bluuebunny/crossref_metadata_2025_split huggingface dataset:
Notch signaling modulates the electrical behavior of cardiomyocytes
Authors: Borghetti Giulia , Eisenberg Carol A. , Signore Sergio , Sorrentino Andrea , Kaur Keerat , Andrade-Vicenty Alejandro , Edwards John G. , Nerkar Mriganka , Qanud Khaled , Sun Dong , Goichberg Polina , Leri Annarosa , Anversa Piero , Eisenberg Leonard M. , Jacobson Jason T. , Hintze Thomas H. , Rota Marcello 
Published: September 2017

Notch receptor signaling is active during cardiac development and silenced in myocytes after birth. Conversely, outward K+Kv currents progressively appear in postnatal myocytes leading to shortening of the action potential (AP) and acquisition of the mature electrical phenotype. In the present study, we tested the possibility that Notch signaling modulates the electrical behavior of cardiomyocytes by interfering with Kv currents. For this purpose, the effects of Notch receptor activity on electrophysiological properties of myocytes were evaluated using transgenic mice with inducible expression of the Notch1 intracellular domain (NICD), the functional fragment of the activated Notch receptor, and in neonatal myocytes after inhibition of the Notch transduction pathway. By patch clamp, NICD-overexpressing cells presented prolonged AP duration and reduced upstroke amplitude, properties that were coupled with reduced rapidly activating Kv and fast Na+currents, compared with cells obtained from wild-type mice. In cultured neonatal myocytes, inhibition of the proteolitic release of NICD with a γ-secretase antagonist increased transcript levels of the Kv channel-interacting proteins 2 (KChIP2) and enhanced the density of Kv currents. Collectively, these results indicate that Notch signaling represents an important regulator of the electrophysiological behavior of developing and adult myocytes by repressing, at least in part, repolarizing Kv currents.NEW & NOTEWORTHY We investigated the effects of Notch receptor signaling on the electrical properties of cardiomyocytes. Our results indicate that the Notch transduction pathway interferes with outward K+Kv currents, critical determinants of the electrical repolarization of myocytes.
Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy
Authors: Huang Wen-Yen , Lai Shih-Fan , Chiu Hsien-Yi , Chang Michael , Plikus Maksim V. , Chan Chih-Chieh , Chen You-Tzung , Tsao Po-Nien , Yang Tsung-Lin , Lee Hsuan-Shu , Chi Peter , Lin Sung-Jan 
Published: September 2017

Abstract
Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region, and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HFs mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin 5+ basal hair bulb progenitors, rather than bulge SCs, were quickly activated to replenish matrix cells and regenerated all concentric layers of HFs, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired an SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SCs, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy. Cancer Res; 77(22); 6083–96. ©2017 AACR.
Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation
Authors: Yang Rui , Chen Lee H. , Hansen Landon J. , Carpenter Austin B. , Moure Casey J. , Liu Heng , Pirozzi Christopher J. , Diplas Bill H. , Waitkus Matthew S. , Greer Paula K. , Zhu Huishan , McLendon Roger E. , Bigner Darell D. , He Yiping , Yan Hai 
Published: September 2017

Abstract
Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human oligodendroglioma cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. In vitro cultured neural stem cells derived from Cic conditional knockout mice bypassed an EGF requirement for proliferation and displayed a defect in their potential for oligodendrocyte differentiation. Cic is known to participate in gene suppression that can be relieved by EGFR signal, but we found that cic also activated expression of a broad range of EGFR-independent genes. In an orthotopic mouse model of glioma, we found that Cic loss potentiated the formation and reduced the latency in tumor development. Collectively, our results define an important role for Cic in regulating neural cell proliferation and lineage specification, and suggest mechanistic explanations for how CIC mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma. Cancer Res; 77(22); 6097–108. ©2017 AACR.
Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability
Authors: Bieg-Bourne Cheyennedra C. , Millis Sherri Z. , Piccioni David E. , Fanta Paul T. , Goldberg Michael E. , Chmielecki Juliann , Parker Barbara A. , Kurzrock Razelle 
Published: September 2017

Abstract
Enhancements in clinical-grade next-generation sequencing (NGS) have fueled the advancement of precision medicine in the clinical oncology field. Here, we survey the molecular profiles of 1,113 patients with diverse malignancies who successfully underwent clinical-grade NGS (236–404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.2%). Among 2,045 molecular aberrations was the involvement of 302 distinct genes. The most commonly altered genes were TP53 (47.0%), CDKN2A (18.0%), TERT (17.0%), and KRAS (16.0%), and the majority of patients had tumors that harbored multiple alterations. Tumors displayed a median of four alterations (range, 0–29). Most individuals had at least one potentially actionable alteration (94.7%), with the median number of potentially actionable alterations per patient being 2 (range, 0–13). A total of 1,048 (94.2%) patients exhibited a unique molecular profile, with either genes altered or loci within the gene(s) altered being distinct. Approximately 13% of patients displayed a genomic profile identical to at least one other patient; although genes altered were the same, the affected loci may have differed. Overall, our results underscore the complex heterogeneity of malignancies and argue that customized combination therapies will be essential to optimize cancer treatment regimens. Cancer Res; 77(22); 6313–20. ©2017 AACR.
Tumor Heterogeneity Predicts Metastatic Potential in Colorectal Cancer
Authors: Joung Je-Gun , Oh Bo Young , Hong Hye Kyung , Al-Khalidi Hisham , Al-Alem Faisal , Lee Hae-Ock , Bae Joon Seol , Kim Jinho , Cha Hong-Ui , Alotaibi Maram , Cho Yong Beom , Hassanain Mazen , Park Woong-Yang , Lee Woo Yong 
Published: September 2017

Abstract
Purpose: Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis.
Experimental Design: Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole-exome sequencing. Tumor clonality was estimated from single-nucleotide and copy-number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated.
Results: Tumor heterogeneity across colorectal cancer samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease-free survival. Highly heterogeneous primary colorectal cancer was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in APC, TP53, and KRAS were frequently detected in highly heterogeneous colorectal cancer. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as PIK3CA and NOTCH1 were low. The number and distribution of primary colorectal cancer subclones were preserved in metastatic tumors.
Conclusions: Heterogeneity of primary colorectal cancer tumors can predict the potential for liver metastasis and thus, clinical outcome of patients. Clin Cancer Res; 23(23); 7209–16. ©2017 AACR.
Integrated Analysis Reveals Tubal- and Ovarian-Originated Serous Ovarian Cancer and Predicts Differential Therapeutic Responses
Authors: Hao Dapeng , Li Jingjing , Jia Shanshan , Meng Yuan , Zhang Chao , Wang Li , Di Li-jun 
Published: September 2017

Abstract
Purpose: The relative importance of fallopian tube (FT) compared with ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs.
Experimental Design: A collection of transcriptome data of 80 FTs, 89 OSEs, and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to reevaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings.
Results: The expression patterns of tissue-specific genes, prognostic genes, and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival (OSE-like vs. FT-like, HR = 4.16; 95% CI, 2.67–6.48; P &lt; 10−9). The pharmacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC.
Conclusions: SOC has two subtypes originated from either FT or OSE, which show different clinical and pathologic features. Clin Cancer Res; 23(23); 7400–11. ©2017 AACR.
Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/β-Catenin and PI3K/Akt Signaling
Authors: Kang Dong Woo , Lee Bo Hui , Suh Young-Ah , Choi Yong-Seok , Jang Se Jin , Kim Yong Man , Choi Kang-Yell , Min Do Sik 
Published: September 2017

Abstract
Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling.
Experimental Design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations.
Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways.
Conclusions: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying APC and PI3KCA mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. Clin Cancer Res; 23(23); 7340–50. ©2017 AACR.
CD90 Expression Controls Migration and Predicts Dasatinib Response in Glioblastoma
Authors: Avril Tony , Etcheverry Amandine , Pineau Raphaël , Obacz Joanna , Jegou Gwénaële , Jouan Florence , Le Reste Pierre-Jean , Hatami Masumeh , Colen Rivka R. , Carlson Brett L. , Decker Paul A. , Sarkaria Jann N. , Vauléon Elodie , Chiforeanu Dan Cristian , Clavreul Anne , Mosser Jean , Chevet Eric , Quillien Véronique 
Published: September 2017

AbstractPurpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells, including glioblastoma (GBM) stem cells (GSC). However, the molecular and cellular functions of CD90 remain unclear.Experimental Design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, in vivo orthotopic mouse models, and GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells and complemented in CD90-negative U87 cells.Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo. Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90-positive cells. Remarkably, dasatinib blunted CD90-dependent GBM cell invasion in vivo and killed CD90high primary GSC lines.Conclusions: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC-dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90high GBM patients. Clin Cancer Res; 23(23); 7360–74. ©2017 AACR.
A Novel Breast Cancer Index for Prediction of Distant Recurrence in HR+ Early-Stage Breast Cancer with One to Three Positive Nodes
Authors: Zhang Yi , Schroeder Brock E. , Jerevall Piiha-Lotta , Ly Amy , Nolan Hannah , Schnabel Catherine A. , Sgroi Dennis C. 
Published: September 2017

AbstractPurpose: The study objective was to characterize the prognostic performance of a novel Breast Cancer Index model (BCIN+), an integration of BCI gene expression, tumor size, and grade, specifically developed for assessment of distant recurrence (DR) risk in HR+ breast cancer patients with one to three positive lymph nodes (pN1).Experimental Design: Analysis was conducted in a well-annotated retrospective series of pN1 patients (N = 402) treated with adjuvant endocrine therapy with or without chemotherapy using a prespecified model. The primary endpoint was time-to-DR. Results were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0–15 years) and late (≥5 years) DR, HRs, and 95% confidence interval (CIs) were estimated. Likelihood ratio statistics assessed relative contributions of prognostic information.Results: BCIN+ classified 81 patients (20%) as low risk with a 15-year DR rate of 1.3% (95% CI, 0.0%–3.7%) versus 321 patients as high risk with a DR rate of 29.0% (95% CI, 23.2%–34.4%). In patients DR-free for ≥5 years (n = 349), the late DR rate was 1.3% (95% CI, 0.0%–3.7%) and 16.1% (95% CI, 10.6%–21.3%) in low- and high-risk groups, respectively. BCI gene expression alone was significantly prognostic (ΔLR-χ2 = 20.12; P &lt; 0.0001). Addition of tumor size (ΔLR-χ2 = 13.29, P = 0.0003) and grade (ΔLR-χ2 = 12.72; P = 0.0004) significantly improved prognostic performance. BCI added significant prognostic information to tumor size (ΔLR-χ2 = 17.55; P &lt; 0.0001); addition to tumor grade was incremental (ΔLR-χ2 = 2.38; P = 0.1) with considerable overlap between prognostic values (ΔLR-χ2 = 17.74).Conclusions: The integrated BCIN+ identified 20% of pN1 patients with limited risk of recurrence over 15 years, in whom extended endocrine treatment may be spared. Ongoing studies will characterize combined clinical-genomic risk assessment in node-positive patients. Clin Cancer Res; 23(23); 7217–24. ©2017 AACR.
A Chemical Modulator of p53 Transactivation that Acts as a Radioprotective Agonist
Authors: Morita Akinori , Takahashi Ippei , Sasatani Megumi , Aoki Shin , Wang Bing , Ariyasu Shinya , Tanaka Kaoru , Yamaguchi Tetsuji , Sawa Akiko , Nishi Yurie , Teraoka Tatsuro , Ujita Shohei , Kawate Yosuke , Yanagawa Chihiro , Tanimoto Keiji , Enomoto Atsushi , Nenoi Mitsuru , Kamiya Kenji , Nagata Yasushi , Hosoi Yoshio , Inaba Toshiya 
Published: September 2017

Abstract
Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives, that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses, including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seem to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in Trp53-KO mice. These results indicate that the pharmacologic upregulation of radioprotective p53 target genes is an effective strategy for addressing the gastrointestinal syndrome. Mol Cancer Ther; 17(2); 432–42. ©2017 AACR.
See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”
Targeting Phosphatidylserine with Calcium-Dependent Protein–Drug Conjugates for the Treatment of Cancer
Authors: Li Ran , Chiguru Srinivas , Li Li , Kim Dongyoung , Velmurugan Ramraj , Kim David , Devanaboyina Siva Charan , Tian Hong , Schroit Alan , Mason Ralph P. , Ober Raimund J. , Ward E. Sally 
Published: September 2017

Abstract
In response to cellular stress, phosphatidylserine is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of phosphatidylserine-specific therapies. The generation of drug-conjugated phosphatidylserine-targeting agents represents an unexplored therapeutic approach, for which antitumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated phosphatidylserine-targeting agents by fusing phosphatidylserine-binding domains to a human IgG1-derived Fc fragment. The tumor localization and pharmacokinetics of several phosphatidylserine-specific Fc fusions have been analyzed in mice and demonstrate that Fc-Syt1, a fusion containing the synaptotagmin 1 C2A domain, effectively targets tumor tissue. Conjugation of Fc-Syt1 to the cytotoxic drug monomethyl auristatin E results in a protein–drug conjugate (PDC) that is internalized into target cells and, due to the Ca2+ dependence of phosphatidylserine binding, dissociates from phosphatidylserine in early endosomes. The released PDC is efficiently delivered to lysosomes and has potent antitumor effects in mouse xenograft tumor models. Interestingly, although an engineered, tetravalent Fc-Syt1 fusion shows increased binding to target cells, this higher avidity variant demonstrates reduced persistence and therapeutic effects compared with bivalent Fc-Syt1. Collectively, these studies show that finely tuned, Ca2+-switched phosphatidylserine-targeting agents can be therapeutically efficacious. Mol Cancer Ther; 17(1); 169–82. ©2017 AACR.