bluuebunny/crossref_metadata_2025_split huggingface dataset:
USEFULNESS OF BRAIDED POLYBLEND POLYETHYLENE SUTURE MATERIAL FOR FLEXOR TENDON REPAIR IN ZONE II BY THE SIDE-LOCKING LOOP TECHNIQUE
Authors: Ryoke Koji , Uchio Yuji , Yamagami Nobuo , Kuwata Suguru , Nozaki Kenji , Yamamoto Soichiro , Tsujimoto Yumiko 
Published: May 2014

Flexor tendon injuries in zone II were treated in 14 fingers of 13 patients with our method. Firstly, a 2-strand core suture was made by the side-locking loop technique using a USP 2-0-sized braided polyblend polyethylene suture, then 7-strand peripheral cross-stitches were added using a USP 5-0-sized monofilament nylon suture. Post-operative exercises included passive flexion and extension without external fixation on the next day of surgery. Average follow-up observation period was 18 months. As results, the Strickland method of assessment for surgical outcome showed excellent in eight digits and good in five digits, though there was a poor outcome in one digit. Our suture method enabled early post-operative mobilisation exercise without using a splint, while preventing adhesion between the repaired tendon and peripheral tissues, which is considered to provide far greater ultimate tensile strength and a smaller gap at the sutured site than by the conventional method.
Genomic Rearrangements Define Lineage Relationships between Adjacent Lepidic and Invasive Components in Lung Adenocarcinoma
Authors: Murphy Stephen J. , Wigle Dennis A. , Lima Joema Felipe , Harris Faye R. , Johnson Sarah H. , Halling Geoffrey , Asiedu Michael K. , Seto Charlie T. , Terra Simone , Kosari Farhad , Peikert Tobias , Yang Ping , Aubry Marie-Christine , Vasmatzis George 
Published: May 2014

AbstractThe development of adenocarcinoma of the lung is believed to proceed from in situ disease (adenocarcinoma in situ, AIS) to minimally invasive disease with prominent lepidic growth (minimally invasive adenocarcinoma, MIA), then to fully invasive adenocarcinoma (AD), but direct evidence for this model has been lacking. Because some lung adenocarcinomas show prominent lepidic growth (AD-L), we designed a study to address the lineage relationship between the lepidic (noninvasive) component (L) and the adjacent nonlepidic growth component representing invasive disease within individual tumors. Lineage relationships were evaluated by next-generation DNA sequencing to define large genomic rearrangements in microdissected tissue specimens collected by laser capture. We found a strong lineage relationship between the majority of adjacent lepidic and invasive components, supporting a putative AIS–AD transition. Notably, many rearrangements were detected in the less aggressive lepidic component, although the invasive component exhibited an overall higher rate of genomic rearrangement. Furthermore, a significant number of genomic rearrangements were present in histologically normal lung adjacent to tumor, but not in host germline DNA, suggesting field defects restricted to zonal regions near a tumor. Our results offer a perspective on the genetic pathogenesis underlying adenocarcinoma development and its clinical management. Cancer Res; 74(11); 3157–67. ©2014 AACR.
miR-155 Drives Telomere Fragility in Human Breast Cancer by Targeting TRF1
Authors: Dinami Roberto , Ercolani Cristiana , Petti Eleonora , Piazza Silvano , Ciani Yari , Sestito Rosanna , Sacconi Andrea , Biagioni Francesca , le Sage Carlos , Agami Reuven , Benetti Roberta , Mottolese Marcella , Schneider Claudio , Blandino Giovanni , Schoeftner Stefan 
Published: May 2014

Abstract
Telomeres consist of DNA tandem repeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved sequence motif in the 3′UTR of TRF1, resulting in its translational repression. miR-155 was upregulated commonly in breast cancer specimens, as associated with reduced TRF1 protein expression, metastasis-free survival, and relapse-free survival in estrogen receptor–positive cases. Modulating miR-155 expression in cells altered TRF1 levels and TRF1 abundance at telomeres. Compromising TRF1 expression by elevating miR-155 increased telomere fragility and altered the structure of metaphase chromosomes. In contrast, reducing miR-155 levels improved telomere function and genomic stability. These results implied that miR-155 upregulation antagonizes telomere integrity in breast cancer cells, increasing genomic instability linked to poor clinical outcome in estrogen receptor–positive disease. Our work argued that miRNA-dependent regulation of shelterin function has a clinically significant impact on telomere function, suggesting the existence of “telo-miRNAs” that have an impact on cancer and aging. Cancer Res; 74(15); 4145–56. ©2014 AACR.
A Recombinant Reporter System for Monitoring Reactivation of an Endogenously DNA Hypermethylated Gene
Authors: Cui Ying , Hausheer Frederick , Beaty Robert , Zahnow Cynthia , Issa Jean Pierre , Bunz Frederick , Baylin Stephen B. 
Published: May 2014

Abstract
Reversing abnormal gene silencing in cancer cells due to DNA hypermethylation of promoter CpG islands may offer new cancer prevention or therapeutic approaches. Moreover, such approaches may be broadly applicable to enhance the efficacy of radiotherapy, chemotherapy, or immunotherapy. Here, we demonstrate the powerful utility of a novel gene reporter system to permit studies of the dynamics, mechanisms, and translational relevance of candidate therapies of this type in human colon cancer cells. The reporter system is based on in situ modification of the endogenous locus of the tumor-suppressor gene SFRP1, a pivotal regulator of the Wnt pathway that is silenced by DNA hypermethylation in many colon cancers. The modified SFRP1-GFP reporter allele used remained basally silent, like the unaltered allele, and it was activated only by drug treatments that derepress gene silencing by reversing DNA hypermethylation. We used the established DNA methyltransferase inhibitor (DNMTi) 5-aza-deoxycitidine (DAC) to show how this system can be used to address key questions in the clinical development of epigenetic cancer therapies. First, we defined conditions for which clinically relevant dosing could induce sustained induction of RNA and protein. Second, we found that, in vivo, a more prolonged drug exposure than anticipated was essential to derepress gene silencing in significant cell numbers, and this has implications for generating effective anticancer responses in patients with hematopoietic or solid tumors. Finally, we discovered how histone deacetylase inhibitors (HDACi) alone, when administered to cells actively replicating DNA, can robustly reexpress the silenced gene with no change in promoter methylation status. Taken together, our findings offer a new tool and insights for devising optimal clinical experiments to evaluate DNMTi and HDACi, alone or in combination, and with other cancer treatments, as agents for the epigenetic management and prevention of cancer. Cancer Res; 74(14); 3834–43. ©2014 AACR.
Breast Cancer Risk after Occupational Solvent Exposure: the Influence of Timing and Setting
Authors: Ekenga Christine C. , Parks Christine G. , D'Aloisio Aimee A. , DeRoo Lisa A. , Sandler Dale P. 
Published: May 2014

Abstract
Organic solvents are ubiquitous in occupational settings where they may contribute to risks for carcinogenesis. However, there is limited information on organic solvents as human breast carcinogens. We examined the relationship between occupational exposure to solvents and breast cancer in a prospective study of 47,661 women with an occupational history in the Sister Study cohort. Occupational solvent exposure was categorized using self-reported job-specific solvent use collected at baseline. Multivariable Cox regression analyses were used to assess breast cancer risk, adjusting for established breast cancer risk factors. A total of 1,798 women were diagnosed with breast cancer during follow-up, including 1,255 invasive cases. Overall the risk of invasive breast cancer was not associated with lifetime exposure to solvents [HR, 1.04; 95% confidence interval (CI), 0.88–1.24]. Parous women who worked with solvents before their first full-term birth had an increased risk of estrogen receptor–positive invasive breast cancer compared with women who never worked with solvents (HR, 1.39; 95% CI, 1.03–1.86). A significantly elevated risk for estrogen receptor–positive invasive breast cancer was associated with solvent exposure among clinical laboratory technologists and technicians (HR, 2.00; 95% CI, 1.07–3.73). Occupational exposure to solvents before first birth, a critical period of breast tissue differentiation, may result in increased vulnerability for breast cancer. Our findings suggest a need for future studies in this area to focus on exposure time windows and solvent types in different occupational settings. Cancer Res; 74(11); 3076–83. ©2014 AACR.
Long-term Ultraviolet Flux, Other Potential Risk Factors, and Skin Cancer Risk: A Cohort Study
Authors: Wu Shaowei , Han Jiali , Laden Francine , Qureshi Abrar A. 
Published: May 2014

Abstract
Background: Few prospective studies have examined the relationship between sun exposure, other potential risk factors, and risk of different skin cancers [including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma] simultaneously.
Methods: We evaluated the association between a number of potential risk factors and skin cancer risk in a cohort of 108,916 US women, the Nurses' Health Study II (1989–2009).
Results: During 2.05 million years of follow-up, we identified 6,955, 880, and 779 diagnoses of BCC, SCC, and melanoma, respectively. Compared with participants in the lowest quintile of cumulative ultraviolet flux in adulthood, participants in the highest quintile had multivariable-adjusted relative risks (RR) of 2.35 (Ptrend &lt; 0.0001) for BCC, 2.53 (Ptrend = 0.009) for SCC, and 0.68 (Ptrend = 0.38) for melanoma. In contrast, the RRs were 1.68 (95% CI, 1.55–1.82) for BCC, 1.68 (95% CI, 1.34–2.11) for SCC, and 1.80 (95% CI, 1.42–2.28) for melanoma for participants with ≥5 blistering sunburns when compared with participants without sunburn between ages 15 and 20 years. We found significant interactions between family history of melanoma, number of blistering sunburns between ages 15 and 20 years and BCC risk, and between sunburn reaction as a child/adolescent and SCC risk (all Pinteraction &lt; 0.05).
Conclusion: In a cohort of U.S. women, we found that sun exposures in both early life and adulthood were predictive of BCC and SCC risks, whereas melanoma risk was predominantly associated with sun exposure in early life.
Impact: Our results may have potential implications for the prevention of skin cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1080–9. ©2014 AACR.
Galeterone Prevents Androgen Receptor Binding to Chromatin and Enhances Degradation of Mutant Androgen Receptor
Authors: Yu Ziyang , Cai Changmeng , Gao Shuai , Simon Nicholas I. , Shen Howard C. , Balk Steven P. 
Published: May 2014

Abstract
Purpose: Galeterone inhibits the enzyme CYP17A1 and is currently in phase II clinical trials for castration-resistant prostate cancer (CRPC). Galeterone is also a direct androgen receptor (AR) antagonist and may enhance AR degradation. This study was undertaken to determine the molecular basis for AR effects and their therapeutic potential.
Experimental Design: Effects of galeterone on AR expression and activities were examined in prostate cancer cell lines.
Results: Similar to the AR antagonist enzalutamide, but in contrast to bicalutamide, galeterone did not induce binding of a constitutively active VP16-AR fusion protein to reporter genes and did not induce AR recruitment to endogenous androgen-regulated genes based on chromatin immunoprecipitation. Galeterone at low micromolar concentrations that did not induce cellular stress responses enhanced AR protein degradation in LNCaP and C4-2 cells, which express a T878A mutant AR, but not in prostate cancer cells expressing wild-type AR. Further transfection studies using stable LNCaP and PC3 cell lines ectopically expressing wild-type or T878A-mutant ARs confirmed that galeterone selectively enhances degradation of the T878A-mutant AR.
Conclusions: Similar to enzalutamide, galeterone may be effective as a direct AR antagonist in CRPC. It may be particularly effective against prostate cancer cells with the T878A AR mutation but may also enhance degradation of wild-type AR in vivo through a combination of direct and indirect mechanisms. Finally, these findings show that conformational changes in AR can markedly enhance its degradation and thereby support efforts to develop further antagonists that enhance AR degradation. Clin Cancer Res; 20(15); 4075–85. ©2014 AACR.
Selective Protection of Normal Cells during Chemotherapy by RY4 Peptides
Authors: Wu Xiao-Rong , Liu Lihua , Zhang Zhi-Fu , Zhang Bing , Sun Hongzhe , Chan Gerald L. , Li Na 
Published: May 2014

Abstract
Mitochondrial targeted Szeto-Schiller (SS) peptides have recently gained attention for their antioxidative stress ability; however, the functional variations between normal and cancer cells have not been determined. Here, we report the results of such experiments conducted with a newly designed class of peptide called RY4, which is based on SS peptide sequence characteristics. The RY4 peptide exhibits distinct differences in antioxidative stress response between normal and cancer cells when challenged with chemotherapeutics like the glycolytic inhibitor dichloroacetate (DCA), the platinating agent carboplatin, and the DNA damage inducer doxorubicin. Interestingly, only normal human cells were protected by the RY4 peptide and catalase (CAT) activity was significantly enhanced in normal but not tumor cells when incubated with RY4. Pull-down, coimmunoprecipitation, and LC/MS-MS proteomic analysis demonstrated that RY4 and catalase are capable of forming protein complexes. Finally, in vivo efficacy was evaluated by intraperitoneal administration of RY4 into a lung cancer xenograft model, which revealed significant myocardiocyte protection from doxorubicin-induced cardiotoxicity without diminishing doxorubicin's tumoricidal effects. Taken together, RY4 offers selective protection to normal cells from chemotherapy-induced toxicity by enhancing the activity of cellular antioxidant enzymes.
Implications: RY4 peptides selectively reduce chemotherapeutic-induced oxidative stress and represent a new class of chemoprotective agents with clinical potential. Mol Cancer Res; 12(10); 1365–76. ©2014 AACR.
NSD3–NUT Fusion Oncoprotein in NUT Midline Carcinoma: Implications for a Novel Oncogenic Mechanism
Authors: French Christopher A. , Rahman Shaila , Walsh Erica M. , Kühnle Simone , Grayson Adlai R. , Lemieux Madeleine E. , Grunfeld Noam , Rubin Brian P. , Antonescu Cristina R. , Zhang Songlin , Venkatramani Rajkumar , Dal Cin Paola , Howley Peter M. 
Published: May 2014

Abstract
NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell carcinoma that typically harbors BRD4/3–NUT fusion oncoproteins that block differentiation and maintain tumor growth. In 20% of cases, NUT is fused to uncharacterized non-BRD gene(s). We established a new patient-derived NMC cell line (1221) and demonstrated that it harbors a novel NSD3–NUT fusion oncogene. We find that NSD3–NUT is both necessary and sufficient for the blockade of differentiation and maintenance of proliferation in NMC cells. NSD3–NUT binds to BRD4, and BRD bromodomain inhibitors induce differentiation and arrest proliferation of 1221 cells. We find further that NSD3 is required for the blockade of differentiation in BRD4–NUT-expressing NMCs. These findings identify NSD3 as a novel critical oncogenic component and potential therapeutic target in NMC.
Significance: The existence of a family of fusion oncogenes in squamous cell carcinoma is unprecedented, and should lead to key insights into aberrant differentiation in NMC and possibly other squamous cell carcinomas. The involvement of the NSD3 methyltransferase as a component of the NUT fusion protein oncogenic complex identifies a new potential therapeutic target. Cancer Discov; 4(8); 928–41. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 855
Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations
Authors: Yang Annan , Rajeshkumar N.V. , Wang Xiaoxu , Yabuuchi Shinichi , Alexander Brian M. , Chu Gerald C. , Von Hoff Daniel D. , Maitra Anirban , Kimmelman Alec C. 
Published: May 2014

Abstract
Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patient-derived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status.
Significance: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials. Cancer Discov; 4(8); 905–13. ©2014 AACR.
See related commentary by Amaravadi and Debnath, p. 873
This article is highlighted in the In This Issue feature, p. 855
Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
Authors: Karsli-Uzunbas Gizem , Guo Jessie Yanxiang , Price Sandy , Teng Xin , Laddha Saurabh V , Khor Sinan , Kalaany Nada Y. , Jacks Tyler , Chan Chang S. , Rabinowitz Joshua D. , White Eileen 
Published: May 2014

Abstract
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer.
Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers. Cancer Discov; 4(8); 914–27. ©2014 AACR.
See related commentary by Amaravadi and Debnath, p. 873
This article is highlighted in the In This Issue feature, p. 855
Estrogen Effects on Vascular Inflammation Are Age Dependent
Authors: Bowling Meaghan R. , Xing Dongqi , Kapadia Akash , Chen Yiu-Fai , Szalai Alexander J. , Oparil Suzanne , Hage Fadi G. 
Published: May 2014

Objective—
17β-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones performed in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age dependent.

Approach and Results—
Young (10 weeks) and aged (52 weeks) female C57BL/6 mice were used as source for primary cultures of bone marrow–derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pretreatment of cells derived from young mice attenuated C-reactive protein (CRP)–induced expression of inflammatory mediators. In contrast, E2 pretreatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER) knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERβ. BMMs derived from aged (versus young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice.

Conclusions—
E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women.