bluuebunny/crossref_metadata_2025_split huggingface dataset:
β-Galactosylceramidase Promotes Melanoma Growth via Modulation of Ceramide Metabolism
Authors: Belleri Mirella , Paganini Giuseppe , Coltrini Daniela , Ronca Roberto , Zizioli Daniela , Corsini Michela , Barbieri Andrea , Grillo Elisabetta , Calza Stefano , Bresciani Roberto , Maiorano Eugenio , Mastropasqua Mauro G. , Annese Tiziana , Giacomini Arianna , Ribatti Domenico , Casas Josefina , Levade Thierry , Fabrias Gemma , Presta Marco 
Published: September 2020

Abstract

Disturbance of sphingolipid metabolism may represent a novel therapeutic target in metastatic melanoma, the most lethal form of skin cancer. β-Galactosylceramidase (GALC) removes β-galactose from galactosylceramide and other sphingolipids. In this study, we show that downregulation of galcb, a zebrafish ortholog of human GALC, affects melanoblast and melanocyte differentiation in zebrafish embryos, suggesting a possible role for GALC in melanoma. On this basis, the impact of GALC expression in murine B16-F10 and human A2058 melanoma cells was investigated following its silencing or upregulation. Galc knockdown hampered growth, motility, and invasive capacity of B16-F10 cells and their tumorigenic and metastatic activity when grafted in syngeneic mice or zebrafish embryos. Galc-silenced cells displayed altered sphingolipid metabolism and increased intracellular levels of ceramide, paralleled by a nonredundant upregulation of Smpd3, which encodes for the ceramide-generating enzyme neutral sphingomyelinase 2. Accordingly, GALC downregulation caused SMPD3 upregulation, increased ceramide levels, and inhibited the tumorigenic activity of human melanoma A2058 cells, whereas GALC upregulation exerted opposite effects. In concordance with information from melanoma database mining, RNAscope analysis demonstrated a progressive increase of GALC expression from common nevi to stage IV human melanoma samples that was paralleled by increases in microphthalmia transcription factor and tyrosinase immunoreactivity inversely related to SMPD3 and ceramide levels. Overall, these findings indicate that GALC may play an oncogenic role in melanoma by modulating the levels of intracellular ceramide, thus providing novel opportunities for melanoma therapy.

Significance:
Data from zebrafish embryos, murine and human cell melanoma lines, and patient-derived tumor specimens indicate that β-galactosylceramidase plays an oncogenic role in melanoma and may serve as a therapeutic target.
Transient Activation of the Hedgehog-Gli Pathway Rescues Radiotherapy-Induced Dry Mouth via Recovering Salivary Gland Resident Macrophages
Authors: Zhao Qingguo , Zhang Linying , Hai Bo , Wang Jun , Baetge Courtney L. , Deveau Michael A. , Kapler Geoffrey M. , Feng Jian Q. , Liu Fei 
Published: September 2020

Abstract

Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head and neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here, we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells, and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single-cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their prorepair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth.

Significance:
These findings illuminate a novel direction for developing effective treatment of irreversible dry mouth, which is common after radiotherapy for head and neck cancer and for which no effective treatments are available.
Protein Arginine Methyltransferase 5 Promotes pICln-Dependent Androgen Receptor Transcription in Castration-Resistant Prostate Cancer
Authors: Beketova Elena , Fang Shuyi , Owens Jake L. , Liu Sheng , Chen Xufeng , Zhang Qingfu , Asberry Andrew M. , Deng Xuehong , Malola Jonathan , Huang Jiaoti , Li Chenglong , Pili Roberto , Elzey Bennett D. , Ratliff Timothy L. , Wan Jun , Hu Chang-Deng 
Published: September 2020

AbstractThe majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. In addition, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation.Significance:This study provides evidence that targeting PRMT5 can eliminate expression of AR and can be explored as a novel therapeutic approach to treat metastatic hormone-naïve and castration-resistant prostate cancer.
Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor–Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer
Authors: Huang Tzu-Ting , Brill Ethan , Nair Jayakumar R. , Zhang Xiaohu , Wilson Kelli M. , Chen Lu , Thomas Craig J. , Lee Jung-Min 
Published: September 2020

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2–M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC.

Significance:
Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.
Rafting Down the Metastatic Cascade: The Role of Lipid Rafts in Cancer Metastasis, Cell Death, and Clinical Outcomes
Authors: Greenlee Joshua D. , Subramanian Tejas , Liu Kevin , King Michael R. 
Published: September 2020

AbstractLipid rafts are tightly packed, cholesterol- and sphingolipid-enriched microdomains within the plasma membrane that play important roles in many pathophysiologic processes. Rafts have been strongly implicated as master regulators of signal transduction in cancer, where raft compartmentalization can promote transmembrane receptor oligomerization, shield proteins from enzymatic degradation, and act as scaffolds to enhance intracellular signaling cascades. Cancer cells have been found to exploit these mechanisms to initiate oncogenic signaling and promote tumor progression. This review highlights the roles of lipid rafts within the metastatic cascade, specifically within tumor angiogenesis, cell adhesion, migration, epithelial-to-mesenchymal transition, and transendothelial migration. In addition, the interplay between lipid rafts and different modes of cancer cell death, including necrosis, apoptosis, and anoikis, will be described. The clinical role of lipid raft–specific proteins, caveolin and flotillin, in assessing patient prognosis and evaluating metastatic potential of various cancers will be presented. Collectively, elucidation of the complex roles of lipid rafts and raft components within the metastatic cascade may be instrumental for therapeutic discovery to curb prometastatic processes.
Validity Coefficient of Repeated Measurements of Urinary Marker of Sugar Intake Is Comparable to Urinary Nitrogen as Marker of Protein Intake in Free-living Subjects
Authors: Abreu Taymara C. , Hulshof Paul J.M. , Boshuizen Hendriek C. , Trijsburg Laura , Gray Nicola , de Vries Jeanne H.M. 
Published: September 2020

AbstractBackground:Studies do not show consistent relationships between self-reported intake of sugar and outcome of disease. To overcome the drawbacks of self-reported intake methods, we investigated whether there is an agreement in ranking of individuals between their self-reported sugar intake and urinary sucrose and fructose.Methods:We used data of 198 Dutch adults (106 women) from the DUPLO study. Sugar intake of all foods and drinks consumed over 24-hour period was estimated by collecting duplicate portions (DP) and 24-hour recalls (24hR), telephone (24hRT) and Web-based (24hRW), while sugar excretion was based on 24-hour urine samples. Sugar content of 24hR was calculated using a newly developed sugar database and sugar content of DPs and urine samples was calculated using high-performance liquid chromatography–atomic emission spectrometry and LC/MS-MS, respectively. Measurement error models assessed validity coefficients (VC) and attenuation factors (AF). Coefficients were compared with those of protein biomarker.Results:The VC for the marker, using DP as reference, showed comparability with substantially better ranking of participants (0.72 for women and 0.93 for men), than 24hRT (0.57 and 0.78) or 24hRW (0.70 and 0.78) as reference in the sucrose models. The VC of the sucrose models was within 10% of the protein models, except for the model with 24hRT as reference, among women. The AF started at higher values and increased by a greater factor compared with the VC.Conclusions:Repeated measurements of urinary sucrose and fructose as a marker of daily sucrose intake had a ranking performance comparable to urinary nitrogen as marker of protein intake in free-living Dutch adults.Impact:The validation of the sugar biomarker in a free-living population with three different dietary assessment methods and its comparable ranking ability with a good recovery biomarker (i.e., protein biomarker) have important research applications. The biomarker may be used for validating dietary assessment methods, for monitoring compliance in human feeding studies, for monitoring the effect of public health interventions, and as a surrogate for ranking subjects according to sucrose intake when information on sucrose in food composition databases is lacking.
Estimating Population-Based Recurrence Rates of Colorectal Cancer over Time in the United States
Authors: Kunst Natalia , Alarid-Escudero Fernando , Aas Eline , Coupé Veerle M.H. , Schrag Deborah , Kuntz Karen M. 
Published: September 2020

Abstract

Background:
Population-based metastatic recurrence rates for patients diagnosed with nonmetastatic colorectal cancer cannot be estimated directly from population-based cancer registries because recurrence information is not reported. We derived population-based colorectal cancer recurrence rates using disease-specific survival data based on our understanding of the colorectal cancer recurrence-death process.

Methods:
We used a statistical continuous-time multistate survival model to derive population-based annual colorectal cancer recurrence rates from 6 months to 10 years after colorectal cancer diagnosis using relative survival data from the Surveillance, Epidemiology, and End Results Program. The model was based on the assumption that, after 6 months of diagnosis, all colorectal cancer–related deaths occur only in patients who experience a metastatic recurrence first, and that the annual colorectal cancer–specific death rate among patients with recurrence was the same as in those diagnosed with de novo metastatic disease. We allowed recurrence rates to vary by post-diagnosis time, age, stage, and location for two diagnostic time periods.

Results:
In patients diagnosed in 1975–1984, annual recurrence rates 6 months to 5 years after diagnosis ranged from 0.054 to 0.060 in stage II colon cancer, 0.094 to 0.105 in stage II rectal cancer, and 0.146 to 0.177 in stage III colorectal cancer, depending on age. We found a statistically significant decrease in colorectal cancer recurrence among patients diagnosed in 1994–2003 compared with those diagnosed in 1975–1984 for 6 months to 5 years after diagnosis (hazard ratios between 0.43 and 0.70).

Conclusions:
We derived population-based annual recurrence rates for up to 10 years after diagnosis using relative survival data.

Impact:
Our estimates can be used in decision-analytic models to facilitate analyses of colorectal cancer interventions that are more generalizable.
Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR+, HER2− Advanced Breast Cancer
Authors: Bardia Aditya , Modi Shanu , Oliveira Mafalda , Cortes Javier , Campone Mario , Ma Brigette , Dirix Luc , Weise Amy , Hewes Becker , Diaz-Padilla Ivan , Han Yu , Deshpande Priya , Samant Tanay S. , Lorenc Karen Rodriguez , He Wei , Su Fei , Chavez-MacGregor Mariana 
Published: September 2020

Abstract

Purpose:
Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).

Patients and Methods:
Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.

Results:
Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.

Conclusions:
Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.
A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
Authors: Zeidan Amer M. , Ridinger Maya , Lin Tara L. , Becker Pamela S. , Schiller Gary J. , Patel Prapti A. , Spira Alexander I. , Tsai Michaela L. , Samuëlsz Errin , Silberman Sandra L. , Erlander Mark , Wang Eunice S. 
Published: September 2020

Abstract

Purpose:
The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML.

Patients and Methods:
Onvansertib was administered orally, in escalating doses, on days 1–5 in combination with either LDAC (20 mg/m2; days 1–10) or decitabine (20 mg/m2; days 1–5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers.

Results:
Forty patients were treated with onvansertib (12–90 mg/m2) in combination with LDAC (n = 17) or decitabine (n = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m2, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts.

Conclusions:
The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
An Antibody-Tumor Necrosis Factor Fusion Protein that Synergizes with Oxaliplatin for Treatment of Colorectal Cancer
Authors: Bajic Davor , Chester Kerry , Neri Dario 
Published: September 2020

Abstract
We have cloned and characterized a novel fusion protein (Sm3E-TNF), consisting of the mAb, S 6m3E, in single-chain Fv fragment format, fused to murine TNF. The protein, which was expressed in mammalian cells and purified as a noncovalent stable homotrimer, bound to the cognate carcinoembryonic antigen (CEA) and retained TNF activity. A quantitative biodistribution experiment, performed in immunocompetent mice with CT26 colon carcinomas transfected with human CEA, revealed that Sm3E-TNF was able to preferentially accumulate in the tumors with excellent selectivity (tumor:blood ratio = 56:1, 24 hours after intravenous administration). The fusion protein mediated a rapid hemorrhagic necrosis of a large portion of the tumor mass, but a rim survived and eventually regrew. Surprisingly, the combination of Sm3E-TNF with 5-fluorouracil led to a reduction of therapeutic activity, while a combination with oxaliplatin led to a prolonged stabilization, with complete tumor eradication in 40% of treated mice. These therapy results were confirmed in a second immunocompetent mouse model of colorectal cancer (CEA-transfected C51 tumors) and provide a rationale for the possible clinical use of oxaliplatin in combination with fully human antibody-TNF fusions.
A Combination of BRD4 and HDAC3 Inhibitors Synergistically Suppresses Glioma Stem Cell Growth by Blocking GLI1/IL6/STAT3 Signaling Axis
Authors: Wang Qian , Jia Shengnan , Wang Ding , Chen Xuyang , Kalvakolanu Dhan V. , Zheng Hongwu , Wei Xiaodong , Wen Naiyan , Liang Hang , Guo Baofeng , Zhang Ling 
Published: September 2020

Abstract
Glioma stem cells (GSC) are essential for tumor maintenance, invasiveness, and recurrence. Using a global epigenetic screening with an shRNA library, we identified HDAC3 as an essential factor for GSC stemness. Here, we demonstrated that GSCs poorly respond to an HDAC3 inhibitor, RGFP966 (HDAC3i), owing to the production of IL6 and STAT3 activation. To enhance GSC sensitivity to HDAC3i, we explored whether cotreatment with a BRD4 inhibitor, JQ1 (BRD4i), in GSCs produced a better antitumor effect. BRD4i synergistically inhibits GSC growth in association with HDAC3i. HDAC3 inhibition upregulated the acetylation of H3K27, which allowed the recruitment of BRD4 to the GLI1 gene promoter and induced its expression. GLI1, a transcription factor, turned on the expression of IL6, which led to the activation of STAT3 signaling pathways. However, BRD4i inhibited transcription of the GLI1 gene, thereby blocking the GLI1/IL6/STAT3 pathway. In vivo, the HDAC3i/BRD4i combination caused stronger tumor growth suppression than either drug alone. Thus, HDAC3i/BRD4i might provide promising therapies for GBM.
Implication of ZNF217 in Accelerating Tumor Development and Therapeutically Targeting ZNF217-Induced PI3K–AKT Signaling for the Treatment of Metastatic Osteosarcoma
Authors: Smeester Branden A. , Draper Garrett M. , Slipek Nicholas J. , Larsson Alex T. , Stratton Natalie , Pomeroy Emily J. , Becklin Kelsie L. , Yamamoto Kenta , Williams Kyle B. , Laoharawee Kanut , Peterson Joseph J. , Abrahante Juan E. , Rathe Susan K. , Mills Lauren J. , Crosby Margaret R. , Hudson Wendy A. , Rahrmann Eric P. , Largaespada David A. , Moriarity Branden S. 
Published: September 2020

Abstract
We previously identified ZNF217 as an oncogenic driver of a subset of osteosarcomas using the Sleeping Beauty (SB) transposon system. Here, we followed up by investigating the genetic role of ZNF217 in osteosarcoma initiation and progression through the establishment of a novel genetically engineered mouse model, in vitro assays, orthotopic mouse studies, and paired these findings with preclinical studies using a small-molecule inhibitor. Throughout, we demonstrate that ZNF217 is coupled to numerous facets of osteosarcoma transformation, including proliferation, cell motility, and anchorage independent growth, and ultimately promoting osteosarcoma growth, progression, and metastasis in part through positive modulation of PI3K–AKT survival signaling. Pharmacologic blockade of AKT signaling with nucleoside analogue triciribine in ZNF217+ orthotopically injected osteosarcoma cell lines reduced tumor growth and metastasis. Our data demonstrate that triciribine treatment may be a relevant and efficacious therapeutic strategy for patients with osteosarcoma with ZNF217+ and p-AKT rich tumors. With the recent revitalization of triciribine for clinical studies in other solid cancers, our study provides a rationale for further evaluation preclinically with the purpose of clinical evaluation in patients with incurable, ZNF217+ osteosarcoma.