bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Usurps Skeletal Muscle as an Energy Repository
Authors: Luo Yi , Yoneda Junya , Ohmori Hitoshi , Sasaki Takamitsu , Shimbo Kazutaka , Eto Sachise , Kato Yumiko , Miyano Hiroshi , Kobayashi Tsuyoshi , Sasahira Tomonori , Chihara Yoshitomo , Kuniyasu Hiroki 
Published: November 2013

Abstract
Cancer cells produce energy through aerobic glycolysis, but contributions of host tissues to cancer energy metabolism are unclear. In this study, we aimed to elucidate the cancer–host energy production relationship, in particular, between cancer energy production and host muscle. During the development and progression of colorectal cancer, expression of the secreted autophagy-inducing stress protein HMGB1 increased in the muscle of tumor-bearing animals. This effect was associated with decreased expression of pyruvate kinase PKM1 and pyruvate kinase activity in muscle via the HMGB1 receptor for advanced glycation endproducts (RAGE). However, muscle mitochondrial energy production was maintained. In contrast, HMGB1 addition to colorectal cancer cells increased lactate fermentation. In the muscle, HMGB1 addition induced autophagy by decreasing levels of active mTOR and increasing autophagy-associated proteins, plasma glutamate, and 13C-glutamine incorporation into acetyl-CoA. In a mouse model of colon carcinogenesis, a temporal increase in HMGB1 occurred in serum and colonic mucosa with an increase in autophagy associated with altered plasma free amino acid levels, increased glutamine, and decreased PKM1 levels. These differences were abolished by administration of an HMGB1 neutralizing antibody. Similar results were obtained in a mouse xenograft model of human colorectal cancer. Taken together, our findings suggest that HMGB1 released during tumorigenesis recruits muscle to supply glutamine to cancer cells as an energy source. Cancer Res; 74(1); 330–40. ©2013 AACR.
Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering
Authors: Romero Ana I. , Chaput Nathalie , Poirier-Colame Vichnou , Rusakiewicz Sylvie , Jacquelot Nicolas , Chaba Kariman , Mortier Erwan , Jacques Yannick , Caillat-Zucman Sophie , Flament Caroline , Caignard Anne , Messaoudene Meriem , Aupérin Anne , Vielh Philippe , Dessen Philippe , Porta Camillo , Mateus Christine , Ayyoub Maha , Valmori Danila , Eggermont Alexander , Robert Caroline , Zitvogel Laurence 
Published: November 2013

Abstract
Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint–blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an “adjuvant” molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I–related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells. Cancer Res; 74(1); 68–80. ©2013 AACR.
14-3-3ζ Orchestrates Mammary Tumor Onset and Progression via miR-221–Mediated Cell Proliferation
Authors: Rehman Sumaiyah K. , Li Shau-Hsuan , Wyszomierski Shannon L. , Wang Qingfei , Li Ping , Sahin Ozgur , Xiao Yi , Zhang Siyuan , Xiong Yan , Yang Jun , Wang Hai , Guo Hua , Zhang Jitao D. , Medina Daniel , Muller William J. , Yu Dihua 
Published: November 2013

Abstract
14-3-3ζ is overexpressed in more than 40% of breast cancers, but its pathophysiologic relevance to tumorigenesis has not been established. Here, we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter-driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors, whereas control mice did not. Whey acidic protein promoter-driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared with MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling, leading to increased miR-221 transcription, which inhibited p27 CDKI translation and, consequently, promoted cell proliferation. Importantly, this 14-3-3ζ–miR-221–p27 proliferation axis is also functioning in breast tumors in patients and is associated with high-grade cancers. Taken together, our findings show that overexpression of 14-3-3ζ has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation. Cancer Res; 74(1); 363–73. ©2013 AACR.
Quantitative ER and PgR Assessment as Predictors of Benefit from Lapatinib in Postmenopausal Women with Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer
Authors: Finn Richard S. , Press Michael F. , Dering Judy , O'Rourke Lisa , Florance Allison , Ellis Catherine , Martin Anne-Marie , Johnston Stephen 
Published: November 2013

AbstractPurpose: Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 inhibitor, remains unproven in non–HER2-amplified metastatic breast cancer (MBC). EGF30008, a phase III trial of letrozole and lapatinib versus letrozole and placebo, demonstrated that lapatinib significantly improves outcome for postmenopausal women with HER2-amplified, but not HER2-negative, MBC. The hypothesis that low hormone receptor status is associated with benefit in this HER2-negative cohort was tested.Experimental Design: A blinded retrospective biomarker evaluation used immunohistochemistry (IHC) to semiquantify estrogen receptor (ER) and progesterone receptor (PgR) expression (n = 821/952). HER2 status was determined by IHC and confirmed by FISH (n = 326). Effects of these biomarkers on progression-free survival (PFS) were examined in patients with available tissue.Results: In HER2-negative, ER-positive MBC, median PFS was analyzed by ER and PgR expression (H-score) by quartile (Q). There was significant improvement in patients with low ER expression (Q1, H-score &lt;160) with lapatinib and letrozole (13.6 vs. 6.7 months; P = 0.01). No benefit was associated with stronger ER expression (Q2/3, H-score ≥160 and &lt;250; 13.6 vs. 14.2 months; Q4, H-score ≥250; 11.2 vs. 14.2 months). There was no association between PgR H-score and benefit from lapatinib.Conclusion: In postmenopausal patients with advanced hormone receptor–positive disease, weak ER expression is associated with worse outcome with letrozole treatment compared with the combination. The addition of lapatinib significantly improved PFS for this patient subgroup and augments data supporting interaction between steroid hormone and peptide hormone signaling. A prospective study validating this hypothesis is required. Clin Cancer Res; 20(3); 736–43. ©2013 AACR.
Metformin Inhibits Skin Tumor Promotion in Overweight and Obese Mice
Authors: Checkley L. Allyson , Rho Okkyung , Angel Joe M. , Cho Jiyoon , Blando Jorge , Beltran Linda , Hursting Stephen D. , DiGiovanni John 
Published: November 2013

Abstract
In the present study, the ability of metformin to inhibit skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was analyzed in mice maintained on either an overweight control diet or an obesity-inducing diet. Rapamycin was included for comparison, and a combination of metformin and rapamycin was also evaluated. Metformin (given in the drinking water) and rapamycin (given topically) inhibited development of both papillomas and squamous cell carcinomas in overweight and obese mice in a dose-dependent manner. A low-dose combination of these two compounds displayed an additive inhibitory effect on tumor development. Metformin treatment also reduced the size of papillomas. Interestingly, all treatments seemed to be at least as effective for inhibiting tumor formation in obese mice, and both metformin and rapamycin were more effective at reducing tumor size in obese mice compared with overweight control mice. The effect of metformin on skin tumor development was associated with a significant reduction in TPA-induced epidermal hyperproliferation. Furthermore, treatment with metformin led to activation of epidermal AMP-activated protein kinase (AMPK) and attenuated signaling through mTOR complex (mTORC)-1 and p70S6K. Combinations of metformin and rapamycin were more effective at blocking epidermal mTORC1 signaling induced by TPA consistent with the greater inhibitory effect on skin tumor promotion. Collectively, the current data demonstrate that metformin given in the drinking water effectively inhibited skin tumor promotion in both overweight and obese mice and that the mechanism involves activation of epidermal AMPK and attenuated signaling downstream of mTORC1. Cancer Prev Res; 7(1); 54–64. ©2013 AACR.
Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer
Authors: Paul Olson Terrah J. , Hadac Jamie N. , Sievers Chelsie K. , Leystra Alyssa A. , Deming Dustin A. , Zahm Christopher D. , Albrecht Dawn M. , Nomura Alice , Nettekoven Laura A. , Plesh Lauren K. , Clipson Linda , Sullivan Ruth , Newton Michael A. , Schelman William R. , Halberg Richard B. 
Published: November 2013

AbstractColorectal cancer often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which polyps progress and which remain benign is difficult. We developed a novel long-lived murine model of colorectal cancer with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk stratification of colonic tumors. Long-lived ApcMin/+ mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas than those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to colorectal cancer. Further characterization of cellular and molecular features is needed to determine which features can be used to risk-stratify polyps for progression to colorectal cancer and potentially guide prevention strategies. Cancer Prev Res; 7(1); 105–13. ©2013 AACR.
Small RNAs Deliver a Blow to Ovarian Cancer
Authors: Kasinski Andrea , Slack Frank J. 
Published: November 2013

Abstract
Summary: Targeted therapeutic approaches have seen tremendous advances in the last decade, for good reason. Specifically intervening with a disease-causing gene can revert the deleterious phenotype while eliminating the toxicity often associated with broad-spectrum agents. Unfortunately, because these selective agents hit one target in a single location, acquired resistance is often high. An arguably better treatment approach includes coupling multiple targeted agents or using an agent that hits an individual target in several independent locations and/or alters multiple relevant targets in the disease-causing pathway(s), precisely the approach taken by Nishimura and colleagues in their recent report aimed at identifying a better treatment option for ovarian cancer. Cancer Discov; 3(11); 1220–1. ©2013 AACR.
See related article by Nishimura et al., p. 1302
Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency
Authors: Pavlova Anna , Geisen Christof , Spannagl Michael , Bergmann Frauke , Krause Manuela , Alesci Sonja , Seifried Erhard , Lindhoff-Last Edelgard , Luxembourg Beate 
Published: November 2013

SummaryMutations in the antithrombin (AT) gene can impair the capacity of AT to bind heparin (AT deficiency type IIHBS), its target proteases such as thrombin (type IIRS), or both (type IIPE). Type II AT deficiencies are almost exclusively caused by missense mutations, whereas type I AT deficiency can originate from missense or null mutations. In a retrospective cohort study, we investigated the impact of the type of mutation and type of AT deficiency on the manifestation of thromboembolic events in 377 patients with hereditary AT deficiencies (133 from our own cohort, 244 reported in the literature). Carriers of missense mutations showed a lower risk of venous thromboembolism (VTE) than those of null mutations (adjusted hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.27–0.58, p<0.001), and the risk of VTE was significantly decreased among patients with type IIHBS AT deficiency compared to patients with other types of AT deficiency (HR 0.23, 95%CI 0.13–0.41, p<0.001). The risk of pulmonary embolism complicating deep-vein thrombosis was lower in all type II AT deficiencies compared to type I AT deficiency (relative risk 0.69, 95%CI 0.56–0.84). By contrast, the risk of arterial thromboembolism tended to be higher in carriers of missense mutations than in those with null mutations (HR 6.08-fold, 95%CI 0.74–49.81, p=0.093) and was 5.9-fold increased (95%CI 1.22–28.62, p=0.028) in type IIHBS versus other types of AT deficiency. Our data indicate that the type of inherited AT defect modulates not only the risk of thromboembolism but also the localisation and encourage further studies to unravel this phenomenon.
Description of Paravulvus moroccanus sp. n. (Nematoda, Dorylaimida, Nygolaimidae) from the High Atlas Mountains, Morocco, with notes on the taxonomy of the genus
Authors: GILARTE PATRICIA , CARREIRA JOSÉ ANTONIO , PEÑA-SANTIAGO REYES 
Published: November 2013

Paravulvus moroccanus sp. n., collected in the Moroccan eastern High Atlas, is described and illustrated. The new species is characterized by its 1.06–1.36 mm long body, lip region offset by marked depression and 11–13 µm broad, mural tooth solididentoid and 5.5–6.5 µm long, neck 229–270 µm long, pharyngeal expansion 108–126 µm long or occupying less than one-half (42–48%) of total neck length, uterus 27–47 μm long or 0.7–1.1 times the corresponding body diameter, V = 46–56, paravulvae absent, female tail rounded conoid (21–27 µm, c = 42–64, c’ = 1.1–1.5), and male unknown. The taxonomy of Paravulvus is updated, with comments on its definition, a discussion of its relationships, and the provision of a list of species along with a key to their identification and a compendium of their morphometrics.
Coastal Jet Adjustment near Point Conception, California, with Opposing Wind in the Bight
Authors: Rahn David A. , Parish Thomas R. , Leon David 
Published: November 2013

Abstract
Typical spring and summer conditions offshore of California consist of strong northerly low-level wind contained within the cool, well-mixed marine boundary layer (MBL) that is separated from the warm and dry free troposphere by a sharp temperature inversion. This system is often represented by two layers constrained by a lateral boundary. Aircraft measurements near Point Conception, California, on 3 June 2012 during the Precision Atmospheric MBL Experiment (PreAMBLE) captured small-scale features associated with northerly flow approaching the point with the added complexity of encountering opposing wind in the Santa Barbara Channel. An extremely sharp cloud edge extends south-southwest of Point Conception and the flight strategy consisted of a spoke pattern to map the features across the cloud edge. Lidar and in situ measurements reveal a nearly vertical jump in the MBL from 500 to 100 m close to the coast and a sharp edge at least 70 km away from the coast. In this case, it is hypothesized that it is not solely hydraulic features responsible for the jump, but the opposing flow in the Santa Barbara Channel is a major factor modifying the flow. Just southeast of Point Conception are three distinct layers: a shallow, cold layer near the surface with northwesterly winds associated with an abrupt decrease in MBL height from the north that thins eastward into the Santa Barbara Channel; a cool middle layer with easterly wind whose top slopes upward to the east; and the warm and dry free troposphere above.
Influence of Cell Differentiation and IL-1β Expression on Clinical Outcomes After Matrix-Associated Chondrocyte Transplantation
Authors: Albrecht Christian , Tichy Brigitte , Zak Lukas , Aldrian Silke , Nürnberger Sylvia , Marlovits Stefan 
Published: November 2013

Background: Several patient- and defect-specific factors influencing clinical outcomes after matrix-associated chondrocyte transplantation (MACT) have been identified, including the patient’s age, location of the defect, or duration of symptoms before surgery. Little is known, however, about the influence of cell-specific characteristics on clinical results after transplantation. Purpose: The aim of the present study was to investigate the influence of cell differentiation and interleukin-1 β (IL-1β) expression on clinical outcomes up to 5 years after MACT. Study Design: Case series; Level of evidence, 4. Methods: Twenty-seven patients who underwent MACT of the tibiofemoral joint area of the knee were included in this study. Clinical assessments were performed preoperatively as well as 6, 12, 24, and 60 months after transplantation by using the following scores: the Knee injury and Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee (IKDC) Subjective Knee Form, the Noyes sports activity rating scale, the Brittberg clinical score, and a visual analog scale (VAS) for pain. The quality of repair tissue was assessed by magnetic resonance imaging using the magnetic resonance observation of cartilage repair tissue (MOCART) score at 1 and 5 years. Cell differentiation (defined as collagen type II:type I expression ratio), aggrecan, and IL-1β expression were determined by real-time polymerase chain reaction in transplant residuals and were correlated with clinical outcomes. Results: The largest improvements in clinical scores were found during the first year. Two years postoperatively, a stable improvement was reached until 5 years after transplantation, with a mean IKDC score of 34.4 ± 8.6 preoperatively to 77.9 ± 16 after 24 months ( P < .001). Cell differentiation showed a significant positive correlation with nearly all clinical scores at different time points, especially after 12 months ( P < .05). IL-1β expression negatively influenced clinical outcomes at 24 months (Brittberg score) and 60 months (Brittberg and VAS scores) after surgery ( P < .05). No correlation was found between the MOCART score and clinical outcomes or gene expression. Conclusion: Our data demonstrate that cell differentiation and IL-1β expression influence clinical outcomes up to 5 years after MACT.
A Qualitative Investigation of the Decision to Return to Sport After Anterior Cruciate Ligament Reconstruction
Authors: Tjong Vehniah K. , Murnaghan M. Lucas , Nyhof-Young Joyce M. , Ogilvie-Harris Darrell J. 
Published: November 2013

Background: Primary anterior cruciate ligament (ACL) reconstruction is known to have excellent outcomes, but many patients do not return to their preinjury level of sport participation. Previous studies have used subjective outcome scores to evaluate this discrepancy, but none to date has used qualitative, in-depth patient interviews. Purpose: To understand the factors influencing a patient’s decision to return to his or her preinjury level of sport after ACL reconstruction. Hypothesis: Extrinsic and intrinsic factors may affect one’s decision to return to sport after primary ACL reconstruction despite good functional knee scores. Study Design: Case series; Level of evidence, 4. Methods: An experienced interviewer conducted qualitative, semistructured interviews of 31 patients, aged 18 to 40 years, who had undergone primary ACL reconstruction surgery. All participated in sport before injury and had a minimum 2-year follow-up with no further surgeries or knee injuries. Qualitative analysis was then performed to derive codes, categories, and themes. An assessment of preinjury and current sport participation by type, level of competition, and Marx activity score, along with patient-reported knee function, was also conducted. Results: Patient interviews revealed 3 overarching themes: fear, lifestyle changes, and innate personality traits. Elements of these factors were shown to largely influence the decision to return to the preinjury sport both in those patients who had returned and those who had not returned to sport. Less common factors included the surgeon’s advice not to return, depressed mood, and persistent knee pain. Conclusion: Patients who did not return to their preinjury level of sport after primary ACL reconstruction despite having good knee function were largely influenced by fear, shifts in priority, and individual personalities. This study highlights the importance for treating physicians to recognize and address psychological factors and lifestyle changes that largely contribute to a patient’s postoperative decision to return to sport. Results from this study will allow surgeons and health care professionals to educate patients contemplating surgery and to better understand the recovery process not only from sport-related surgeries but other surgical interventions with the goal of returning to activity.