bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Depletion of the Ras Association Domain Family 1, Isoform A–Associated Novel Microtubule-Associated Protein, C19ORF5/MAP1S, Causes Mitotic Abnormalities
Authors: Dallol Ashraf , Cooper Wendy N. , Al-Mulla Fahd , Agathanggelou Angelo , Maher Eamonn R. , Latif Farida
Published: March 2023

Abstract
Ras association domain family 1, isoform A (RASSF1A) is a novel tumor suppressor gene that is found to be inactivated in more than 40 types of sporadic cancers. In addition, mouse Rassf1a knockout models have an increased frequency of spontaneous and induced tumors. The mechanisms by which RASSF1A exerts its tumor suppression activities or the pathways it can regulate are not yet fully understood. Using yeast two-hybrid system, we have previously identified C19ORF5/MAP1S as the major RASSF1A-interacting protein. C19ORF5 has two conserved microtubule-associated regions and may function to anchor RASSF1A to the centrosomes. In this study, we have analyzed the cellular functions of C19ORF5. By using small interfering RNA–mediated depletion and time-lapse video microscopy, we show that C19ORF5 knockdown causes mitotic abnormalities that consist of failure to form a stable metaphase plate, premature sister chromatid separation, lagging chromosomes, and multipolar spindles. We also show that a fraction of C19ORF5 localizes to the spindle microtubules. Additionally, we show here that C19ORF5 localizes to the microtubule-organizing centers during microtubule regrowth after nocodazole washout. Knockdown of C19ORF5 disrupts the microtubule-organizing center and results in microtubule nucleation from several sites. Whereas the localization of pericentrin is not affected, α- and γ-tubulin localization and sites of nucleation are greatly altered by C19ORF5 depletion. This may indicate that C19ORF5 plays a role in anchoring the microtubule-organizing center to the centrosomes. In addition, we show that the NH2 terminus of C19ORF5 is essential for this process. This novel role for C19ORF5 could explain the resulting mitotic abnormalities that occur on its depletion and can potentially provide an underlying mechanism for the frequent centrosome and microtubule abnormalities detected in several cancers. [Cancer Res 2007;67(2):492–500]
Data from Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates
Authors: Gius David , Funk Margo C. , Chuang Eric Y. , Feng Sheng , Huettner Phyllis C. , Nguyen Loan , Bradbury C. Matthew , Mishra Mark , Gao Shuping , Buttin Barbara M. , Cohn David E. , Powell Matthew A. , Horowitz Neil S. , Whitcomb Bradford P. , Rader Janet S.
Published: March 2023

Abstract
This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions. [Cancer Res 2007;67(15):7113–23]
Data from Gene Expression Profiling of Childhood Adrenocortical Tumors
Authors: West Alina Nico , Neale Geoffrey A. , Pounds Stanley , Figueredo Bonald C. , Rodriguez Galindo Carlos , Pianovski Mara Albonei D. , Oliveira Filho Antonio G. , Malkin David , Lalli Enzo , Ribeiro Raul , Zambetti Gerard P.
Published: March 2023

Abstract
Pediatric adrenocortical tumors (ACT) are rare and often fatal malignancies; little is known regarding their etiology and biology. To provide additional insight into the nature of ACT, we determined the gene expression profiles of 24 pediatric tumors (five adenomas, 18 carcinomas, and one undetermined) and seven normal adrenal glands. Distinct patterns of gene expression, validated by quantitative real-time PCR and Western blot analysis, were identified that distinguish normal adrenal cortex from tumor. Differences in gene expression were also identified between adrenocortical adenomas and carcinomas. In addition, pediatric adrenocortical carcinomas were found to share similar patterns of gene expression when compared with those published for adult ACT. This study represents the first microarray analysis of childhood ACT. Our findings lay the groundwork for establishing gene expression profiles that may aid in the diagnosis and prognosis of pediatric ACT, and in the identification of signaling pathways that contribute to this disease. [Cancer Res 2007;67(2):600–8]
Data from Caveolin-1 Reduces Osteosarcoma Metastases by Inhibiting c-Src Activity and Met Signaling
Authors: Cantiani Lara , Manara Maria Cristina , Zucchini Cinzia , De Sanctis Paola , Zuntini Monia , Valvassori Luisa , Serra Massimo , Olivero Martina , Di Renzo Maria Flavia , Colombo Mario Paolo , Picci Piero , Scotlandi Katia
Published: March 2023

Abstract
Caveolin-1 (Cav-1) is highly expressed in normal osteoblasts. This article reports that Cav-1 down-regulation is part of osteoblast transformation and osteosarcoma progression and validates its role as oncosuppressor in human osteosarcoma. A survey of 6-year follow-up indicates a better overall survival for osteosarcoma expressing a level of Cav-1 similar to osteoblasts. However, the majority of primary osteosarcoma shows significantly lower levels of Cav-1 than normal osteoblasts. Accordingly, Met-induced osteoblast transformation is associated with Cav-1 down-regulation. In vitro, osteosarcoma cell lines forced to overexpress Cav-1 show reduced malignancy with inhibited anchorage-independent growth, migration, and invasion. In vivo, Cav-1 overexpression abrogates the metastatic ability of osteosarcoma cells. c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, colocalize with Cav-1 and are inhibited on Cav-1 overexpression. Thus, Cav-1 behaves as an oncosuppressor in osteosarcoma. Altogether, data suggest that Cav-1 down-modulation might function as a permissive mechanism, which, by unleashing c-Src and Met signaling, enables osteosarcoma cells to invade neighboring tissues. These data strengthen the rationale to target c-Src family kinases and/or Met receptor to improve the extremely poor prognosis of metastatic osteosarcoma. [Cancer Res 2007;67(16):7675–85]
Data from Tripeptidyl-peptidase II Controls DNA Damage Responses and In vivo γ-Irradiation Resistance of Tumors
Authors: Hong Xu , Lei Lu , Künert Brita , Naredla Rajender , Applequist Steven E. , Grandien Alf , Glas Rickard
Published: March 2023

Abstract
Cellular responses to γ-irradiation exposure are controlled by phosphatidylinositol 3-kinase–related kinases (PIKK) in the nucleus, and in addition, cytosolic PIKKs may have a role in such responses. Here, we show that the expression of tripeptidyl-peptidase II (TPPII), a high molecular weight cytosolic peptidase, required PIKK signaling and that TPPII was rapidly translocated into the nucleus of γ-irradiated cells. These events were dependent on mammalian target of rapamycin, a cytosolic/mitochondrial PIKK that is activated by γ-irradiation. Lymphoma cells with inhibited expression of TPPII failed to efficiently stabilize p53 and had reduced ability to arrest proliferation in response to γ-irradiation. We observed that TPPII contains a BRCA COOH-terminal–like motif, contained within sequences of several proteins involved in DNA damage signaling pathways, and this motif was important for nuclear translocation of TPPII and stabilization of p53. Novel tripeptide-based inhibitors of TPPII caused complete in vivo tumor regression in mice in response to relatively low doses of γ-irradiation (3–4 Gy/wk). This was observed with established mouse and human tumors of diverse tissue backgrounds, with no tumor regrowth after cancellation of treatment. These TPPII inhibitors had minor effects on tumor growth as single agent and had low cellular toxicity. Our data indicated that TPPII connects signaling by cytosolic/mitochondrial and nuclear PIKK-dependent pathways and that TPPII can be targeted for inhibition of tumor therapy resistance. [Cancer Res 2007;67(15):7165–74]
Data from Differential Regulation of Hypoxia-Induced CXCR4 Triggering during B-Cell Development and Lymphomagenesis
Authors: Piovan Erich , Tosello Valeria , Indraccolo Stefano , Masiero Massimo , Persano Luca , Esposito Giovanni , Zamarchi Rita , Ponzoni Maurilio , Chieco-Bianchi Luigi , Dalla-Favera Riccardo , Amadori Alberto
Published: March 2023

Abstract
The chemokine receptor CXCR4 plays a central role in organ-specific homing and tumor spreading and is induced by hypoxia. B lymphocytes are exposed to low oxygen tensions during their development, but the influence of hypoxia on their physiology is poorly understood. Here, we show that hypoxia is associated with up-regulation of CXCR4 expression in human normal and malignant B cells, through both transcriptional and posttranslational mechanisms. However, a dichotomic functional response to CXCR4 triggering was observed: both peripheral B cells and lymphomas arising from mature B cells displayed increased responses to CXCR4 triggering under hypoxia, whereas germinal center (GC) B cells as well as GC-derived lymphomas showed CXCR4 receptor desensitization. This phenomenon was associated with differential modulation of key signal-transducing molecules, including mitogen-activated protein kinase phosphatase-1 and regulator of G protein signaling molecule-1. The unresponsiveness of GC-derived lymphomatous B cells to CXCR4 triggering under hypoxia may have implications for the development and pathogenesis of GC-derived lymphoid tumors. [Cancer Res 2007;67(18):8605–14]
Data from Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α5-Integrin, which Is a Therapeutic Target
Authors: Sawada Kenjiro , Mitra Anirban K. , Radjabi A. Reza , Bhaskar Vinay , Kistner Emily O. , Tretiakova Maria , Jagadeeswaran Sujatha , Montag Anthony , Becker Amy , Kenny Hilary A. , Peter Marcus E. , Ramakrishnan Vanitha , Yamada S. Diane , Lengyel Ernst
Published: March 2023

Abstract
E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of α5-integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an α5β1-integrin–blocking antibody. When E-cadherin is silenced, α5-integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1–mitogen-activated protein kinase–dependent signaling pathway and not through the canonical E-cadherin/β-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of α5-integrin, i.p. treatment with an α5β1-integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P < 0.0005). α5-Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had α5-integrin overexpression, and 39% had some level of α5-integrin expression. The median survival for patients with high α5-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified α5-integrin up-regulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients. [Cancer Res 2008;68(7):2329–39]
Data from c-myc Repression of TSC2 Contributes to Control of Translation Initiation and Myc-Induced Transformation
Authors: Ravitz Michael J. , Chen Li , Lynch Mary , Schmidt Emmett V.
Published: March 2023

Abstract
The c-myc oncogene plays a key role in cellular growth control, and translation initiation factors are among the transcriptional targets of Myc. Here, we describe a defect in translation initiation control in myc-null cells due to alterations in the mammalian target of rapamycin (mTOR) pathway. Myc loss increased sensitivity to dominant inhibition of eukaryotic translation initiation factor 4E function. Polysomal profiles of myc−/− cells revealed decreased translation initiation rates, which were accompanied by decreased 40S/60S ribosomal subunit ratios. Because the 40S small ribosomal subunit contains the key regulatory ribosomal protein S6 (rpS6), we considered that myc loss might affect expression of components of the mTOR signaling pathway that regulate rpS6 function. Among mTOR signaling components, Myc directly affected transcription of tuberous sclerosis 2 (TSC2), as shown by quantitative mRNA analysis and by Myc binding to its promoter in chromatin immunoprecipitation assays. Importantly, Myc acted as a strong and direct repressor for TSC2 expression because its loss increased TSC2 mRNA in myc-null and in HL60 shRNA experiments, activation of a mycER construct in myc−/− cells suppressed TSC2 induction in a myc box II–dependent manner, and mycER activation recruited Myc to the TSC2 promoter. The biological significance of the effect of Myc on TSC2 expression was shown by markedly reduced TSC2 mRNA levels in myc-transformed cells, stimulation of S6 kinase activity in myc-null cells by TSC2 siRNA, and decreased Myc-induced soft agar colony formation following retroviral transduction of TSC2. Together, these findings show that regulation of TSC2 can contribute to the effects of Myc on cell proliferation and neoplastic growth. [Cancer Res 2007;67(23):11209–17]
Data from Gene Amplification and Overexpression of PRDM14 in Breast Cancers
Authors: Nishikawa Noriko , Toyota Minoru , Suzuki Hiromu , Honma Toshio , Fujikane Tomoko , Ohmura Tousei , Nishidate Toshihiko , Ohe-Toyota Mutsumi , Maruyama Reo , Sonoda Tomoko , Sasaki Yasushi , Urano Takeshi , Imai Kohzoh , Hirata Koichi , Tokino Takashi
Published: March 2023

Abstract
Several genes that encode PR (PRDI-BF1 and RIZ) domain proteins (PRDM) have been linked to human cancers. To explore the role of the PR domain family genes in breast carcinogenesis, we examined the expression profiles of 16 members of the PRDM gene family in a panel of breast cancer cell lines and primary breast cancer specimens using semiquantitative real-time PCR. We found that PRDM14 mRNA is overexpressed in about two thirds of breast cancers; moreover, immunohistochemical analysis showed that expression of PRDM14 protein is also up-regulated. Analysis of the gene copy number revealed that PRDM14 is a target of gene amplification on chromosome 8q13, which is a region where gene amplification has frequently been detected in various human tumors. Introduction of PRDM14 into cancer cells enhanced cell growth and reduced their sensitivity to chemotherapeutic drugs. Conversely, knockdown of PRDM14 by siRNA induced apoptosis in breast cancer cells and increased their sensitivity to chemotherapeutic drugs, suggesting that up-regulated expression of PRDM14 may play an important role in the proliferation of breast cancer cells. That little or no expression of PRDM14 is seen in noncancerous tissues suggests that PRDM14 could be an ideal therapeutic target for the treatment of breast cancer. [Cancer Res 2007;67(20):9649–57]
Data from Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment
Authors: Augustine Christina K. , Yoshimoto Yasunori , Gupta Mukur , Zipfel Patricia A. , Selim M. Angelica , Febbo Phillip , Pendergast Ann Marie , Peters William P. , Tyler Douglas S.
Published: March 2023

Abstract
Malignant transformation in melanoma is characterized by a phenotype “switch” from E- to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherin–expressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma. [Cancer Res 2008;68(10):3777–84]
Data from Neuronal Differentiation and Synaptogenesis in Retinoblastoma
Authors: Johnson Dianna A. , Zhang Jiakun , Frase Sharon , Wilson Matthew , Rodriguez-Galindo Carlos , Dyer Michael A.
Published: March 2023

Abstract
Retinoblastomas initiate in the developing retina in utero and are diagnosed during the first few years of life. We have recently generated a series of knockout mouse models of retinoblastoma that recapitulate the timing, location, and progression of human retinoblastoma. One of the most important benefits of these preclinical models is that we can study the earliest stages of tumor initiation and expansion. This is not possible in human retinoblastoma because tumors initiate in utero and are not diagnosed until they are at an advanced stage. We found that mouse retinoblastoma cells exhibit a surprising degree of differentiation, which has not been previously reported for any neural tumor. Early-stage mouse retinoblastoma cells express proteins found normally in retinal plexiform layers. They also extend neurites and form synapses. All of these features, which were characterized by immunostaining, Golgi-Cox staining, scanning electron microscopy, and transmission electron microscopy, suggest that mouse retinoblastoma cells resemble amacrine/horizontal cells from the retina. As late-stage retinoblastoma cells expand and invade the surrounding tissue, they lose their differentiated morphology and become indistinguishable from human retinoblastomas. Taken together, our data suggest that neuronal differentiation is a hallmark of early-stage retinoblastoma and is lost as cells become more aggressive and invasive. We also show that rosette formation is not a hallmark of retinoblastoma differentiation, as previously believed. Instead, rosette formation reflects extensive cell-cell contacts between retinoblastoma cells in both early-stage (differentiated) and late-stage (dedifferentiated) tumors. [Cancer Res 2007;67(6):2701–11]
Data from RAD001 (Everolimus) Delays Tumor Onset and Progression in a Transgenic Mouse Model of Ovarian Cancer
Authors: Mabuchi Seiji , Altomare Deborah A. , Connolly Denise C. , Klein-Szanto Andres , Litwin Samuel , Hoelzle Matthew K. , Hensley Harvey H. , Hamilton Thomas C. , Testa Joseph R.
Published: March 2023

Abstract
The mammalian target of rapamycin (mTOR) is thought to play a critical role in regulating cell growth, cell cycle progression, and tumorigenesis. Because the AKT-mTOR pathway is frequently hyperactivated in ovarian cancer, we hypothesized that the mTOR inhibitor RAD001 (Everolimus) would inhibit ovarian tumorigenesis in transgenic mice that spontaneously develop ovarian carcinomas. We used TgMISIIR-TAg transgenic mice, which develop bilateral ovarian serous adenocarcinomas accompanied by ascites and peritoneal dissemination. Fifty-eight female TgMISIIR-TAg mice were treated with 5 mg/kg RAD001 or placebo twice weekly from 5 to 20 weeks of age. To monitor tumor development, mice were examined biweekly using magnetic resonance microimaging. In vivo effects of RAD001 on Akt-mTOR signaling, tumor cell proliferation, and blood vessel area were analyzed by immunohistochemistry and Western blot analysis. RAD001 treatment markedly delayed tumor development. Tumor burden was reduced by ∼84%. In addition, ascites formation, together with peritoneal dissemination, was detected in only 21% of RAD001-treated mice compared with 74% in placebo-treated animals. Approximately 30% of RAD001-treated mice developed early ovarian carcinoma confined within the ovary, whereas all placebo-treated mice developed advanced ovarian carcinoma. Treatment with RAD001 diminished the expression of vascular endothelial growth factor in tumor-derived cell lines and inhibited angiogenesis in vivo. RAD001 also attenuated the expression of matrix metalloproteinase-2 and inhibited the invasiveness of tumor-derived cells. Taken together, these preclinical findings suggest that mTOR inhibition, alone or in combination with other molecularly targeted drugs, could represent a promising chemopreventive strategy in women at high familial risk of ovarian cancer. [Cancer Res 2007;67(6):2408–13]
Data from An Anti–Transforming Growth Factor β Antibody Suppresses Metastasis via Cooperative Effects on Multiple Cell Compartments
Authors: Nam Jeong-Seok , Terabe Masaki , Mamura Mizuko , Kang Mi-Jin , Chae Helen , Stuelten Christina , Kohn Ethan , Tang Binwu , Sabzevari Helen , Anver Miriam R. , Lawrence Scott , Danielpour David , Lonning Scott , Berzofsky Jay A. , Wakefield Lalage M.
Published: March 2023

Abstract
Overexpression of transforming growth factor β (TGF-β) is frequently associated with metastasis and poor prognosis, and TGF-β antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti–TGF-β antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell–mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rae1γ) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-β expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-β antibodies reverse this effect, and the absence of a major effect of TGF-β antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications. [Cancer Res 2008;68(10):3835–43]
Data from Abnormal Cytokinesis after X-Irradiation in Tumor Cells that Override the G2 DNA Damage Checkpoint
Authors: Huang Haomin , Fletcher Lynda , Beeharry Neil , Daniel Rene , Kao Gary , Yen Tim J. , Muschel Ruth J.
Published: March 2023

Abstract
X-irradiation–induced DNA damage perturbs the G1, S, and G2 phases of the cell cycle. The behavior of cells after they have experienced a DNA damage checkpoint delay is poorly characterized. We therefore examined the fates of irradiated tumor cells that have overcome a prolonged G2 checkpoint delay. Most irradiated cells progressed through mitosis without significant delay, but failed to complete cytokinesis as they remained tethered to each other at the midbody. We observed that the movement of centrioles at the time of cytokinesis was impaired in the irradiated, bridged cells. We attribute the perturbation of centriole dynamics to the presence of chromatin bridges that spanned the daughter cells. The bridged cells exhibited different fates that included death, fusion that formed multinucleated cells, or another round of mitosis with no noticeable cell cycle delays. The presence of γH2AX foci in the bridge as well as in the separated nuclei indicated that cells were proliferating despite the presence of DNA damage. It seems that DNA damage checkpoints were not reactivated in cells that overrode a prolonged G2 delay. Cells deficient in ATM, H2AX, XRCC3, or ligase 4 exhibited a higher frequency of radiation-induced bridges than controls, suggesting that the DNA bridges resulted from inadequate DNA repair. These data show a previously unappreciated cytologic hallmark of DNA damage in dividing cells. Chromatin bridges that interfere with cytokinesis are likely to contribute to the replication failure and clonogenic death of cells exposed to irradiation. [Cancer Res 2008;68(10):3724–32]
Data from Involvement of the Leptin Receptor in the Immune Response in Intestinal Cancer
Authors: Aloulou Nijez , Bastuji-Garin Sylvie , Le Gouvello Sabine , Abolhassani Mohammad , Chaumette Marie Thérèse , Charachon Antoine , Leroy Karen , Sobhani Iradj
Published: March 2023

Abstract
The incidence of colorectal cancers (CRC) may be influenced by environmental factors, including nutrition. The role of peptides regulating food intake in controlling the growth and recurrence of human tumors is controversial. Leptin, a cytokine-like peptide, regulates food intake. We investigated the expression of leptin and its receptor in 171 consecutive patients (78 female and 93 male; 71 years) with CRC. Leptin concentrations in the serum (ELISA) were determined before tumor removal. ObRb was characterized in tumors and normal homologous tissues and culture cells (HT29, HCT116, and HCT116 with a transferred chromosome 3) by using immunocytochemistry, immunohistochemistry, reverse transcription-PCR (RT-PCR), and Western blotting. Microsatellite instability (MSI) phenotype was characterized by immunohistochemistry and pentaplex PCR. mRNAs of cytokines and chemokines were quantified in tumors and in normal homologous tissues (RT-PCR) in 43 patients. Adequate statistical tests, including multivariate analysis adjusted for pathologic tumor-node-metastasis (pTNM), MSI-H, and ObRb phenotypes, were used. Higher expression of ObRb in tumors compared with the homologous normal mucosa, pTNM staging but not leptin serum level, was associated with patients' progression-free survival (PFS). Tumor ObRb phenotype and pTNM were independent predictive factors of PFS. ObRb was more strongly expressed in HCT116 cells than in HCT116-Ch3 cells as well as in MSI-H tumors than in microsatellite stability and potentially associated with efficient cytotoxic antitumoral response as assessed by immunohistochemistry and RT-PCR measurements. We suggest that leptin receptor expression in tumors is involved in adaptive immune response in sporadic colon and rectal tumors likely via MSI-H phenotype orientation. [Cancer Res 2008;68(22):9413–22]
Supplementary Table S5 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riuye , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: March 2023

Adverse Events: Grade 3
Supplementary Table S1 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riuye , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: March 2023

Baseline advanced adenoma characteristics
Supplementary Figure S2 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riuye , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: March 2023

MUC1 expression and immune infiltrate in baseline and recurrent adenoma pairs
Data from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riuye , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: March 2023

AbstractPurpose:
To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation.
Patients and Methods:
Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.
Results:
Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9–17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60–1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15–1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events.
Conclusions:
An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.
Data from The Road to Personalized Myeloma Medicine: Patient-specific Single-domain Antibodies for Anti-idiotypic Radionuclide Therapy
Authors: Puttemans Janik , Stijlemans Benoit , Keyaerts Marleen , Vander Meeren Sam , Renmans Wim , Fostier Karel , Debie Pieterjan , Hanssens Heleen , Rodak Magdalena , Pruszynski Marek , De Veirman Kim , Vanderkerken Karin , Lahoutte Tony , Morgenstern Alfred , Bruchertseifer Frank , Devoogdt Nick , D'Huyvetter Matthias
Published: March 2023

Abstract
To this day, multiple myeloma remains an incurable cancer. For many patients, recurrence is unavoidably a result of lacking treatment options in the minimal residual disease stage. This is due to residual and treatment-resistant myeloma cells that can cause disease relapse. However, patient-specific membrane-expressed paraproteins could hold the key to target these residual cells responsible for disease recurrence. Here, we describe the therapeutic potential of radiolabeled, anti-idiotypic camelid single-domain antibody fragments (sdAbs) as tumor-restrictive vehicles against a membrane-bound paraprotein in the syngeneic mouse 5T33 myeloma model and analogously assess the feasibility of sdAb-based personalized medicine for patients with multiple myeloma. Llamas were immunized using extracts containing paraprotein from either murine or human sera, and selective sdAbs were retrieved using competitive phage display selections of immune libraries. An anti-5T33 idiotype sdAb was selected for targeted radionuclide therapy with the β−-particle emitter 177Lu and the α-particle emitter 225Ac. sdAb-based radionuclide therapy in syngeneic mice with a low 5T33 myeloma lesion load significantly delayed tumor progression. In five of seven patients with newly diagnosed myeloma, membrane expression of the paraprotein was confirmed. Starting from serum-isolated paraprotein, for two of three selected patients anti-idiotype sdAbs were successfully generated.
Table S1 from Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions
Authors: Silvestri Giovannino , Trotta Rossana , Stramucci Lorenzo , Ellis Justin J. , Harb Jason G. , Neviani Paolo , Wang Shuzhen , Eisfeld Ann-Kathrin , Walker Christopher J. , Zhang Bin , Srutova Klara , Gambacorti-Passerini Carlo , Pineda Gabriel , Jamieson Catriona H. M. , Stagno Fabio , Vigneri Paolo , Nteliopoulos Georgios , May Philippa C. , Reid Alistair G. , Garzon Ramiro , Roy Denis-Claude , Moutuou Moutuaata M. , Guimond Martin , Hokland Peter , Deininger Michael W. , Fitzgerald Garrett , Harman Christopher , Dazzi Francesco , Milojkovic Dragana , Apperley Jane F. , Marcucci Guido , Qi Jianfei , Polakova Katerina Machova , Zou Ying , Fan Xiaoxuan , Baer Maria R. , Calabretta Bruno , Perrotti Danilo
Published: March 2023

Range values of controls for the indicated experiments
Supplementary Figure 5 from Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions
Authors: Silvestri Giovannino , Trotta Rossana , Stramucci Lorenzo , Ellis Justin J. , Harb Jason G. , Neviani Paolo , Wang Shuzhen , Eisfeld Ann-Kathrin , Walker Christopher J. , Zhang Bin , Srutova Klara , Gambacorti-Passerini Carlo , Pineda Gabriel , Jamieson Catriona H. M. , Stagno Fabio , Vigneri Paolo , Nteliopoulos Georgios , May Philippa C. , Reid Alistair G. , Garzon Ramiro , Roy Denis-Claude , Moutuou Moutuaata M. , Guimond Martin , Hokland Peter , Deininger Michael W. , Fitzgerald Garrett , Harman Christopher , Dazzi Francesco , Milojkovic Dragana , Apperley Jane F. , Marcucci Guido , Qi Jianfei , Polakova Katerina Machova , Zou Ying , Fan Xiaoxuan , Baer Maria R. , Calabretta Bruno , Perrotti Danilo
Published: March 2023

Figure S5. BMM-induced MIR300 anti-proliferative and PP2A-activating functions impair NK cell immune-response. A, PP2A-dependent regulation of MIR300 and miR-155 validated pathways predicted to occur also in the bone marrow endosteal niche. B, Effect of hypoxia (1% O2, 7 days) on CFSE+NK cell proliferation (% CFSE mean of fluorescence). C, HS-5 exosomal miRNAs reported as negative regulators of NK cell proliferation/activity and their experimentally validated targets. miRNA RNAseq was performed on an Illumina platform using libraries derived from 100 ng RNA/sample from HS-5 exosome purifications (n=3). D, Precursor (pre-miR-155) miR-155 (BIC) levels in resting and IL-12/IL-18 (18h)-stimulated NK cells exposed (48h) to HS-5 exosomes. E, Effect of hypoxia (1% O2) and HS-5 CM (48h) on TUG1 expression in CD56+CD3- primary NK and NK-92 cells. F, Effect of CpG-TUG1-shRNA and CpG-scramble (200-500 nM, 5 days) on IL-2-induced NK cell proliferation (% cell number). Data are represented as mean+/-SEM.
Data from Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions
Authors: Silvestri Giovannino , Trotta Rossana , Stramucci Lorenzo , Ellis Justin J. , Harb Jason G. , Neviani Paolo , Wang Shuzhen , Eisfeld Ann-Kathrin , Walker Christopher J. , Zhang Bin , Srutova Klara , Gambacorti-Passerini Carlo , Pineda Gabriel , Jamieson Catriona H. M. , Stagno Fabio , Vigneri Paolo , Nteliopoulos Georgios , May Philippa C. , Reid Alistair G. , Garzon Ramiro , Roy Denis-Claude , Moutuou Moutuaata M. , Guimond Martin , Hokland Peter , Deininger Michael W. , Fitzgerald Garrett , Harman Christopher , Dazzi Francesco , Milojkovic Dragana , Apperley Jane F. , Marcucci Guido , Qi Jianfei , Polakova Katerina Machova , Zou Ying , Fan Xiaoxuan , Baer Maria R. , Calabretta Bruno , Perrotti Danilo
Published: March 2023

Abstract
Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that MIR300 has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. MIR300 is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates MIR300 in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating TUG1 long noncoding RNA that uncouples and limits MIR300 function to cytostasis. Genetic and pharmacologic MIR300 modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis in vitro and in patient-derived xenografts; hence, the importance of MIR300 and PP2A activity for CML development and therapy.
Significance:
Tumor-naïve microenvironment–induced MIR300 is the only tumor suppressor miRNA that induces CML LSC quiescence while inhibiting NK cell antitumor immune response, and CML LSC/progenitor cell apoptosis through its anti-proliferative and PP2A-activating functions, respectively. Thus, the importance of MIR300 and PP2A-activating drugs for formation/survival and eradication of drug-resistant CML LSCs, respectively.

See related commentary by Broxmeyer, p. 13.

This article is highlighted in the In This Issue feature, p. 5
Supplementary Figure S7 from Predictive and Prognostic Implications of Circulating CX3CR1+ CD8+ T Cells in Non–Small Cell Lung Cancer Patients Treated with Chemo-Immunotherapy
Authors: Abdelfatah Eihab , Long Mark D. , Kajihara Ryutaro , Oba Takaaki , Yamauchi Takayoshi , Chen Hongbin , Sarkar Joy , Attwood Kristopher , Matsuzaki Junko , Segal Brahm H. , Dy Grace K. , Ito Fumito
Published: March 2023

Supplementary Figure 7. Related to Fig. 3 Bar graphs displaying the counts of tumor-infiltrating lymphocytes (TILs) expressing a given TCRβ clonotype on the y axis and individual TIL clonotypes ordered by increasing frequency on the x axis for a patient in supplementary figure 4.
Supplementary Fig. S6 from The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin
Authors: Dellavedova Giulia , Decio Alessandra , Formenti Laura , Albertella Mark R. , Wilson Joanne , Staniszewska Anna D. , Leo Elisabetta , Giavazzi Raffaella , Ghilardi Carmen , Bani Maria Rosa
Published: March 2023

Fig. S6 shows the effect of the combination with suboptimal doses of CPT or AZD5305
Supplementary Figure S9 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Cytokine antibody array to identify differentially secreted factors from isolated mutant and non-mutant cells.
Supplementary Figure S11 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Histologic appearance of two cases of desmoid tumors with different patterns of CD142 expression
Data from CD142 Identifies Neoplastic Desmoid Tumor Cells, Uncovering Interactions Between Neoplastic and Stromal Cells That Drive Proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin A.
Published: March 2023

The interaction between neoplastic and stromal cells within a tumor mass plays an important role in cancer biology. However, it is challenging to distinguish between tumor and stromal cells in mesenchymal tumors because lineage-specific cell surface markers typically used in other cancers do not distinguish between the different cell subpopulations. Desmoid tumors consist of mesenchymal fibroblast-like cells driven by mutations stabilizing beta-catenin. Here we aimed to identify surface markers that can distinguish mutant cells from stromal cells to study tumor–stroma interactions. We analyzed colonies derived from single cells from human desmoid tumors using a high-throughput surface antigen screen, to characterize the mutant and nonmutant cells. We found that CD142 is highly expressed by the mutant cell populations and correlates with beta-catenin activity. CD142-based cell sorting isolated the mutant population from heterogeneous samples, including one where no mutation was previously detected by traditional Sanger sequencing. We then studied the secretome of mutant and nonmutant fibroblastic cells. PTX3 is one stroma-derived secreted factor that increases mutant cell proliferation via STAT6 activation. These data demonstrate a sensitive method to quantify and distinguish neoplastic from stromal cells in mesenchymal tumors. It identifies proteins secreted by nonmutant cells that regulate mutant cell proliferation that could be therapeutically.
Significance:
Distinguishing between neoplastic (tumor) and non-neoplastic (stromal) cells within mesenchymal tumors is particularly challenging, because lineage-specific cell surface markers typically used in other cancers do not differentiate between the different cell subpopulations. Here, we developed a strategy combining clonal expansion with surface proteome profiling to identify markers for quantifying and isolating mutant and nonmutant cell subpopulations in desmoid tumors, and to study their interactions via soluble factors.
Conceptualization of Stress-Related Disorders and PTSD by Cognitive Behavior Therapists
Authors: Lindauer Marlena , Linden Michael , Muschalla Beate
Published: March 2023

Background: Many people experience stressful life events like social conflicts, accidents, or physical violence. Some develop post-traumatic stress disorders (PTSD) thereafter. A diagnostic problem is the differentiation between causal stressful events, occasional causes, pseudo-causes or retrospective reinterpretations. This study investigates how often the diagnosis PTSD is mentioned in outpatient behavioral therapy patients, and which causes, findings, and therapeutic measures are reported. Patients and Method: In 1,480 behavioral therapy case reports the assignment of the diagnosis PTSD was explored. Cases with PTSD (N = 106) were compared with other cases without PTSD (N = 95). Results: In 7.16% the diagnosis PTSD was given. In both groups 90% reported earlier stressful experiences. In only 17% of the PTSD cases an “extraordinary threat of catastrophic proportions” was reported. In a quarter, the trauma assumption was based only on therapist or patient suggestions. Dissociative symptoms or intrusion were described only in the PTSD cases. Discussion: The data suggest that (a) almost all patients report stressful experiences, (b) the diagnosis of PTSD is given only in a limited number of patients, (c) in PTSD cases, intrusion and dissociation are reported only in a minority of cases, and (d) in PTSD cases, the full spectrum of exposure techniques is mentioned. Conclusion: Stress-associated disorders need precise description and differentiation.
Giant Hydronephrosis: A Rare Case Report and Literature Review
Authors: Wirtzfeld Nathan , Leduc Frédéric , Vaesen Roland
Published: March 2023

Giant hydronephrosis (GH), characterized by the presence of more than 1 L of fluid in the renal collecting system, is a rare urological condition, particularly in adults. Obstruction of the pyeloureteral junction is the most common cause of GH. We report the case of a 51-year-old man who presented with dyspnea, edema of the lower limbs, and major abdominal distension. The patient was diagnosed with obstruction of the pyeloureteral junction, causing a left giant hydronephrotic kidney. After renal drainage of 27 L of urine, a laparoscopic nephrectomy was performed. GH usually manifests as asymptomatic abdominal distension or vague symptoms. However, very few published reports describe cases of GH initially presenting with respiratory and vascular manifestations.
Single Cell Analysis of the Fate of Injected Oncogenic RasV12 Cells in Adult Wild Type Drosophila
Authors: Chen Di , Lan Xiao , Huang Xiaoming , Huang Jieqing , Zhou Xiaojing , Miao Zhichao , Ma Yuting , Goto Akira , Ji Shanming , Hoffmann Jules A.
Published: March 2023

We have injected dish-cultured oncogenic RasV12 cells into adult male flies and analyzed by single cell transcriptomics their destiny within the host after 11 days. We identified in the preinjection samples and in the 11-day postinjection samples in all 16 clusters of cells, of which 5 disappeared during the experiment in the host. The other cell clusters expanded and expressed genes involved in the regulation of cell cycle, metabolism, and development. In addition, three clusters expressed genes related to inflammation and defense. Predominant among these were genes coding for phagocytosis and/or characteristic for plasmatocytes (the fly equivalent of macrophages). A pilot experiment indicated that the injection into flies of oncogenic cells, in which two of most strongly expressed genes had been previously silenced by RNA interference, into flies resulted in a dramatic reduction of their proliferation in the host flies as compared to controls. As we have shown earlier, the proliferation of the injected oncogenic cells in the adult flies is a hallmark of the disease and induces a wave of transcriptions in the experimental flies. We hypothesize that this results from a bitter dialogue between the injected cells and the host, while the experiments presented here should contribute to deciphering this dialogue.