bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying threshold concepts in postgraduate general practice training: a focus group, qualitative study
Authors: Hall Katherine , Chae Anna 
Published: June 2022

ObjectiveTo identify threshold concepts (TCs) for physicians undergoing postgraduate medical education (PGME) in general practice.DesignAn explorative, qualitative study with 65 min focus group interviews and thematic analysis was used. Participants were asked to describe their most transformative learning experiences. Heuristical TCs were identified from the thematic analysis.SettingAotearoa/New Zealand (A/NZ).ParticipantsFifty participants, mostly comprising current trainees and educators from urban centres, and of NZ/European ethnicity.ResultsTwenty TCs covering many aspects of postgraduate general practice experience were derived from themes identified in the data. Presented in medical proverbial form for ease of recollection, these included: Money makes the practice go round; Be a legal eagle; Manage time or it will manage you; Guidelines, GPs’ little helpers; Right tool, right word, right place; The whole of the practice is greater than the sum of the parts; The personal enhances the professional; Beat biases by reflection; Chew the Complexity, Unpredictability, Diversity; Embrace the uncertainty; Not knowing is knowing; Seek and you shall find; Waiting and seeing, waiting and being; Look, listen, think between the lines; Treat the patient beyond the disease; No patient is an island; Words work wonders; Hearing is healing; Being you and being there; and; The relationship is worth a thousand consults. These TCs mapped onto core competencies in A/NZ’s PGME in general practice curriculum.ConclusionsParticipants readily identified transformative and troublesome moments in their PGME in general practice. These findings confirmed evidence for a wide range of TCs with many newly identified in this study. All TCs were fundamentally based on the doctor–patient relationship, although often involving the context and culture of general practice. Actively incorporating and teaching these identified TCs in PGME in general practice may enable trainees to grasp these important learning thresholds earlier and more easily and aid in identity and role formation.
Conservation implications of white shark (Carcharodon carcharias) behaviour at the northern extent of their range in the Northwest Atlantic
Authors: Bowlby Heather D. , Joyce Warren N. , Winton Megan V. , Coates Peterson J. , Skomal Gregory B. 
Published: June 2022

Assessing progress for the endangered white shark ( Carcharodon carcharias) relative to Canadian conservation objectives requires understanding distribution patterns. From the largest tagging data set in the Northwest Atlantic (2010–2020; 272 deployments), we determined the proportion of the population detected in Canadian waters, characterized patterns in occupancy, and explored the behavioural characteristics of animals while in Canadian waters versus elsewhere in their range. The component of the population detected in Canadian waters annually was highly variable, yet proportionately small. Juveniles and subadults were 4.7 and 3.4 times more likely, respectively, to move northward than adults. From June to November, all pop-up satellite archival tagged white sharks remained primarily in coastal locations within the 200 m bathymetric contour and exhibited shallow diving behaviour within the top 100 m of the water column. However, individuals in Canadian waters experienced a more restricted temperature range and used proportionately less of the water column. Accounting for behavioural effects on distribution when predicting habitat use from environmental associations will become critical to evaluate the population-level impact of recovery actions implemented under Canadian legislation.
Modeling and Performance Optimization of a Compact Three-Petalled Flower-Like Microstrip Patch Antenna for IoT Applications
Authors: Gupta Nancy , Gill Navneet , Maniraguha Fidele 
Published: June 2022

The article is aimed at proposing the design and investigating the performance of a three-petalled flower-shaped wideband microstrip patch antenna for IoT and next-generation wireless applications. The proposed printed monopole antenna is provided with a microstrip feed line for excitation with a defected ground plane. The antenna is designed and analyzed using a finite-element-based simulator HFSS (version 15.0). The Optimetrics feature in the simulator is used for the performance optimization of the designed antenna that results in wide impedance bandwidth between 2.5 and 5.5 GHz, with add-on benefits such as less human efforts along with fast optimum results. The designed antenna holds an advantage of being low profile and reduced in size as overall diminutive dimensions of the proposed patch antenna are

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, making it suitable for use in Wi-Max- and WLAN-enabled IoT applications. The paper is aimed at proposing an innovative optimal design aiming at the concerns about the risks in the growth of IoT and mobile computing, particularly in wireless and mobile networks. The anticipated antenna, owing to its simple and compact design, can be easily integrated into portable mobile devices, and thus, it is considered suitable for 4G and 5G and other next-generation communication applications of IoT devices.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

AbstractOvarian 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

Abstract
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

AbstractAntibody 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 &gt; H435R &gt; H435Q &gt; I253A &gt; H310A &gt; 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

Abstract
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

Abstract
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.