bluuebunny/crossref_metadata_2025_split huggingface dataset:
SIGLEC1 is a biomarker of disease activity and indicates extraglandular manifestation in primary Sjögren's syndrome
Authors: Rose Thomas , Szelinski Franziska , Lisney Anna , Reiter Karin , Fleischer Sarah J , Burmester Gerd R , Radbruch Andreas , Hiepe Falk , Grützkau Andreas , Biesen Robert , Dörner Thomas 
Published: December 2016

ObjectivesTo evaluate the interferon (IFN) biomarkers sialic acid binding Ig like lectin 1 (SIGLEC1, CD169) and IFN-γ-inducible protein-10 (IP-10) in patients with primary Sjögren's syndrome (pSS).Methods31 patients fulfilling the American-European criteria for pSS were included. Disease activity was obtained by EULAR Sjögren's syndrome disease activity index (ESSDAI). SIGLEC1 expression on monocytes was analysed using flow cytometry. IP-10 concentrations were determined using Bioplex human Cytokine 27-plex kit. Spearman rank test (SRT) was used for correlation analysis and Mann-Whitney U (MWU) to test for differences between glandular and extraglandular manifestations.ResultsAn activated IFN system was detected by an upregulation of SIGLEC1 expression in 64.5% and by elevated serum level of IP-10 in 78.9% of our patients with pSS. In a subsequent analysis SIGLEC1 expression was found to be upregulated more frequently in patients with extraglandular manifestations (16/16, 100%) compared to patients with exclusively glandular involvement (4/15, 27%). SIGLEC1 expression could significantly discriminate between these two disease subgroups (p=0.0001, MWU) with a positive predictive value (PPV) of 80% for extraglandular disease. Moreover, the expression correlated with disease activity (p=0.005, r=0.54, SRT). Serum IP-10 levels neither differed significantly between glandular and extraglandular disease nor correlated with ESSDAI.ConclusionsOur results indicate that increased SIGLEC1 expression characterises patients with systemic involvement and high disease activity. Therefore, SIGLEC1 determination might be of value for subset definition, risk stratification and differential therapeutic considerations in pSS.
Gut microbiota differs between children with Inflammatory Bowel Disease and healthy siblings in taxonomic and functional composition: a metagenomic analysis
Authors: Knoll Rebecca L. , Forslund Kristoffer , Kultima Jens Roat , Meyer Claudius U. , Kullmer Ulrike , Sunagawa Shinichi , Bork Peer , Gehring Stephan 
Published: December 2016

Current treatment for pediatric inflammatory bowel disease (IBD) patients is often ineffective, with serious side effects. Manipulating the gut microbiota via fecal microbiota transplantation (FMT) is an emerging treatment approach but remains controversial. We aimed to assess the composition of the fecal microbiome through a comparison of pediatric IBD patients to their healthy siblings, evaluating risks and prospects for FMT in this setting. A case-control (sibling) study was conducted analyzing fecal samples of six children with Crohn’s disease (CD), six children with ulcerative colitis (UC) and 12 healthy siblings by metagenomic sequencing. In addition, lifetime antibiotic intake was retrospectively determined. Species richness and diversity were significantly reduced in UC patients compared with control [Mann-Whitney U-test false discovery rate (MWU FDR) = 0.011]. In UC, bacteria positively influencing gut homeostasis, e.g., Eubacterium rectale and Faecalibacterium prausnitzii, were significantly reduced in abundance (MWU FDR = 0.05). Known pathobionts like Escherichia coli were enriched in UC patients (MWU FDR = 0.084). Moreover, E. coli abundance correlated positively with that of several virulence genes (SCC > 0.65, FDR < 0.1). A shift toward antibiotic-resistant taxa in both IBD groups distinguished them from controls [MWU Benjamini-Hochberg-Yekutieli procedure (BY) FDR = 0.062 in UC, MWU BY FDR = 0.019 in CD). The collected results confirm a microbial dysbiosis in pediatric UC, and to a lesser extent in CD patients, replicating associations found previously using different methods. Taken together, these observations suggest microbiotal remodeling therapy from family donors, at least for children with UC, as a viable option.NEW & NOTEWORTHY In this sibling study, prior reports of microbial dysbiosis in IBD patients from 16S rRNA sequencing was verified using deep shotgun sequencing and augmented with insights into the abundance of bacterial virulence genes and bacterial antibiotic resistance determinants, seen against the background of data on the specific antibiotic intake of each of the study participants. The observed dysbiosis, which distinguishes patients from siblings, highlights such siblings as potential donors for microbiotal remodeling therapy in IBD.
Caveolae-specific activation loop between CaMKII and L-type Ca2+channel aggravates cardiac hypertrophy in α1-adrenergic stimulation
Authors: Tonegawa Kota , Otsuka Wataru , Kumagai Shohei , Matsunami Sachi , Hayamizu Nao , Tanaka Shota , Moriwaki Kazumasa , Obana Masanori , Maeda Makiko , Asahi Michio , Kiyonari Hiroshi , Fujio Yasushi , Nakayama Hiroyuki 
Published: December 2016

Activation of CaMKII induces a myriad of biological processes and plays dominant roles in cardiac hypertrophy. Caveolar microdomain contains many calcium/calmodulin-dependent kinase II (CaMKII) targets, including L-type Ca2+channel (LTCC) complex, and serves as a signaling platform. The location of CaMKII activation is thought to be critical; however, the roles of CaMKII in caveolae are still elusive due to lack of methodology for the assessment of caveolae-specific activation. Our aim was to develop a novel tool for the specific analysis of CaMKII activation in caveolae and to determine the functional role of caveolar CaMKII in cardiac hypertrophy. To assess the caveolae-specific activation of CaMKII, we generated a fusion protein composed of phospholamban and caveolin-3 (cPLN-Cav3) and GFP fusion protein with caveolin-binding domain fused to CaMKII inhibitory peptide (CBD-GFP-AIP), which inhibits CaMKII activation specifically in caveolae. Caveolae-specific activation of CaMKII was detected using phosphospecific antibody for PLN (Thr17). Furthermore, adenoviral overexpression of LTCC β2a-subunit (β2a) in NRCMs showed its constitutive phosphorylation by CaMKII, which induces hypertrophy, and that both phosphorylation and hypertrophy are abolished by CBD-GFP-AIP expression, indicating that β2aphosphorylation occurs specifically in caveolae. Finally, β2aphosphorylation was observed after phenylephrine stimulation in β2a-overexpressing mice, and attenuation of cardiac hypertrophy after chronic phenylephrine stimulation was observed in nonphosphorylated mutant of β2a-overexpressing mice. We developed novel tools for the evaluation and inhibition of caveolae-specific activation of CaMKII. We demonstrated that phosphorylated β2adominantly localizes to caveolae and induces cardiac hypertrophy after α1-adrenergic stimulation in mice.NEW & NOTEWORTHY While signaling in caveolae is thought to be important in cardiac hypertrophy, direct evidence is missing due to lack of tools to assess caveolae-specific signaling. This is the first study to demonstrate caveolae-specific activation of CaMKII signaling in cardiac hypertrophy induced by α1-adrenergic stimulation using an originally developed tool.
Molecular Pathways: Mucins and Drug Delivery in Cancer
Authors: Rao Chinthalapally V. , Janakiram Naveena B. , Mohammed Altaf 
Published: December 2016

AbstractOver the past few decades, clinical and preclinical studies have clearly demonstrated the role of mucins in tumor development. It is well established that mucins form a barrier impeding drug access to target sites, leading to cancer chemoresistance. Recently gained knowledge regarding core enzyme synthesis has opened avenues to explore the possibility of disrupting mucin synthesis to improve drug efficacy. Cancer cells exploit aberrant mucin synthesis to efficiently mask the epithelial cells and ensure survival under hostile tumor microenvironment conditions. However, O-glycan synthesis enzyme core 2 beta 1,6 N-acetylglucosaminyltransferase (GCNT3/C2GnT-2) is overexpressed in Kras-driven mouse and human cancer, and inhibition of GCNT3 has been shown to disrupt mucin synthesis. This previously unrecognized developmental pathway might be responsible for aberrant mucin biosynthesis and chemoresistance. In this Molecular Pathways article, we briefly discuss the potential role of mucin synthesis in cancers, ways to improve drug delivery and disrupt mucin mesh to overcome chemoresistance by targeting mucin synthesis, and the unique opportunity to target the GCNT3 pathway for the prevention and treatment of cancers. Clin Cancer Res; 23(6); 1373–8. ©2016 AACR.
Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo
Authors: Cecil Denise L. , Slota Meredith , O'Meara Megan M. , Curtis Benjamin C. , Gad Ekram , Dang Yushe , Herendeen Daniel , Rastetter Lauren , Disis Mary L. 
Published: December 2016

Abstract
Purpose: Triple-negative breast cancer (TNBC) represents a cancer stem cell–enriched phenotype. Hypoxia-inducible factor-1α (HIF-1α) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1α was immunogenic and whether vaccination targeting HIF-1α would impact the growth of basal-like mammary tumors in transgenic mice.
Experimental Design: We evaluated HIF-1α–specific IgG in sera from controls and patients with breast cancer. Class II epitopes derived from the HIF-1α protein sequence were validated by ELISPOT. To assess therapeutic efficacy, we immunized Tg-MMTVneu and C3(1)Tag mice with HIF-1α Th1-inducing peptides. Stem cells were isolated via magnetic bead separation. Levels of HIF-1α and stem cells in the tumor were quantitated by Western blotting and flow cytometry.
Results: The magnitude (P &lt; 0.001) and incidence (P &lt; 0.001) of HIF-1α–specific IgG were elevated in TNBC patients compared with controls. Both breast cancer patients and donors showed evidence of HIF-1α–specific Th1 and Th2 immunity. Three HIF-1α–specific Th1 class II restricted epitopes that were highly homologous between species elicited type I immunity in mice. After HIF-1α vaccination, mammary tumor growth was significantly inhibited in only C3(1)Tag (basal-like/stem cellhigh; P &lt; 0.001) not TgMMTV-neu (luminal/neu/stem celllow; P = 0.859) murine models. Vaccination increased type I T cells in the tumor (P = 0.001) and decreased cells expressing the stem cell marker, Sca-1, compared with controls (P = 0.004).
Conclusions: An HIF-1α vaccine may be uniquely effective in limiting tumor growth in TNBC. Inhibiting outgrowth of breast cancer stem cells via active immunization in the adjuvant setting may impact disease recurrence. Clin Cancer Res; 23(13); 3396–404. ©2016 AACR.
Potent Anti-leukemia Activities of Chimeric Antigen Receptor–Modified T Cells against CD19 in Chinese Patients with Relapsed/Refractory Acute Lymphocytic Leukemia
Authors: Hu Yongxian , Wu Zhao , Luo Yi , Shi Jimin , Yu Jian , Pu Chengfei , Liang Zuyu , Wei Guoqing , Cui Qu , Sun Jie , Jiang Jing , Xie Jue , Tan Yamin , Ni Wanmao , Tu Jifang , Wang Jinping , Jin Aiyun , Zhang Hao , Cai Zhen , Xiao Lei , Huang He 
Published: December 2016

Abstract
Purpose: Patients with relapsed/refractory acute lymphocytic leukemia (R/R ALL) have a poor prognosis. Chimeric antigen receptor–modified T cells against CD19 (CART19) have displayed anti-leukemia activities. However, data from systemic trials in Chinese patients are limited.
Experimental Design: T cells transduced with CD19-directed CAR lentiviral vectors were infused in patients with R/R ALL under fludarabine- and cyclophosphamide-based lymphodepletion. The postinfusion responses, toxicities, expansion, and persistence of CART19s in enrolled patients were observed and monitored.
Results: We enrolled 15 patients with R/R ALL. The median transduction efficiency of CART19s was 33%. In vitro cytotoxicity assays were conducted and showed prominent antileukemia activities with CART19s. The patients received CART19s infusion at doses of 1.1 × 106/kg to 9.8 × 106/kg. Twelve patients achieved complete remission 1 month after CART19s infusion. CART19s expanded and persisted in peripheral blood and bone marrow. At 150 days, the overall survival rate and leukemia-free survival rate were 65.5% and 37.8%, respectively. The cumulative incidence of relapse and the nonrelapse mortality rate were 54.5% and 7.7%, respectively. Four patients underwent subsequent haploidentical hematopoietic stem cell transplantation. In this trial, 10 patients experienced cytokine release syndrome (CRS). Grade 3 CRS developed in 40% of patients and was associated with a higher disease burden on day −1 and a higher number of previous relapses.
Conclusions: This trial demonstrated potent antileukemia activities of CART19s in Chinese patients with R/R ALL. Disease relapse remained the main obstacle. However, patients with a high risk of relapse after CART19s might benefit from subsequent haploidentical hematopoietic stem cell transplantation. Clin Cancer Res; 23(13); 3297–306. ©2016 AACR.
Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways
Authors: Derakhshan Adeeb , Chen Zhong , Van Waes Carter 
Published: December 2016

Abstract
The Cancer Genome Atlas (TCGA) has unveiled genomic deregulation of various components of the extrinsic and intrinsic apoptotic pathways in different types of cancers. Such alterations are particularly common in head and neck squamous cell carcinomas (HNSCC), which frequently display amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAP) that complex with members of the TNF receptor family. Second mitochondria-derived activator of caspases (SMAC) mimetics, modeled after the endogenous IAP antagonist SMAC, and IAP inhibitors represent important classes of novel small molecules currently in phase I/II clinical trials. Here we review the physiologic roles of IAPs, FADD, and other components involved in cell death, cell survival, and NF-κB signaling pathways in cancers, including HNSCC. We summarize the results of targeting IAPs in preclinical models of HNSCC using SMAC mimetics. Synergistic activity of SMAC mimetics together with death agonists TNFα or TRAIL occurred in vitro, whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFα in vivo. In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized. As we achieve a deeper understanding of the genomic alterations and molecular mechanisms underlying deregulated death and survival pathways in different cancers, the role of SMAC mimetics and IAP inhibitors in cancer treatment will be elucidated. Such developments could enhance precision therapeutics and improve outcomes for cancer patients. Clin Cancer Res; 23(6); 1379–87. ©2016 AACR.
Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma
Authors: Dong Zhong-Yi , Zhong Wen-Zhao , Zhang Xu-Chao , Su Jian , Xie Zhi , Liu Si-Yang , Tu Hai-Yan , Chen Hua-Jun , Sun Yue-Li , Zhou Qing , Yang Jin-Ji , Yang Xue-Ning , Lin Jia-Xin , Yan Hong-Hong , Zhai Hao-Ran , Yan Li-Xu , Liao Ri-Qiang , Wu Si-Pei , Wu Yi-Long 
Published: December 2016

Abstract
Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non–small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.
Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.
Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.
Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti–PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012–24. ©2016 AACR.
Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade
Authors: Williams Michelle M. , Lee Linus , Hicks Donna J. , Joly Meghan M. , Elion David , Rahman Bushra , McKernan Courtney , Sanchez Violeta , Balko Justin M. , Stricker Thomas , Estrada Monica Valeria , Cook Rebecca S. 
Published: December 2016

Abstract
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα+ tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα+ breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured in situ using Mcl-1/Bim proximity ligation assays. Importantly, MCL1 gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of BCL2 or BCL2L1 and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1–selective inhibitors for targeted tumor cell killing.
Implications: Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. Mol Cancer Res; 15(3); 259–68. ©2016 AACR.
Immunophenotyping and Transcriptomic Outcomes in PDX-Derived TNBC Tissue
Authors: Snowden Eileen , Porter Warren , Hahn Friedrich , Ferguson Mitchell , Tong Frances , Parker Joel S. , Middlebrook Aaron , Ghanekar Smita , Dillmore W. Shannon , Blaesius Rainer 
Published: December 2016

Abstract
Cancer tissue functions as an ecosystem of a diverse set of cells that interact in a complex tumor microenvironment. Genomic tools applied to biopsies in bulk fail to account for this tumor heterogeneity, whereas single-cell imaging methods limit the number of cells which can be assessed or are very resource intensive. The current study presents methods based on flow cytometric analysis and cell sorting using known cell surface markers (CXCR4/CD184, CD24, THY1/CD90) to identify and interrogate distinct groups of cells in triple-negative breast cancer clinical biopsy specimens from patient-derived xenograft (PDX) models. The results demonstrate that flow cytometric analysis allows a relevant subgrouping of cancer tissue and that sorting of these subgroups provides insights into cancer cell populations with unique, reproducible, and functionally divergent gene expression profiles. The discovery of a drug resistance signature implies that uncovering the functional interaction between these populations will lead to deeper understanding of cancer progression and drug response.
Implications: PDX-derived human breast cancer tissue was investigated at the single-cell level, and cell subpopulations defined by surface markers were identified which suggest specific roles for distinct cellular compartments within a solid tumor. Mol Cancer Res; 15(4); 429–38. ©2016 AACR.
Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth
Authors: Guan Xiangnan , LaPak Kyle M. , Hennessey Rebecca C. , Yu Christina Y. , Shakya Reena , Zhang Jianying , Burd Christin E. 
Published: December 2016

AbstractSenescent cells within the tumor microenvironment (TME) adopt a proinflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression, and therapeutic resistance. Here, exposure to palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage–independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-κB activation. Based upon these observations, it was hypothesized that the exposure of nontransformed stromal cells to PD-0332991 would promote tumor growth. Ongoing clinical trials of CDK4/6 inhibitors in melanoma prompted a validation of this hypothesis using a suite of genetically defined melanoma cells (i.e., Ras mutant, Braf mutant, and Ras/Braf wild-type). When cultured in the presence of CDK4/6i-induced senescent fibroblasts, melanoma cell lines exhibited genotype-dependent proliferative responses. However, in vivo, PD-0332991–treated fibroblasts enhanced the growth of all melanoma lines tested and promoted the recruitment of Gr-1–positive immune cells. These data indicate that prolonged CDK4/6 inhibitor treatment causes normal fibroblasts to enter senescence and adopt a robust SASP. Such senescent cells suppress the antitumor immune response and promote melanoma growth in immunocompetent, in vivo models.Implications: The ability of prolonged CDK4/6 inhibitor treatment to induce cellular senescence and a robust SASP in primary cells may hinder therapeutic efficacy and promote long-term, gerontogenic consequences that should be considered in clinical trials aiming to treat melanoma and other cancer types. Mol Cancer Res; 15(3); 237–49. ©2016 AACR.