bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Cystine Deprivation Triggers Programmed Necrosis in VHL-Deficient Renal Cell Carcinomas
Authors: Tang Xiaohu , Wu Jianli , Ding Chien-Kuang , Lu Min , Keenan Melissa M. , Lin Chao-Chieh , Lin Chih-An , Wang Charles C. , George Daniel , Hsu David S. , Chi Jen-Tsan
Published: April 2023

Abstract
Oncogenic transformation may reprogram tumor metabolism and render cancer cells addicted to extracellular nutrients. Deprivation of these nutrients may therefore represent a therapeutic opportunity, but predicting which nutrients cancer cells become addicted remains difficult. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear cell renal cancer cells (ccRCC), with or without VHL, upon the deprivation of individual amino acids. We found that cystine deprivation triggered rapid programmed necrosis in VHL-deficient cell lines and primary ccRCC tumor cells, but not in VHL-restored counterparts. Blocking cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status, suggesting that metabolic responses alone are not sufficient to explain the observed distinct fates of VHL-deficient and restored cells. Instead, we found that increased levels of TNFα associated with VHL loss forced VHL-deficient cells to rely on intact RIPK1 to inhibit apoptosis. However, the preexisting elevation in TNFα expression rendered VHL-deficient cells susceptible to necrosis triggered by cystine deprivation. We further determined that reciprocal amplification of the Src–p38 (MAPK14)–Noxa (PMAIP1) signaling and TNFα–RIP1/3 (RIPK1/RIPK3)–MLKL necrosis pathways potentiated cystine-deprived necrosis. Together, our findings reveal that cystine deprivation in VHL-deficient RCCs presents an attractive therapeutic opportunity that may bypass the apoptosis-evading mechanisms characteristic of drug-resistant tumor cells. Cancer Res; 76(7); 1892–903. ©2016 AACR.
Data from Low Levels of Circulating Adiponectin Are Associated with Multiple Myeloma Risk in Overweight and Obese Individuals
Authors: Hofmann Jonathan N. , Birmann Brenda M. , Teras Lauren R. , Pfeiffer Ruth M. , Wang Ye , Albanes Demetrius , Baris Dalsu , Colditz Graham A. , De Roos Anneclaire J. , Giles Graham G. , Hosgood H. Dean , Lan Qing , Landgren Ola , Liao Linda M. , Rothman Nathaniel , Weinstein Stephanie J. , Pollak Michael N. , Neuhouser Marian L. , Purdue Mark P.
Published: April 2023

Abstract
The association between obesity and multiple myeloma risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate multiple myeloma risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 multiple myeloma cases and 1,246 individually matched controls from seven cohorts participating in the Multiple Myeloma Cohort Consortium. Analysis of circulating analyte levels measured by ELISA revealed that higher total adiponectin levels were associated with reduced multiple myeloma risk overall [highest quartile vs. lowest: OR, 0.64; 95% confidence interval (CI) 0.47–0.85; Ptrend = 0.001]. This association was apparent among cases diagnosed six or more years after blood collection (OR, 0.60; 95% CI, 0.40–0.90; Ptrend = 0.004) and was similar in magnitude for men and women (OR, 0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR, 0.41; 95% CI, 0.26–0.65) or obese (OR, 0.41; 95% CI, 0.17–0.98) but not among those with normal weight (OR, 1.20; 95% CI, 0.73–2.00; overweight/obese vs. normal weight, Pinteraction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against multiple myeloma development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. Cancer Res; 76(7); 1935–41. ©2016 AACR.
Data from Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis
Authors: Quick Laura , Young Robert , Henrich Ian C. , Wang Xiaoke , Asmann Yan W. , Oliveira Andre M. , Chou Margaret M.
Published: April 2023

Abstract
Bone and soft tissue tumors (BSTT) are relatively poorly understood, hampering the development of effective therapies. Here we report a critical effector pathway for the ubiquitin-specific protease 6 (USP6)/TRE17 oncogene, which is overexpressed upon chromosome translocation in various human tumors, including aneurysmal bone cyst (ABC) and the related benign lesion nodular fasciitis. Ectopic expression of USP6 is known to drive formation of tumors, which recapitulate key features of ABC and nodular fasciitis; however, the identity of USP6′s relevant substrates has been obscure. Here we report that the Jak1–STAT3 signaling pathway serves as an essential effector of USP6 in BSTT formation. We found that USP6 directly deubiquitinated Jak1, leading to its stabilization and activation of STAT3. The tumorigenic potential of USP6 was attenuated significantly by CRISPR-mediated deletion of Jak1 or STAT3, or by administration of a Jak family inhibitor. Analysis of primary clinical samples of nodular fasciitis confirmed the activation of a Jak1–STAT3 gene signature in vivo. Together, our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression. Cancer Res; 76(18); 5337–47. ©2016 AACR.
Data from Mesenchymal Tumorigenesis Driven by TSC2 Haploinsufficiency Requires HMGA2 and Is Independent of mTOR Pathway Activation
Authors: D'Armiento Jeanine , Shiomi Takayuki , Marks Sarah , Geraghty Patrick , Sankarasharma Devipriya , Chada Kiran
Published: April 2023

Abstract
Tuberous sclerosis (TSC) is a tumor suppressor gene syndrome that is associated with the widespread development of mesenchymal tumor types. Genetically, TSC is said to occur through a classical biallelic inactivation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is implicated in the induction of the mTOR pathway and subsequent tumorigenesis. High Mobility Group A2 (HMGA2), an architectural transcription factor, is known to regulate mesenchymal differentiation and drive mesenchymal tumorigenesis in vivo. Here, we investigated the role of HMGA2 in the pathogenesis of TSC using the TSC2+/− mouse model that similarly mirrors human disease and human tumor samples. We show that HMGA2 expression was detected in 100% of human and mouse TSC tumors and that HMGA2 activation was required for TSC mesenchymal tumorigenesis in genetically engineered mouse models. In contrast to the current dogma, the mTOR pathway was not activated in all TSC2+/− tumors and was elevated in only 50% of human mesenchymal tumors. Moreover, except for a subset of kidney tumors, tuberin was expressed in both human and mouse tumors. Therefore, haploinsufficiency of one TSC tumor suppressor gene was required for tumor initiation, but further tumorigenesis did not require the second hit, as previously postulated. Collectively, these findings demonstrate that tissue-specific genetic mechanisms are employed to promote tumor pathogenesis in TSC and identify a novel, critical pathway for potential therapeutic targeting. Cancer Res; 76(4); 844–54. ©2016 AACR.
Data from Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression
Authors: Linn Douglas E. , Penney Kathryn L. , Bronson Roderick T. , Mucci Lorelei A. , Li Zhe
Published: April 2023

Abstract
TMPRSS2–ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ∼3-Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS2–ERG insertion or deletion events in the background of prostate-specific PTEN deficiency. We found that only the mice that lacked the interstitial region developed prostate adenocarcinomas marked by poor differentiation and epithelial-to-mesenchymal transition. Mechanistic investigations identified several interstitial genes, including Ets2 and Bace2, whose reduced expression correlated in the gene homologs in human prostate cancer with biochemical relapse and lethal disease. Accordingly, PTEN-deficient mice with prostate-specific knockout of Ets2 exhibited marked progression of prostate adenocarcinomas that was partly attributed to activation of MAPK signaling. Collectively, our findings established that Ets2 is a tumor suppressor gene in prostate cancer, and its loss along with other genes within the TMPRSS2–ERG interstitial region contributes to disease progression. Cancer Res; 76(7); 1869–81. ©2016 AACR.
Data from miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer
Authors: Orso Francesca , Quirico Lorena , Virga Federico , Penna Elisa , Dettori Daniela , Cimino Daniela , Coppo Roberto , Grassi Elena , Elia Angela Rita , Brusa Davide , Deaglio Silvia , Brizzi Maria Felice , Stadler Michael B. , Provero Paolo , Caselle Michele , Taverna Daniela
Published: April 2023

Abstract
miR-214 and miR-148b have been proposed to antagonize the effects of each other in enabling or blocking metastasis, respectively. In this study, we provide evidence deepening their role and interrelationship in the process of metastatic dissemination. Depleting miR-214 or elevating miR-148b blocked the dissemination of melanoma or breast cancer cells, an effect that could be accentuated by dual alteration. Mechanistic investigations indicated that dual alteration suppressed passage of malignant cells through the blood vessel endothelium by reducing expression of the cell adhesion molecules ITGA5 and ALCAM. Notably, transendothelial migration in vitro and extravasation in vivo impaired by singly alternating miR-214 or miR-148b could be overridden by overexpression of ITGA5 or ALCAM in the same tumor cells. In clinical specimens of primary breast cancer or metastatic melanoma, we found a positive correlation between miR-214 and ITGA5 or ALCAM along with an inverse correlation of miR-214 and miR-148b in the same specimens. Our findings define an antagonistic relationship of miR-214 and miR-148b in determining the dissemination of cancer cells via tumor–endothelial cell interactions, with possible implications for microRNA-mediated therapeutic interventions aimed at blocking cancer extravasation. Cancer Res; 76(17); 5151–62. ©2016 AACR.
Data from Dual Targeting of CDK4 and ARK5 Using a Novel Kinase Inhibitor ON123300 Exerts Potent Anticancer Activity against Multiple Myeloma
Authors: Perumal Deepak , Kuo Pei-Yu , Leshchenko Violetta V. , Jiang Zewei , Divakar Sai Krishna Athaluri , Cho Hearn Jay , Chari Ajai , Brody Joshua , Reddy M.V. Ramana , Zhang Weijia , Reddy E. Premkumar , Jagannath Sundar , Parekh Samir
Published: April 2023

Abstract
Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma. Cancer Res; 76(5); 1225–36. ©2016 AACR.
Data from Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells
Authors: Bourcy Morgane , Suarez-Carmona Meggy , Lambert Justine , Francart Marie-Emilie , Schroeder Hélène , Delierneux Céline , Skrypek Nicolas , Thompson Erik W. , Jérusalem Guy , Berx Geert , Thiry Marc , Blacher Silvia , Hollier Brett G. , Noël Agnès , Oury Cécile , Polette Myriam , Gilles Christine
Published: April 2023

Abstract
Epithelial–mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties, and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT–TF regulatory axis that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs. Cancer Res; 76(14); 4270–82. ©2016 AACR.
Data from Agonists of the TRAIL Death Receptor DR5 Sensitize Intestinal Stem Cells to Chemotherapy-Induced Cell Death and Trigger Gastrointestinal Toxicity
Authors: Finnberg Niklas K. , Gokare Prashanth , Navaraj Arunasalam , Lang Kuhs Krystle A. , Cerniglia George , Yagita Hideo , Takeda Kazuyoshi , Motoyama Noboru , El-Deiry Wafik S.
Published: April 2023

Abstract
The combination of TRAIL death receptor agonists and radiochemotherapy to treat advanced cancers continues to be investigated in clinical trials. We previously showed that normal cells with a functional DNA damage response (DDR) upregulate the expression of death-inducing receptor DR5/TRAILR2/TNFRSF10B in a p53-dependent manner that sensitizes them to treatment with DR5 agonists. However, it is unclear if targeting DR5 selectively sensitizes cancer cells to agonist treatment following exposure to DNA-damaging chemotherapy, and to what extent normal tissues are targeted. Here, we show that the combined administration of the DR5 agonistic monoclonal antibody (mAb) and chemotherapy to wild-type mice triggered synergistic gastrointestinal toxicities (GIT) that were associated with the death of Lgr5+ crypt base columnar stem cells in a p53- and DR5-dependent manner. Furthermore, we confirmed that normal human epithelial cells treated with the human DR5-agonistic mAb and chemotherapeutic agents were also greatly sensitized to cell death. Interestingly, our data also indicated that genetic or pharmacologic targeting of Chk2 may counteract GIT without negatively affecting the antitumor responses of combined DR5 agonist/chemotherapy treatment, further linking the DDR to TRAIL death receptor signaling in normal cells. In conclusion, the combination of DR5-targeting agonistic mAbs with DNA damaging chemotherapy may pose a risk of developing toxicity-induced conditions, and the effects of mAb-based strategies on the dose-limiting toxicity of chemotherapy must be considered when establishing new combination therapies. Cancer Res; 76(3); 700–12. ©2015 AACR.
Data from Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers
Authors: Kaczkowski Bogumil , Tanaka Yuji , Kawaji Hideya , Sandelin Albin , Andersson Robin , Itoh Masayoshi , Lassmann Timo , Hayashizaki Yoshihide , Carninci Piero , Forrest Alistair R.R.
Published: April 2023

Abstract
Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression profiles from 225 different cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the The Cancer Genome Atlas and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer RNAs, which are upregulated in cancer, defining promoters that overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall, our genome-wide expression profiling approach identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective and pathogenic significance of repetitive elements that are frequently activated during cancer progression. Cancer Res; 76(2); 216–26. ©2015 AACR.
Data from Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α
Authors: Schönenberger Désirée , Harlander Sabine , Rajski Michal , Jacobs Robert A. , Lundby Anne-Kristine , Adlesic Mojca , Hejhal Tomas , Wild Peter J. , Lundby Carsten , Frew Ian J.
Published: April 2023

Abstract
The von Hippel–Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1α has been implicated as a renal tumor suppressor, whereas HIF2α is considered an oncoprotein. In this study, we investigated the contributions of HIF1α and HIF2α to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1α and HIF2α differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1α, but not HIF2α, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1α and HIF2α exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025–36. ©2016 AACR.
Data from Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma
Authors: Delgado-Calle Jesus , Anderson Judith , Cregor Meloney D. , Hiasa Masahiro , Chirgwin John M. , Carlesso Nadia , Yoneda Toshiyuki , Mohammad Khalid S. , Plotkin Lilian I. , Roodman G. David , Bellido Teresita
Published: April 2023

Abstract
In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3–dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma. Cancer Res; 76(5); 1089–100. ©2016 AACR.
Data from A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution
Authors: Walsh Kyle M. , de Smith Adam J. , Hansen Helen M. , Smirnov Ivan V. , Gonseth Semira , Endicott Alyson A. , Xiao Jianqiao , Rice Terri , Fu Cecilia H. , McCoy Lucie S. , Lachance Daniel H. , Eckel-Passow Jeanette E. , Wiencke John K. , Jenkins Robert B. , Wrensch Margaret R. , Ma Xiaomei , Metayer Catherine , Wiemels Joseph L.
Published: April 2023

Abstract
Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case–control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10−9) and Hispanic children (OR, 2.77; P = 3.78 × 10−4). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS “hits” and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors. Cancer Res; 75(22); 4884–94. ©2015 AACR.
Data from The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models
Authors: Oplustil O'Connor Lenka , Rulten Stuart L. , Cranston Aaron N. , Odedra Rajesh , Brown Henry , Jaspers Janneke E. , Jones Louise , Knights Charlotte , Evers Bastiaan , Ting Attilla , Bradbury Robert H. , Pajic Marina , Rottenberg Sven , Jonkers Jos , Rudge David , Martin Niall M.B. , Caldecott Keith W. , Lau Alan , O'Connor Mark J.
Published: April 2023

Abstract
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. Cancer Res; 76(20); 6084–94. ©2016 AACR.
Data from Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α
Authors: Lim Sangbin , Liu Hao , da Silva Luciana Madeira , Arora Ritu , Liu Zixing , Phillips Joshua B. , Schmitt David C. , Vu Tung , McClellan Steven , Lin Yifeng , Lin Wensheng , Piazza Gary A. , Fodstad Oystein , Tan Ming
Published: April 2023

Abstract
B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo. We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3–expressing cells. B7-H3 also increased the protein levels of HIF1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species–dependent stabilization of HIF1α by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression. Cancer Res; 76(8); 2231–42. ©2016 AACR.
Supplementary Methods and Materials. Supplementary Tables S1-S4 from Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm
Authors: Sun Xiangqing , Elston Robert C. , Barnholtz-Sloan Jill S. , Falk Gary W. , Grady William M. , Faulx Ashley , Mittal Sumeet K. , Canto Marcia , Shaheen Nicholas J. , Wang Jean S. , Iyer Prasad G. , Abrams Julian A. , Tian Ye D. , Willis Joseph E. , Guda Kishore , Markowitz Sanford D. , Chandar Apoorva , Warfe James M. , Brock Wendy , Chak Amitabh
Published: April 2023

Supplementary Methods of imputation of age and estimating the parameters of the prediction model. Supplementary Table S1 Missing rates on the 8 covariates in the training and validation datasets. Supplementary Table S2 Stepwise removal of covariates in the MLM model on the basis of LRT tests and AIC. Supplementary Table S3. Description of the eight predictor covariates. Supplementary Table S4 Number of informative pedigrees without missing covariate data.
Supplementary Figure S1 from Aspirin Use and Risk of Breast Cancer: Systematic Review and Meta-analysis of Observational Studies
Authors: Zhong Shanliang , Chen Lin , Zhang Xiaohui , Yu Dandan , Tang Jinhai , Zhao Jianhua
Published: April 2023

Funnel plot of studies on aspirin use and breast cancer risk. The solid line in the center is the natural logarithm of pooled relative risk, and two oblique dotted lines are pseudo 95% CIs. Closed circles indicate the estimates of each individual study. Open circles indicate the estimates of the potential missing studies according to the trim-and-fill method.
Data from Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer
Authors: Long Jirong , Zheng Wei , Xiang Yong-Bing , Lose Felicity , Thompson Deborah , Tomlinson Ian , Yu Herbert , Wentzensen Nicolas , Lambrechts Diether , Dörk Thilo , Dubrowinskaja Natalia , Goodman Marc T. , Salvesen Helga B. , Fasching Peter A. , Scott Rodney J. , Delahanty Ryan , Zheng Ying , O'Mara Tracy , Healey Catherine S. , Hodgson Shirley , Risch Harvey , Yang Hannah P. , Amant Frederic , Turmanov Nurzhan , Schwake Anita , Lurie Galina , Trovik Jone , Beckmann Matthias W. , Ashton Katie , Ji Bu-Tian , Bao Ping-Ping , Howarth Kimberly , Lu Lingeng , Lissowska Jolanta , Coenegrachts Lieve , Kaidarova Dilyara , Dürst Matthias , Thompson Pamela J. , Krakstad Camilla , Ekici Arif B. , Otton Geoffrey , Shi Jiajun , Zhang Ben , Gorman Maggie , Brinton Louise , Coosemans An , Matsuno Rayna K. , Halle Mari K. , Hein Alexander , Proietto Anthony , Cai Hui , Lu Wei , Dunning Alison , Easton Douglas , Gao Yu-Tang , Cai Qiuyin , Spurdle Amanda B. , Shu Xiao-Ou
Published: April 2023

Abstract
Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer.

Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb).

Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5).

Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.

Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980–7. ©2012 AACR.
Data from Aspirin Use Reduces the Risk of Aggressive Prostate Cancer and Disease Recurrence in African-American Men
Authors: Smith Cheryl Jacobs , Dorsey Tiffany H. , Tang Wei , Jordan Symone V. , Loffredo Christopher A. , Ambs Stefan
Published: April 2023

Abstract
Background: Men of African descent experience a disproportionately high prostate cancer mortality. Intratumoral inflammation was found to be associated with aggressive prostate cancer. We and others have shown that prostate tumors in African-American (AA) patients harbor a distinct immune and inflammation signature when compared with European-American (EA) patients. These observations suggest that inflammation could be a driver of aggressive disease in men of African descent, leading to the hypothesis that an anti-inflammatory drug like aspirin could prevent disease progression.

Methods: We examined the relationship between aspirin use and prostate cancer in the NCI-Maryland Prostate Cancer Case-Control Study consisting of 823 men with incident prostate cancer (422 AA and 401 EA) and 1,034 population-based men without the disease diagnosis (486 AA and 548 EA).

Results: We observed a significant inverse association between regular aspirin use and prostate cancer among AA men. Stratification of AA patients by disease stage showed that daily and long-term (>3 years) aspirin use significantly decreased the risk of advanced disease [adjusted ORs for T3/T4 disease: 0.35, 95% confidence interval (CI), 0.17–0.73; and 0.22, 95% CI, 0.08–0.60, respectively], but not early-stage disease (T1/T2). Regular aspirin use also reduced disease recurrence in AA men.

Conclusions: Regular aspirin use is associated with a decreased risk of advanced stage prostate cancer and increased disease-free survival in AA men.

Impact: Regular aspirin use before and after a prostate cancer diagnosis may prevent the development of aggressive disease in AA men who are at risk of a lethal malignancy. Cancer Epidemiol Biomarkers Prev; 26(6); 845–53. ©2017 AACR.
Data from Association of Prostate Cancer Risk Variants with Gene Expression in Normal and Tumor Tissue
Authors: Penney Kathryn L. , Sinnott Jennifer A. , Tyekucheva Svitlana , Gerke Travis , Shui Irene M. , Kraft Peter , Sesso Howard D. , Freedman Matthew L. , Loda Massimo , Mucci Lorelei A. , Stampfer Meir J.
Published: April 2023

Abstract
Background: Numerous germline genetic variants are associated with prostate cancer risk, but their biologic role is not well understood. One possibility is that these variants influence gene expression in prostate tissue. We therefore examined the association of prostate cancer risk variants with the expression of genes nearby and genome-wide.

Methods: We generated mRNA expression data for 20,254 genes with the Affymetrix GeneChip Human Gene 1.0 ST microarray from normal prostate (N = 160) and prostate tumor (N = 264) tissue from participants of the Physicians' Health Study and Health Professionals Follow-up Study. With linear models, we tested the association of 39 risk variants with nearby genes and all genes, and the association of each variant with canonical pathways using a global test.

Results: In addition to confirming previously reported associations, we detected several new significant (P < 0.05) associations of variants with the expression of nearby genes including C2orf43, ITGA6, MLPH, CHMP2B, BMPR1B, and MTL5. Genome-wide, five genes (MSMB, NUDT11, RBPMS2, NEFM, and KLHL33) were significantly associated after accounting for multiple comparisons for each SNP (P < 2.5 × 10−6). Many more genes had an FDR <10%, including SRD5A1 and PSCA, and we observed significant associations with pathways in tumor tissue.

Conclusions: The risk variants were associated with several genes, including promising prostate cancer candidates and lipid metabolism pathways, suggesting mechanisms for their impact on disease. These genes should be further explored in biologic and epidemiologic studies.

Impact: Determining the biologic role of these variants can lead to improved understanding of prostate cancer etiology and identify new targets for chemoprevention. Cancer Epidemiol Biomarkers Prev; 24(1); 255–60. ©2014 AACR.
Data from Tonsillectomy and Incidence of Oropharyngeal Cancers
Authors: Chaturvedi Anil K. , Song Huan , Rosenberg Phillip S. , Ramqvist Torbjorn , Anderson William F. , Munck-Wikland Eva , Ye Weimin , Dalianis Tina
Published: April 2023

Abstract
Background: Rising incidence of oropharyngeal cancers in numerous countries since the 1970s has been attributed to increased oral human papillomavirus (HPV) exposure. However, the contribution of coincidental declines in the surgical removal of the tonsils (tonsillectomy) is unknown. We quantified the association of tonsillectomy with risk of tonsillar, other oropharyngeal, and other head and neck cancers and the contribution of declines in tonsillectomies to cancer incidence trends.

Methods: We conducted a nation-wide cohort study in Sweden (1970–2009). Tonsillectomies (N = 225,718) were identified through national patient registers, which were linked with the cancer register. Cancer incidence in the tonsillectomy cohort was compared with Sweden's general population through standardized incidence ratios (SIR).

Results: Tonsillectomies were associated with reduced risk of tonsil cancers [SIRs 1+ years post-tonsillectomy = 0.31; 95% confidence interval (CI), 0.08–0.79 and 5+ years post-tonsillectomy = 0.17; 95% CI, 0.02–0.62], but unrelated to other oropharyngeal or other head and neck cancers (SIRs 1+ years post-tonsillectomy = 1.61; 95% CI, 0.77–2.95 and 0.92; 95% CI, 0.64–1.27, respectively). The cumulative incidence of tonsillectomy declined significantly (40%–50%) during 1970–2009. However, tonsil cancer incidence significantly increased during 1970–2009 both without and with corrections for declines in tonsillectomies (relative risks per 5-year periods = 1.23, P < 0.001 and 1.20, P < 0.001, respectively).

Conclusions: The reduced tonsil cancer risk with tonsillectomy reflects the removal of most of the relevant tissue. The absence of associations with other head and neck cancers indicates that tonsillectomy may not impact carcinogenesis at other sites.

Impact: The significant increases in oropharyngeal cancer incidence since the 1970s in Sweden appear independent of declines in tonsillectomies, reinforcing increased oral HPV exposure as the likely cause. Cancer Epidemiol Biomarkers Prev; 25(6); 944–50. ©2016 AACR.
Table S3 from Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer
Authors: Lee Keun-Wook , Lee Sung Sook , Hwang Jun-Eul , Jang Hee-Jin , Lee Hyun-Sung , Oh Sang Cheul , Lee Sang Ho , Sohn Bo Hwa , Kim Sang Bae , Shim Jae-Jun , Jeong Woojin , Cha Minse , Cheong Jae-Ho , Cho Jae Yong , Lim Jae Yun , Park Eun Sung , Kim Sang Cheol , Kang Yoon-Koo , Noh Sung Hoon , Ajani Jaffer A. , Lee Ju-Seog
Published: April 2023

Univariate and Multivariate Cox Regression Analyses of Recurrence Free Survival Durations of Patients in the Validation Cohort.
Supplementary figures 1-3 from Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma
Authors: Tierny Dominique , Serres François , Segaoula Zacharie , Bemelmans Ingrid , Bouchaert Emmanuel , Pétain Aurélie , Brel Viviane , Couffin Stéphane , Marchal Thierry , Nguyen Laurent , Thuru Xavier , Ferré Pierre , Guilbaud Nicolas , Gomes Bruno
Published: April 2023

Supplementary figures 1-3. Supplementary Figure 1: F14512 structure (A) and effects on Namalwa lymphoma cell line (B-E). Supplementary Figure 2: DNA damage induced by F14512 in Namalwa cells. Supplementary Figure 3: Illustration of decreased cell count and cell viability in tumoral lymph nodes after F14512 infusion.
Figure S8 from Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer
Authors: Lee Keun-Wook , Lee Sung Sook , Hwang Jun-Eul , Jang Hee-Jin , Lee Hyun-Sung , Oh Sang Cheul , Lee Sang Ho , Sohn Bo Hwa , Kim Sang Bae , Shim Jae-Jun , Jeong Woojin , Cha Minse , Cheong Jae-Ho , Cho Jae Yong , Lim Jae Yun , Park Eun Sung , Kim Sang Cheol , Kang Yoon-Koo , Noh Sung Hoon , Ajani Jaffer A. , Lee Ju-Seog
Published: April 2023

ROC curves showing the predictive accuracy for recurrence.
Table S3 from RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non–Small Cell Lung Carcinomas Sensitive to MEK Inhibition
Authors: Hayashi Takuo , Desmeules Patrice , Smith Roger S. , Drilon Alexander , Somwar Romel , Ladanyi Marc
Published: April 2023

Clinicopathological Features of Patients with RASA1 and NF1 Mutated Lung Cancer in MSKCC cohort.
Figure S6 from Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer
Authors: Lee Keun-Wook , Lee Sung Sook , Hwang Jun-Eul , Jang Hee-Jin , Lee Hyun-Sung , Oh Sang Cheul , Lee Sang Ho , Sohn Bo Hwa , Kim Sang Bae , Shim Jae-Jun , Jeong Woojin , Cha Minse , Cheong Jae-Ho , Cho Jae Yong , Lim Jae Yun , Park Eun Sung , Kim Sang Cheol , Kang Yoon-Koo , Noh Sung Hoon , Ajani Jaffer A. , Lee Ju-Seog
Published: April 2023

Recurrence risk score and its clinical significance.
Table S1 from RASA1 and NF1 are Preferentially Co-Mutated and Define A Distinct Genetic Subset of Smoking-Associated Non–Small Cell Lung Carcinomas Sensitive to MEK Inhibition
Authors: Hayashi Takuo , Desmeules Patrice , Smith Roger S. , Drilon Alexander , Somwar Romel , Ladanyi Marc
Published: April 2023

Antibodies for western blot analysis.
Supplementary Table 1 from Image Analysis–based Assessment of PD-L1 and Tumor-Associated Immune Cells Density Supports Distinct Intratumoral Microenvironment Groups in Non–small Cell Lung Carcinoma Patients
Authors: Parra Edwin R. , Behrens Carmen , Rodriguez-Canales Jaime , Lin Heather , Mino Barbara , Blando Jorge , Zhang Jianjun , Gibbons Don L. , Heymach John V. , Sepesi Boris , Swisher Stephen G. , Weissferdt Annikka , Kalhor Neda , Izzo Julie , Kadara Humam , Moran Cesar , Lee Jack J. , Wistuba Ignacio I.
Published: April 2023

Correlation of airflow limitation (positive and negative) with PD-L1 H-score and median TAIC density by mm2 in the intratumoral and peritumoral compartments in lung ADC and SqCC specimens.
Supplementary Figure 2 from Image Analysis–based Assessment of PD-L1 and Tumor-Associated Immune Cells Density Supports Distinct Intratumoral Microenvironment Groups in Non–small Cell Lung Carcinoma Patients
Authors: Parra Edwin R. , Behrens Carmen , Rodriguez-Canales Jaime , Lin Heather , Mino Barbara , Blando Jorge , Zhang Jianjun , Gibbons Don L. , Heymach John V. , Sepesi Boris , Swisher Stephen G. , Weissferdt Annikka , Kalhor Neda , Izzo Julie , Kadara Humam , Moran Cesar , Lee Jack J. , Wistuba Ignacio I.
Published: April 2023

Microphotographs of representative examples of the algorithms used to analyze TAICs density. A) Representative positive CD3 staining (brown) in an ADC showing five random square areas (1 mm2 each; green outlined boxes) in both intratumoral (right) and peritumoral (left) compartments divided by a red line. B) High power images of CD3 IHC expression (left) and image analysis quantification using the nuclear algorithm (right). C) High power images of CD4 IHC expression (left) and image analysis quantification using the nuclear algorithm (right); the algorithm excluded a macrophage cell from analysis as indicated by the arrows. D) higher power images of granzyme B IHC expression (left) and image analysis quantification using the nuclear algorithm (right); E) High power images of FOXP3 IHC expression (left) and image analysis quantification using the nuclear algorithm (right). F) High power images of CD68 (macrophages) IHC expression (left) and image analysis quantification using the cytoplasmic algorithm (right).
Supplementary Figure 1 from Image Analysis–based Assessment of PD-L1 and Tumor-Associated Immune Cells Density Supports Distinct Intratumoral Microenvironment Groups in Non–small Cell Lung Carcinoma Patients
Authors: Parra Edwin R. , Behrens Carmen , Rodriguez-Canales Jaime , Lin Heather , Mino Barbara , Blando Jorge , Zhang Jianjun , Gibbons Don L. , Heymach John V. , Sepesi Boris , Swisher Stephen G. , Weissferdt Annikka , Kalhor Neda , Izzo Julie , Kadara Humam , Moran Cesar , Lee Jack J. , Wistuba Ignacio I.
Published: April 2023

Microphotographs of representative examples of the computer algorithm (Aperio GENIE) used to analyze the IHC PD-L1 expression (brown staining) in malignant cells (MCs) and tumor associated macrophages (TAMs). (A) Whole histology section image of a representative ADC stained with PD-L1 IHC processed using the Aperio GENIE image analysis algorithm depicting areas tumor, stroma and macrophages infiltration. B) Higher power images of H&E (left upper), CD68 (right upper), PD-L1 positive expression in tumor MCs (left lower), and illustration of the GENIE algorithm for membrane staining and the computer generated data on intensity and extension of IHC expression (right lower). C) Higher power images of H&E (left upper), CD68 (right upper), PD-L1 positive expression in tumor TAMs (left lower) and illustration of the GENIE algorithm for membrane staining and the computer generated data on intensity and extension of IHC expression (right lower).
Supplemental Figures Legend from A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Galloway Thomas J. , Wirth Lori J. , Colevas Alexander D. , Gilbert Jill , Bauman Julie E. , Saba Nabil F. , Raben David , Mehra Ranee , Ma Anna W. , Atoyan Ruzanna , Wang Jing , Burtness Barbara , Jimeno Antonio
Published: April 2023

Supplemental Figures Legend
Supplementary Materials and Methods from A Novel CDC25B Promoter–Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models
Authors: Weber Helga L. , Gidekel Manuel , Werbajh Santiago , Salvatierra Edgardo , Rotondaro Cecilia , Sganga Leonardo , Haab Gabriela Acosta , Curiel David T. , Cafferata Eduardo G. , Podhajcer Osvaldo L.
Published: April 2023

Supplementary Materials and Methods
Table S1 and S2 from Phase I Clinical Trial to Determine the Feasibility and Maximum Tolerated Dose of Panitumumab to Standard Gemcitabine-Based Chemoradiation in Locally Advanced Pancreatic Cancer
Authors: van Zweeden Annette A. , van der Vliet Hans J. , Wilmink Johanna W. , Meijerink Martijn R. , Meijer Otto W.M. , Bruynzeel Anna M.E. , van Tienhoven Geertjan , Giovannetti Elisa , Kazemier Geert , Jacobs Maarten A.J.M. , Verheul Henk M.W.
Published: April 2023

Table S1 and S2. Suplementary Table 1. Adverse events during chemoradiation with panitumumab, according to CTCAE criteria (after 43 days). Suplementary Table 2. Tumor-size and radiation fields between cohorts.
Supplementary Figures 1-3 from Combined MEK and PI3K Inhibition in a Mouse Model of Pancreatic Cancer
Authors: Alagesan Brinda , Contino Gianmarco , Guimaraes Alexander R. , Corcoran Ryan B. , Deshpande Vikram , Wojtkiewicz Gregory R. , Hezel Aram F. , Wong Kwok-Kin , Loda Massimo , Weissleder Ralph , Benes Cyril , Engelman Jeffrey A. , Bardeesy Nabeel
Published: April 2023

Supplementary Figures 1-3. 1. MEK/PI3K signaling in human PDA 2. Prevention study 3. Treatment study
Supplementary Table 6 from FGFR1/3 Tyrosine Kinase Fusions Define a Unique Molecular Subtype of Non–Small Cell Lung Cancer
Authors: Wang Rui , Wang Lei , Li Yuan , Hu Haichuan , Shen Lei , Shen Xuxia , Pan Yunjian , Ye Ting , Zhang Yang , Luo Xiaoyang , Zhang Yiliang , Pan Bin , Li Bin , Li Hang , Zhang Jie , Pao William , Ji Hongbin , Sun Yihua , Chen Haiquan
Published: April 2023

PDF file - 77KB, Clinicopathologic Characteristics of 734 Patients with NSCLC in Survival analysis.