bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclization of Peptides through a Urea Bond: Application to the Arg‐Gly‐Asp Tripeptide
Authors: Schmidt Julien , Garambois Véronique , Rocheblave Luc , Martinez Jean , Pèlegrin André , Cavelier Florine , Vivès Eric
Published: April 2010

Various synthetic cyclopeptides bind different cellular proteins with high affinity and specificity. In this study, we designed a new series of cyclic tetrapeptides containing the RGD sequence, a ligand for the αvβ3 integrin receptor, in which the ring closure was performed through a urea bond between the α‐amino group of the peptide and either the α‐ or the ε‐amino group of an additional lysine. Interestingly, we showed that the urea‐closed peptide had a higher affinity for αvβ3 receptors than a reference pentacyclopeptide. Moreover, the synthetic strategy allows coupling of the resulting cyclic tetrapeptide through the carboxylic acid moiety of its lysine residue to fluorescent molecules or drugs. In addition, this strategy could be easily adapted for the cyclization of any other peptides.
LICRED: A Versatile Drop‐In Vector for Rapid Generation of Redox‐Self‐Sufficient Cytochrome P450s
Authors: Sabbadin Federico , Hyde Ralph , Robin Aelig , Hilgarth Eva‐Maria , Delenne Marie , Flitsch Sabine , Turner Nicholas , Grogan Gideon , Bruce Neil C.
Published: April 2010

Cytochromes P450 (P450s) are a family of haem‐containing oxidases with considerable potential as tools for industrial biocatalysis. Organismal genomes are revealing thousands of gene sequences that encode P450s of as yet unknown function, the exploitation of which will require high‐throughput tools for their isolation and characterisation. In this report, a ligationindependent cloning vector “LICRED” is described that enables the high‐throughput generation of libraries of redox‐self‐sufficient P450s by fusing a range of P450 haem domains to the reductase of P450RhF (RhF‐Red) in a robust and generically applicable way. Cloning and expression of fusions of RhF‐Red with the haem domains of P450cam and P450‐XplA resulted in soluble, active, redox‐self‐sufficient, chimeric enzymes. In vitro studies also revealed that electron transfer from NADPH to haem was primarily intramolecular. The general applicability of the LICRED platform was then demonstrated through the creation of a library of RhF‐Red fusion constructs by using the diverse complement of P450 haem domains identified in the genome of Nocardia farcinica. The resultant fusion‐protein library was then screened against a panel of substrates; this revealed chimeric enzymes competent for the hydroxylation of testosterone and methyltestosterone, and the dealkylation of 7‐ethoxycoumarin.
Breast cancer risk estimation with artificial neural networks revisited
Authors: Ayer Turgay , Alagoz Oguzhan , Chhatwal Jagpreet , Shavlik Jude W. , Kahn Charles E. , Burnside Elizabeth S.
Published: April 2010

BACKGROUND:

Discriminating malignant breast lesions from benign ones and accurately predicting the risk of breast cancer for individual patients are crucial to successful clinical decisions. In the past, several artificial neural network (ANN) models have been developed for breast cancer‐risk prediction. All studies have reported discrimination performance, but not one has assessed calibration, which is an equivalently important measure for accurate risk prediction. In this study, the authors have evaluated whether an artificial neural network (ANN) trained on a large prospectively collected dataset of consecutive mammography findings can discriminate between benign and malignant disease and accurately predict the probability of breast cancer for individual patients.

METHODS:

Our dataset consisted of 62,219 consecutively collected mammography findings matched with the Wisconsin State Cancer Reporting System. The authors built a 3‐layer feedforward ANN with 1000 hidden‐layer nodes. The authors trained and tested their ANN by using 10‐fold cross‐validation to predict the risk of breast cancer. The authors used area the under the receiver‐operating characteristic curve (AUC), sensitivity, and specificity to evaluate discriminative performance of the radiologists and their ANN. The authors assessed the accuracy of risk prediction (ie, calibration) of their ANN by using the Hosmer‐Lemeshow (H‐L) goodness‐of‐fit test.

RESULTS:

Their ANN demonstrated superior discrimination (AUC, 0.965) compared with the radiologists (AUC, 0.939;P< .001). The authors' ANN was also well calibrated as shown by an H‐L goodness of fitP‐value of .13.

CONCLUSIONS:

The authors' ANN can effectively discriminate malignant abnormalities from benign ones and accurately predict the risk of breast cancer for individual abnormalities. Cancer 2010. © 2010 American Cancer Society.
A phase 3 randomized, placebo‐controlled, double‐blind, clinical trial of the effect of modafinil on cancer‐related fatigue among 631 patients receiving chemotherapy
Authors: Jean‐Pierre Pascal , Morrow Gary R. , Roscoe Joseph A. , Heckler Charles , Mohile Supriya , Janelsins Michelle , Peppone Luke , Hemstad Amy , Esparaz Benjamin T. , Hopkins Judith O.
Published: April 2010

BACKGROUND:

Cancer‐related fatigue is a debilitating symptom affecting psychosocial functioning and quality of life in 70% to 100% of cancer patients during and after treatment. The authors examined the effect of 200 mg of modafinil daily on the severity of cancer‐related fatigue.

METHODS:

The authors conducted a multicenter, randomized, double‐blind, placebo‐controlled, phase 3, clinical trial to examine the effect of modafinil on patient‐reported fatigue in cancer patients undergoing chemotherapy. A sample of 877 cancer patients beginning chemotherapy at 23 geographically separate University of Rochester Cancer Center (URCC) Community Clinical Oncology Program (CCOP) affiliates were assessed for fatigue. Patients who reported fatigue (N = 867) were randomly assigned to receive either 200 mg of oral modafinil (Provigil) daily or a placebo. Treatment began on Day 5 of Cycle 2 and ended after Day 7 of Cycle 4. Fatigue and depression were assessed during Cycles 2 to 4 by using psychometrically valid measures. Group differences (treatment vs control) in the worst level of fatigue during the previous week at Cycle 4 were examined by using an analysis of covariance (ANCOVA) adjusting for baseline fatigue (Cycle 2).

RESULTS:

There were 631 patients (315 modafinil, 316 placebo) who provided evaluable data. ANCOVA showed a significant interaction between treatment condition and baseline fatigue (P = .017), where patients with severe baseline fatigue (n = 458) benefited from modafinil, whereas patients with mild or moderate fatigue did not. Modafinil had no statistically significant effect on depression (P > .05).

CONCLUSIONS:

Modafinil may be useful in controlling cancer‐related fatigue in patients who present with severe fatigue but is not useful in patients with mild or moderate fatigue. Cancer 2010. © 2010 American Cancer Society.
Protein kinase gene expression profiling and in vitro functional experiments identify novel potential therapeutic targets in adult acute lymphoblastic leukemia
Authors: Messina Monica , Chiaretti Sabina , Tavolaro Simona , Peragine Nadia , Vitale Antonella , Elia Loredana , Sica Simona , Levis Alessandro , Guarini Anna , Foà Robin
Published: April 2010

BACKGROUND:

Despite recent improvements in the treatment of acute lymphoblastic leukemia (ALL), adult patients still have an overall poor outcome. The future of ALL management relies on the introduction of novel targeted therapies. The authors sought to assess if protein kinases (PKs), frequently deregulated in cancer, show an altered expression pattern and can be considered as suitable therapeutic targets in adult ALL.

METHODS:

The authors studied the PK gene expression profile by oligonucleotide arrays in 133 adult ALL samples at the onset of the disease and subsequently performed in vitro experiments to evaluate the sensitivity to first‐ and second‐generation PK inhibitors of a set of ALL cell lines, as well as of primary ALL cells.

RESULTS:

The study documents a distinctive PK signature for different adult ALL subgroups; the PKs identified include several tyrosine kinase (TK) genes, especially in E2A/PBX+ B‐lineage ALL (B‐ALL), B‐ALL without known molecular abnormalities, and T‐lineage ALL. Consistently, cell lines and primary samples belonging to these groups proved susceptible to TK inhibitors.

CONCLUSIONS:

These results indicate that second‐generation TK inhibitors may be effective in ALL subsets other than BCR/ABL+ B‐ALL and provide the rationale for testing the impact of the newly developed TK inhibitors in the management of adult ALL patients. Cancer 2010. © 2010 American Cancer Society.
Management of adult patients with acute lymphoblastic leukemia in first complete remission
Authors: Ram Ron , Gafter‐Gvili Anat , Vidal Liat , Paul Mical , Ben‐Bassat Isaac , Shpilberg Ofer , Raanani Pia
Published: April 2010

BACKGROUND:

The optimal postremission therapy in adults with acute lymphoblastic leukemia (ALL) is still a matter of debate. The objective of this study was to compare the various potential therapeutic options for patients who achieved first complete remission.

METHODS:

The authors conducted a systematic review and meta‐analysis of randomized trials, including patients with standard‐risk (SR) All and high‐risk (HR) ALL who received first postremission therapy. Outcomes assessed were all‐cause mortality (ACM), disease recurrence (relapse), and nonrelapse mortality (NRM). Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled.

RESULTS:

Overall, there was a significant reduction in ACM in the allogenic stem cell transplantation (alloSCT) arm (RR, 0.88; 95% CI, 0.8‐0.97) compared with autologous stem cell transplantation (ASCT) or chemotherapy. Subgroup analyses revealed a similar pattern among SR patients (RR, 0.8; 95% CI, 0.68‐0.94) but a nonsignificant advantage for alloSCT among HR patients (RR, 0.88; 95% CI, 0.76‐1.01). There was an increase in NRM (RR, 2.99; 95% CI, 1.37‐6.53) and a decrease in the relapse rate in the alloSCT arm (RR, 0.52; 95% CI, 0.33‐0.83). There was no difference in ACM or the relapse rate between the ASCT and chemotherapy arms.

CONCLUSIONS:

Overall, alloSCT was superior to ASCT or chemotherapy for patients with ALL in first complete remission. The survival advantage was of greater statistical significance for patients with SR ALL than for patients with HR ALL. Cancer 2010. © 2010 American Cancer Society.
Number of lymph nodes identified at axillary dissection
Authors: Boughey Judy C. , Donohue John H. , Jakub James W. , Lohse Christine M. , Degnim Amy C.
Published: April 2010

BACKGROUND:

Several reports have shown a significantly lower number of axillary lymph nodes (AxLNs) found at axillary lymph node dissection (ALND) after neoadjuvant chemotherapy. The objective of the current study was to investigate the factors affecting the number of AxLNs identified at ALND.

METHODS:

Medical records of patients seen at the study institution, a tertiary center, from 2004 to 2007 who underwent ALND for breast cancer were reviewed.

RESULTS:

Among the 698 patients who met study criteria, the mean number of AxLNs resected was 20.4. There were 649 (93%) patients with at least 10 AxLNs recovered. Seventy‐one (10%) patients received neoadjuvant chemotherapy and 627 (90%) underwent surgical resection first. The mean number of AxLNs in the patients treated with neoadjuvant chemotherapy was 21.9 (range, 4‐56 AxLNs) compared with 20.2 (range, 5‐65 AxLNs) in the group treated with surgical resection first (P = .13). The number of patients with <10 AxLNs found at ALND was 44 of 627 (7.0%) in the surgical resection first group and 5 of 71 (7.0%) in the neoadjuvant chemotherapy group (P = 1.0). The mean number of AxLNs was higher in the 599 (86%) ALNDs performed at the study center compared with the 99 cases from outside institutions (21.2 vs 15.2 AxLNs; P <.001). Among the cases performed at the study institution, 367 (61%) were performed by surgeons with oncologic training and 232 (39%) were not. Surgical oncologists recovered an average of 23 AxLNs, which was significantly higher than the 18.4 resected by the remaining surgeons (P <.001).

CONCLUSIONS:

The number of AxLNs recovered at ALND does not appear to be affected by neoadjuvant chemotherapy. Surgeons with oncologic training appear to retrieve more AxLNs. Cancer 2010. © 2010 American Cancer Society.
Ferromagnetic Tetranuclear and Pentanuclear Copper(II) Complexes Constructed from Cu2 Blocks
Authors: Fondo Matilde , Ocampo Noelia , García‐Deibe Ana M. , Sanmartín Jesús
Published: April 2010

The new complexes [(Cu2L1)2(p‐OOC‐C6H4‐COO)]·7H2O (1·7H2O), [(Cu2L2)2(p‐OOC‐C6H4‐COO)]·2H2O (2·2H2O), [(Cu2L1)2Cu(O2C‐CH2‐CO2)2]·9H2O (3·9H2O) and [(Cu2L2)2(OOC‐CH2‐COO)]·5.5H2O (4·5.5H2O) have been obtained by interaction of either [(Cu2L1)2(CO3)]·8H2O or [Cu2L2(OH)]·1.125H2O with the corresponding dicarboxylic acid. Recrystallisation of 1·7H2O in methanol/ethanol yields single crystals of 1·2EtOH·2H2O, whereas recrystallisation of 3·9H2O and 4·5.5H2O in methanol allows crystals of 3·9H2O and 4·5.5H2O·1.25MeOH, respectively, to be isolated, which were suitable for X‐ray diffraction studies. The X‐ray characterisation of 1·2EtOH·2H2O, 3·9H2O and 4·5.5H2O·1.25MeOH shows that both the Cu4 and Cu5 clusters can be understood as being built from two dinuclear [Cu2Lx]+ (x = 1 or 2) blocks with different connectors. Magnetic analyses of 1·7H2O, 3·9H2O and 4·5.5H2O reveal that the three complexes are ferromagnetic, and the magnetic exchange mediated by the carboxylate ligands is weak.
A Lipophilic, Fluorine‐Free, Thermostable, Inexpensive, S4‐Symmetric, Highly Soluble, Weakly Coordinating, Protolabile Aluminate (Eur. J. Inorg. Chem. 13/2010)
Authors: Straub Bernd F. , Wrede Michael , Schmid Karin , Rominger Frank
Published: April 2010

The cover picture shows a Madagascar day gecko (Phelsuma madagascariensis grandis) in a coconut with a locust on top. Gecko toes hold on to slithery and vertical surfaces due to van der Waals forces, which are also relevant for the lipophilic altebate anion (left space‐filling model). Its sterically demanding substituents shield the nucleophilic center, making diethyl ether a better hydrogen bond acceptor in comparison (middle X‐ray structure). The high symmetry and the positive (blue) partial charges on the molecular surface are reflected in the right fractal‐like model. Details are discussed in the Short Communication by B. F. Straub et al. on p. 1907 ff. Photograph by Michael Wrede, artwork by Bernd F. Straub.
Solvent‐Free Olefin Hydroformylation Using Hemispherical Diphosphites
Authors: Monnereau Laure , Sémeril David , Matt Dominique
Published: April 2010

With rhodium complexes containing hemispherical diphosphite ligands derived from a calixarene skeleton, olefins can be hydroformylated efficiently undersolvent‐freeconditions. For example, in the hydroformylation of 1‐octene (T= 80 °C,P= 20 bar, olefin:Rh = 200 000:1) one of the catalysts investigated resulted in a TOF of 17290 mol (converted 1‐octene)·mol(Rh)–1·h–1, the regioselectivity towards the linear aldehyde reaching then 97.9 %.
Enantiomeric separation of cis‐bifenthrin by CD‐MEKC: Quantitative analysis in a commercial insecticide formulation
Authors: Pérez‐Fernández Virginia , García Maria Ángeles , Marina Maria Luisa
Published: April 2010

The first CE method enabling the enantiomeric separation of the synthetic pyrethroid cis‐bifenthrin (BF) was developed in this work. CD‐MEKC was the CE mode employed for this purpose. The influence of several experimental parameters such as temperature, voltage, type and concentration of surfactant (chiral and achiral) and CD was investigated. The use of the bile salt sodium cholate at a concentration of 100 mM in the presence of 20 mM heptakis (2,3,6‐tri‐O‐methyl)‐β‐CD enabled the separation of cis‐BF enantiomers in less than 10 min and with a resolution of 2.8. The analytical characteristics of the developed methodology were evaluated allowing its application to the quantitation of cis‐BF in a polyvalent commercial insecticide formulation.
The “Task B problem” and other considerations in developmental functional neuroimaging
Authors: Church Jessica A. , Petersen Steven E. , Schlaggar Bradley L.
Published: April 2010

Functional neuroimaging provides a remarkable tool to allow us to study cognition across the lifespan and in special populations in a safe way. However, experimenters face a number of methodological issues, and these issues are particularly pertinent when imaging children. This brief article discusses assessing task performance, strategies for dealing with group performance differences, controlling for movement, statistical power, proper atlas registration, and data analysis strategies. In addition, there will be discussion of two other topics that have important implications for interpreting fMRI data: the question of whether functional neuroanatomical differences between adults and children are the consequence of putative developmental neurovascular differences, and the issue of interpreting negative blood oxygenation‐level dependent (BOLD) signal change. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.
Endoscopic carbon dioxide laser diverticulostomy versus endoscopic staple‐assisted diverticulostomy to treat Zenker's diverticulum
Authors: Verhaegen Veronique J. O. , Feuth Ton , van den Hoogen Frank J. A. , Marres Henri A. M. , Takes Robert P.
Published: April 2010

Background

The 2 most frequently used endoscopic methods to treat Zenker's diverticulum are staple‐assisted and CO2 laser esophagodiverticulostomy.

Methods

The study centered around a retrospective evaluation of 107 patients with Zenker's diverticulum who were treated endoscopically by CO2 laser (n = 72) or staple‐assisted diverticulostomy (n = 35).

Results

Patients in the staple‐assisted group had a shorter duration of postoperative hospitalization, attributed to earlier oral intake, than patients in the CO2 laser group. There were no serious postoperative complications in either group. Postoperative fever and emphysema in the neck or mediastinum occurred more frequently in the CO2 laser group, but this did not lead to any complications. Most patients reported partial or complete relief of their symptoms and there was no significant difference in the number of reoperations between the 2 treatment groups.

Conclusions

Zenker's diverticulum was treated safely and effectively by the 2 endoscopic techniques, but the staple‐assisted method seemed to be the most favorable. © 2010 Wiley Periodicals, Inc. Head Neck, 2011
A Flippase-Independent Function of Atp8b1, the Protein Affected in Familial Intrahepatic Cholestasis Type 1, Is Required for Apical Protein Expression and Microvillus Formation in Polarized Epithelial Cells
Authors: Verhulst Patricia M. , van der Velden Lieke M. , Oorschot Viola , van Faassen Ernst E. , Klumperman Judith , Houwen Roderick H.J. , Pomorski Thomas G. , Holthuis Joost C.M. , Klomp Leo W.J.
Published: April 2010

Mutations in

ATP8B1

cause familial intrahepatic cholestasis type 1, a spectrum of disorders characterized by intrahepatic cholestasis, reduced growth, deafness, and diarrhea. ATP8B1 belongs to the P4 P-type adenosine triphosphatase (ATPase) family of putative aminophospholipid translocases, and loss of aminophospholipid asymmetry in the canalicular membranes of ATP8B1-deficient liver cells has been proposed as the primary cause of impaired bile salt excretion. To explore the origin of the hepatic and extrahepatic symptoms associated with ATP8B1 deficiency, we investigated the impact of ATP8B1 depletion on the domain-specific aminophospholipid translocase activities and polarized organization of polarized epithelial Caco-2 cells. Caco-2 cells were stably transfected with short hairpin RNA constructs to block ATP8B1 expression. Aminophospholipid translocase activity was assessed using spin-labeled phospholipids. The polarized organization of these cells was determined by pulse-chase analysis, cell-fractionation, immunocytochemistry, and transmission electron microscopy. ATP8B1 was abundantly expressed in the apical membrane of Caco-2 cells, and its expression was markedly induced during differentiation and polarization. Blocking ATP8B1 expression by RNA interference (RNAi) affected neither aminophospholipid transport nor the asymmetrical distribution of aminophospholipids across the apical bilayer. Nonetheless, ATP8B1-depleted Caco-2 cells displayed profound perturbations in apical membrane organization, including a disorganized apical actin cytoskeleton, a loss in microvilli, and a posttranscriptional defect in apical protein expression.

Conclusion:

Our findings point to a critical role of ATP8B1 in apical membrane organization that is unrelated to its presumed aminophospholipid translocase activity, yet potentially relevant for the development of cholestasis and the manifestation of extrahepatic features associated with ATP8B1 deficiency. (Hepatology 2010)
Cx3Cr1 and Vascular Adhesion Protein-1-Dependent Recruitment of Cd16+ Monocytes Across Human Liver Sinusoidal Endothelium
Authors: Aspinall Alexander I. , Curbishley Stuart M. , Lalor Patricia F. , Weston Chris J. , Miroslava Blahova  , Liaskou Evaggelia , Adams Rebecca M. , Holt Andrew P. , Adams David H.
Published: April 2010

The liver contains macrophages and myeloid dendritic cells (mDCs) that are critical for the regulation of hepatic inflammation. Most hepatic macrophages and mDCs are derived from monocytes recruited from the blood through poorly understood interactions with hepatic sinusoidal endothelial cells (HSECs). Human CD16+ monocytes are thought to contain the precursor populations for tissue macrophages and mDCs. We report that CD16+ cells localize to areas of active inflammation and fibrosis in chronic inflammatory liver disease and that a unique combination of cell surface receptors promotes the transendothelial migration of CD16+ monocytes through human HSECs under physiological flow. CX3CR1 activation was the dominant pertussis-sensitive mechanism controlling transendothelial migration under flow, and expression of the CX3CR1 ligand CX3CL1 is increased on hepatic sinusoids in chronic inflammatory liver disease. Exposure of CD16+ monocytes to immobilized purified CX3CL1 triggered β1-integrin-mediated adhesion to vascular cell adhesion molecule-1 and induced the development of a migratory phenotype. Following transmigration or exposure to soluble CX3CL1, CD16+ monocytes rapidly but transiently lost expression of CX3CR1. Adhesion and transmigration across HSECs under flow was also dependent on vascular adhesion protein-1 (VAP-1) on the HSECs.

Conclusion

: Our data suggest that CD16+ monocytes are recruited by a combination of adhesive signals involving VAP-1 and CX3CR1 mediated integrin-activation. Thus a novel combination of surface molecules, including VAP-1 and CX3CL1 promotes the recruitment of CD16+ monocytes to the liver, allowing them to localize at sites of chronic inflammation and fibrosis. (Hepatology 2010)
Perivascular expression of CXCL9 and CXCL12 in primary central nervous system lymphoma: T‐cell infiltration and positioning of malignant B cells
Authors: Venetz Daniel , Ponzoni Maurilio , Schiraldi Milena , Ferreri Andrés J.M. , Bertoni Francesco , Doglioni Claudio , Uguccioni Mariagrazia
Published: April 2010

Primary central nervous system lymphomas (PCNSL) are aggressive malignancies confined to the CNS, mostly of diffuse large B‐cell histotype. Despite improved understanding of the malignant B cells, little is known on the tumor microenvironment and on the response of the adaptive immunity against PCNSL. We investigated the phenotype of tumor infiltrating lymphocytes (TILs), and the expression of chemokines that could affect malignant B cells and trafficking of TILs. TILs and chemokine expression were evaluated by immunohistochemistry and in situ hybridization. Furthermore, we performed in vitro migration assays to analyze the migratory capacity of lymphocytes and malignant B cells toward chemokines and chemokine heterocomplexes. We show in 22 cases of PCNSL from immunocompetent patients that CD8+ T cells represent the majority of TILs in the tumor mass. They tend to accumulate in perivascular areas, show Granzyme B expression and proliferate in situ. Their localization and density correlates with the expression of the inflammatory chemokine CXCL9, which is transcribed and translated by perivascular macrophages and pericytes in the perivascular microenvironment. Moreover, CXCL9 and CXCL12 are coexpressed on the tumor vasculature and form heterocomplexes. In the presence of CXCL9, CXCL12‐induced migration is enhanced not only on CXCR4+/CXCR3+/CD8+ T cells but also on CXCR4+/CXCR3− malignant B cells. These findings indicate the presence of a strong chemoattractant stimulus in the perivascular microenvironment, which might serve as regulator for the recruitment of TILs and for the angiocentric positioning of malignant B cells in the perivascular cuff.
An alternative splicing isoform of eukaryotic initiation factor 4H promotes tumorigenesis in vivo and is a potential therapeutic target for human cancer
Authors: Wu Di , Matsushita Kazuyuki , Matsubara Hisahiro , Nomura Fumio , Tomonaga Takeshi
Published: April 2010

Deregulation of protein synthesis plays a critical role in cell transformation. Several translation initiation factors (eIFs) have been implicated in malignant transformation; thus, suppression of eIFs could be a potential cancer therapy if cancer cells are selectively killed without damaging healthy cells. One of the potential molecular targets is a cancer‐specific splicing variant. We have previously shown that one of the splicing variants of eIF4H (isoform 1) was overexpressed in primary human colorectal cancer. Our study aimed to explore whether eIF4H isoform 1 contributes to carcinogenesis and could be an efficient molecular target for human cancer therapy. We found that its overexpression in immortalized mouse fibroblasts, NIH3T3 cells, generated tumors in nude mice. Conversely, suppression of eIF4H isoform 1 expression using specific siRNA inhibited the proliferation of colon cancer cells in vitro and subcutaneously implanted tumor in vivo. Strikingly, eIF4H isoform 1 specific siRNA showed no effect on the growth of immortalized human fibroblasts. More interestingly, ectopic expression of eIF4H isoform 1 greatly increased the cyclin D1 level. On the other hand, cyclin D1 decreased by shRNA‐mediated suppression of eIF4H isoform 1. Moreover, cotransfection of eIF4H isoform 1 siRNA and cyclin D1 expression plasmid was able to reverse the growth suppression effect of eIF4H isoform 1 knockdown. These results suggest that eIF4H isoform 1 plays an important role in carcinogenesis through the activation of oncogenic signaling and could be a promising molecular target for cancer therapy.
A functional TNFRSF5 polymorphism and risk of non‐Hodgkin lymphoma, a pooled analysis
Authors: Nieters Alexandra , Bracci Paige M. , de Sanjosé Silvia , Becker Nikolaus , Maynadié Marc , Benavente Yolanda , Foretova Lenka , Cocco Pierluigi , Staines Anthony , Holly Elizabeth A. , Boffetta Paolo , Brennan Paul , Skibola Christine F.
Published: April 2010

Interaction between CD40 and its ligand, CD154, has a key function in immune regulation. Recent experimental data support a role of deregulated CD40 signalling in lymphomagenesis. Data from earlier studies that are part of this pooling study implicate a functional polymorphism (−1C>T, rs1883832) in the TNFRSF5 gene encoding CD40 in the etiology of follicular lymphoma. Here, the association of this variant with non‐Hodgkin lymphoma (NHL) risk was replicated in a European multicenter study of 855 NHL cases and 1,206 controls. In the combined analysis of 2,617 cases and 3,605 controls, carrying the TT genotype was associated with an increased risk for all NHL (OR = 1.4; p for linear trend = 0.00009), diffuse large B‐cell lymphoma (OR = 1.6; p for linear trend = 0.002) and follicular lymphoma (OR = 1.6; p for linear trend = 0.001). These data suggest a possible role of this functional polymorphism in lymphomas originating within the germinal center.
Gallbladder cancer: Incidence and survival in a high‐risk area of Chile
Authors: Bertran Enriqueta , Heise Katy , Andia Marcelo E. , Ferreccio Catterina
Published: April 2010

We assessed population incidence rates 1998–2002 and 5‐year survival rates of 317 primary gallbladder cancer (GBC) entered in the population‐based cancer registry in Valdivia. We analyzed GBC incidence (Poisson regression) and GBC survival (Cox regression). Cases were identified by histology (69.4%), clinical work‐up (21.8%), or death certificate only (8.8%). Main symptoms were abdominal pain (82.8%), jaundice (53.6%) nausea (42.6%), and weight loss (38.2%); at diagnosis, 64% had Stage TNM IV. In the period, 4% of histopathological studies from presumptively benign cholecystectomies presented GBC. GBC cases were mainly females (76.0%), urban residents (70.3%), Hispanic (83.7%) of low schooling <4 years (64.0%). GBC standardized incidence rate per 100,000 (SIR) were all 17.5 (95%CI: 15.5–19.4), women 24.3, and men 8.6 (p < 0.00001); Mapuche 25.0, Hispanic 16.2 (p = 0.09). The highest SIRs were in Mapuche (269.2) and Hispanic women (199.6) with <4 years of schooling. Lowest SIRs were among Hispanic men (19.8) and women (21.9) with >8 years of schooling. Low schooling, female and urban residence were independent risk factors. By December 31, 2007, 6 (1.9%) cases were living, 280 (88.3%) died from GBC, 32 (10.1%) were lost of follow‐up. Kaplan Meier Global 5‐year survival was: 10.3%, 85% at stage I and 1.9% at stage IV; median survival: 3.4 months. Independent poor prognostic factors were TNM IV, jaundice and nonincidental diagnoses. Our results suggest that women of Mapuche ancestry with low schooling (>50 years) are at the highest risk of presenting and dying from GBC and should be the target for early detection programs.
De novo constitutional MLH1 epimutations confer early‐onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one
Authors: Goel Ajay , Nguyen Thuy‐Phuong , Leung Hon‐Chiu E. , Nagasaka Takeshi , Rhees Jennifer , Hotchkiss Erin , Arnold Mildred , Banerji Pia , Koi Minoru , Kwok Chau‐To , Packham Deborah , Lipton Lara , Boland C. Richard , Ward Robyn L. , Hitchins Megan P.
Published: April 2010

Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Constitutional epimutations of the MLH1 gene, characterized by soma‐wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the de novo occurrence of a constitutional MLH1 epimutation and somatic loss‐of‐heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional MLH1 epimutations showed eight tumors had lost the second MLH1 allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in KRAS. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in MLH1 epimutation‐associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair–deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in MLH1.
The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial
Authors: Heiss Markus M. , Murawa Pawel , Koralewski Piotr , Kutarska Elzbieta , Kolesnik Olena O. , Ivanchenko Vladimir V. , Dudnichenko Alexander S. , Aleknaviciene Birute , Razbadauskas Arturas , Gore Martin , Ganea‐Motan Elena , Ciuleanu Tudor , Wimberger Pauline , Schmittel Alexander , Schmalfeldt Barbara , Burges Alexander , Bokemeyer Carsten , Lindhofer Horst , Lahr Angelika , Parsons Simon L.
Published: April 2010

Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti‐epithelial cell‐adhesion molecule x anti‐CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004‐000723‐15; NCT00836654), cancer patients (n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 μg, respectively. The primary efficacy endpoint was puncture‐free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture‐free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer (n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile.
Clinicopathological significance of cell cycle regulation markers in a large series of genetically confirmed Ewing's Sarcoma Family of Tumors
Authors: López‐Guerrero José Antonio , Machado Isidro , Scotlandi Katia , Noguera Rosa , Pellín Antonio , Navarro Samuel , Serra Massimo , Calabuig‐Fariñas Silvia , Picci Piero , Llombart‐Bosch Antonio
Published: April 2010

More than 90% of all Ewing's Sarcoma Family of Tumors (ESFT) exhibit specific chromosomal rearrangements between theEWSgene on chromosome 22 and various members of theETSgene family of transcription factors. The gene fusion type and other secondary genetic alterations, mainly involving cell cycle regulators, have been shown to be of prognostic relevance in ESFT. However, no conclusive results have been reported. We analyzed the clinicopathological significance of relevant cell cycle regulators in genetically confirmed ESFT. A total of 324 cases were analyzed for the immunohistochemical expression of p53, p21Waf1/Cip1, p27Kip1and Ki67 and the chromosomal alterations of thep53and9p21locus by fluorescent in situ hybridization. We observed that expression of p53 (p= 0.025), p21Waf1/Cip1(p= 0.015) and p27Kip1(p= 0.013) was higher in disseminated than in localized disease. Furthermore, a cohort of 217 patients with localized disease was considered for studying the prognosis involvement of these factors on patient follow‐up. The median follow‐up was 39 months (range: 0.17–452) with an overall survival (OS) of 55%. Ki67 was expressed in 34% of cases and constituted an independent prognostic factor for progression free survival and OS independently of the type of treatment [hazard ratio of 2.0 (95% CI: 1.3–3.1;p= 0.003) and 1.9 (95% IC: 1.3–2.9;p= 0.007) for progression free survival and OS, respectively, being especially relevant in the group of patients which incorporated radiotherapy in their regimen schedules. In conclusion, this study demonstrates that Ki67 expression constitutes a valuable indicator of poor prognosis in localized ESFT.
Antioxidant intake and risk of endometrial cancer: Results from the Nurses' Health Study
Authors: Cui Xiaohui , Rosner Bernard , Willett Walter C. , Hankinson Susan E.
Published: April 2010

To investigate the associations between antioxidant intake and risk of endometrial cancer, the authors analyzed data from the prospective Nurses' Health Study. From 1980 to 2006, 669 invasive adenocarcinoma cases were identified over 1.3 million person‐years of follow‐up. Information on dietary intake was collected in 1980 and updated every 2–4 years. Cox proportional hazard models were used to calculate the multivariate relative risks (RR), controlling for total energy and potential risk factors for endometrial cancer. Overall, the authors found no association between intakes of vitamins A, C, E or carotenoids from foods or supplements and cancer risk. The RR and 95% confidence intervals (CI) for the highest vs. lowest quintiles of vitamins A, C, E and total carotenoids were 1.09 (95% CI: 0.85–1.39), 0.98 (95% CI: 0.76–1.25), 1.07 (95% CI: 0.83–1.38) and 1.12 (95% CI: 0.86–1.45), respectively. Similarly, the use of multivitamins or specific vitamins A, C or E supplements was unassociated with risk. In subgroup analyses, several associations seemed to vary by postmenopausal hormone use. Our results suggest that there is no overall association between dietary antioxidant intake or use of antioxidant supplements with risk of endometrial cancer.
Pancreatic cancer incidence and outcome in relation to ABO blood groups among Han Chinese patients: A case–control study
Authors: Ben Qiwen , Wang Kaixuan , Yuan Yaozong , Li Zhaoshen
Published: April 2010

The aim of the current study was to determine the association between ABO blood group and the risk and progression of pancreatic ductal adenocarcinoma (PDAC) in the Han Chinese ethnic group. During the period of 2000–2009, 1,431 patients with PDAC and 1,449 age‐ and sex‐matched controls were recruited in two university‐affiliated hospitals. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (ORs). The relationship between patient ABO blood group and clinicopathologic features was also analyzed. Compared with subjects having blood group O, a modestly higher risk was observed among cases with blood group A or AB with adjusted ORs (95% confidence interval) of 1.368 (1.127–1.661) and 1.391 (1.053–1.838), respectively. The TNM stages of tumors in patients with non‐O blood groups (A, B or AB) were more highly advanced than in patients with blood group O (p < 0.001). Among patients who underwent a potentially curative operation, the median survival time of patients with blood group O was significantly longer than that of patients with non‐O blood groups (16.0 months vs. 11.0 months, p = 0.001, log‐rank test). This study shows evidence of an association between blood group type and risk for development and progression of PDAC. These findings merit further confirmation in a large population‐based prospective study in patients of the Han Chinese ethnic group.
Trafficking and signaling in mammalian autophagy
Authors: Tooze Sharon A. , Jefferies Harold B. J. , Kalie Eyal , Longatti Andrea , Mcalpine Fiona E. , Mcknight Nicole C. , Orsi Andrea , Polson Hannah E. J. , Razi Minoo , Robinson Deborah J. , Webber Jemma L.
Published: April 2010

Macroautophagy, here called autophagy, is literally a “self‐eating” catabolic process, which is evolutionarily conserved. Autophagy is initiated by cellular stress pathways, resulting in the sequestration or engulfment of cytosolic proteins, membranes, and organelles in a double membrane structure that fuses with endosomes and lysosomes, thus delivering the sequestered material for degradation. Autophagy is implicated in a number of human diseases, many of which can either be characterized by an imbalance in protein, organelle, or cellular homeostasis, ultimately resulting in an alteration of the autophagic response. Here, we will review the recent progress made in understanding the induction of autophagy, with emphasis on the contributions from our laboratory. © 2010 IUBMB IUBMB Life 62(7): 503–508, 2010
Species and strain identification of lactic acid bacteria using FTIR spectroscopy and artificial neural networks
Authors: Wenning Mareike , Büchl Nicole R. , Scherer Siegfried
Published: April 2010

Lactic acid bacteria (LAB) are a heterogeneous group of micro‐organisms with high relevance for fermented food and beverages as well as human and animal health. Identification of LAB is complicated by species richness, a high degree of heterogeneity between species and the presence of very closely related species at the same time. In the present study we developed identification systems based on FTIR spectra and artificial neural networks (ANNs) for species identification of 92 LAB species out of nine genera and strain identification of probiotic and environmental Enterococcus faecium strains used as additives for animal feed. The reference databases established in this work permit reliable identification of LAB with accuracies of 93.2% at species and 97.1% at strain level for Ec. faecium, demonstrating the excellent suitability of FTIR spectroscopy as a technique applicable for simultaneous species and strain identification. (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The effect of the association of near infrared laser therapy, bone morphogenetic proteins, and guided bone regeneration on tibial fractures treated with internal rigid fixation: A Raman spectroscopic study
Authors: Lopes Cibele B. , Pacheco Marcos T. T. , Silveira Landulfo , Cangussú Maria Cristina T. , Pinheiro Antonio L. B.
Published: April 2010

Fractures have different etiology and treatment and may be associated or not to bone losses. Laser light has been shown to improve bone healing. We aimed to assess, through Raman spectroscopy, the level of CHA (∼958 cm−1) on complete fractures animals treated with IRF treated or not with Low Level Laser Therapy—LLLT and associated or not to BMPs and GBR. Complete tibial fractures were created on 15 animals that were divided into five groups. LLLT (Laser Unit, Kondortech, São Carlos, SP, Brazil, λ790 nm, 4 J/cm2/point, 40 mW, ϕ ∼ 0.5 cm2, 16 J/cm2 session) started immediately after surgery and repeated at 48 h interval (2 weeks). Animal death occurred after 30 days. Raman spectroscopy was performed at the surface of the fracture. Our results showed significant differences between the groups IRF + BL /IRF_NBL (p = 0.05); between all experimental groups and untreated bone; bone/IRF + BL; IRF + BL + Bio + GBR; IRF + BL + LLLT; IRF + BL + Bio + GBR + LLLT; IRF_NBL (p < 0.001, all); IRF_NBL/IRF + BL + LLLT (p = 0.03); IRF_NBL/IRF + BL + Bio + GBR + LLLT (p = 0.02); IRF + BL/IRF + BL + LLLT (p = 0.04); IRF + BL/IRF + BL + Bio + GBR + LLLT (p = 0.002); IRF + BL + Bio + GBR/IRF + BL + Bio + GBR + LLLT (p = 0.05). It is concluded that the use of NIR LLLT associated to BMPs and GBR was effective in improving bone healing on fractured bones due to increased levels of CHA. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010.
A comparison of imaging methodologies for 3D tissue engineering
Authors: Smith Louise E. , Smallwood Rod , Macneil Sheila
Published: April 2010

Imaging of cells in two dimensions is routinely performed within cell biology and tissue engineering laboratories. When biology moves into three dimensions imaging becomes more challenging, especially when multiple cell types are used. This review compares imaging techniques used regularly in our laboratory in the culture of cells in both two and three dimensions. The techniques reviewed include phase contrast microscopy, fluorescent microscopy, confocal laser scanning microscopy, electron microscopy, and optical coherence tomography. We compare these techniques to the current “gold standard” for imaging three‐dimensional tissue engineered constructs, histology. Microsc. Res. Tech. 73:1123–1133, 2010. © 2010 Wiley‐Liss, Inc.
Confocal microscopy for the analysis of siRNA delivery by polymeric nanoparticles
Authors: Portis Amanda M. , Carballo Georgina , Baker Gregory L. , Chan Christina , Walton S. Patrick
Published: April 2010

Clinical applications of genetic therapies, including delivery of short, interfering RNAs (siRNAs) for RNA interference (RNAi), are limited due to the difficulty of delivering nucleic acids to specific cells of interest while at the same time minimizing toxicity and immunogenicity. The use of cationic polymers to deliver nucleic acid therapeutics has the potential to address these complex issues but is currently limited by low‐delivery efficiencies. Although cell culture studies have shown that some polymers can be used to deliver siRNAs and achieve silencing, it is still not clear what physical or chemical properties are needed to ensure that the polymers form active polymer‐siRNA complexes. In this study, we used multicolor fluorescence confocal microscopy to analyze the cellular uptake of siRNAs delivered by novel propargyl glycolide polymeric nanoparticles (NPs). Delivery by these vehicles was compared with delivery by linear polyethyleneimine (LPEI) and Lipofectamine 2000 (LF2K), which are both known as effective delivery vehicles for siRNAs. Our results showed that when LF2K and LPEI were used, large quantities of siRNA were delivered rapidly, presumably overwhelming the basal levels of mRNA to initiate silencing. In contrast, our novel polymeric NPs showed delivery of siRNAs but at concentrations that were initially too low to achieve silencing. Nonetheless, the exceptionally low cytotoxicity of our NPs, and the simplicity with which they can be modified, makes them good candidates for further study to optimize their delivery profiles and, in turn, achieve efficient silencing. Microsc. Res. Tech. 73:878–885, 2010. © 2010 Wiley‐Liss, Inc.
Multiphoton fluorescence lifetime imaging of 3D‐stem cell spheroids during differentiation
Authors: König Karsten , Uchugonova Aisada , Gorjup Erwin
Published: April 2010

Long‐term high‐resolution multiphoton imaging of nonlabeled human salivary gland stem cell spheroids has been performed with submicron spatial resolution, 10.5‐nm spectral resolution, and picosecond temporal resolution. In particular, the two‐photon‐excited coenzyme NAD(P)H and flavins have been detected by time‐correlated single photon counting (TCSPC). Stem cells increased their autofluorescence lifetimes and decreased their total fluorescence intensity during the adipogenic‐differentiation process. In addition, the onset of the biosynthesis of lipid vacuoles was monitored over a period of several weeks in stem‐cell spheroids. Time‐resolved multiphoton autofluorescence imaging microscopes may become a promising tool for marker‐free stem‐cell characterization and cell sorting. Microsc. Res. Tech. 74:9‐17, 2011. © 2010 Wiley‐Liss, Inc.