bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Reduced Argininosuccinate Synthetase Is a Predictive Biomarker for the Development of Pulmonary Metastasis in Patients with Osteosarcoma
Authors: Kobayashi Eisuke , Masuda Mari , Nakayama Robert , Ichikawa Hitoshi , Satow Reiko , Shitashige Miki , Honda Kazufumi , Yamaguchi Umio , Shoji Ayako , Tochigi Naobumi , Morioka Hideo , Toyama Yoshiaki , Hirohashi Setsuo , Kawai Akira , Yamada Tesshi
Published: April 2023

Abstract
Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 × 10−5). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P < 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G0-G1 arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. Mol Cancer Ther; 9(3); 535–44
Data from CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model
Authors: Ma Xinrong , Norsworthy Kelly , Kundu Namita , Rodgers William H. , Gimotty Phyllis A. , Goloubeva Olga , Lipsky Michael , Li Yanchun , Holt Dawn , Fulton Amy
Published: April 2023

Abstract
Breast tumor cells express the chemokine receptor CXCR3, which binds the ligands CXCL9, CXCL10, and CXCL11. CXCR3 and other chemokine receptors may mediate tumor metastasis by supporting migration of tumor cells to sites of ligand expression including the lymph nodes, lungs, and bone marrow. We examined the relationship of CXCR3 expression to clinical outcome in 75 women diagnosed with early-stage breast cancer. We detected CXCR3 in malignant epithelium from all tumors. Twelve percent were weakly positive and 64% had moderate levels of CXCR3. Strong CXCR3-positive staining was observed in 24% of tumors. Kaplan-Meier survival curves showed that high CXCR3 expression was associated with poorer overall survival; the unadjusted hazard ratio was 1.56 and it was marginally significant (P = 0.07). When interactions between lymph node status and CXCR3 were considered, the adjusted hazard ratio for CXCR3 was 2.62 (P = 0.02) for women with node-negative disease at diagnosis, whereas the hazard ratio for CXCR3 was not significant for those with node-positive disease. CXCR3 gene silencing inhibited lung colonization and spontaneous lung metastasis from mammary gland–implanted tumors in a murine model. The size or growth rate of the locally growing tumors was not affected. The antimetastatic effect of CXCR3 gene silencing was compromised in mice depleted of Natural Killer cells or with mutations in IFN-γ, suggesting that the role of CXCR3 is not simply to mediate tumor cell trafficking. These studies support the continued examination of CXCR3 as a potential therapeutic target in patients with breast cancer. [Mol Cancer Ther 2009;8(3):490–8]
Data from Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index
Authors: McDonagh Charlotte F. , Kim Kristine M. , Turcott Eileen , Brown Lindsay L. , Westendorf Lori , Feist Tiffany , Sussman Django , Stone Ivan , Anderson Martha , Miyamoto Jamie , Lyon Robert , Alley Stephen C. , Gerber Hans-Peter , Carter Paul J.
Published: April 2023

Abstract
An anti-CD70 antibody conjugated to monomethylauristatin F (MMAF) via a valine-citrulline dipeptide containing linker has been shown previously to have potent antitumor activity in renal cell cancer xenograft studies. Here, we generated a panel of humanized anti-CD70 antibody IgG variants and conjugated them to MMAF to study the effect of isotype (IgG1, IgG2, and IgG4) and Fcγ receptor binding on antibody-drug conjugate properties. All IgG variants bound CD70+ 786-O cells with an apparent affinity of ∼1 nmol/L, and drug conjugation did not impair antigen binding. The parent anti-CD70 IgG1 bound to human FcγRI and FcγRIIIA V158 and mouse FcγRIV and this binding was not impaired by drug conjugation. In contrast, binding to these Fcγ receptors was greatly reduced or abolished in the variant, IgG1v1, containing the previously described mutations, E233P:L234V:L235A. All conjugates had potent cytotoxic activity against six different antigen-positive cancer cell lines in vitro with IC50 values of 30 to 540 pmol/L. The IgGv1 conjugate with MMAF displayed improved antitumor activity compared with other conjugates in 786-O and UMRC3 models of renal cell cancer and in the DBTRG05-MG glioblastoma model. All conjugates were tolerated to ≥40 mg/kg in mice. Thus, the IgG1v1 MMAF conjugate has an increased therapeutic index compared with the parent IgG1 conjugate. The improved antitumor activity of the IgG1v1 auristatin conjugates may relate to increased exposure as suggested by pharmacokinetic analysis. The strategy used here for enhancing the therapeutic index of antibody-drug conjugates is independent of the antigen-binding variable domains and potentially applicable to other antibodies. [Mol Cancer Ther 2008;7(9):2913–23]
Data from Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells
Authors: Morales Cristina , García Maria J. , Ribas Maria , Miró Rosa , Muñoz Mar , Caldas Carlos , Peinado Miguel A.
Published: April 2023

Abstract
Gene amplification is one of the most frequent manifestations of genomic instability in human tumors and plays an important role in tumor progression and acquisition of drug resistance. To better understand the factors involved in acquired resistance to cytotoxic drugs via gene amplification, we have analyzed the structure and dynamics of dihydrofolate reductase (DHFR) gene amplification in HT29 cells treated with methotrexate (MTX). Analysis of the DHFR gene amplification process shows that the amplicon exhibits a complex structure that is consistently reproduced in independent treatments. The cytogenetic manifestation of the amplification in advanced stages of the treatment may be in the form of double minutes or as a homogeneously stained region. To get insights into the mechanisms of resistance, we have also investigated the sensitization to MTX of MTX-resistant cells after drug withdrawal and reexposure to MTX. Passive loss of the DHFR amplicon by withdrawal of the drug results in MTX-sensitive cells exhibiting a substantial reduction of their capacity or even an incapacity to generate resistance when submitted to a second cycle of MTX treatment. On a second round of drug administration, the resistant cells generate a different amplicon structure, suggesting that the formation of the amplicon as in the first cycle of treatment is not feasible. These results indicate that DHFR gene amplification is a “wear and tear” process in HT29 cells and that MTX-resistant cells may become responsive to a second round of treatment if left untreated during a sufficient period of time. [Mol Cancer Ther 2009;8(2):424–32]
Data from Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma
Authors: Ekshyyan Oleksandr , Rong Youhua , Rong Xiaohua , Pattani Kavita M. , Abreo Fleurette , Caldito Gloria , Chang John Kai Siung , Ampil Federico , Glass Jonathan , Nathan Cherie-Ann O.
Published: April 2023

Abstract
To determine if the mammalian target of rapamycin (mTOR) inhibitor CCI-779 can sensitize head and neck squamous cell carcinoma (HNSCC) to radiotherapy (XRT) and compare the radiosensitizing effects to cisplatin with its known considerable toxicity. Radiosensitizing effects of CCI-779 were assayed on HNSCC cell lines in vitro. CCI-779 (5 mg/kg), cisplatin (1 mg/kg), and XRT (2 Gy) alone and in combination were evaluated for antitumor activity in mice bearing FaDu and SCC40 xenografts. Effects of CCI-779 on radiation-induced activation of the Akt/mTOR pathway were analyzed. Although CCI-779 did not sensitize HNSCC cells to ionizing radiation in vitro, combination of CCI-779 and XRT significantly augmented the in vivo tumor growth-inhibitory effects of XRT and CCI-779 (P < 0.05). In addition, CCI-779 + XRT suppressed tumor growth more effectively than cisplatin + XRT (P < 0.05). CCI-779 + XRT significantly improved survival compared with XRT alone in both cisplatin-sensitive FaDu (P < 0.01) and cisplatin-resistant SCC40 (P < 0.05) xenograft mice. There were no additional benefits of adding cisplatin to CCI-779 + XRT. CCI-779 significantly attenuated irradiation-induced up-regulation of the mTOR pathway, increased apoptosis and displayed potent antiangiogenic activity in FaDu xenografts that was further enhanced by its combination with XRT (P < 0.05), which may explain the mechanism of its selective radiosensitizing effects in vivo and not in vitro. Antitumor activity of XRT was enhanced when combined with CCI-779 in HNSCC xenograft model. CCI-779 + XRT showed antitumor activity superior to conventional chemoradiotherapy with cisplatin. These results pave the way for clinical trials using molecular targeted therapy with CCI-779 in combination with XRT for HNSCC treatment. [Mol Cancer Ther 2009;8(8):2255–65]
Data from Effect of autophagy on multiple myeloma cell viability
Authors: Hoang Bao , Benavides Angelica , Shi Yijiang , Frost Patrick , Lichtenstein Alan
Published: April 2023

Abstract
Because accumulation of potentially toxic malfolded protein may be extensive in immunoglobulin-producing multiple myeloma (MM) cells, we investigated the phenomenon of autophagy in myeloma, a physiologic process that can protect against malfolded protein under some circumstances. Autophagy in MM cell lines that express and secrete immunoglobulin and primary specimens was significantly increased by treatment with the endoplasmic reticulum stress–inducing agent thapsigargin, the mammalian target of rapamycin inhibitor rapamycin, and the proteasome inhibitor bortezomib. Inhibition of basal autophagy in these cell lines and primary cells by use of the inhibitors 3-methyladenine and chloroquine resulted in a cytotoxic effect that was associated with enhanced apoptosis. Use of small interfering RNA to knock down expression of beclin-1, a key protein required for autophagy, also inhibited viable recovery of MM cells. Because the data suggested that autophagy protected MM cell viability, we predicted that autophagy inhibitors would synergize with bortezomib for enhanced antimyeloma effects. However, the combination of these drugs resulted in an antagonistic response. In contrast, the autophagy inhibitor 3-methyladenine did synergize with thapsigargin for an enhanced cytotoxic response. These data suggest that autophagy inhibitors have therapeutic potential in myeloma but caution against combining such drugs with bortezomib. [Mol Cancer Ther 2009;8(7):1974–84]
Data from Inhibition of the Insulin-Like Growth Factor I Receptor by Epigallocatechin Gallate Blocks Proliferation and Induces the Death of Ewing Tumor Cells
Authors: Kang Hyung-Gyoo , Jenabi Jasmine M. , Liu Xian Fang , Reynolds C. Patrick , Triche Timothy J. , Sorensen Poul H.B.
Published: April 2023

Abstract
The insulin-like growth factor I receptor (IGFIR) has emerged as a key therapeutic target in many human malignancies, including childhood cancers such as Ewing family tumors (EFT). In this study, we show that IGFIR is constitutively activated in EFTs and that the major catechin derivative found in green tea, (−)-epigallocatechin gallate (EGCG), can inhibit cell proliferation and survival of EFT cells through the inhibition of IGFIR activity. Treatment of EFT cell lines with EGCG blocked the autophosphorylation of IGFIR tyrosine residues and inhibited its downstream pathways including phosphoinositide 3-kinase-Akt, Ras-Erk, and Jak-Stat cascades. EGCG treatment was associated with dose- and time-dependent inhibition of cellular proliferation, viability, and anchorage-independent growth, as well as with the induction of cell cycle arrest and apoptosis. Apoptosis in EFT cells by EGCG correlated with altered expression of Bcl-2 family proteins, including increased expression of proapoptotic Bax and decreased expression of prosurvival Bcl2, Bcl-XL, and Mcl-1 proteins. Our results provide further evidence that IGFIR is an attractive therapeutic target in EFTs and that EGCG is an effective inhibitor of this receptor tyrosine kinase. EGCG may be a useful agent for targeting IGFIR, either alone or in combination, with other potentially more toxic IGFIR inhibitors for the management of EFTs. Mol Cancer Ther; 9(5); 1396–407. ©2010 AACR.
Data from Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid
Authors: Domhan Sophie , Muschal Stefan , Schwager Christian , Morath Christian , Wirkner Ute , Ansorge Wilhelm , Maercker Christian , Zeier Martin , Huber Peter E. , Abdollahi Amir
Published: April 2023

Abstract
The relative risk for the development of malignancies following solid organ transplantation seems to be decreased in patients treated with the immunosuppressive agent mycophenolic acid (MPA). However, the molecular mechanisms of the antineoplastic effects of MPA are not completely understood. Here, we report that human endothelial cells and fibroblasts are highly sensitive to MPA treatment. We found that U87 glioblastoma cells were resistant to MPA treatment in vitro. However, U87 tumor growth was markedly inhibited in vivo in BALB/c nude mice, suggesting that MPA exerted its antitumor effects via modulation of the tumor microenvironment. Accordingly, microvascular density and pericyte coverage were markedly reduced in MPA-treated tumors in vivo. Using functional in vitro assays, we showed that MPA potently inhibited endothelial cell and fibroblast proliferation, invasion/migration, and endothelial cell tube formation. To identify the genetic participants governing the antiangiogenic and antifibrotic effects of MPA, we performed genome-wide transcriptional analysis in U87, endothelial and fibroblast cells at 6 and 12 h after MPA treatment. Network analysis revealed a critical role for MYC signaling in endothelial cells treated with MPA. Moreover, we found that the antiangiogenic effects of MPA were organized by coordinated communications between MYC and NDRG1, YYI, HIF1A, HDAC2, CDC2, GSK3B, and PRKACB signaling. The regulation of these “hub nodes” was confirmed by real-time quantitative reverse transcription-PCR and protein analysis. The critical involvement of MYC in the antiangiogenic signaling of MPA was further shown by gene knockdown experiments. Together, these data provide a molecular basis for the antiangiogenic and antifibrotic effects of MPA, which warrants further clinical investigations. [Mol Cancer Ther 2008;7(6):1656–68]
Data from Anticancer activity of targeted proapoptotic peptides and chemotherapy is highly improved by targeted cell surface calreticulin–inducer peptides
Authors: Obeid Michel
Published: April 2023

Abstract
We have recently identified (a) ectocalreticulin as the main source of immunogenicity of cancer cell death induced by chemotherapy or radiotherapy, (b) ectoERP57 as critical protein for inducing cell surface exposure of calreticulin, and (c) that ectoERP57 and ectocalreticulin are cotranslocated together to the tumor cell surface by the mediator of the inhibition of PP1/GADD34 complex. Here, I report that the immunogenicity of cancer cell death induced by anticancer targeted proapoptotic peptides is also dictated by ectocalreticulin. To improve the anticancer activity of these proapoptotic peptides, I have designed several targeted chimeric inhibitor peptides of the PP1/GADD34 complex, which are comprised of an inhibitor peptide of the PP1/GADD34 complex fused to a protein transduction domain-5, to prostate homing peptide, or to the tumor antigen BiP/GRP78-binding peptide motifs. These inhibitor peptides (a) induce ectocalreticulin and ectoERP57 in a variety of tumor cell lines by the mediator of the inhibition of the interaction between PP1 and GADD34, (b) increase the phagocytosis of anticancer targeted proapoptotic peptide-treated tumor cells by dendritic cells, and (c) improve highly the anticancer activity of proapoptotic peptides and chemotherapy by suppressing or reducing the tumor growth in several isogenic mouse models of colon, mammary, and fibrosarcoma tumors and by increasing the lifespan of transgenic adenocarcinoma mouse prostate mice. These results suggest (a) that the inhibition of PP1/GADD34 complex is a key element to improve the anticancer activity of targeted proapoptotic peptides and chemotherapy and (b) that these targeted peptides combination approach could serve as a new powerful autonomous anticancer therapy. [Mol Cancer Ther 2009;8(9):2693–707]
Data from Sensitization to Radiation and Alkylating Agents by Inhibitors of Poly(ADP-ribose) Polymerase Is Enhanced in Cells Deficient in DNA Double-Strand Break Repair
Authors: Löser Dana A. , Shibata Atsushi , Shibata Akiko K. , Woodbine Lisa J. , Jeggo Penny A. , Chalmers Anthony J.
Published: April 2023

Abstract
As single agents, chemical inhibitors of poly(ADP-ribose) polymerase (PARP) are nontoxic and have clinical efficacy against BRCA1- and BRCA2-deficient tumors. PARP inhibitors also enhance the cytotoxicity of ionizing radiation and alkylating agents but will only improve clinical outcomes if tumor sensitization exceeds effects on normal tissues. It is unclear how tumor DNA repair proficiency affects the degree of sensitization. We have previously shown that the radiosensitizing effect of PARP inhibition requires DNA replication and will therefore affect rapidly proliferating tumors more than normal tissues. Because many tumors exhibit defective DNA repair, we investigated the impact of double-strand break (DSB) repair integrity on the sensitizing effects of the PARP inhibitor olaparib. Sensitization to ionizing radiation and the alkylating agent methylmethane sulfonate was enhanced in DSB repair–deficient cells. In Artemis−/− and ATM−/− mouse embryo fibroblasts, sensitization was replication dependent and associated with defective repair of replication-associated damage. Radiosensitization of Ligase IV−/− mouse embryo fibroblasts was independent of DNA replication and is explained by inhibition of "alternative" end joining. After methylmethane sulfonate treatment, PARP inhibition promoted replication-independent accumulation of DSB, repair of which required Ligase IV. Our findings predict that the sensitizing effects of PARP inhibitors will be more pronounced in rapidly dividing and/or DNA repair defective tumors than normal tissues and show their potential to enhance the therapeutic ratio achieved by conventional DNA-damaging agents. Mol Cancer Ther; 9(6); 1775–87. ©2010 AACR.
Data from Cucurbitacin I Suppressed Stem-Like Property and Enhanced Radiation-Induced Apoptosis in Head and Neck Squamous Carcinoma–Derived CD44+ALDH1+ Cells
Authors: Chen Yi-Wei , Chen Kuan-Hsuan , Huang Pin-I , Chen Yu-Chih , Chiou Guang-Yu , Lo Wen-Liang , Tseng Ling-Ming , Hsu Han-Sui , Chang Kuo-Wei , Chiou Shih-Hwa
Published: April 2023

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer worldwide. Signal transducers and activators of transcription 3 (STAT3) signaling is reported to promote tumor malignancy and recurrence in HNSCC. Cucurbitacins, triterpenoid derivatives, are strong STAT3 inhibitors with anticancer properties. Recent studies have shown aldehyde dehydrogenase 1 (ALDH1) to be a marker of cancer stem cells (CSC) in HNSCC. The aim of this study was to investigate the therapeutic effect of cucurbitacin I in HNSCC-derived CSCs. Using immunohistochemical analysis, we firstly showed that CD44, ALDH1, and phosphorylated STAT3 (p-STAT3) were higher in high-grade HNSCCs, and that triple positivity for CD44/ALDH1/p-STAT3 indicated a worse prognosis for HNSCC patients. Secondly, CD44+ALDH1+ cells isolated from seven HNSCC patients showed greater tumorigenicity, radioresistance, and high expression of stemness (Bmi-1/Oct-4/Nanog) and epithelial-mesenchymal-transitional (Snail/Twist) genes as p-STAT3 level increased. Furthermore, we found that cucurbitacin I (JSI-124) can effectively inhibit the expression of p-STAT3 and capacities for tumorigenicity, sphere formation, and radioresistance in HNSCC-CD44+ALDH1+. Notably, 150 nmol/L cucurbitacin I effectively blocked STAT3 signaling and downstream survivin and Bcl-2 expression, and it induced apoptosis in HNSCC-CD44+ALDH1+. Moreover, microarray data indicated that 100 nmol/L cucurbitacin I facilitated CD44+ALDH1+ cells to differentiate into CD44−ALDH1− and enhanced the radiosensitivity of HNSCC-CD44+ALDH1+. Xenotransplant experiments revealed that cucurbitacin I combined with radiotherapy significantly suppressed tumorigenesis and lung metastasis and further improved the survival rate in HNSCC-CD44+ALDH1+-transplanted immunocompromised mice. Taken together, our data show that cucurbitacin I, STAT3 inhibitor, reduces radioresistant, distant-metastatic, and CSC-like properties of HNSCC-CD44+ALDH1+ cells. The potential of cucurbitacin I as a radiosensitizer should be verified in future anti-CSC therapy. Mol Cancer Ther; 9(11); 2879–92. ©2010 AACR.
Data from The Novel Tryptamine Derivative JNJ-26854165 Induces Wild-Type p53- and E2F1-Mediated Apoptosis in Acute Myeloid and Lymphoid Leukemias
Authors: Kojima Kensuke , Burks Jared K. , Arts Janine , Andreeff Michael
Published: April 2023

Abstract
The development of small-molecule activators of p53 is currently focused on malignancies containing a wild-type p53 genotype, which is present in most leukemias. JNJ-26854165 is one such p53-activating agent, but its mechanism of action remains to be elucidated. Here, we report the effects of JNJ-26854165 in acute leukemias. JNJ-26854165 treatment induced p53-mediated apoptosis in acute leukemia cells with wild-type p53, in which p53 rapidly drives transcription-independent apoptosis followed by activation of a transcription-dependent pathway. JNJ-26854165 accelerated the proteasome-mediated degradation of p21 and antagonized the transcriptional induction of p21 by p53. Interestingly, JNJ-26854165 induced S-phase delay and upregulated E2F1 expression in p53 mutant cells, resulting in apoptosis preferentially of S-phase cells. E2F1 knockdown blocked apoptosis induced by JNJ-26854165 in p53 mutant cells. Apoptotic activity of JNJ-26854165 against primary acute leukemia cells was maintained in leukemia/stroma cocultures, unlike doxorubicin, which has reduced cytrotoxicity in coculture systems. JNJ-26854165 synergizes with 1-β-arabinofuranosylcytosine or doxorubicin to induce p53-mediated apoptosis. Our data suggest that JNJ-26854165 may provide a novel therapeutic approach for the treatment of acute leukemias. The presence of p53-independent apoptotic activity in addition to p53-mediated apoptosis induction, if operational in vivo, may prevent the selection of p53 mutant subclones during therapy. Mol Cancer Ther; 9(9); 2545–57. ©2010 AACR.
Data from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor
Authors: Parry David , Guzi Timothy , Shanahan Frances , Davis Nicole , Prabhavalkar Deepa , Wiswell Derek , Seghezzi Wolfgang , Paruch Kamil , Dwyer Michael P. , Doll Ronald , Nomeir Amin , Windsor William , Fischmann Thierry , Wang Yaolin , Oft Martin , Chen Taiying , Kirschmeier Paul , Lees Emma M.
Published: April 2023

Abstract
Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC50 values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. Mol Cancer Ther; 9(8); 2344–53. ©2010 AACR.
Data from Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes
Authors: Shkreta Lulzim , Froehlich Ulrike , Paquet Éric R. , Toutant Johanne , Elela Sherif Abou , Chabot Benoit
Published: April 2023

Abstract
Inducing an apoptotic response is the goal of most current chemotherapeutic interventions against cancer. However, little is known about the effect of chemotherapeutic agents on the alternative splicing of apoptotic genes. Here, we have tested 20 of the mainstream anticancer drugs for their ability to influence the production of Bcl-x splice isoforms. We find that many drugs shift splicing toward the proapoptotic Bcl-xS splice variant in 293 cells. The drugs modulate splicing decisions most likely through signaling events because the splicing switch is not compromised by inhibiting de novo protein synthesis or the activity of caspases. Several drugs also shift Bcl-x splicing in cancer cell lines (MCF-7, HeLa, PC-3, PA-1, and SKOV-3), but the set of active drugs varies between cell lines. We also examined the effect of anticancer agents on the alternative splicing of 95 other human apoptotic genes in different cell lines. Almost every drug can alter a subset of alternative splicing events in each cell line. Although drugs of the same class often influence the alternative splicing of the same units in individual cell lines, these units differ considerably between cell lines, indicating cell line–specific differences in the pathways that control splicing. [Mol Cancer Ther 2008;7(6):1398–409]
Data from Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth
Authors: Takahashi Tetsuyuki , Uehara Hisanori , Bando Yoshimi , Izumi Keisuke
Published: April 2023

Abstract
Prostaglandin E2 (PGE2) plays a key role in osteolytic bone metastasis as well as roles in inflammation, cell growth, and tumor development. PGE2 exerts its effects by binding and activating E-prostanoid receptor (EP). In this study, we propose a new approach for blocking EP-mediated cell signaling using a soluble chimeric EP2 fragment. Mammalian expression vectors encoding several human EP2 cDNAs were introduced into 293 cells and the culture medium was tested for their function as a decoy receptor for PGE2. PGE2 binding assays revealed that culture medium containing the second extracellular region of EP2 (FuEP2/Ex2) had binding activity. FuEP2/Ex2 neutralized PGE2-induced cyclic AMP production, cyclic AMP–responsive element binding protein phosphorylation, and subsequent induction of cyclooxygenase-2, interleukin (IL)-1β, and IL-6 mRNAs. In human osteoblasts, this culture medium neutralized the induction of receptor activator of nuclear factor-κB ligand mRNA. A stable transfectant expressing FuEP2/Ex2 was established from human prostate cancer PC-3 cells (PC3-FuEP2/Ex2). PC3-FuEP2/Ex2 cells grew at similar rates to vector control cells under normal culture conditions, although PGE2-induced growth stimulation was suppressed. Intraosseous injection of PC3-FuEP2/Ex2 cells into the tibia of athymic nude mice revealed that the degrees of tumor growth and osteolysis were decreased compared with control cell-injected mice, with decreased osteoclasts and increased apoptotic cells. Furthermore, the cyclooxygenase-2, IL-1β, and IL-6 mRNA levels were reduced in the tumor lesions. These data suggest that FuEP2/Ex2 is useful for treating osteolytic bone metastasis and cancers that depend on EP signaling for their growth and development. [Mol Cancer Ther 2008;7(9):2807–16]
Data from Modulation of the expression of the invasion-suppressor CRMP-1 by cyclooxygenase-2 inhibition via reciprocal regulation of Sp1 and C/EBPα
Authors: Wu Cheng-Chung , Lin Jau-Chen , Yang Shuenn-Chen , Lin Chiu-Wen , Chen Jeremy J.W. , Shih Jin-Yuan , Hong Tse-Ming , Yang Pan-Chyr
Published: April 2023

Abstract
Collapsin response mediator protein-1 (CRMP-1) controls neural development and axonal growth but also acts as a cancer invasion suppressor. In this study, we investigated the transcriptional regulation of CRMP-1 expression. Using a serial deletion strategy, we identified a basal promoter region between nucleotides -100 and -180 in the 5′ flanking region of CRMP-1 (nucleotides -1,920 to +50) that contains multiple putative Sp1 and C/EBPα sites. Site-directed mutagenesis and deletion analysis revealed that the two C/EBPα sites, from nucleotides -122 to -133 and from nucleotides -101 to -113, are the most important regulatory elements. Gel-shift and antibody supershift assays showed that Sp1 protein was also present at this C/EBPα site, which overlaps with a Sp1 site. Overexpression of Sp1 decreased CRMP-1 promoter activity and protein expression, whereas overexpression of C/EBPα produced the opposite effect. Chromatin immunoprecipitation assays confirmed that Sp1 and C/EBPα compete for binding at the overlapping C/EBPα and Sp1 sites and reciprocally regulate CRMP-1 expression. Overexpression of cyclooxygenase-2 (COX-2) decreased CRMP-1 mRNA and protein expression. Conversely, the COX-2 inhibitor, celecoxib, induced a dose-dependent increase in CRMP-1 expression. COX-2 inhibition also decreased Sp1-DNA complex formation and inhibited cell invasion. We conclude that transcription of the invasion suppressor, CRMP-1, is reciprocally regulated at the promoter region by C/EBPα and Sp1. COX-2 inhibitors increase CRMP-1 expression by inhibiting Sp1-DNA complex formation and enhancing DNA binding of C/EBPα at the promoter. [Mol Cancer Ther 2008;7(6):1365–75]
Direct Integration of Perovskite Solar Cells with Carbon Fiber Substrates
Authors: Game Onkar S. , Thornber Timothy , Cepero‐Mejías Fernando , Infante‐Ortega Luis C. , Togay Mustafa , Cassella Elena J. , Kilbride Rachel C. , Gordon Robert H. , Mullin Nic , Greenhalgh Rachael C. , Isherwood Patrick J. M. , Walls J. Michael , Fairclough J. Patrick A. , Lidzey David G.
Published: April 2023

Integrating photovoltaic devices onto the surface of carbon‐fiber‐reinforced polymer substrates should create materials with high mechanical strength that are also able to generate electrical power. Such devices are anticipated to find ready applications as structural, energy‐harvesting systems in both the automotive and aeronautical sectors. Here, the fabrication of triple‐cation perovskite n–i–p solar cells onto the surface of planarized carbon‐fiber‐reinforced polymer substrates is demonstrated, with devices utilizing a transparent top ITO contact. These devices also contain a “wrinkled” SiO2 interlayer placed between the device and substrate that alleviates thermally induced cracking of the bottom ITO layer. Devices are found to have a maximum stabilized power conversion efficiency of 14.5% and a specific power (power per weight) of 21.4 W g−1 (without encapsulation), making them highly suitable for mobile power applications.
Synthesis of 4‐Phosphinylpyrrolidin‐3‐ones via [3+2] Cycloaddition of Nitrones with Phosphinylallenes
Authors: Hammami Rayhane , Maldivi Pascale , Philouze Christian , Carret Sébastien , Darses Benjamin , Touil Soufiane , Poisson Jean‐François
Published: April 2023

A variety of 4‐phosphinylpyrrolidin‐3‐ones was prepared via a [3+2] cycloaddition between aryl aldonitrones and phosphinylallenes. The products were isolated as unique 4,5‐trans diastereomers, in yields between 47% and 80%, over 23 examples. In the case of chiral racemic allenes, a 2:1 to 4:1 moderate 2,5‐diastereoselectivity was observed. Under the reaction conditions, the cycloadducts directly undergo a rearrangement to afford selectively the corresponding pyrrolidin‐3‐ones. DFT calculations provide some insights into the mechanism, involving the homolytic cleavage of the N−O bond of the cycloadduct.

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Influence of Fe2O3‐FeS on the structure of iron‐containing clusters in aluminosilicate melts
Authors: Baoliang Xia , Facun Jiao , Lirui Mao , Yuanchun Zhang , Ying Xie , Hanxu Li
Published: April 2023

Iron compounds addition on the melt is a more complex issue. Uncertainties in industrial applications are caused by crystallization and depolymerization phenomena. Most of the current studies have discussed FeO and Fe2O3, ignoring the influence of FeS in the glass structure. This study designed and simulated artificial ash close to coal ash to interact with the glass melt at high temperatures. Coulomb titration, X‐ray diffraction (XRD), and Raman analyses were carried out to determine the percentage and composition of crystalline and noncrystalline materials in the glass. Samples of FeS‐Fe2O3 were subjected to the enumeration of the glass structure and quantitative calculations of the degree of polymerization. The results showed that 15‐wt% Fe2O3 promoted crystallization in the system and accelerates the depolymerization of FeS. The introduction of FeS increases the amorphous materials, and the obtained amorphous materials are Si dominated network structures and [SiO4]‐[FeO4]‐[SiO4] clusters. The network tends to change from [FeOn] and [AlO4] to [SiO4]. In addition, aluminosilicate may enter FeS particles and unreacted FeS may deposit on the aluminosilicate surface.
Impact of COVID‐19 on percutaneous coronary intervention utilization and mortality in New York
Authors: Hannan Edward L. , Zhong Ye , Cozzens Kimberly , Osinaga Alda , Efferen Linda , Jacobs Alice K. , Ling Frederick S. K. , Gary Walford , Venditti Ferdinand J. , Berger Peter B. , Tamis‐Holland Jacqueline , King Spencer B.
Published: April 2023

Background

COVID‐19 has disrupted the care of all patients, and little is known about its impact on the utilization and short‐term mortality of percutaneous coronary intervention (PCI) patients, particularly nonemergency patients.

Methods

New York State's PCI registry was used to study the utilization of PCI and the presence of COVID‐19 in four patient subgroups ranging in severity from ST‐elevation myocardial infarction (STEMI) to elective patients before (December 01, 2018–February 29, 2020) and during the COVID‐19 era (March 01, 2020–May 31, 2021), as well as to examine the impact of different COVID severity levels on the mortality of different types of PCI patients.

Results

Decreases in the mean quarterly PCI volume from the prepandemic period to the first quarter of the pandemic ranged from 20% for STEMI patients to 61% for elective patients, with the other two subgroups having decreases in between these values. PCI quarterly volume rebounds from the prepandemic period to the second quarter of 2021 were in excess of 90% for all patient subgroups, and 99.7% for elective patients. Existing COVID‐19 was rare among PCI patients, ranging from 1.74% for STEMI patients to 3.66% for elective patients. PCI patients with COVID‐19 and acute respiratory distress syndrome (ARDS) who were not intubated, and PCI patients with COVID‐19 and ARDS who were either intubated or were not intubated because of Do Not Resuscitate//Do Not Intubate status had higher risk‐adjusted mortality ([adjusted ORs = 10.81 [4.39, 26.63] and 24.53 [12.06, 49.88], respectively]) than patients who never had COVID‐19.

Conclusions

There were large decreases in the utilization of PCI during COVID‐19, with the percentage of decrease being highly sensitive to patient acuity. By the second quarter of 2021, prepandemic volumes were nearly restored for all patient subgroups. Very few PCI patients had current COVID‐19 throughout the pandemic period, but the number of PCI patients with a COVID‐19 history increased steadily during the pandemic. PCI patients with COVID‐19 accompanied by ARDS were at much higher risk of short‐term mortality than patients who never had COVID‐19. COVID‐19 without ARDS and history of COVID‐19 were not associated with higher mortality for PCI patients as of the second quarter of 2021.
Excited State Processes in Supramolecular Complexes of Cyclic Dibenzopyrrolopyrrole Isomers with C60 Fullerene
Authors: George Gibu , Stasyuk Olga. A. , Voityuk Alexander A. , Stasyuk Anton J. , Solà Miquel
Published: April 2023

An approach to modulating the properties of carbon nanorings by incorporating pyrrolo[3,2‐b]pyrrole units is of particular interest due to the combined effect of heteroatom and antiaromatic character on electronic properties. The inclusion of units other than phenylene leads to the formation of stereoisomers. In this work, we computationally study how the spatial orientation of monomeric units in the ring affects the properties of cyclic dibenzopyrrolo[3,2‐b]pyrroles and their complexes with C60 fullerene. For [4]PP and [4]DHPP, the most symmetrical AAAA isomer is the most stable and forms stronger interactions with fullerene than the isomers where one or two monomeric units are flipped, mostly due to less Pauli repulsion. π‐Electron delocalization in the monomeric unit is crucial for directing the electron transfer (from or to nanoring). The energy of excited states with charge transfer depends on the HOMO–LUMO gap, which varies from one stereoisomer to another only for [4]DHPP⊃C60 with aromatic 1,4‐dihydropyrrolo[3,2‐b]pyrrole units. The rates of electron transfer and charge recombination reactions are relatively weakly dependent of the spatial isomerism of nanorings.
Associations between household income and disordered eating differ across sex and racial identity in a population‐based sample of adults
Authors: Mikhail Megan E. , Ackerman Lindsay S. , Anaya Carolina , Culbert Kristen M. , Burt S. Alexandra , Klump Kelly L.
Published: April 2023

Background

Most research on socioeconomic status (SES) and eating disorders (EDs) has focused on young White women. Consequently, little is known regarding how SES may relate to EDs/disordered eating in older adults, men, or people with different racial identities. We examined whether associations between SES and EDs/disordered eating differed across age, sex, and racial identity in a large, population‐based sample spanning early‐to‐later adulthood.

Methods

Analyses included 2797 women and 2781 men ages 18–65 (Mage = 37.41, SD = 7.38) from the population‐based Michigan State University Twin Registry. We first examined associations between SES and dimensional ED symptoms, binge eating (BE), and self‐reported ED diagnoses across age and sex in the full sample. We then examined the impact of racial identity on associations by conducting within‐ and between‐group analyses among Black and White participants.

Results

In the full sample, lower SES was associated with significantly greater odds of BE and lifetime EDs in men, but not women, across adulthood. The association between lower SES and greater BE risk was stronger for Black men than for White men, though significant in both groups. Conversely, Black women showed a positive association between SES and dimensional ED symptoms that significantly differed from effects for Black men and White women.

Conclusions

Associations between socioeconomic disadvantage and EDs/disordered eating may be particularly robust for men in adulthood, especially men with a marginalized racial identity. Oppositely, Black women may encounter social pressures and minority stress in higher SES environments that could contribute to somewhat heightened ED risk.

Public Significance

Little is known regarding how associations between socioeconomic status (SES) and eating disorders (EDs) may differ across age/sex or racial identity. We found lower SES was associated with greater odds of a lifetime ED or binge eating in men only, with a particularly strong association between lower SES and binge eating for Black men. Results highlight the importance of examining how SES‐ED associations may differ across other aspects of identity.
Cheilolejeunea zhui (Lejeuneaceae, Marchantiophyta), a new species with moniliate ocelli from Guangxi, China
Authors: Wei Yu‐Mei , Ye Wen , Ho Boon‐Chuan , Tang Qi‐Ming , Harris AJ
Published: April 2023

A new ocellate liverwort species, Cheilolejeunea zhui (Lejeuneaceae), is described from Guangxi, China. The new species is similar to the neotropical C. urubuensis in having moniliate ocelli in the leaf lobes and in general appearances but differs in having obliquely spreading leaves, obtuse to subacute leaf apex, thin‐walled leaf cells with distinct trigones, shallowly bifid female bracteole apex, and numerous ocelli in its perianths. Molecular phylogeny of data from three regions (nrITS, trnL–F, and trnG) confirmed the systematic position of this new species to be sister to C. urubuensis, well apart from the remaining members of the genus. Based on morphological and molecular evidence, Cheilolejeunea sect. Moniliocella sect. nov. is proposed to accommodate C. urubuensis and C. zhui. The discovery of C. zhui represents the fourth known species in Cheilolejeunea with linearly arranged ocelli.
Intraspecific trait plasticity to N and P of the wetland invader, Alternanthera philoxeroides under flooded conditions
Authors: Harms Nathan E. , Knight Ian A. , DeRossette A. Blake , Williams Dean A.
Published: April 2023

Interactions between invaders and resource availability may explain variation in their success or management efficacy. For widespread invaders, regional variation in plant response to nutrients can reflect phenotypic plasticity of the invader, genetic structure of invading populations, or a combination of the two. The wetland weed Alternanthera philoxeroides (alligatorweed) is established throughout the southeastern United States and California and has high genetic diversity despite primarily spreading clonally. Despite its history in the United States, the role of genetic variation for invasion and management success is only now being uncovered. To better understand how nutrients and genotype may influence A. philoxeroides invasion, we measured the response of plants from 26 A. philoxeroides populations (three cp haplotypes) to combinations of nitrogen (4 or 200 mg/L N) and phosphorus (0.4 or 40 mg/L P). We measured productivity (biomass accumulation and allocation), plant architecture (stem diameter and thickness, branching intensity), and foliar traits (toughness, dry matter content, percent N, and percent P). A short‐term developmental assay was also conducted by feeding a subset of plants from the nutrient experiment to the biological control agent Agasicles hygrophila, to determine whether increased availability of N or P to its host influenced agent performance, as has been previously suggested. Alternanthera philoxeroides haplotype Ap1 was more plastic than other haplotypes in response to nutrient amendments, producing more than double the biomass from low to high N and 50%–68% higher shoot: root ratio than other haplotypes in the high N treatment. Alternanthera philoxeroides haplotypes differed in seven of 10 variables in response to increased N. We found no differences in short‐term A. hygrophila development between haplotypes but mass was 23% greater in high than low N treatments. This study is the first to explore the interplay between nutrient availability, genetic variation, and phenotypic plasticity in invasive characteristics of the global invader, A. philoxeroides.
Prescribed fire alters nematode communities in an old‐field grassland
Authors: Song Min , McDaniel Marshall D. , Zhu Chen , Lin Feng , Zhang Yaojun
Published: April 2023

Fire is a common disturbance in many biomes, with both beneficial and detrimental effects on soil biology, which largely depend on fire intensity. However, little is known about the impact of fire on soil nematode communities in terrestrial ecosystem. In the present study, we investigated the effects of short‐term prescribed fire on soil nematode communities and soil properties in an old‐field grassland in Northern China. The results showed that burning significantly increased soil nematode abundance by 77% and genus richness by 49% compared to the control. Burning also decreased taxon dominance by 45% (Simpson's D) and increased nematode diversity by 31% (Shannon‐Weaver H'). However, burning increased plant parasites (particularly genera Cephalenchus and Pratylenchus) and shifted community to more bacterial‐feeding genera (i.e., decreased Channel Index). Generally, burning increased soil bio‐available nitrogen (NH4+–N and NO3−–N) content, which would be the main drivers causing nematode community to flourish via a “bottom‐up” effect. These results suggest that prescribed fire increases nematode diversity and alters community composition toward more plant parasites and bacterial feeders. Our findings highlight the importance of prescribed fire management in shaping short‐term nematode community structure and function, but the long‐term effects and impacts of these changes on soil nutrient and carbon cycling remain unknown.
View cells in the hippocampus and prefrontal cortex of macaques during virtual navigation
Authors: Corrigan Benjamin W. , Gulli Roberto A. , Doucet Guillaume , Mahmoudian Borna , Abbass Mohamad , Roussy Megan , Luna Rogelio , Sachs Adam J. , Martinez‐Trujillo Julio C.
Published: April 2023

Cells selectively activated by a particular view of an environment have been found in the primate hippocampus (HPC). Whether view cells are present in other brain areas, and how view selectivity interacts with other variables such as object features and place remain unclear. Here, we explore these issues by recording the responses of neurons in the HPC and the lateral prefrontal cortex (LPFC) of rhesus macaques performing a task in which they learn new context‐object associations while navigating a virtual environment using a joystick. We measured neuronal responses at different locations in a virtual maze where animals freely directed gaze to different regions of the visual scenes. We show that specific views containing task relevant objects selectively activated a proportion of HPC units, and an even higher proportion of LPFC units. Place selectivity was scarce and generally dependent on view. Many view cells were not affected by changing the object color or the context cue, two task relevant features. However, a small proportion of view cells showed selectivity for these two features. Our results show that during navigation in a virtual environment with complex and dynamic visual stimuli, view cells are found in both the HPC and the LPFC. View cells may have developed as a multiarea specialization in diurnal primates to encode the complexities and layouts of the environment through gaze exploration which ultimately enables building cognitive maps of space that guide navigation.