bluuebunny/crossref_metadata_2025 huggingface dataset:
Doses and Timing of 2, 4-D Application for Broadleaf Weed Control, Botanical Compositions, Productivity, and Nutritive Value of Natural Pasture
Authors: Faji Mulisa , Kebede Gezahagn , Feyissa Fekede , Mohammed Kedir , Mengistu Gezahagn , Terefe Geberemariyam
Published: June 2022

2,4-Dichlorophenoxyacetic acid (2,4-D) is among the most common and inexpensive herbicides used to control broadleaf weeds in natural pasture. However, different studies have pointed out the risk of forage injury. Consequently, no research data on the productivity and nutritive value of natural pasture in response to different rates and times of 2,4-D application exists in Ethiopia. Therefore, this study was conducted to investigate natural pasture yield and nutritive response to 2,4-D application at different rates (1, 1.5, and 2 L·ha−1) and time (mid-July, early, and mid-August) with control. The experiment was designed as a factorial randomized complete block design with three replicates for two years. Grasses and legume proportions in the pasture were significantly influenced by the rate and time (

P
<
0.05

) of 2, 4-D application and their interaction (

P
<
0.001

). Interaction of rate and time of 2, 4-D application had a significant (

P
<
0.05

) influence on dry matter yield of legumes and non-significant (

P
>
0.05

) effect on forage portions (grasses + legumes) and grasses. Crude protein and in vitro dry matter digestible yield of pasture forage portions were not significantly (

P
>
0.05

) influenced by the rate and time of 2, 4-D application and their interaction. Weed dry matter yield was significantly affected by the interaction of rate and time of 2, 4-D application and mid-July application at 1.5 and 2 L·ha−1 gave the lowest yield. Therefore, to produce optimum quality and quantity of forage from natural pasture, the application of 2, 4-D in mid-July at 1.5 L·ha−1 is recommended.
Structural Design and Test of a Piezoelectric Flextensional Transducer for Passive Detection of Frogmen
Authors: Sun Yuchen , Chen Weiyi , Li Zongji , Wang Pingbo , Dong Li , Zhu Yongyong , Wang Shizhe
Published: June 2022

A piezoelectric flextensional transducer was designed using the finite element method (FEM) for the passive detection of underwater frogmen. By studying the main performance parameters of sonar transducers for the detection of frogmen around the world, this paper presents the advantages of active and passive sonar in this task and proposes a passive method for the detection of frogmen. Subsequently, a Cymbal transducer was selected considering the needs of the research. After introducing the principles and methods of the FEM analysis, the acoustic and electromechanical characteristics of the Cymbal transducer were verified under the influence of structural dimensions, e.g., resonance frequency, conductance, and susceptance. The electromechanical performance of the Cymbal transducer was simulated with a FEM to study how it is affected by static water pressure and processing errors and to demonstrate the feasible application of the Cymbal transducer in practical applications. In the end, a Cymbal prototype was tested to verify that the designed Cymbal transducer performs in compliance with the requirements and can be used for the passive detection of underwater frogmen with open-circuit breathing.
Utilizing Blockchain Technology to Manage the Dark and Bright Sides of Supply Network Complexity to Enhance Supply Chain Sustainability
Authors: Yin Weili , Ran Wenxue
Published: June 2022

The supply network becomes more fragile as it becomes more complex, affecting the core firm’s performance. While previous research on supply network complexity existence paradox. Therefore, to study the nature of supply network complexity, this paper divides the supply chain complexity utility into positive and negative valences based on the valence framework and divides supply chain complexity into supply base complexity, customer base complexity, and logistics base complexity. Based on the trustworthiness and transparency characteristics of blockchain technology, this paper investigates how to use blockchain technology to reduce the negative valence of supply chain complexity while adapting to or improving the positive valence to improve enterprise competitiveness and supply chain sustainability. As a result, the focus of this paper is on how to better manage supply chain complexity using blockchain technologies to increase supply chain sustainability and viability.
A Grid Fusion Lifting Surface and Its Flow Control Mechanism at High Angles of Attack
Authors: Hua-yu Fan , Bai-gang Mi , Han-yu Liu , Jing-yi Yu
Published: June 2022

A grid fusion lifting surface suitable for large subsonic angles of attack was designed. The influence of the grid position, grid diversion angle, and grid number on the aerodynamic performance of the grid fusion lifting surface under subsonic conditions was studied by numerical simulations. Based on the summary and analysis of the grid in the hypersonic state, the CFD numerical simulation method, which solves unsteady Reynolds averaged Navier-Stokes equations, was used to complete the research of the flow mechanism of the grid fin in the subsonic state. At low speed and subsonic conditions, the results show that the negative front grid fusion lift surface has better aerodynamic characteristics with a high angle of attack. Under subsonic conditions, the stall angle of attack of the front grid fusion lifting surface with a diversion angle of 20° increases by 16°, and the maximum lift coefficient increases by 22.1% compared to that of the conventional flat wing. The number of grids has an insignificant effect on the aerodynamic performance of the grid fusion lifting surface at a large angle of attack.
Prognostic and Immunological Value of GNB4 in Gastric Cancer by Analyzing TCGA Database
Authors: Liu Binghui , Chen Lingbin , Huang He , Huang Huifeng , Jin Hui , Fu Chenglin
Published: June 2022

Background. Gastric cancer (GC) represents a universal malignant tumor of the digestive system. Stromal and immune cells belong to two main nontumor components exerting a vital function in the tumor microenvironment. Methods. Based on TCGA database, this study downloaded clinical information and gene profiles of GC. The ESTIMATE algorithm was adopted for evaluating the score of immune-infiltrating cells. This work employed Sangerbox to explore the differentially denoted genes (DEGs) related to stromal, immunity, and prognosis. Besides, the STRING database was involved in order to detect the association among the proteins. The MCODE module of Cytoscape software was used to screen key genes. Oncomine and GEPIA databases were used, aiming to study the differences in key genes in healthy gastric mucosa and GC. At last, we adopted TISDIB and TIMER databases for analyzing the association of guanine nucleotide binding protein subunit-4 (GNB4) between gastric cancer and tumor immune cells. qRT-PCR was applied for exploring differential GNB4 expression between GC and normal gastric mucosa and investigating the relation of GNB4 with tumor-infiltrating lymphocytes (TILs). Results. Patients undergoing a great stromal score exhibited worse prognostic outcome, and cases having a low immune score had better prognosis. Overall, altogether 656 genes were upregulated with 5 genes being downregulated, which were matrix immune-related differential genes. Furthermore, 18 genes were screened as hub genes on the basis of the univariate Cox risk model of TCGA database (82 differential genes predicted poor GC survival). Oncomine and GEPIA databases revealed that GNB4 expression in gastric cancer was obviously higher in comparison with that in normal gastric mucosa. The GSEA, TISDIB, and TIMER databases revealed that GNB4 is involved in various tumor signal pathways and immune and metabolic processes. qRT-PCR demonstrated that GNB4 expression in gastric cancer was notably higher in comparison with that in normal gastric mucosa, showing significant association with matrix TILs. Conclusion. The selected key gene GNB4 is a potential biomarker to guide the immunotherapy of gastric cancer.
Presenting a Management Model for a Multiobjective Sustainable Supply Chain in the Cellulosic Industry and Its Implementation by the NSGA‐II Meta‐Heuristic Algorithm
Authors: Mehri Charvadeh Meisam , Pourmousa Shademan , Tajdini Ajang , Tamjidi Abbas , Safdari Vahidreza
Published: June 2022

In recent years, with changing conditions in global markets and competition between supply chains, organizations have realized that in order to grow and survive in today’s turbulent environment, they must make every effort to create and maintain a sustainable competitive advantage. Therefore, in this research, a multiobjective, multilevel, multiperiod, and multicommodity mathematical model is presented. The proposed model has five levels in the direct direction and three levels in the reverse direction. This research is one of the few studies that has considered the sustainable closed‐loop supply chain of cellulosic‐based products (paper and corrugated board) in the model and has considered it at all levels of the chain. Also, the quality of returned products in the reverse supply chain and its impact on the collection and recycling of products and returning to the supply chain are other contributions of this research. The results show, by increasing the transportation costs, the number of established distribution centers increases to a certain extent and finally remains constant. As it is shown, the reduction of transportation costs to the point of establishing four centers in the recession scenario and five centers in the boom scenario becomes saturated and is no longer able to minimize the number of established centers.
A Novel Hybrid Control Algorithm Sliding Mode‐PID for the Active Suspension System with State Multivariable
Authors: Nguyen Duc Ngoc , Nguyen Tuan Anh
Published: June 2022

This paper introduces a novel method to control the operation of the active suspension system. In this research, a quarter‐dynamic model is used to simulate the vehicle’s vibrations. Besides, the sliding mode‐PID‐integrated algorithm with five state variables is proposed to be used. This is a completely original and novel algorithm. The process of establishing the control algorithm is clearly described. The simulation is performed by the MATLAB software. The results of the paper have shown the advantages of the sliding mode‐PID algorithm used in this research. Accordingly, the displacement and acceleration of the sprung mass were significantly reduced when this algorithm was used. The maximum and average values of the displacement of the sprung mass are only 1.31% and 1.29%, respectively, compared with the situation of the vehicle using a passive suspension. Similarly, the value of the acceleration is 6.98% and 2.94%, respectively. In addition, the phenomenon of “chattering” has also been significantly reduced when using this controller. In the future, some more complex algorithms can be proposed.
Effect of Different Growing Niches on Stand Structure of Highland Bamboo (Yushania alpina) in West Amhara, Northern Ethiopia
Authors: Alamerew Amsalu , Mulu Menale , Abtew Asmamaw , Fanta Demel , Alem Beyene , Mekonnen Melkamu , Asres Mulugeta
Published: June 2022

The study was conducted to investigate the effects of different growing niches on the stand structure of highland bamboo (Yushania alpina) in west Amhara national regional state, northern Ethiopia. Four districts were selected purposively based on the existence of bamboo in different agroforestry practices. Inventory was carried out from 324 randomly selected plots of bamboo stands. The height of bamboo culms ranged between 12.2 ± 0.14 and 14.7 ± 0.12 m, and the diameter was between 4.9 ± 0.12 and 6.1 ± 0.11 cm with a mean value of 5.7 ± 0.102 cm. Growth performance (diameter and height size) based population distribution (histogram visualization) of bamboo stand indicated the normal distribution of height and diameter of culms. Density of culm varies between 19,188 ± 336 and 23,129 ± 390 culms ha−1 with an age composition of 26 : 45 : 29 ratio with 1 and 3 age classes. Diameters of the bamboo culms have inverse relationship with the age of bamboo culm. Clump stocking of highland bamboo varies between 953 ± 40 and 1220 ± 48 clump ha−1 with a culm : clump ratio of 1 : 47 ± 5 and 1 : 82 ± 6. Information on the stand structure of bamboo culms across niches is important to identify the productive plantation niche and develop a management plan for sustainable management and utilization of the bamboo resource.
An Exact and Comparative Analysis of MHD Free Convection Flow of Water-Based Nanoparticles via CF Derivative
Authors: Rehman Aziz-Ur- , Riaz Muhammad Bilal , Saeed Syed Tauseef , Jarad Fahd , Jasim Hayder Natiq , Enver Aytekin
Published: June 2022

Convective flow is a self-sustained flow with the effect of the temperature gradient. The density is nonuniform due to the variation in temperature. The effect of the magnetic flux plays a major role in convective flow. The process of heat transfer is accompanied by a mass transfer process, for instance, condensation, evaporation, and chemical process. Combination of water as base fluid and three types of nanoparticles named as copper, titanium dioxide, and aluminum oxide is taken into account. Due to the applications of the heat and mass transfer combined effects in different fields, the main aim of this paper is to do a comprehensive analysis of heat and mass transfer of MHD natural convection flow of water-based nano-particles in the presence of ramped conditions with Caputo–Fabrizio fractional time derivative. The exact fractional solutions of temperature, concentration, and velocity have been investigated by means of integral transform. The classical calculus is assumed as the instant rate of change of the output when the input level changes. Therefore, it is not able to include the previous state of the system called the memory effect. But, in the fractional calculus (FC), the rate of change is affected by all points of the considered interval to incorporate the previous history/memory effects of any system. Due to this reason, we applied the modern definition of fractional derivative. Here, the order of the fractional derivatives will be treated as an index of memory. The influence of physical parameters and flow is analyzed graphically via computational software (MATHCAD-15). Our results suggest that the incremental value of the M is observed for a decrease in the velocity field, which reflects to control resistive force.
Polymorphisms in Genes Related to Oxidative Stress (MPO, MnSOD, CAT) and Survival After Treatment for Breast Cancer
Authors: Ambrosone Christine B. , Ahn Jiyoung , Singh Keshav K. , Rezaishiraz Hamed , Furberg Helena , Sweeney Carol , Coles Brian , Trovato Andrew
Published: June 2022

The proximate cause of cancer cell death by radiation therapy and a number of therapeutic agents is through generation of reactive oxygen species, resulting in DNA damage as well as mitochondrial membrane disruption, triggering the apoptotic cascade. Because mitochondrial manganese superoxide dismutase catalyzes conversion of superoxide radicals to H2O2, with catalase neutralizing H2O2 and myeloperoxidase converting H2O2 to highly reactive hypochlorous acid, we hypothesized that gene variants could impact the efficacy of treatment for breast cancer and improve survival. Women who were treated with radiation and/or chemotherapy for incident breast cancer at the Arkansas Cancer Research Center from 1985 to 1996 were identified. DNA was extracted from paraffin-embedded normal tissue (n = 279), and MnSOD, CAT, and MPO genotypes were determined using mass spectrometry. Cox proportional hazards models were adjusted for age, race, stage with node status, and estrogen receptor and progesterone receptor status. Women who were homozygous for MPO G alleles, associated with increased transcription, had better survival (hazard ratio, 0.60; 95% confidence interval, 0.38-0.95; P = 0.03) than those with common alleles. Both CAT TT and MnSOD CC genotypes were associated with nonsignificant reduced hazard of death. When we combined genotypes associated with higher levels of reactive oxygen species for MnSOD and MPO, women with MnSOD CC and MPO GG genotypes had a 3-fold decrease in hazard of death (hazard ratio, 0.33; 95% confidence interval, 0.13-0.80; P = 0.01). These data indicate that gene variants that impact oxidative stress modify prognosis after treatment for breast cancer.
Acceleration of Smad2 and Smad3 Phosphorylation via c-Jun NH2-Terminal Kinase during Human Colorectal Carcinogenesis
Authors: Yamagata Hideo , Matsuzaki Koichi , Mori Shigeo , Yoshida Katsunori , Tahashi Yoshiya , Furukawa Fukiko , Sekimoto Go , Watanabe Toshihiko , Uemura Yoshiko , Sakaida Noriko , Yoshioka Kazuhiko , Kamiyama Yasuo , Seki Toshihito , Okazaki Kazuichi
Published: June 2022

Conversion of normal epithelial cells to tumors is associated with a shift in transforming growth factor-β (TGF-β) function: reduction of tumor suppressor activity and increase of oncogenic activity. However, specific mechanisms of this functional alteration during human colorectal carcinogenesis remain to be elucidated. TGF-β signaling involves Smad2/3 phosphorylated at linker regions (pSmad2/3L) and COOH-terminal regions (pSmad2/3C). Using antibodies specific to each phosphorylation site, we herein showed that Smad2 and Smad3 were phosphorylated at COOH-terminal regions but not at linker regions in normal colorectal epithelial cells and that pSmad2/3C were located predominantly in their nuclei. However, the linker regions of Smad2 and Smad3 were phosphorylated in 31 sporadic colorectal adenocarcinomas. In particular, late-stage invasive and metastatic cancers typically showed a high degree of phosphorylation of Smad2/3L. Their extent of phosphorylation in 11 adenomas was intermediate between those in normal epithelial cells and adenocarcinomas. Whereas pSmad2L remained in the cytoplasm, pSmad3L was located exclusively in the nuclei of Ki-67-immunoreactive adenocarcinomas. In contrast, pSmad3C gradually decreased as the tumor stage progressed. Activated c-Jun NH2-terminal kinase in cancers could directly phosphorylate Smad2/3L. Although Mad homology 2 region sequencing in the Smad4 gene revealed a G/A substitution at codon 361 in one adenocarcinoma, the mutation did not correlate with phosphorylation. No mutations in the type II TGF-β receptor and Smad2 genes were observed in the tumors. In conclusion, pSmad3C, which favors tumor suppressor activity of TGF-β, was found to decrease, whereas c-Jun NH2-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence.
Cellular Targets of Gefitinib
Authors: Brehmer Dirk , Greff Zoltán , Godl Klaus , Blencke Stephanie , Kurtenbach Alexander , Weber Martina , Müller Stefan , Klebl Bert , Cotten Matt , Kéri György , Wissing Josef , Daub Henrik
Published: June 2022

Targeted inhibition of protein kinases with small molecule drugs has evolved into a viable approach for anticancer therapy. However, the true selectivity of these therapeutic agents has remained unclear. Here, we used a proteomic method to profile the cellular targets of the clinical epidermal growth factor receptor kinase inhibitor gefitinib. Our data suggest alternative cellular modes of action for gefitinib and provide rationales for the development of related drugs.
Synergism between the Anticancer Actions of 2-Methoxyestradiol and Microtubule-Disrupting Agents in Human Breast Cancer
Authors: Han Gui-Zhen , Liu Zhi-Jian , Shimoi Kayoko , Zhu Bao Ting
Published: June 2022

2-Methoxyestradiol (2-MeO-E2), a well-known nonpolar endogenous metabolite of 17β-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions in vitro and in vivo at pharmacologic concentrations. We determined in the present study whether 2-MeO-E2 can enhance the anticancer actions of paclitaxel or vinorelbine (two commonly used microtubule-disrupting agents) in several human breast cancer cell lines, including the estrogen receptor–positive MCF-7 and T-47D cells and the receptor-negative MDA-MB-435s and MDA-MB-231 cells. 2-MeO-E2 in combination with paclitaxel or vinorelbine exhibited a synergistic anticancer effect in these human breast cancer cells in vitro, and this synergistic effect was more pronounced when each of the drugs was used at relatively low concentrations. Additional experiments using female athymic BALB/c nu/nu mice showed that p.o. administration of 2-MeO-E2 at 30 mg/kg body weight, once a week for 6 weeks, markedly enhanced the activity of paclitaxel or vinorelbine against the growth of the estrogen receptor–negative MDA-MB-231 human breast cancer xenografts in these animals. By contrast, combination of 2-MeO-E2 with 5-fluorouracil only had a partial additive effect against the growth of these cell lines in culture, and no synergistic effect was observed. Interestingly, when doxorubicin was used in combination with 2-MeO-E2, the antiproliferative effect of 2-MeO-E2 was somewhat antagonized by doxorubicin when it was present at high concentrations. Our results showed that 2-MeO-E2 at nontoxic or subtoxic doses selectively enhanced the effects of certain microtubule-disrupting agents (such as paclitaxel and vinorelbine) against the growth of the receptor-negative human breast cancer cells in culture and also in athymic nude mice.
Genetic Mapping of a Third Li-Fraumeni Syndrome Predisposition Locus to Human Chromosome 1q23
Authors: Bachinski Linda L. , Olufemi Shodimu-Emmanuel , Zhou Xiaojun , Wu Chih-Chieh , Yip Linwah , Shete Sanjay , Lozano Guillermina , Amos Christopher I. , Strong Louise C. , Krahe Ralf
Published: June 2022

Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. Most cases (∼70%) identified and characterized to date are associated with dominantly inherited germ line mutations in the tumor suppressor gene TP53 (p53) in chromosome 17p13.1. In a subset of non-p53 patients with LFS, CHEK2 in chromosome 22q11 has been identified as another predisposing locus. Studying a series of non-p53 LFS kindred, we have shown that there is additional genetic heterogeneity in LFS kindred with inherited predisposition at loci other than p53 or CHEK2. Using a genome-wide scan for linkage with complementing parametric and nonparametric analysis methods, we identified linkage to a region of approximately 4 cM in chromosome 1q23, a genomic region not previously implicated in this disease. Identification ofa third predisposing gene and its underlying mutation(s) should provide insight into other genetic events that predispose to the genesis of the diverse tumor types associated with LFS and its variants.
CXCL12 and Vascular Endothelial Growth Factor Synergistically Induce Neoangiogenesis in Human Ovarian Cancers
Authors: Kryczek Ilona , Lange Andrzej , Mottram Peter , Alvarez Xavier , Cheng Pui , Hogan Melina , Moons Lieve , Wei Shuang , Zou Linhua , Machelon Véronique , Emilie Dominique , Terrassa Margarita , Lackner Andrew , Curiel Tyler J. , Carmeliet Peter , Zou Weiping
Published: June 2022

Ovarian carcinomas have a poor prognosis, often associated with multifocal i.p. dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites and tumors of patients with untreated ovarian carcinoma. We observed that malignant ascites fluid induced potent in vivo neovascularization in Matrigel assay. We detected a sizable amount of vascular endothelial cell growth factor (VEGF) in malignant ascites. However, pathologic concentration of VEGF is insufficient to induce in vivo angiogenesis. We show that ovarian tumors strongly express CXC chemokine stromal-derived factor (SDF-1/CXCL12). High concentration of CXCL12, but not the pathologic concentration of CXCL12 induces in vivo angiogenesis. Strikingly, pathologic concentrations of VEGF and CXCL12 efficiently and synergistically induce in vivo angiogenesis. Migration, expansion, and survival of vascular endothelial cells (VEC) form the essential functional network of angiogenesis. We further provide a mechanistic basis for explaining the interaction between CXCL12 and VEGF. We show that VEGF up-regulates the receptor for CXCL12, CXCR4 expression on VECs, and synergizes CXCL12-mediated VEC migration. CXCL12 synergizes VEGF-mediated VEC expansion and synergistically protects VECs from sera starvation-induced apoptosis with VEGF. Finally, we show that hypoxia synchronously induces tumor CXCL12 and VEGF production. Therefore, hypoxia triggered tumor CXCL12 and VEGF form a synergistic angiogenic axis in vivo. Hypoxia-induced signals would be the important factor for initiating and maintaining an active synergistic angiogeneic pathway mediated by CXCL12 and VEGF. Thus, interrupting this synergistic axis, rather than VEGF alone, will be a novel efficient antiangiogenesis strategy to treat cancer.
Effective Gene Therapy of Biliary Tract Cancers by a Conditionally Replicative Adenovirus Expressing Uracil Phosphoribosyltransferase: Significance of Timing of 5-Fluorouracil Administration
Authors: Seo Emiko , Abei Masato , Wakayama Mariko , Fukuda Kuniaki , Ugai Hideyo , Murata Takehide , Todoroki Takeshi , Matsuzaki Yasushi , Tanaka Naomi , Hamada Hirofumi , Yokoyama Kazunari K.
Published: June 2022

In order to enhance the efficacy of conditionally replicating adenoviruses (CRAd) in the treatment of cancers of the biliary tract, we studied the efficacy in vitro and in vivo of AxE1CAUP, a CRAd vector that carries a gene for uracil phosphoribosyltransferase (UPRT), which converts 5-fluorouracil (5-FU) directly to 5-fluorouridine monophosphate and greatly enhances the cytotoxicity of 5-FU. AxE1CAUP replicated and induced an increased UPRT expression in biliary cancer cells more efficiently than AxCAUP, a nonreplicative adenovirus carrying the UPRT gene. Whereas AxCAUP and AxE1AdB, a CRAd without the UPRT gene, modestly increased the sensitivity of BC cells to 5-FU, AxE1CAUP markedly increased the sensitivity, especially when the timing of 5-FU administration was appropriately chosen. AxE1CAUP replicated much less efficiently in normal WI-38 fibroblasts without any change in the sensitivity to 5-FU. In nude mice with s.c. biliary cancer xenografts, i.t. AxE1CAUP/5-FU therapy inhibited tumor growth significantly more strongly than AxCAUP/5-FU or AxE1AdB/5-FU therapy. Furthermore, in mice with peritoneally disseminated biliary cancer, i.p. AxE1CAUP efficiently proliferated in the tumors, decreased the tumor burden, and prolonged the survival of the mice when 5-FU was started 10 or 15 days after the vector inoculation, whereas earlier initiation of 5-FU resulted in early eradication of the vector and no survival benefit. The present study shows that the CRAd expressing UPRT was a more potent sensitizer of biliary cancer to 5-FU, than was a nonreplicative UPRT-encoding vector or a CRAd without UPRT gene, even at a lower dose of the vector, and that timing of 5-FU administration was a key factor to maximize the efficacy. This gene therapy with appropriately timed administration of 5-FU should be useful in overcoming the resistance of biliary cancers to 5-FU.
Tailoring the Pharmacokinetics and Positron Emission Tomography Imaging Properties of Anti–Carcinoembryonic Antigen Single-Chain Fv-Fc Antibody Fragments
Authors: Kenanova Vania , Olafsen Tove , Crow Desiree M. , Sundaresan Gobalakrishnan , Subbarayan Murugesan , Carter Nora H. , Ikle David N. , Yazaki Paul J. , Chatziioannou Arion F. , Gambhir Sanjiv S. , Williams Lawrence E. , Shively John E. , Colcher David , Raubitschek Andrew A. , Wu Anna M.
Published: June 2022

Antibody fragments are recognized as promising vehicles for delivery of imaging and therapeutic agents to tumor sites in vivo. The serum persistence of IgG1 and fragments with intact Fc region is controlled by the protective neonatal Fc receptor (FcRn) receptor. To modulate the half-life of engineered antibodies, we have mutated the Fc-FcRn binding site of chimeric anti–carcinoembryonic antigen (CEA) antibodies produced in a single-chain Fv-Fc format. The anti-CEA T84.66 single-chain Fv-Fc format wild-type and five mutants (I253A, H310A, H435Q, H435R, and H310A/H435Q, Kabat numbering system) expressed well in mammalian cell culture. After purification and characterization, effective in vitro antigen binding was shown by competition ELISA. Biodistribution studies in BALB/c mice using 125I- and 131I-labeled fragments revealed blood clearance rates from slowest to fastest as follows: wild-type > H435R > H435Q > I253A > H310A > H310A/H435Q. The terminal half-lives of the mutants ranged from 83.4 to 7.96 hours, whereas that of the wild-type was ∼12 days. Additionally, 124I-labeled wild-type, H435Q, I253A, H310A, and H310A/H435Q variants were evaluated in LS174T xenografted athymic mice by small animal positron emission tomography imaging, revealing localization to the CEA-positive xenografts. The slow clearing wild-type and H435Q constructs required longer to localize to the tumor and clear from the circulation. The I253A and H310A fragments showed intermediate behavior, whereas the H310A/H435Q variant quickly localized to the tumor site, rapidly cleared from the animal circulation and produced clear images. Thus, attenuating the Fc-FcRn interaction provides a way of controlling the antibody fragment serum half-life without compromising expression and tumor targeting.
Positherapy: Targeted Nuclear Therapy of Breast Cancer with 18F-2-Deoxy-2-Fluoro-d-Glucose
Authors: Moadel Renee M. , Weldon Richard H. , Katz Ellen B. , Lu Ping , Mani Joseph , Stahl Mark , Blaufox M. Donald , Pestell Richard G. , Charron Maureen J. , Dadachova Ekaterina
Published: June 2022

Breast cancer remains a major cause of cancer death in women in the United States. Novel therapies are needed for patients when standard treatments are ineffective. We have recently shown on a cellular level the therapeutic potential of positrons in malignancy. Here, we report for the first time positron therapy with 18F-2-deoxy-2-fluoro-d-glucose (18F-FDG) in a breast cancer animal model to affect tumor growth rate and survival (positherapy). We used xenografted mammary tumors in nude mice using Notch mammary cancer cells which also express ras oncogene. Notch xenografted tumors actively took up 18F-FDG with a tumor to normal tissue ratio of 3.24. Tumor-bearing mice were treated with 2.5 mCi 18F-FDG, which is equivalent to the physiological human maximum tolerated dose. Positherapy resulted in both significant prolongation of survival and decrease in tumor growth rate in comparison with nontreated controls. Immunoblot of Notch tumors showed the presence of glucose transporters (GLUT) 1, 4, and 8. Substantial differences between GLUT1, GLUT4, and GLUT8 were observed in their distribution within the tumor mass. Whereas GLUT4 and GLUT8 were distributed relatively homogeneously throughout the tumor, GLUT1 was confined to necrotic areas. Immunofluorescence double labeling was used to determine cellular localization of GLUTs. GLUT1 was expressed mostly at the cell membrane. GLUT4 and GLUT8 were mostly localized to cytoplasmic compartments with some GLUT4 expressed at or near the cell membrane in close proximity to GLUT1. Thus, GLUT1 was likely responsible for the 18F-FDG uptake by tumor cells with some possible contribution from GLUT4. These results are important for the development of positherapy with 18F-FDG for refractory metastatic breast and other cancers.
ΔNp63α Up-Regulates the Hsp70 Gene in Human Cancer
Authors: Wu Guojun , Osada Motonobu , Guo Zhongmin , Fomenkov Alexey , Begum Shahnaz , Zhao Ming , Upadhyay Sunil , Xing Mingzhao , Wu Feng , Moon Chulso , Westra William H. , Koch Wayne M. , Mantovani Roberto , Califano Joseph A. , Ratovitski Edward , Sidransky David , Trink Barry
Published: June 2022

HSP70, a stress response protein, is known to be a determinant of cell death and cell transformation. We show that different isoforms of p63 have different transcriptional activities on hsp70 genes. ΔNp63α, an abundantly expressed isoform of p63, activates (in vitro and in vivo), whereas TAp63γ down-regulates the expression of hsp70. We further show that the transactivation domain at the NH2 terminus of p63 represses, whereas the COOH terminus activates hsp70 transcription. In addition, ΔNp63α regulates transcription of the hsp70 gene through its interaction with the CCAAT binding factor and NF-Y transcription factors which are known to form a complex with the CCAAT box located in the hsp70 promoter. Moreover, ΔNp63α expression correlates with HSP70 expression in all head and neck cancer cell lines. Finally, we show colocalization of ΔNp63α and HSP70 in the epithelium and coexpression of both proteins in 41 primary head and neck cancers. Our study provides strong evidence for the physiologic association between ΔNp63α and hsp70 in human cancer, thus further supporting the oncogenic potential of ΔNp63α.
CpG Island Methylator Phenotype Is a Strong Determinant of Poor Prognosis in Neuroblastomas
Authors: Abe Masanobu , Ohira Miki , Kaneda Atsushi , Yagi Yukiko , Yamamoto Seiichiro , Kitano Yoshihiro , Takato Tsuyoshi , Nakagawara Akira , Ushijima Toshikazu
Published: June 2022

Neuroblastoma, one of the most common pediatric solid tumors, is characterized by two extreme disease courses, spontaneous regression and life-threatening progression. Here, we conducted a genome-wide search for differences in DNA methylation that distinguish between neuroblastomas of the two types. Three CpG islands (CGI) and two groups of CGIs were found to be methylated specifically in neuroblastomas with a poor prognosis. By quantitative analysis of 140 independent cases, methylation of all the five CGI (groups) was shown to be closely associated with each other, conforming to the CpG island methylator phenotype (CIMP) concept. The presence of CIMP was sensitively detected by methylation of the PCDHB CGIs and associated with significantly poor survival (hazard ratio, 22.1; 95% confidence interval, 5.3-93.4; P < 0.0001). Almost all cases with N-myc amplification (37 of 38 cases) exhibited CIMP. Even in 102 cases without N-myc amplification, the presence of CIMP (30 cases) strongly predicted poor survival (hazard ratio, 12.4; 95% confidence interval, 2.6-58.9; P = 0.002). Methylation of PCDHB CGIs, located in their gene bodies, did not suppress gene expression or induce histone modifications. However, CIMP was significantly associated with methylation of promoter CGIs of the RASSF1A and BLU tumor suppressor genes. The results showed that neuroblastomas with CIMP have a poor prognosis and suggested induction of silencing of important genes as an underlying mechanism.
Heterozygosity for p53 (Trp53
+/−) Accelerates Epithelial Tumor Formation in Fanconi Anemia Complementation Group D2 (Fancd2) Knockout Mice
Authors: Houghtaling Scott , Granville Laura , Akkari Yassmine , Torimaru Yumi , Olson Susan , Finegold Milton , Grompe Markus
Published: June 2022

Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure and an increased susceptibility to cancer. FA is genetically heterogeneous, consisting of at least 11 complementation groups, FA-A through L, including FA-D1 (BRCA2) and D2. We have previously reported an increased incidence of epithelial tumors in Fancd2 knockout mice. To further investigate the role of the FA pathway in tumor prevention, Fancd2 mutant mice were crossed to mice with a null mutation in the tumor suppressor gene, Trp53. The tumor spectrum in Fancd2−/−/Trp53+/− mice included sarcomas expected in Trp53 heterozygotes, as well as mammary and lung adenocarcinomas that occur rarely in Trp53 heterozygotes. These tumors occurred earlier than in Fancd2−/− control mice. Therefore, the Fancd2−/−/Trp53+/− mice represent an improved model for the study of adenocarcinoma in FA. In addition, it was found that Fancd2−/− mouse embryonic fibroblasts but not Fancd2−/−/Trp53−/− mouse embryonic fibroblasts arrest following DNA damage. Therefore, Trp53 is required for the S phase checkpoint activation observed in Fancd2 mutant cells. Fancd2−/−/Trp53−/− cells showed an increase in aneuploidy and had multiple gross chromosomal rearrangements.
Transcriptional Coactivator Drosophila Eyes Absent Homologue 2 Is Up-Regulated in Epithelial Ovarian Cancer and Promotes Tumor Growth
Authors: Zhang Lin , Yang Nuo , Huang Jia , Buckanovich Ronald J. , Liang Shun , Barchetti Andrea , Vezzani Cristina , O'Brien-Jenkins Ann , Wang Jennifer , Ward Michelle Renee , Courreges Maria C. , Fracchioli Stefano , Medina Angelica , Katsaros Dionyssios , Weber Barbara L. , Coukos George
Published: June 2022

Epithelial ovarian cancer is the most frequent cause of gynecologic malignancy-related mortality in women. To identify genes up-regulated in ovarian cancer, PCR-select cDNA subtraction was done and Drosophila Eyes Absent Homologue 2 (EYA2) was isolated as a promising candidate. The transcriptional coactivator eya controls essential cellular functions during organogenesis of Drosophila. EYA2 mRNA was found to be up-regulated in ovarian cancer by real-time reverse transcription–PCR, whereas its protein product was detected in 93.6% of ovarian cancer specimens by immunohistochemistry (n = 140). EYA2 was amplified in 14.8% of ovarian carcinomas, as detected by array-based comparative genomic hybridization (n = 88). Most importantly, EYA2 overexpression was significantly associated with short overall survival in advanced ovarian cancer (n = 99, P = 0.0361). EYA2 was found to function as transcriptional activator in ovarian cancer cells by Gal4 assay and to promote tumor growth in vivo in xenograft models. Therefore, this study suggests an important role of EYA2 in ovarian cancer and its potential application as a therapeutic target.
ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression
Authors: Luo Qingyu , Wu Xiaowei , Chang Wan , Zhao Pengfei , Zhu Xiaolin , Chen Hongyan , Nan Yabing , Luo Aiping , Zhou Xuantong , Su Dan , Jiao Wenjie , Liu Zhihua
Published: June 2022

Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes have a mutation rate of approximately 20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin-remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The anti-inflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat patients with SCC with low ARID1A expression.

Significance:

This study reveals novel inactivation mechanisms and tumor-suppressive roles of ARID1A in SCC and proposes parthenolide as an effective treatment for patients with SCC with low ARID1A expression.
Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment
Authors: Jang Hee-Jin , Lee Hyun-Sung , Yu Wendong , Ramineni Maheshwari , Truong Cynthia Y. , Ramos Daniela , Splawn Taylor , Choi Jong Min , Jung Sung Yun , Lee Ju-Seog , Wang Daniel Y. , Sederstrom Joel M. , Pietropaolo Massimo , Kheradmand Farrah , Amos Christopher I. , Wheeler Thomas M. , Ripley R. Taylor , Burt Bryan M.
Published: June 2022

Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here, we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of preinvasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, complementary capabilities of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry was leveraged to identify cellular and spatial immune contextures in LUAD. Comprehensive investigation of mouse and human LUAD using these single-cell proteomics platforms showed that LUAD progression is associated with spatiotemporal evolution of tumor-associated macrophages in the tumor-immune microenvironment, which governs tumor response to immunotherapy. PD-1 was expressed in a highly plastic tumor-promoting subtype of tumor-associated macrophages that develops during tumor progression from preinvasive to invasive adenocarcinoma, controls the lymphocyte-depleted niche of invasive tumors, and protects tumor cells in the solid histologic components of the tumor. Longitudinal, multidimensional single-cell analyses of LUAD tumorigenesis revealed dynamic alteration of immunoregulatory PD-1–expressing tumor-associated macrophages that can be targeted to overcome resistance to checkpoint immunotherapy.

Significance:

Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy.

See related commentary by Lee et al., p. 2515
Human Papillomavirus Integration Strictly Correlates with Global Genome Instability in Head and Neck Cancer
Authors: Labarge Brandon , Hennessy Max , Zhang Lijun , Goldrich David , Chartrand Scott , Purnell Carson , Wright Sage , Goldenberg David , Broach James R.
Published: June 2022

Human papillomavirus (HPV)-positive head and neck cancers, predominantly oropharyngeal squamous cell carcinoma (OPSCC), exhibit epidemiologic, clinical, and molecular characteristics distinct from those OPSCCs lacking HPV. We applied a combination of whole-genome sequencing and optical genome mapping to interrogate the genome structure of HPV-positive OPSCCs. We found that the virus had integrated in the host genome in two thirds of the tumors examined but resided solely extrachromosomally in the other third. Integration of the virus occurred at essentially random sites within the genome. Focal amplification of the virus and the genomic sequences surrounding it often occurred subsequent to integration, with the number of tandem repeats in the chromosome accounting for the increased copy number of the genome sequences flanking the site of integration. In all cases, viral integration correlated with pervasive genome-wide somatic alterations at sites distinct from that of viral integration and comprised multiple insertions, deletions, translocations, inversions, and point mutations. Few or no somatic mutations were present in tumors with only episomal HPV. Our data could be interpreted by positing that episomal HPV is captured in the host genome following an episode of global genome instability during tumor development. Viral integration correlated with higher grade tumors, which may be explained by the associated extensive mutation of the genome and suggests that HPV integration status may inform prognosis.

Implications:

Our results indicate that HPV integration in head and neck cancer correlates with extensive pangenomic structural variation, which may have prognostic implications.
A Decade Later on How to “Use It” So We Don’t “Lose It”: An Update on the Unanswered Questions about the Influence of Activity Participation on Cognitive Performance in Older Age
Authors: Bielak Allison A.M. , Gow Alan J.
Published: June 2022

Activity engagement is a modifiable factor that has been widely-cited as being good for the aging brain and cognition and represents a valuable target for reducing dementia risk. However, specific issues about activity engagement (mental, social, and physical) and cognition in older adulthood remain, and Bielak [Gerontology 2010;56: 507-519] reviewed seven major methodological and theoretical questions about this relationship. We present an updated reflection on these key questions, focusing on research published in the last 10 years. For some questions, a significant amount of work has been done and conclusions have become clearer; for others, there have been few additions to the literature and our knowledge remains much the same as it was a decade ago. We review the issues identified in the 2010 paper including the directionality and temporal nature of the relationship; whether specific activity domains offer different benefits to cognition and what domain(s) of cognition are affected; variation in the relation by age, gender, or education; potential mechanisms involved; and how activity engagement is assessed. For each, we present the most up-to-date research, discuss remaining challenges and possible future directions. This formal unifying of the information in the field is intended as a guide to support continued progress by spurring on studies addressing specific questions while reminding researchers of critical issues. We conclude with recommendations that future studies investigating the link between activity engagement and cognitive performance in adulthood should consider.
Neuroimaging of Diabetic Striatopathy: More Questions than Answers
Authors: Dubey Souvik , Biswas Payel , Ghosh Ritwik , Chatterjee Subhankar , Kanti Ray Biman , Benito-León Julián
Published: June 2022

Background: Diabetic striatopathy (DS), coined as a generic term, has been defined as a hyperglycemic condition associated with either one of the two following conditions: chorea/ballism or striatal hyperdensity on computed tomography or striatal hyperintensity on T1-weighted magnetic resonance imaging. This review highlights those “gray areas,” which need further exploration to understand better hyperglycemia-induced striatal changes and diverse movement disorder phenotypes associated with these changes. Results and Discussion: We searched in PubMed and Google Scholar the terms “diabetes mellitus,” “movement disorders,” “diabetic striatopathy,” “chorea,” “hemichorea,” “ballism,” “hemichorea-hemiballism,” and “neuroradiology” in various combinations (time range from 1980 to March 2022). We selected the publications about our topic of discussion. Summary: Hemichorea-hemiballismus is the most commonly associated movement disorder in DS, and the putamen is the most frequently affected anatomical region. The exact pathophysiological mechanisms remain elusive. Clinical-radiological discordance is not rare. Complete reversal of symptoms with the resolution of the imaging findings is the most prevalent outcome in patients with DS. Dramatic improvement of chorea can be achieved by either insulin monotherapy or combination therapy of insulin and D2-blocker or, in some cases, even spontaneously. Conclusion: The term “diabetic striatopathy” is ambiguous and controversial. Pathological mechanisms behind clinical-radiological discordance in hyperglycemia-induced striatopathy need further exploration through well-designed studies. We propose a classification of DS that includes symptomatic DS (striatal neuroimaging lesions in association with a clinically evident movement disorder and hyperglycemia), clinically isolated DS (clinically evident movement disorders without striatal changes in neuroimaging), and radiologically isolated DS.