bluuebunny/crossref_metadata_2025_split huggingface dataset:
Japanese POEMS syndrome with Thalidomide (J-POST) Trial: study protocol for a phase II/III multicentre, randomised, double-blind, placebo-controlled trial
Authors: Katayama Kanako , Misawa Sonoko , Sato Yasunori , Sobue Gen , Yabe Ichiro , Watanabe Osamu , Nishizawa Masatoyo , Kusunoki Susumu , Kikuchi Seiji , Nakashima Ichiro , Ikeda Shu-ichi , Kohara Nobuo , Kanda Takashi , Kira Jun-ichi , Hanaoka Hideki , Kuwabara Satoshi 
Published: January 2015

IntroductionPolyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a fatal systemic disorder associated with plasma cell dyscrasia and the overproduction of the vascular endothelial growth factor (VEGF). Recently, the prognosis of POEMS was substantially improved by introduction of therapeutic intervention for myeloma. However, no randomised clinical trial has been performed because of the rarity and severity of the disease.Methods and analysisThe Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome, with an additional 48-week open-label safety study. Adults with POEMS syndrome who have no indication for transplantation are assessed for eligibility at 12 tertiary neurology centres in Japan. Patients who satisfy the eligibility criteria are randomised (1:1) to receive thalidomide (100–300 mg daily) plus dexamethasone (12 mg/m2on days 1–4 of a 28-day cycle) or placebo plus dexamethasone. Both treatments were administered for 24 weeks (six cycles; randomised comparative study period). Patients who complete the randomised study period or show subacute deterioration during the randomised period participate in the subsequent 48-week open-label safety study (long-term safety period). The primary end point of the study is the reduction rate of serum VEGF levels at 24 weeks.Ethics and disseminationThe protocol was approved by the Institutional Review Board of each hospital. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, Japan (No. 22-1716). The J-POST Trial is currently ongoing and is due to finish in August 2015. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations and will also be disseminated to participants.Trial registration numberUMIN000004179 and JMA-IIA00046.
Endothelin-1 and endothelin B receptor expression in pancreatic adenocarcinoma
Authors: Cook N , Brais R , Qian W , Chan Wah Hak C , Corrie P G 
Published: January 2015

BackgroundEndothelin-1 (ET-1) acting through endothelin A and B receptors (ETAR and ETBR) has been implicated in the development of cancer. The endothelin axis has not previously been characterised in human pancreatic adenocarcinoma (PAC).MethodsExpression of ET-1, ETAR, ETBR, vascular endothelial growth factor and microvessel density (MVD) was determined by immunohistochemistry in 45 surgically resected human PACs and 15 non-cancer human pancreas samples.ResultsPAC had the highest staining intensity for ET-1 and ETBR: 38% PAC samples scored 2+ or more compared with 7% non-cancer sample in ET-1; 58% PAC samples scored 2+ compared with 0% non-cancer samples in ETBR. MVD was significantly lower in PAC compared with non-cancer tissue (p<0.0001).ConclusionsPAC was characterised by greater expression of ET-1 and ETBR compared with normal pancreas.
Low health literacy predicts decline in physical function among older adults: findings from the LitCog cohort study
Authors: Smith Samuel G , O'Conor Rachel , Curtis Laura M , Waite Katie , Deary Ian J , Paasche-Orlow Michael , Wolf Michael S 
Published: January 2015

BackgroundLimited health literacy is associated with worse physical function in cross-sectional studies. We aimed to determine if health literacy is a risk factor for decline in physical function among older adults.MethodsA longitudinal cohort of 529 community-dwelling American adults aged 55–74 years were recruited from an academic general internal medicine clinic and federally qualified health centres in 2008–2011. Health literacy (Newest Vital Sign), age, gender, race, education, chronic conditions, body mass index, alcohol consumption, smoking status and exercise frequency were included in multivariable analyses. The 10-item PROMIS (Patient-Reported Outcomes Measurement Information System) physical function scale was assessed at baseline and follow-up (mean=3.2 years, SD=0.39).ResultsNearly half of the sample (48.2%) had either marginal (25.5%) or low health literacy (22.7%). Average physical function at baseline was 83.2 (SD=16.6) of 100, and health literacy was associated with poorer baseline physical function in multivariable analysis (p=0.004). At follow-up, physical function declined to 81.9 (SD=17.3; p=0.006) and 20.5% experienced a meaningful decline (>0.5 SD of baseline score). In multivariable analyses, participants with marginal (OR 2.62; 95%CI 1.38 to 4.95; p=0.003) and low (OR 2.57; 95%CI 1.22 to 5.44; p=0.013) health literacy were more likely to experience meaningful decline in physical function than the adequate health literacy group. Entering cognitive abilities to these models did not substantially attenuate effect sizes. Health literacy attenuated the relationship between black race and decline in physical function by 32.6%.ConclusionsLower health literacy increases the risk of exhibiting faster physical decline over time among older adults. Strategies that reduce literacy disparities should be designed and evaluated.
A REVIEW OF THE EFFECTS OF BODY TEMPERATURE VARIATIONS ON RESPIRATORY MECHANICS: MEASUREMENTS BY THE END-INFLATION OCCLUSION METHOD IN THE RAT
Authors: RUBINI ALESSANDRO , CATENA VINCENZO , MONTE DANIELE DEL , CARNIEL EMANUELE LUIGI 
Published: January 2015

The temperature of body fluids is expected to affect tissues mechanical properties, including respiratory system tissues. This is because of the changes in airway smooth muscle tone and contractile properties, influencing airway frictional resistance to airflow, and because of the temperature effects on the stress–strain relationships of elastin and collagen, which determinates the elastic behavior of the lungs as reflected by their pressure–volume relationship. Alveolar surfactant biological and physical properties have also been shown to be affected by temperature changes, suggesting influences on the respiratory system hysteretic properties. Experimental works describing the effects of body temperature variations on respiratory mechanics are reviewed, including recent findings dealing with investigations on respiratory mechanics carried out by the end-inflation occlusion method in the rat. This method allows to determine, together with the elastance of the respiratory system, its resistive properties too. In particular, both the ohmic airway resistance due to frictional forces in the airway and the additional visco-elastic resistance exerted because of tissues stress-relaxation may be quantified. The effects of body temperature variations were assessed, and experimentally induced temperature increments and/or decrements allowed to conclude that respiratory system tissues stiffness, both the ohmic and the stress-relaxation linked resistances, and the hysteretic behavior of the respiratory system, decrease with temperature increments. The mechanisms responsible for these effects are analyzed.
RAGE Mediates S100A7-Induced Breast Cancer Growth and Metastasis by Modulating the Tumor Microenvironment
Authors: Nasser Mohd W. , Wani Nissar Ahmad , Ahirwar Dinesh K. , Powell Catherine A. , Ravi Janani , Elbaz Mohamad , Zhao Helong , Padilla Laura , Zhang Xiaoli , Shilo Konstantin , Ostrowski Michael , Shapiro Charles , Carson William E. , Ganju Ramesh K. 
Published: January 2015

Abstract
RAGE is a multifunctional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer (TNBC) cells, both in primary tumors and in lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found that RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the proinflammatory ligand S100A7 and mediated its ability to activate ERK, NF-κB, and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for TNBCs, and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development. Cancer Res; 75(6); 974–85. ©2015 AACR.
Effective Targeting of the P53–MDM2 Axis in Preclinical Models of Infant MLL-Rearranged Acute Lymphoblastic Leukemia
Authors: Richmond Jennifer , Carol Hernan , Evans Kathryn , High Laura , Mendomo Agnes , Robbins Alissa , Meyer Claus , Venn Nicola C. , Marschalek Rolf , Henderson Michelle , Sutton Rosemary , Kurmasheva Raushan T. , Kees Ursula R. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B. 
Published: January 2015

Abstract
Purpose: Although the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor-suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts.
Experimental Design: Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell-cycle arrest, and apoptosis in vivo was evaluated.
Results: Gene-expression analysis revealed that MLL-ALL, B-lineage ALL, and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be overexpressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly upregulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 upregulation, cell-cycle arrest, and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft.
Conclusions: The utility of targeting the p53–MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation. Clin Cancer Res; 21(6); 1395–405. ©2015 AACR.
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: January 2015

Abstract
Purpose: CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin–radiotherapy in the treatment of HNSCC.
Experimental Design: CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m2 every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks.
Results: Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-negative. The MTD of CUDC-101–based combination therapy was established at 275 mg/m2/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression.
Conclusions: CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration. Clin Cancer Res; 21(7); 1566–73. ©2015 AACR.
Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells
Authors: Zhang Yan , Wang Qing , Chen Li , Yang Hsin-Sheng 
Published: January 2015

Abstract
Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single-agent targeting IGF-1R, attempts in later studies failed because of resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor OSI-906 in colorectal cancer cells and the mechanism underlying this impact. Using OSI-906–resistant and –sensitive colorectal cancer cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a colorectal cancer xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured colorectal cancer cells. Furthermore, the combination of OSI-906 and PF-4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906–resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to the IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in colorectal cancer cells in vitro and in vivo, providing a novel venue to overcome the resistance to the IGF-1R inhibitor in treating colorectal cancer. Mol Cancer Ther; 14(3); 799–809. ©2015 AACR.
Mutant p53 Amplifies Epidermal Growth Factor Receptor Family Signaling to Promote Mammary Tumorigenesis
Authors: Yallowitz Alisha R. , Li Dun , Lobko Anthony , Mott Daniel , Nemajerova Alice , Marchenko Natalia 
Published: January 2015

Abstract
The EGFR family (ErbB2/Her2 and EGFR/ErbB1/Her1) often modulates the transcriptional program involved in promoting mammary tumorigenesis. In humans, the majority of ErbB2-positive sporadic breast cancers harbor p53 mutations, which correlate with poor prognosis. Also, the extremely high incidence of ErbB2-positive breast cancer in women with p53 germline mutations (Li–Fraumeni syndrome) suggests a key role of mutant p53 specifically in ErbB2-mediated mammary tumorigenesis. To examine the role of mutant p53 during ErbB2-mediated mammary tumorigenesis, a mutant p53 allele (R172H) was introduced into the (MMTV)-ErbB2/Neu mouse model system. Interestingly, we show in heterozygous p53 mice that mutant p53 R172H is a more potent activator of ErbB2-mediated mammary tumorigenesis than simple loss of p53. The more aggressive disease in mutant p53 animals was reflected by earlier tumor onset, increased mammary tumor multiplicity, and shorter survival. These in vivo and in vitro data provide mechanistic evidence that mutant p53 amplifies ErbB2 and EGFR signaling to promote the expansion of mammary stem cells and induce cell proliferation.
Implications: This study identifies mutant p53 as an essential player in ErbB2 and EGFR-mediated mammary tumorigenesis and indicates the potential translational importance of targeting mutant p53 in this subset of patients with breast cancer. Mol Cancer Res; 13(4); 743–54. ©2015 AACR.
Autophagy Supports Breast Cancer Stem Cell Maintenance by Regulating IL6 Secretion
Authors: Maycotte Paola , Jones Kenneth L. , Goodall Megan L. , Thorburn Jacqueline , Thorburn Andrew 
Published: January 2015

Abstract
Autophagy is a mechanism by which cells degrade cellular material to provide nutrients and energy for survival during stress. The autophagy is thought to be a critical process for cancer stem cell (CSC) or tumor-initiating cell maintenance but the mechanisms by which autophagy supports survival of CSCs remain poorly understood. In this study, inhibition of autophagy by knockdown of ATG7 or BECN1 modified the CD44+/CD24low/− population in breast cancer cells by regulating CD24 and IL6 secretion. In a breast cancer cell line that is independent of autophagy for survival, autophagy inhibition increased IL6 secretion to the media. On the other hand, in an autophagy-dependent cell line, autophagy inhibition decreased IL6 secretion, cell survival, and mammosphere formation. In these cells, IL6 treatment or conditioned media from autophagy-competent cells rescued the deficiency in mammosphere formation induced by autophagy inhibition. These results reveal that autophagy regulates breast CSC maintenance in autophagy-dependent breast cancer cells by modulating IL6 secretion implicating autophagy as a potential therapeutic target in breast cancer.
Implications: Modulation of autophagy in breast cancer has different and even opposite effects, indicating the need for a selection strategy when trying to manipulate autophagy in the context of cancer therapy. Mol Cancer Res; 13(4); 651–8. ©2015 AACR.
The Antigenic Repertoire of Premalignant and High-Risk Lesions
Authors: Marquez Juan Pablo , Stanton Sasha E. , Disis Mary L. 
Published: January 2015

Abstract
Prophylactic vaccines have been a major advance in preventing the development of infections after exposure to pathogens. When contemplating an effective approach to cancer prevention, vaccines offer unique advantages over other more standard approaches: First, once appropriately stimulated, antigen-specific T cells will travel to all sites of disease and eradicate cells bearing the proteins to which the T cells have been primed by vaccination. Second, successful immunization will further result in the development of immunologic memory, providing lifelong immunologic surveillance. There is evidence of an adaptive tumor immune infiltrate even at the earliest stages of breast and colon cancer development. Furthermore, there is measurable immunity to lesion-associated antigens present in patients who will eventually develop malignancy even before cancer is clinically evident. Recent studies are beginning to unmask the preinvasive antigenic repertoire for these two malignancies. Preliminary experiments in transgenic mouse models of mammary and intestinal tumors suggest that immunization against antigens expressed in preinvasive and high-risk lesions may be effective in preventing the development of invasive malignancy. Cancer Prev Res; 8(4); 266–70. ©2015 AACR.
JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response
Authors: Kleppe Maria , Kwak Minsuk , Koppikar Priya , Riester Markus , Keller Matthew , Bastian Lennart , Hricik Todd , Bhagwat Neha , McKenney Anna Sophia , Papalexi Efthymia , Abdel-Wahab Omar , Rampal Raajit , Marubayashi Sachie , Chen Jonathan J. , Romanet Vincent , Fridman Jordan S. , Bromberg Jacqueline , Teruya-Feldstein Julie , Murakami Masato , Radimerski Thomas , Michor Franziska , Fan Rong , Levine Ross L. 
Published: January 2015

AbstractThe identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations.Significance: Our results demonstrate that JAK–STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs. Cancer Discov; 5(3); 316–31. ©2015 AACR.See related commentary by Belver and Ferrando, p. 234This article is highlighted in the In This Issue feature, p. 213