bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas
Authors: Bouillez Audrey , Rajabi Hasan , Pitroda Sean , Jin Caining , Alam Maroof , Kharbanda Akriti , Tagde Ashujit , Wong Kwok-Kin , Kufe Donald 
Published: February 2016

Abstract
Dysregulation of MYC expression is a hallmark of cancer, but the development of agents that target MYC has remained challenging. The oncogenic MUC1-C transmembrane protein is, like MYC, aberrantly expressed in diverse human cancers. The present studies demonstrate that MUC1-C induces MYC expression in KRAS mutant non–small cell lung cancer (NSCLC) cells, an effect that can be suppressed by targeting MUC1-C via shRNA silencing, CRISPR editing, or pharmacologic inhibition with GO-203. MUC1-C activated the WNT/β-catenin (CTNNB1) pathway and promoted occupancy of MUC1-C/β-catenin/TCF4 complexes on the MYC promoter. MUC1-C also promoted the recruitment of the p300 histone acetylase (EP300) and, in turn, induced histone H3 acetylation and activation of MYC gene transcription. We also show that targeting MUC1-C decreased the expression of key MYC target genes essential for the growth and survival of NSCLC cells, such as TERT and CDK4. Based on these results, we found that the combination of GO-203 and the BET bromodomain inhibitor JQ1, which targets MYC transcription, synergistically suppressed MYC expression and cell survival in vitro as well as tumor xenograft growth. Furthermore, MUC1 expression significantly correlated with that of MYC and its target genes in human KRAS mutant NSCLC tumors. Taken together, these findings suggest a therapeutic approach for targeting MYC-dependent cancers and provide the framework for the ongoing clinical studies addressing the efficacy of MUC1-C inhibition in solid tumors. Cancer Res; 76(6); 1538–48. ©2016 AACR.
The Cancer Stem Cell Fraction in Hierarchically Organized Tumors Can Be Estimated Using Mathematical Modeling and Patient-Specific Treatment Trajectories
Authors: Werner Benjamin , Scott Jacob G. , Sottoriva Andrea , Anderson Alexander R.A. , Traulsen Arne , Altrock Philipp M. 
Published: February 2016

Abstract
Many tumors are hierarchically organized and driven by a subpopulation of tumor-initiating cells (TIC), or cancer stem cells. TICs are uniquely capable of recapitulating the tumor and are thought to be highly resistant to radio- and chemotherapy. Macroscopic patterns of tumor expansion before treatment and tumor regression during treatment are tied to the dynamics of TICs. Until now, the quantitative information about the fraction of TICs from macroscopic tumor burden trajectories could not be inferred. In this study, we generated a quantitative method based on a mathematical model that describes hierarchically organized tumor dynamics and patient-derived tumor burden information. The method identifies two characteristic equilibrium TIC regimes during expansion and regression. We show that tumor expansion and regression curves can be leveraged to infer estimates of the TIC fraction in individual patients at detection and after continued therapy. Furthermore, our method is parameter-free; it solely requires the knowledge of a patient's tumor burden over multiple time points to reveal microscopic properties of the malignancy. We demonstrate proof of concept in the case of chronic myeloid leukemia (CML), wherein our model recapitulated the clinical history of the disease in two independent patient cohorts. On the basis of patient-specific treatment responses in CML, we predict that after one year of targeted treatment, the fraction of TICs increases 100-fold and continues to increase up to 1,000-fold after 5 years of treatment. Our novel framework may significantly influence the implementation of personalized treatment strategies and has the potential for rapid translation into the clinic. Cancer Res; 76(7); 1705–13. ©2016 AACR.
Micrometastasis Volume in Lymph Nodes Determines Disease Recurrence Rate of Stage II Colorectal Cancer: A Prospective Multicenter Trial
Authors: Yamamoto Hirofumi , Murata Kohei , Fukunaga Mutsumi , Ohnishi Tadashi , Noura Shingo , Miyake Yasuhiro , Kato Takeshi , Ohtsuka Masahisa , Nakamura Yurika , Takemasa Ichiro , Mizushima Tsunekazu , Ikeda Masataka , Ohue Masayuki , Sekimoto Mitsugu , Nezu Riichiro , Matsuura Nariaki , Monden Morito , Doki Yuichiro , Mori Masaki 
Published: February 2016

Abstract
Purpose: We reported in a retrospective study that the presence of micrometastasis in lymph nodes, when assessed by carcinoembryonic antigen (CEA)-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer. The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial.
Experimental Design: From November 2001 to December 2005, a total of 419 colorectal cancer cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II colorectal cancer cases were enrolled. After RNA quality check, 304 colorectal cancer cases were analyzed for CEA mRNA in lymph nodes by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method.
Results: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Postoperative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-fluorouracil derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for 1 year, whereas chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (high MMV, n = 95) was an independent poor prognostic factor for 5-year disease-free survival (DFS; P = 0.001) and 5-year overall survival (OS; P = 0.016).
Conclusions: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II colorectal cancer. Clin Cancer Res; 22(13); 3201–8. ©2016 AACR.
Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma
Authors: Kwiatkowski David J. , Choueiri Toni K. , Fay André P. , Rini Brian I. , Thorner Aaron R. , de Velasco Guillermo , Tyburczy Magdalena E. , Hamieh Lana , Albiges Laurence , Agarwal Neeraj , Ho Thai H. , Song Jiaxi , Pignon Jean-Christophe , Barrios Pablo M. , Michaelson M. Dror , Van Allen Eliezer M. , Krajewski Katherine M. , Porta Camillo , Pal Sumanta Kumar , Bellmunt Joaquim , McDermott David F. , Heng Daniel Y.C. , Gray Kathryn P. , Signoretti Sabina 
Published: February 2016

Abstract
Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).
Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.
Results: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.
Conclusions: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445–52. ©2016 AACR.
See related commentary by Voss and Hsieh, p. 2320
Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress
Authors: Wang Chun Yan , Guo Su Tang , Wang Jia Yu , Liu Fen , Zhang Yuan Yuan , Yari Hamed , Yan Xu Guang , Jin Lei , Zhang Xu Dong , Jiang Chen Chen 
Published: February 2016

Abstract
Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy. Mol Cancer Ther; 15(3); 448–59. ©2016 AACR.
The Case for a Pre-Cancer Genome Atlas (PCGA)
Authors: Campbell Joshua D. , Mazzilli Sarah A. , Reid Mary E. , Dhillon Samjot S. , Platero Suso , Beane Jennifer , Spira Avrum E. 
Published: February 2016

Abstract
Understanding the earliest molecular and cellular events associated with cancer initiation remains a key bottleneck to transforming our approach to cancer prevention and detection. While TCGA has provided unprecedented insights into the genomic events associated with advanced stage cancer, there have been few studies comprehensively profiling premalignant and early-stage disease or elucidating the role of the microenvironment in premalignancy and tumor initiation. In this article, we make a call for development of a “Pre-Cancer Genome Atlas (PCGA),” a concerted initiative to characterize the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment associated with progression to invasive carcinoma. This initiative will require a multicenter coordinated effort to comprehensively profile (cellular and molecular) premalignant lesions and their corresponding “field of injury” collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types. Genomic characterization of alterations in premalignant lesions and their microenvironment, for both bulk tissue and single cells, will enable development of biomarkers for early detection and risk stratification as well as allow for the development of novel targeted cancer interception strategies. The multi-institutional and multidisciplinary collaborative “big-data” effort underlying the PCGA will help usher in a new era of precision medicine for cancer detection and prevention. Cancer Prev Res; 9(2); 119–24. ©2016 AACR.
Attitudes towards depression, psychiatric medication and help-seeking intentions amid financial crisis: Findings from Athens area
Authors: Economou Marina , Bergiannaki Joanna Despina , Peppou Lily Evangelia , Karayanni Ismini , Skalkotos George , Patelakis Athanasios , Souliotis Kyriakos , Stefanis Costas 
Published: February 2016

Background: The financial crisis has yielded adverse effects on the population worldwide, as evidenced by elevated rates of major depression. International recommendations for offsetting the mental health impact of the recession highlight the need for effective treatment, including reduction in the stigma attached to the disorder. Aims: This study endeavoured to explore lay attitudes to depression and psychiatric medication during a period of financial crisis and to identify their correlates. Furthermore, it investigated their link to help-seeking intentions. Method: A random and representative sample of 621 respondents from Athens area participated in the study (Response Rate = 81.7%). The telephone interview schedule consisted of the Personal Stigma Scale, a self-constructed scale tapping attitudes to psychiatric medication and one question addressing help-seeking intentions. Results: The preponderant stigmatising belief about depression pertains to perceiving the disorder as a sign of personal weakness. In addition, stereotypes of unpredictability and dangerousness were popular among the sample. Nonetheless, stigmatising beliefs are much stronger with regard to psychiatric medication; perceived as addictive, capable of altering one’s personality, less effective than homeopathic remedies and doing more harm than good. Help-seeking intentions were predicted by education, unemployment and attitudes to psychiatric medication solely. Conclusion: Research on the mental health effects of the global recession should encompass studies investigating the stigma attached to mental disorders and its implications.
Intra-articular Autologous Conditioned Plasma Injections Provide Safe and Efficacious Treatment for Knee Osteoarthritis
Authors: Smith Patrick A. 
Published: February 2016

Background: Platelet-rich plasma (PRP) injections have become an intriguing treatment option for osteoarthritis (OA), particularly OA of the knee. Despite the plethora of PRP-related citations, there is a paucity of high-level evidence that is comparable, cohort specific, dose controlled, injection protocol controlled, and double-blinded. Purpose: To determine the safety and efficacy of leukocyte-poor PRP autologous conditioned plasma (ACP) for knee OA treatment through a feasibility trial regulated by the US Food and Drug Administration (FDA). Study Design: Randomized controlled trial; Level of evidence, 1. Methods: In accordance with FDA protocol, patient selection was based on strict inclusion/exclusion criteria; 114 patients were screened, and 30 were ultimately included in the study. These patients were randomized to receive either ACP (n = 15) or saline placebo (n = 15) for a series of 3 weekly injections. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores served as the primary efficacy outcome measure. Patients were followed for 1 year. Results: No adverse events were reported for ACP administration. Furthermore, the results demonstrated no statistically significant difference in baseline WOMAC scores between the 2 groups. However, in the ACP group, WOMAC scores at 1 week were significantly decreased compared with baseline scores, and the scores for this group remained significantly lower throughout the study duration. At the study conclusion (12 months), subjects in the ACP group had improved their overall WOMAC scores by 78% from their baseline score, compared with 7% for the placebo group. Conclusion: ACP is safe and provides quantifiable benefits for pain relief and functional improvement with regard to knee OA. No adverse events were reported for ACP administration. After 1 year, WOMAC scores for the ACP subjects had improved by 78% from their baseline score, whereas scores for the placebo control group had improved by only 7%. Other joints affected with OA may also benefit from this treatment.
Gender difference in effect of positive emotion on consolidation of memory for definitions of English vocabulary
Authors: Wang Bo 
Published: February 2016

Research questions: This study examined gender difference in the effect of post-learning positive emotion on consolidation of memory for definitions of English vocabulary. Methodology: A 2 (emotion group: neutral and positive) × 2 (gender: male and female) × 2 (emotion duration: 3 and 9 min) design was used. Participants memorized Chinese definitions of English words, took an immediate test, watched a neutral (lasting for 3 or 9 min) or positive (lasting for 3 or 9 min) video, and took a delayed memory test. Data and Analysis: Data of male ( n = 59) and female ( n = 67) participants were analyzed. For evaluation of emotion induction, a 3 (time: before watching, during watching, and after watching) × 2 (emotion group: neutral and positive) × 2 (gender: male and female) × 2 (emotion duration: 3 and 9 min) was respectively conducted on pleasure and arousal ratings. For memory performance, a similar analysis of variance without time as a factor was conducted. Findings: With a 3-min duration, positive emotion had little effect on memory consolidation. However, with a 9-min duration, positive emotion tended to impair memory consolidation for males but not for females. Originality: Extending the literature showing females’ superiority in memory for words and pictures, this study shows that female students also have memory advantage in English vocabulary. Furthermore, this is the first study suggesting that memory consolidation of male students is more likely to be disrupted by a relatively long duration of positive emotion after learning. Significance/implications: The current finding on gender difference may shed new light on employing emotion as a strategy of memory intervention. There seems to be a need to keep males rather than females from post-learning positive emotion, especially when emotion duration is relatively long.
Risk Stratification for Ulnar Collateral Ligament Injury in Major League Baseball Players
Authors: DeFroda Steven F. , Kriz Peter K. , Hall Amber M. , Zurakowski David , Fadale Paul D. 
Published: February 2016

Background: Ulnar collateral ligament (UCL) injury has become increasingly common in Major League Baseball (MLB) players in recent years. Hypothesis: There is a significant difference in preinjury fastball velocity between MLB pitchers with tears and matched controls without UCL injury. Pitchers with injuries are throwing harder and getting injured earlier in their MLB careers. Study Design: Cohort study; Level of evidence, 3. Methods: From 2007 to 2014, a total of 170 documented UCL injuries (156 pitchers, 14 position players) occurred in MLB. Inclusion criteria for this study consisted of any player who tore his UCL in MLB during this time frame. There were 130 regular-season tears (April-September). From this group, 118 players who pitched more than 100 innings prior to tear were matched to subjects with no tear and were compared using a logistic regression analysis. A subgroup of “early tear” players who threw less than 100 career innings (n = 37) was also identified and compared with the larger tear group using a logistic regression analysis. Results: Of the 130 tears that occurred during the regular season, a significantly larger number (62%) occurred in the first 3 months ( P = .011). The rate of UCL tears per MLB player ( P = .001) was statistically significant. In the group of 118 matched tears, the mean fastball velocity was greater in the tear group (91.7 mph) compared with the control group (91.0 mph; P = .014). Furthermore, relief pitchers made up a greater percentage of the early tear group (<100 innings) compared with the later tear group ( P = .011). Sixteen of the 170 UCL tears (9.4%) were recurrent tears, with 5 of 16 experiencing both tear and retear within the past 4 years. Conclusion: There is a statistically significant difference in the mean fastball velocity of pitchers who injure their UCL. Small increases in pitcher fastball velocity are a main contribution to the increased rate of tear in MLB. In addition, there has been an increased incidence of injury in the first 3 months of the season. Finally, early tears are more likely to occur in relief pitchers than starters.
The role of autologous stem cell transplantation in primary central nervous system lymphoma
Authors: Ferreri Andrés J. M. , Illerhaus Gerald 
Published: February 2016

Abstract
Primary central nervous system lymphoma (PCNSL) treatment includes 2 phases: induction and consolidation. Induction consists of high-dose methotrexate–based polychemotherapy for most patients, with regimen and dose variations according to patient characteristics and country. Several strategies have been proposed for the consolidation phase, with whole-brain irradiation (WBRT) the most common. However, some authorities recommend avoiding WBRT because of its related risk of severe neurotoxicity. The most relevant alternatives to WBRT are high-dose chemotherapy supported by autologous stem cell transplantation (HDC/ASCT) or nonmyeloablative chemotherapy, the former supported by several single-arm phase 2 trials. Moreover, HDC/ASCT is the only strategy that is assessed in comparison with WBRT in ongoing randomized trials. The rationale for using HDC/ASCT in PCNSL patients is based on the fact that the delivery of high doses could achieve therapeutic drug concentrations in the brain and cerebrospinal fluid, and that non–cross-resistant drugs used for conditioning (eg, alkylating agents) could favor elimination of residual chemoresistant lymphoma cells. Worldwide experience with HDC/ASCT is limited to few single-arm phase 2 trials, but overall results are encouraging, mostly when thiotepa-containing conditioning regimens are used, both in newly diagnosed and relapsed patients. However, several questions on efficacy and feasibility of HDC/ASCT, as well as the best candidates for this strategy, the optimal conditioning regimen, the best time for response assessment, and acute and late effects, remain unanswered. In this review, we critically analyze reported studies on HDC/ASCT in PCNSL and discuss its current role and future perspectives in treating this aggressive malignancy.