less than or equal to 1.5; group 2 (n=17) with a score ranging from 1.6 to 1.9; group 3 (n=46) with a score 2.0 to 2.5; and group 4 (n=22) with a score greater than or equal to 2.6. FISH was performed on all of the 108 cases using the PathVysion HER-2/neu DNA probe kit from Vysis Inc. All cases were also manually reviewed and graded as negative, 1+, 2+, and 3+ according to the DAKO HercepTest grading scheme. Cases with negative and 1+immunostaining were considered as HER-2 not overexpressed, and cases with 2+ and 3+ staining were classified as showing HER-2 overexpression. In group 1, 1 of 23 (4%), in group 2, 2 of 17 (12%), in group 3, 5 of 46 (11%), and in group 4, 19 of 22 (86%) cases showed gene amplification by FISH. Furthermore, in group 4 all 15 (100%) cases with an ACIS score of 3 or greater were FISH positive. Correlation with manual IHC score and FISH showed that 2 of the 23 (9%) IHC negative (0 and 1+) cases and 25 of the 85 (29%) IHC positive (2+ and 3+) cases showed gene amplification by FISH. This study shows that the amplification of the HER-2/neu gene correlates better with overexpression of the HER-2/neu protein by IHC when the score is either less than 1.5 or greater than 2.6 by ACIS. Therefore, FISH may be useful to better evaluate HER-2/neu status in breast cancer in cases where the ACIS score by immunohistochemistry is 1.6 to 2.5, and since the correlation is so good, FISH may not be needed for HER-2 evaluation in cases with ACIS scores less than 1.5 and greater than 2.6.
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