bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary Levels of Cigarette Smoke Constituent Metabolites Are Prospectively Associated with Lung Cancer Development in Smokers
Authors: Yuan Jian-Min , Gao Yu-Tang , Murphy Sharon E. , Carmella Steven G. , Wang Renwei , Zhong Yan , Moy Kristin A. , Davis Andrew B. , Tao Li , Chen Menglan , Han Shaomei , Nelson Heather H. , Yu Mimi C. , Hecht Stephen S.
Published: October 2011

Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case–control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00–2.88), 1.07 (0.62–1.84), 1.48 (0.86–2.53), and 2.34 (1.33–4.11), respectively, relative to the lowest quartile (Ptrend = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk. Cancer Res; 71(21); 6749–57. ©2011 AACR.
Smad7 Expression in T cells Prevents Colitis-Associated Cancer
Authors: Rizzo Angelamaria , Waldner Maximilian J. , Stolfi Carmine , Sarra Massimiliano , Fina Daniele , Becker Christoph , Neurath Markus F. , Macdonald Thomas T. , Pallone Francesco , Monteleone Giovanni , Fantini Massimo C.
Published: October 2011

Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer due to chronic inflammation. In IBD, chronic inflammation relies upon a TGFβ signaling blockade, but its precise mechanistic relationship to colitis-associated colorectal cancer (CAC) remains unclear. In this study, we investigated the role of the TGFβ signaling inhibitor Smad7 in CAC pathogenesis. In human colonic specimens, Smad7 was downregulated in CD4+ T cells located in the lamina propria of patients with complicated IBD compared with uncomplicated IBD. Therefore, we assessed CAC susceptibility in a transgenic mouse model where Smad7 was overexpressed specifically in T cells. In this model, Smad7 overexpression increased colitis severity, but the mice nevertheless developed fewer tumors than nontransgenic mice. Protection was associated with increased expression of IFNγ and increased accumulation of cytotoxic CD8+ and natural killer T cells in the tumors and peritumoral areas. Moreover, genetic deficiency in IFNγ abolished the Smad7-dependent protection against CAC. Taken together, our findings defined a novel and unexpected role for Smad7 in promoting a heightened inflammatory response that protects against CAC. Cancer Res; 71(24); 7423–32. ©2011 AACR.
Is Co-option a Prevailing Mechanism during Cancer Progression?
Authors: Billaud Marc , Santoro Massimo
Published: October 2011

Cancer progression results from the accumulation of genetic and epigenetic alterations that provide tumor cells with a selective advantage. The consecutive cycles of mutations, selections, and clonal expansions generate, over time, descendant cells with increasing malignant properties. Although this conception of tumor development rests on solid experimental foundations, it has also raised several persisting questions. Does the succession of mutations dictate the progression of each cancer type or does the disturbance of an invariant set of regulatory circuits govern tumor evolution regardless of the linear order of genetic events? Is the ability of malignant cells to disseminate and spawn metastasis a property acquired at late stages of tumor development or is the proclivity to metastasize implanted early during cancer formation? Considering these issues, we elaborate here on the concept of co-option that refers to the emergence of novel functions from ancestral characters during episodes of organismal evolution. As discussed in this Perspective, co-option seems to be a key mechanism propelling the molecular engine that drives malignant transformation. Hence, this notion may constitute a unifying principle that connects a large body of experimental results to clinical observations. Cancer Res; 71(21); 6572–5. ©2011 AACR.
[18F]-3′Deoxy-3′-Fluorothymidine Positron Emission Tomography and Breast Cancer Response to Docetaxel
Authors: Contractor Kaiyumars B. , Kenny Laura M. , Stebbing Justin , Rosso Lula , Ahmad Rizvana , Jacob Jimmy , Challapalli Amarnath , Turkheimer Federico , Al-Nahhas Adil , Sharma Rohini , Coombes R. Charles , Aboagye Eric O.
Published: October 2011

Purpose: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [18F]-3′deoxy-3′-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer.

Experimental Design: This was a prospective unblinded study in 20 patients with American Joint Committee on Cancer (AJCC) stage II–IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan 2 weeks after initiating the first or second cycle of docetaxel. PET variables were compared with anatomic response midtherapy (after 3 cycles).

Results: Average and maximum tumor standardized uptake values at 60 minutes (SUV60,av and SUV60,max) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 × 10−5 m2/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P = 0.0003 for SUV60,av and P = 0.0002 for SUV60,max). Reduction in tumor SUV60,av was associated with target lesion size changes midtherapy (Pearson R for SUV60,av = 0.64; P = 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV60,av in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, Ki). Docetaxel significantly reduced Ki by 51.1% (±28.4%, P = 0.0009).

Conclusion: Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response midtherapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non–FLT-PET response. Clin Cancer Res; 17(24); 7664–72. ©2011 AACR.
Polycomb Repressor Complex-2 Is a Novel Target for Mesothelioma Therapy
Authors: Kemp Clinton D. , Rao Mahadev , Xi Sichuan , Inchauste Suzanne , Mani Haresh , Fetsch Patricia , Filie Armando , Zhang Mary , Hong Julie A. , Walker Robert L. , Zhu Yuelin J. , Ripley R. Taylor , Mathur Aarti , Liu Fang , Yang Maocheng , Meltzer Paul A. , Marquez Victor E. , De Rienzo Assunta , Bueno Raphael , Schrump David S.
Published: October 2011

Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM).

Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep.

Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment.

Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy. Clin Cancer Res; 18(1); 77–90. ©2011 AACR.
A Dose-Escalation and Signal-Generating Study of the Immunocytokine L19-IL2 in Combination with Dacarbazine for the Therapy of Patients with Metastatic Melanoma
Authors: Eigentler Thomas K. , Weide Benjamin , de Braud Filippo , Spitaleri Gianluca , Romanini Antonella , Pflugfelder Annette , González-Iglesias Reinerio , Tasciotti Annaelisa , Giovannoni Leonardo , Schwager Kathrin , Lovato Valeria , Kaspar Manuela , Trachsel Eveline , Menssen Hans D. , Neri Dario , Garbe Claus
Published: October 2011

Purpose: L19-IL2 is an immunocytokine composed of an antibody fragment specific to the EDB domain of fibronectin, a tumor angiogenesis marker, and of human interleukin-2 (IL2). L19-IL2 delivers IL2 to the tumor site exploiting the selective expression of EDB on newly formed blood vessels. Previously, the recommended dose of L19-IL2 monotherapy was defined as 22.5 million international units (Mio IU) IL2 equivalents. In this study, safety and clinical activity of L19-IL2 in combination with dacarbazine were assessed in patients with metastatic melanoma.

Experimental Design: The first 10 studied patients received escalating doses of L19-IL2 on days 1, 3, and 5 in combination with 1 g/m2 of dacarbazine on day 1 of a 3-weekly therapy cycle. Subsequently, 22 patients received L19-IL2 at recommended dose plus dacarbazine. Up to six treatment cycles were given, followed by a maintenance regimen with biweekly L19-IL2.

Results: The recommended dose of L19-IL2 in combination with dacarbazine was defined as 22.5 Mio IU. Toxicity was manageable and reversible, with no treatment-related deaths. Twenty-nine patients were evaluable for efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST). In a centralized radiology analysis, eight of 29 (28%) patients achieved a RECIST-confirmed objective response, including a complete response still ongoing 21 months after treatment beginning. The 12-month survival rate and median overall survival of the recommended dose–treated patients (n = 26) were 61.5% and 14.1 months, respectively.

Conclusions: The repeated administration of L19-IL2 in combination with dacarbazine is safe and shows encouraging signs of clinical activity in patients with metastatic melanoma. This combination therapy is currently evaluated in a randomized phase II trial with patients with metastatic melanoma. Clin Cancer Res; 17(24); 7732–42. ©2011 AACR.
Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates
Authors: Perkins Janelle B. , Goldstein Steven C. , Dawson Jana L. , Kim Jongphil , Field Teresa L. , Partyka James S. , Fields Karen K. , Maddox Beth L. , Simonelli Christine E. , Neuger Anthony M. , Lush Richard M. , Sullivan Daniel M.
Published: October 2011

Purpose: To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies.

Experimental Design: Patients were treated with (in mg/m2/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days −8 through −6 and etoposide 500 (days −5 through −3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured.

Results: The topotecan MTD in this regimen was 64 mg/m2 (21.3 mg/m2/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose.

Conclusion: Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy. Clin Cancer Res; 17(24); 7743–53. ©2011 AACR.
Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown
Authors: Previdi Sara , Abbadessa Giovanni , Dalò Francesca , France Dennis S. , Broggini Massimo
Published: October 2011

Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. We have shown the involvement of the HGF/c-MET system in tumor–bone interaction contributing to human breast cancer metastasis. Therefore, disruption of HGF/c-MET signaling is a potential targeted approach to treating metastatic bone disease. In this study, we evaluated the effects of c-MET inhibition by both an oral, selective, small-molecule c-MET inhibitor, tivantinib, and a specific short hairpin RNA (shRNA) against c-MET in a mouse model of human breast cancer. Tivantinib exhibited dose-dependent antimetastatic activity in vivo, and the 120 mg/kg dose, proven to be suboptimal in reducing subcutaneous tumor growth, induced significant inhibition of metastatic growth of breast cancer cells in bone and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-MET silencing did not affect in vitro proliferation of bone metastatic cells, but significantly reduced their migration, and this effect was further enhanced by tivantinib. Both observations were confirmed in vivo. Indeed, more pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival were achieved by dual c-MET inhibition using both tivantinib and RNA interference strategies. Overall, our findings highlighted the effectiveness of c-MET inhibition in delaying the onset and progression of bone metastases and strongly suggest that targeting c-MET may have promising therapeutic value in the treatment of bone metastases from breast cancer. Mol Cancer Ther; 11(1); 214–23. ©2011 AACR.
A Polymeric Nanoparticle Encapsulated Small-Molecule Inhibitor of Hedgehog Signaling (NanoHHI) Bypasses Secondary Mutational Resistance to Smoothened Antagonists
Authors: Chenna Venugopal , Hu Chaoxin , Pramanik Dipankar , Aftab Blake T. , Karikari Collins , Campbell Nathaniel R. , Hong Seung-Mo , Zhao Ming , Rudek Michelle A. , Khan Saeed R. , Rudin Charles M. , Maitra Anirban
Published: October 2011

Aberrant activation of the hedgehog (Hh) signaling pathway is one of the most prevalent abnormalities in human cancer. Tumors with cell autonomous Hh activation (e.g., medulloblastomas) can acquire secondary mutations at the Smoothened (Smo) antagonist binding pocket, which render them refractory to conventional Hh inhibitors. A class of Hh pathway inhibitors (HPI) has been identified that block signaling downstream of Smo; one of these compounds, HPI-1, is a potent antagonist of the Hh transcription factor Gli1 and functions independent of upstream components in the pathway. Systemic administration of HPI-1 is challenging due to its minimal aqueous solubility and poor bioavailability. We engineered a polymeric nanoparticle from [poly(lactic-co-glycolic acid); (PLGA)] conjugated with polyethylene glycol (PEG), encapsulating HPI-1 (NanoHHI). NanoHHI particles have an average diameter of approximately 60 nm, forms uniform aqueous suspension, and improved systemic bioavailability compared with the parent compound. In contrast to the prototype targeted Smo antagonist, HhAntag (Genentech), NanoHHI markedly inhibits the growth of allografts derived from Ptch−/+; Trp53−/− mouse medulloblastomas that harbor a SmoD477G binding site mutation (P < 0.001), which is accompanied by significant downregulation of mGli1 as well as bona fide Hh target genes (Akna, Cltb, and Olig2). Notably, NanoHHI combined with gemcitabine also significantly impedes the growth of orthotopic Pa03C pancreatic cancer xenografts that have a ligand-dependent, paracrine mechanism of Hh activation when compared with gemcitabine alone. No demonstrable hematologic or biochemical abnormalities were observed with NanoHHI administration. NanoHHI should be amenable to clinical translation in settings where tumors acquire mutational resistance to current Smo antagonists. Mol Cancer Ther; 11(1); 165–73. ©2011 AACR.
MUC13 Mucin Augments Pancreatic Tumorigenesis
Authors: Chauhan Subhash C. , Ebeling Mara C. , Maher Diane M. , Koch Michael D. , Watanabe Akira , Aburatani Hiroyuki , Lio Yuhlong , Jaggi Meena
Published: October 2011

The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early detection and underlying molecular mechanisms of its aggressive pathogenesis. Although MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian and gastro-intestinal cancers, its role in pancreatic cancer is unknown. Herein, we investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic cancer was investigated using a recently generated monoclonal antibody (clone PPZ0020) and pancreatic tissue microarrays. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with normal/nonneoplastic pancreatic tissues. For functional analyses, full-length MUC13 was expressed in MUC13 null pancreatic cancer cell lines, MiaPaca and Panc1. MUC13 overexpression caused a significant (P < 0.05) increase in cell motility, invasion, proliferation, and anchorage-dependent or -independent clonogenicity while decreasing cell–cell and cell-substratum adhesion. Exogenous MUC13 expression significantly (P < 0.05) enhanced pancreatic tumor growth and reduced animal survival in a xenograft mouse model. These tumorigenic characteristics correlated with the upregulation/phosphorylation of HER2, p21-activated kinase 1 (PAK1), extracellular signal-regulated kinase (ERK), Akt, and metastasin (S100A4), and the suppression of p53. Conversely, suppression of MUC13 in HPAFII pancreatic cancer cells by short hairpin RNA resulted in suppression of tumorigenic characteristics, repression of HER2, PAK1, ERK, and S100A4, and upregulation of p53. MUC13 suppression also significantly (P < 0.05) reduced tumor growth and increased animal survival. These results imply a role of MUC13 in pancreatic cancer and suggest its potential use as a diagnostic and therapeutic target. Mol Cancer Ther; 11(1); 24–33. ©2011 AACR.
A 71-Gene Signature of TRAIL Sensitivity in Cancer Cells
Authors: Chen Jun-Jie , Knudsen Steen , Mazin Wiktor , Dahlgaard Jesper , Zhang Baolin
Published: October 2011

TNF-related apoptosis inducing ligand (TRAIL) is a promising anticancer agent because of its ability to selectively induce apoptosis in cancer cells but not in most normal cells. However, some cancer cells are resistant to TRAIL cytotoxicity thereby limiting its therapeutic efficacy. Using genome-wide mRNA expression profiles from the NCI60 panel and their differential sensitivities to TRAIL-induced apoptosis, we have identified 71 genes whose expression levels are systemically higher in TRAIL-sensitive cell lines than resistant lines. The elevated expression of the 71 genes was able to accurately predict TRAIL sensitivity in the NCI60 training set and two test sets consisting of a total of 95 human cancer cell lines. Interestingly, the 71-gene signature is dominated by two functionally related gene families—interferon (IFN)-induced genes and the MHC genes. Consistent with this result, treatment with IFN-γ augmented TRAIL-induced apoptosis. The 71-gene signature could be evaluated clinically for predicting tumor response to TRAIL-related therapies. Mol Cancer Ther; 11(1); 34–44. ©2011 AACR.
Phase II Prospective Randomized Trial of a Low-Fat Diet with Fish Oil Supplementation in Men Undergoing Radical Prostatectomy
Authors: Aronson William J. , Kobayashi Naoko , Barnard R. James , Henning Susanne , Huang Min , Jardack Patricia M. , Liu Bingrong , Gray Ashley , Wan Junxiang , Konijeti Ramdev , Freedland Stephen J. , Castor Brandon , Heber David , Elashoff David , Said Jonathan , Cohen Pinchas , Galet Colette
Published: October 2011

Preclinical studies suggest lowering dietary fat and decreasing the ratio of omega-6 to omega-3 polyunsaturated fatty acids decreases the risk of prostate cancer development and progression. We conducted a phase II randomized trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on biomarkers related to prostate cancer development and progression. Patients undergoing radical prostatectomy were randomly assigned to receive a low-fat diet with 5 grams of fish oil daily (dietary omega-6:omega-3 ratio of 2:1) or a control Western diet (omega-6:omega-3 ratio of 15:1) for four to six weeks prior to surgery. The primary endpoint was change in serum insulin-like growth factor I (IGF-1) between arms. Secondary endpoints were serum IGFBP-1, prostate prostaglandin E2 levels, omega-6:omega-3 fatty acid ratios, COX-2, and markers of proliferation and apoptosis. Fifty-five patients were randomized and 48 completed the trial. There was no treatment difference in the primary outcome. Positive secondary outcomes in the low-fat fish oil versus Western group were reduced benign and malignant prostate tissue omega-6:omega-3 ratios, reduced proliferation (Ki-67 index), and reduced proliferation in an ex vivo bioassay when patient sera was applied to prostate cancer cells in vitro. In summary, four to six weeks of a low-fat diet and fish oil capsules to achieve an omega-6:omega-3 fatty acid ratio of 2:1 had no effect on serum IGF-1 levels, though in secondary analyses, the intervention resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios. These results support further studies evaluating reduction of dietary fat with fish oil supplementation on modulating prostate cancer biology. Cancer Prev Res; 4(12); 2062–71. ©2011 AACR.
Opportunistic Screening of Hospital Staff Using Primary Colonoscopy: Participation, Discomfort and Willingness to Repeat the Procedure
Authors: Khalid-de Bakker C.A. , Jonkers D.M. , Hameeteman W. , de Ridder R.J. , Masclee A.A. , Stockbrügger R.W.
Published: October 2011

Background: Participation in and tolerability of primary colonoscopy screening are presumed to be relatively low. The present study aimed to test its feasibility in a well-informed population of hospital staff using an intensive information campaign, and to identify factors associated with screening colonoscopy rated as uncomfortable. Methods: Data were collected using standardized forms. Results: Out of 1,090 invited employees (50–65 years), 447 (41.0%) participated. Bowel preparation and colonoscopy were rated as ‘somewhat to very uncomfortable’ by 79.5 and 21.9%, respectively. 96.3% of participants were willing to repeat colonoscopy in the future. Participants rating colonoscopy as uncomfortable were more likely unwilling to repeat the procedure (OR 8.026, CI 2.667–24.154). Multivariate analysis (age- and gender-adjusted) showed an association of colonoscopy rated as uncomfortable with: abdominal pain during colonoscopy (OR 3.185, CI 1.642–6.178), other pain (OR 2.428, CI 1.335–4.416), flatulence (OR 2.175, CI 1.219–3.881), embarrassment (OR 2.843, CI 1.350–5.989), abdominal pain after colonoscopy (OR 1.976, CI 1.041–3.751), and a prolonged procedure time (OR 1.000, CI 1.000–1.001). Conclusions: Acceptance of primary colonoscopy screening for colorectal neoplasia was high, although participants with symptoms during and after colonoscopy were more likely to rate colonoscopy as uncomfortable. This type of opportunistic screening procedure is suitable for the introduction of screening programs and may be useful in areas that have no access to population-based screening.
From Stress to Postpartum Mood and Anxiety Disorders: How Chronic Peripartum Stress Can Impair Maternal Adaptations
Authors: Hillerer Katharina M. , Neumann Inga D. , Slattery David A.
Published: October 2011

The peripartum period, in all mammalian species, is characterised by numerous adaptations at neuroendocrine, molecular and behavioural levels that prepare the female for the challenges of motherhood. These changes have been well characterised and, while they are necessary to ensure the survival and nurturance of the offspring, there is growing belief that they are also required for maternal mental health. Thus, while increased calmness and attenuated stress responsivity are common characteristics of the peripartum period, it also represents a time of increased susceptibility to mood disorders. While a number of risk factors for these disorders are known, their underlying aetiology remains poorly understood, due at least in part to a lack of appropriate animal models. One translatable risk factor is stress exposure during the peripartum period. In the following review we first describe common peripartum adaptations and the impact postpartum mood disorders have on these. We then discuss the known consequences of peripartum stress exposure on such maternal adaptations that have been described in basic research.
Does Ranibizumab (Lucentis®) Change Retrobulbar Blood Flow in Patients with Neovascular Age-Related Macular Degeneration?
Authors: Mete Ahmet , Saygili Oguzhan , Mete Alper , Gungor Kivanc , Bayram Metin , Bekir Necdet
Published: October 2011

Purpose: To investigate the effects of intravitreal ranibizumab on retrobulbar blood flow in patients with neovascular age-related macular degeneration (AMD). Methods:Thirty-one eyes of 30 patients with neovascular AMD were examined prospectively by both color Doppler imaging and fundus fluorescein angiography. Color Doppler imaging was used to measure the maximum and minimum velocities of the central retinal vein, peak systolic/end-diastolic velocities of blood flows, and pulsatility index and resistivity index values in the central retinal artery, nasal/temporal posterior ciliary arteries (NPCA/TPCA) and ophthalmic artery. The t test for paired samples was used for comparing retrobulbar blood flow values before and after intravitreal ranibizumab (Lucentis®) injection in the study and control groups. Results:There was a statistically significant (p < 0.05) difference between the pre-injection and post-injection end-diastolic velocities of the NPCA and TPCA and resistivity index values of TPCA. The other parameters showed no statistically significant difference. Conclusion: Our results show that intravitreal ranibizumab injection increases retrobulbar blood flow.
The Role of Liver Transplantation for Intrahepatic Cholangiocarcinoma: A Single-Center Experience
Authors: Fu B.-S. , Zhang T. , Li H. , Yi S.-H. , Wang G.-S. , Xu C. , Yang Y. , Cai C.-J. , Lu M.-Q. , Chen G.-H.
Published: October 2011

Background/Aim: Intrahepatic cholangiocarcinoma (ICC) is not a widely accepted indication for liver transplantation (LT). The present study describes our institutional experience with patients who underwent transplantation for ICC. Methods: A retrospective analysis was performed on 11 consecutive patients with ICC who underwent LT between October 2003 and November 2008 at our institution. Results: At a median patient follow-up interval of 10 months (2–56), the median survival time was 9 months (2.5–53). The perioperative mortality and the recurrence rate were 0 and 45.5%, respectively. Five patients are currently alive 10, 12, 41, 51 and 53 months after LT, respectively. One patient died 3 months after LT as a result of bile leak and toxic shock, and 5 patients died of tumor recurrences at 2.5, 8, 8, 9 and 10 months post-LT, respectively. The 1-, 2-, 3- and 4-year disease-free survival rates and overall survival rates of all the patients were 51.9, 51.9, 51.9 and 51.9%, and 50.5, 50.5, 50.5 and 50.5%, respectively. Conclusion: With better and strict patient selection, the prognosis of LT for ICC could be improved. ICC patients with lymph node involvement, vascular or bile duct invasion are contraindicated for LT.
Factors Associated with Insulin Resistance among Children and Adolescents Perinatally Infected with HIV-1 in the Pediatric HIV/AIDS Cohort Study
Authors: Geffner Mitchell E. , Patel Kunjal , Miller Tracie L. , Hazra Rohan , Silio Margarita , Van Dyke Russell B. , Borkowsky William , Worrell Carol , DiMeglio Linda A. , Jacobson Denise L. ,   for the Pediatric HIV/AIDS Cohort Study
Published: October 2011

Background/Aims: Because of prior inconsistent findings, we studied a large cohort of HIV-infected children to determine: (1) prevalence of insulin resistance (IR); (2) anthropometric and clinical correlates of IR, and (3) concomitant abnormalities of glucose tolerance. Methods: The study population consisted of 451 children from the Pediatric HIV/AIDS Cohort Study. The outcome of interest was HOMA-IR. Covariates included demographic, metabolic, growth, body composition, HIV laboratory tests, and treatment characteristics. Children meeting triggers for IR underwent oral glucose tolerance tests and hemoglobin A1c (HbA1c) measurements. Results: Among 402 children with glucose and insulin measurements, 15.2% had IR of whom 79% were pubertal. IR was associated with higher alanine aminotransferase, body mass index, and nadir CD4%, Tanner stage 5, and ever having received amprenavir. Of those with IR, three had impaired fasting glucose (IFG), three impaired glucose tolerance (IGT), one IFG and IGT, none diabetic glucose tolerance, and three HbA1c between 6.1 and 6.5%. Conclusion: In our cohort of HIV-infected adolescents, we observed a 15.2% prevalence of IR more closely linked to obesity than any other variable. This finding mirrors the high prevalence of obesity-mediated IR in American youth. However, associations with CD4 count and use of protease inhibitors may indicate some effect of HIV and/or its treatment.
Heat Shock Factor 1 Protects against Lung Mycoplasma pneumoniae Infection in Mice
Authors: Gally Fabienne , Minor Maisha N. , Smith Sean K. , Case Stephanie R. , Chu Hong Wei
Published: October 2011

Heat shock factor 1 (HSF1) is a transcriptional factor that controls the induction of heat shock proteins (e.g. HSP70) in response to stress. Bacterial infections contribute to the pathobiology of chronic lung diseases such as chronic obstructive pulmonary disease and asthma. Whether HSF1 is critical to lung bacterial infection remains unknown. This study is aimed at investigating the impact of HSF1 deficiency on lung Mycoplasma pneumoniae (Mp) infection and elucidating the underlying molecular mechanisms, such as Toll-like receptor 2 (TLR2) signaling. HSF1–/– and HSF1+/+ mice were intranasally infected with Mp or saline and sacrificed 4, 24 and 72 h after treatment. HSF1–/– mice had a higher lung Mp load than HSF1+/+ mice. Mp-induced lung TLR2, nuclear factor-ĸB and associated inflammation [e.g. keratinocyte-derived chemokine (KC), neutrophils and histopathology] were delayed in HSF1–/– mice as compared to HSF1+/+ mice. HSP70 protein levels in bronchoalveolar lavage fluid of HSF1–/– mice were decreased. Furthermore, in response to Mp infection, HSF1–/– alveolar macrophages had less TLR2 mRNA expression and KC production than HSF1+/+ counterparts. Nuclear factor-ĸB activity and KC production in HSF1–/– macrophages could be rescued by addition of exogenous HSP70 protein. These data suggest that HSF1 is necessary to initiate host defense against bacterial infection partly through promoting early TLR2 signaling activation.
Baclofen Toxicity in Patients with Advanced Nephropathy: Proposal for New Labeling
Authors: El-Husseini Amr , Sabucedo Alberto , Lamarche Jorge , Courville Craig , Peguero Alfredo
Published: October 2011

Background: Despite several reports in the literature of baclofen toxicity in patients with renal dysfunction, the drug is being used for many patients. Methods: Herein we report a case of baclofen-induced encephalopathy in a patient with pre-end-stage renal disease and review the literature regarding the magnitude of baclofen toxicity in patients with renal insufficiency. A Medline search for studies in English was performed. Twenty-one case reports involving 41 patients (including our patient) were identified. Results: The majority of patients were elderly (62.5% above 60 years) males (56.3%) on dialysis (62.9%). Neurotoxicities were almost always present at presentation. Manifestations of baclofen toxicity usually started 2–3 days after starting baclofen; however, periods as long as 16 weeks have been reported. The daily dose of baclofen ranged from 5 to 60 mg with a mean dose of 20 mg. Hemodialysis (HD) was the most common treatment modality used for drug elimination (65.7%). The recovery time ranged from 2 h in patients who received HD, to 8 days with conservative treatment. Conclusion: The literature does not mention a clear recommendation about baclofen safety and dose adjustment, or a minimum level of kidney function below which the drug should not be used.
Renal Dysfunction in the Presence of Normoalbuminuria in Type 2 Diabetes: Results from the DEMAND Study
Authors: Dwyer Jamie P. , Parving Hans-Henrik , Hunsicker Lawrence G. , Ravid Moti , Remuzzi Giuseppe , Lewis Julia B. ,   for the DEMAND Investigators
Published: October 2011

Background/Aims: Microalbuminuria is associated with diabetes and is an independent risk factor for developing diabetic nephropathy. We have previously reported the overall prevalence of normoalbuminuria, microalbuminuria, and macroalbuminuria to be 51, 39, and 9.8%, respectively, in an unselected population of patients with type 2 diabetes. Renal dysfunction was present in a large proportion of these patients without proteinuria, assessed by a single random albumin-to-creatinine ratio (ACR) . We therefore undertook to characterize the nature of this association of non-proteinuric renal dysfunction in type 2 diabetes. Methods: In the DEMAND (Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes) study, a global, cross-sectional study which described the prevalence and risk factors for albuminuria in a clinic-based cohort, kidney function was assessed in 11,573 patients; ACR was measured using the Bayer reagent strip Multistix® 10SG. Normoalbuminuria was defined as ACR <30 mg/g, microalbuminuria as 30–299 mg/g, and macroalbuminuria as >300 mg/g. Results: Among the patients with estimated kidney function determined, chronic kidney disease was noted in 17% of those with normoalbuminuria (stage 3–5), and significant kidney dysfunction was found in 27% of those with microalbuminuria and 31% of those with overt proteinuria. CrCl was <60 ml/min in 20.5% of normoalbuminurics, 30.7% of microalbuminurics, and 35.0% of macroalbuminurics (p < 0.0001). Conclusion: A large proportion of diabetic patients with completely normal urinary albumin excretion or microalbuminuria presented with significant kidney dysfunction. Therefore, further investigation is warranted.
Predictors and Implications of Stent Thrombosis in Non–ST-Segment Elevation Acute Coronary Syndromes
Authors: Palmerini Tullio , Dangas George , Mehran Roxana , Caixeta Adriano , Généreux Philippe , Fahy Martin P. , Xu Ke , Cristea Ecaterina , Lansky Alexandra J. , Stone Gregg W.
Published: October 2011

Background—

The frequency, predictors, and consequences of stent thrombosis (ST) in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) have been incompletely studied. We sought to investigate the incidence, predictors, and clinical implications of ST occurring within 1 year after percutaneous coronary intervention in patients with NSTE-ACS.

Methods and Results—

The Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial was a large-scale, prospective, randomized trial of antithrombotic regimens in patients with NSTE-ACS. The present analysis includes 7162 patients in whom stents were implanted. At 1 year, definite/probable ST occurred in 146 patients (2.2%), including 94 definite and 52 probable events. There were 100 episodes (1.4%) of early ST (within the first 30 days) and 46 episodes (0.8%) of late ST (between 30 days and 1 year). The incidence of ST within 1 year was similar in patients treated with drug-eluting stents or bare metal stents (hazard ratio, 0.86; 95% confidence interval, 0.62–1.20;
P
=0.38) and was independent of procedural antithrombotic treatment. Patients with ST compared with those without ST had strikingly higher 1-year rates of cardiac mortality (32.4% versus 2.9%,
P
<0.0001), myocardial infarction (82.6% versus 7.6%,
P
<0.0001), and target vessel revascularization (79.6% versus 7.4%,
P
<0.0001). Independent predictors of 1-year definite/probable ST were insulin-treated diabetes mellitus, number of diseased vessels, and ST-segment deviation ≥1 mm.

Conclusions—

Compared with elective stent implantation, ST occurs with increased frequency in the first year after stent implantation in patients with NSTE-ACS, especially within the first 30 days, and is associated with marked increases in cardiac mortality and adverse events. Insulin-treated diabetes, number of diseased vessels, and dynamic ST-segment changes were independent predictors of 1-year ST in NSTE-ACS.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00093158.
The effect of heat treatment conditions using the drawing process on the properties of PET filament sewing thread
Authors: Rudolf Andreja , Geršak Jelka , Smole Majda Sfiligoj
Published: October 2011

For the production of drawn poly(ethylene terephthalate) (PET) filament threads it is useful to determine the relationship between the drawing process conditions and the resulting product properties. Drawing at an elevated temperature over a defined time usually causes changes of the polymer structural parameters that influence the mechanical properties of the filaments. In order to elucidate the physical background of the drawing process for developing the production process of PET filament sewing thread, the thread was drawn by varying the treatment temperature and contact time. The effect of the treatment conditions on the structural and mechanical properties of the drawn threads was investigated, such as the birefringence, crystallinity, and dynamic mechanical properties of the threads’ filaments, as well as the mechanical properties and shrinkage of the treated threads. Using the drawing process, higher temperature and contact time up to the critical values ( T2 = 220°C, n2 = 9 turns) change the structural parameters and, consequently, any modifications influence changes in the mechanical properties of the threads. Namely, a higher treatment temperature and contact time increases the degree of crystallinity, the birefringence, and the maxima of the loss tangent and loss modulus temperature, and a significant increase in the breaking tenacity, elastic modulus and the thread’s tension at the yield point, and a decrease of the breaking extension is achieved. The observed deterioration of the thread’s mechanical properties above the critical treatment conditions is attributed to the destructive phenomena of the supra-molecular structure, resulting in an imperfect structure of the thread’s filaments.
The effects of tandem and conventional vacuum steaming methods on the properties of yarns
Authors: Şardağ Sibel , Özdemir Özcan
Published: October 2011

This study was performed in order to investigate the effects of tandem and conventional vacuum steaming on the physical properties of 100% cotton and 100% viscose yarns. The yarns with different twisting coefficients and numbers were twisted and exposed to tandem and conventional vacuum steaming at different temperatures. Tenacity, unevenness, hairiness, twist liveliness, package hardness values, and spirality of knitted fabrics produced from these yarns were measured before and after vacuum steaming. The results obtained were assessed by means of COSTAT statistical analysis program. Variation analysis and SNK test were carried out at 5% (0.05) level of significance.

The findings of this study indicate that the effects of vacuum steaming methods on the tenacity, unevenness, hairiness, twist liveliness and package hardness values of yarns are statistically significant. Although the effects of tandem vacuum steaming vary depending on the temperature applied and the raw material used, decreases are observed in unevenness, hairiness, twist liveliness and package hardness values of yarns.
An optimized design of compression sportswear fabric using numerical simulation and the response surface method
Authors: Lin Yinglei , Choi Ka-fai , Zhang Ming , Li Yi , Luximon Ameersing , Yao Lei , Hu Junyan
Published: October 2011

Well-designed compression sportswear can be used for the enhancement of athletic performance and reduction of injury. The material and geometric properties of fabric for compression sportswear are vital in achieving compression effects. This study evaluated and optimized the performance of fabric using the design of experiment (DOE) methods, the response surface method (RSM) and the finite element (FE) model. The evaluation and optimization procedure consisted of three phases. The first phase involved developing the FE model of a fabric tube and cylinder, and validated it by compression experiments involving different fabrics. The second phase evaluated the FE prediction using a five-factor experimental design, namely, hyperelastic properties, thickness, density, friction, and tensile strain. The third and final phase was an optimization process using RSM based on the evaluation results. Findings show that the FE predictions approach closely the results of validation experiments. The nonlinear elastic material properties (hyperelastic properties) and shape dimensions (thickness and tensile strain) of fabric tube were found to be important design factors in influencing contact pressure, while the density of fabric and interface friction coefficient played less important roles. The optimal FE model was determined using RSM analysis. The statistically based FE model was found to be an effective approach for evaluating and optimizing the design parameters of fabric for compression sportswear. The results can be applied to make sportswear that has different compression effects at selected anatomical locations to enhance performance and reduce injuries.
Recurrent Acute Rhinosinusitis
Authors: Bhattacharyya Neil , Grebner Jeff , Martinson Noel G.
Published: October 2011

Objectives

To determine the epidemiology of recurrent acute rhinosinusitis (RARS) and to understand direct health care costs attributable to RARS as a potentially underdiagnosed form of chronic rhinosinusitis.

Study Design

Retrospective longitudinal analysis of a medical claims database.

Setting

Academic medical center.

Methods

Medical claims data (2003–2008) from a large payer database were analyzed. Adult patients with RARS (defined as at least 4 acute rhinosinusitis claims each with a filled oral antibiotic prescription in a 12‐month period) were extracted. Sinonasal diagnostic procedures, provider visits, and medical costs were determined.

Results

A total of 4588 patients were identified (mean age, 43.5 years; 72.1% female) among 13.1 million patients, for a point prevalence of 0.035%, which remained consistent across years. After 1, 2, and 4 years, 2.4%, 5.4%, and 9.2% of patients subsequently received nasal endoscopy and 11.4%, 23.5%, and 39.9% received paranasal sinus computed tomography, respectively. RARS patients averaged 3.8 antibiotic prescriptions, 5.6 other sinus‐related prescriptions, and 5.6 provider visits per year. Total direct health care costs related to RARS averaged $1091/patient‐year, with oral antibiotic and nasal prescription costs averaging $210 and $452 per year, respectively.

Conclusions

RARS may affect approximately 1 in 3000 adults per year. Despite significant direct health care costs of more than $1000/year per individual patient with RARS, nasal endoscopy and computed tomography are not commonly obtained early after potential diagnosis. RARS is likely an underdiagnosed condition warranting further study.
Pediatric Laryngeal Diadochokinetic Rates
Authors: Maturo Steve , Hill Courtney , Bunting Glenn , Ballif Cathy , Maurer Rie , Hartnick Christopher
Published: October 2011

Objective

Laryngeal diadochokinetic (L‐DDK) rate is a measure of laryngeal neural integrity. The objectives for this study included the following: (1) establish the first comprehensive pediatric normative database for L‐DDK rates (DDK) using the Voice Evaluation Suite, a computerized voice analysis program; and (2) analyze normal L‐DDK rates for age and gender differences.

Study Design

Cross‐sectional study with planned data collection.

Setting

Outpatient pediatric otolaryngology clinic.

Subjects and Methods

Three hundred seven children aged 4 to 18 with normal voices. L‐DDK rates were collected during a 6‐month period. Main outcome measures included age, gender, and L‐DDK rates.

Results

Three hundred seven children (151 girls and 156 boys) were evaluated. There was no statistically significant difference between the overall mean L‐DDK rate of boys (2.69 syllables/s) compared to girls (2.55 syllables/s; P >. 05). Further analysis of all individual age groups did not reveal any statistical significance between boys and girls. There was a statistically significant difference among children aged 4 to 11 compared to those 12 to 18 years old. Among boys aged 4 to 11, the mean rate was 2.49 syllables per second, whereas among 12‐ to 18‐year‐olds, the rate was 2.95 syllables per second (P <. 01). The mean rate was 2.40 syllables per second among girls aged 4 to 11 and 2.74 syllables per second for those aged 12 to 18 (P <. 01).

Conclusion

This is the largest normative pediatric L‐DDK analysis in the English literature. The findings suggest that neurolaryngeal development approaches adult maturation at the beginning of the teenage years. These data have the potential application for objective measurement of neurolaryngeal coordination in children with neurologic impairment and also in children who have undergone nerve reinnervation procedures.