bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic analysis and relatedness of P2-like phages of the Burkholderia cepacia complex
Authors: Lynch Karlene H , Stothard Paul , Dennis Jonathan J
Published: October 2010

Background

The Burkholderia cepacia complex (BCC) is comprised of at least seventeen Gram-negative species that cause infections in cystic fibrosis patients. Because BCC bacteria are broadly antibiotic resistant, phage therapy is currently being investigated as a possible alternative treatment for these infections. The purpose of our study was to sequence and characterize three novel BCC-specific phages: KS5 (vB_BceM-KS5 or vB_BmuZ-ATCC 17616), KS14 (vB_BceM-KS14) and KL3 (vB_BamM-KL3 or vB_BceZ-CEP511).

Results

KS5, KS14 and KL3 are myoviruses with the A1 morphotype. The genomes of these phages are between 32317 and 40555 base pairs in length and are predicted to encode between 44 and 52 proteins. These phages have over 50% of their proteins in common with enterobacteria phage P2 and so can be classified as members of the Peduovirinae subfamily and the "P2-like viruses" genus. The BCC phage proteins similar to those encoded by P2 are predominantly structural components involved in virion morphogenesis. As prophages, KS5 and KL3 integrate into an AMP nucleosidase gene and a threonine tRNA gene, respectively. Unlike other P2-like viruses, the KS14 prophage is maintained as a plasmid. The P2 E+E' translational frameshift site is conserved among these three phages and so they are predicted to use frameshifting for expression of two of their tail proteins. The lysBC genes of KS14 and KL3 are similar to those of P2, but in KS5 the organization of these genes suggests that they may have been acquired via horizontal transfer from a phage similar to λ. KS5 contains two sequence elements that are unique among these three phages: an ISBmu 2-like insertion sequence and a reverse transcriptase gene. KL3 encodes an EcoRII-C endonuclease/methylase pair and Vsr endonuclease that are predicted to function during the lytic cycle to cleave non-self DNA, protect the phage genome and repair methylation-induced mutations.

Conclusions

KS5, KS14 and KL3 are the first BCC-specific phages to be identified as P2-like. As KS14 has previously been shown to be active against Burkholderia cenocepacia in vivo, genomic characterization of these phages is a crucial first step in the development of these and similar phages for clinical use against the BCC.
A transcriptomic analysis of gene expression in the venom gland of the snake Bothrops alternatus (urutu)
Authors: Cardoso Kiara C , Da Silva Márcio J , Costa Gustavo GL , Torres Tatiana T , Del Bem Luiz Eduardo V , Vidal Ramon O , Menossi Marcelo , Hyslop Stephen
Published: October 2010

Background

The genus Bothrops is widespread throughout Central and South America and is the principal cause of snakebite in these regions. Transcriptomic and proteomic studies have examined the venom composition of several species in this genus, but many others remain to be studied. In this work, we used a transcriptomic approach to examine the venom gland genes of Bothrops alternatus, a clinically important species found in southeastern and southern Brazil, Uruguay, northern Argentina and eastern Paraguay.

Results

A cDNA library of 5,350 expressed sequence tags (ESTs) was produced and assembled into 838 contigs and 4512 singletons. BLAST searches of relevant databases showed 30% hits and 70% no-hits, with toxin-related transcripts accounting for 23% and 78% of the total transcripts and hits, respectively. Gene ontology analysis identified non-toxin genes related to general metabolism, transcription and translation, processing and sorting, (polypeptide) degradation, structural functions and cell regulation. The major groups of toxin transcripts identified were metalloproteinases (81%), bradykinin-potentiating peptides/C-type natriuretic peptides (8.8%), phospholipases A2 (5.6%), serine proteinases (1.9%) and C-type lectins (1.5%). Metalloproteinases were almost exclusively type PIII proteins, with few type PII and no type PI proteins. Phospholipases A2 were essentially acidic; no basic PLA2 were detected. Minor toxin transcripts were related to L-amino acid oxidase, cysteine-rich secretory proteins, dipeptidylpeptidase IV, hyaluronidase, three-finger toxins and ohanin. Two non-toxic proteins, thioredoxin and double-specificity phosphatase Dusp6, showed high sequence identity to similar proteins from other snakes. In addition to the above features, single-nucleotide polymorphisms, microsatellites, transposable elements and inverted repeats that could contribute to toxin diversity were observed.

Conclusions

Bothrops alternatus venom gland contains the major toxin classes described for other Bothrops venoms based on trancriptomic and proteomic studies. The predominance of type PIII metalloproteinases agrees with the well-known hemorrhagic activity of this venom, whereas the lower content of serine proteases and C-type lectins could contribute to less marked coagulopathy following envenoming by this species. The lack of basic PLA2 agrees with the lower myotoxicity of this venom compared to other Bothrops species with these toxins. Together, these results contribute to our understanding of the physiopathology of envenoming by this species.
Retrospective analyses of cisplatin-based doublet combination chemotherapy in patients with advanced gastric cancer
Authors: Lim Do Hyoung , Park Se Hoon , Park Keon Woo , Kang Jung Hun , Oh Sung Yong , Hwang In Gyu , Kwon Jung Mi , Lee Sang-Cheol , Lee Hui-Young , Kim Hyeong Su , Lim Ho Yeong , Kang Won Ki
Published: October 2010

Backgrounds

Cisplatin-based chemotherapy, in combination with fluoropyrimidines or taxanes, have demonstrated efficacy against advanced gastric cancer (AGC). This retrospective study was performed with the data obtained from our cancer chemotherapy registry and eight another cancer centers.

Methods

In 2008, a total of 283 AGC patients were treated with cisplatin-based doublet chemotherapy in the first-line setting: capecitabine plus cisplatin (XP, n = 77), S-1 plus cisplatin (SP, n = 97), taxanes (docetaxel, paclitaxel) plus cisplatin (TP, n = 72), and 5-fluorouracil plus platinum (FP, n = 37). The primary endpoint of this study was overall survival (OS) and the secondary endpoints were safety, response rate and progression-free survival (PFS).

Results

The median age was 54 years with a range of 28-78 years and median delivered number of chemotherapy cycles were XP: 4, SP: 5, TP: 5 and FP: 5, respectively. Objective tumor responses (38%; 95% CI, 32-43%) were 40% for XP, 42% for SP, 36% for DP, and 24% for FP. The estimated median PFS was 4.5 months (95% CI, 3.6-5.4 months) and the median OS was 12.3 months (95% CI, 10.8-13.7 months). No statistically significant difference was found between each regimen used as first-line chemotherapy. At multivariate analysis, independent prognostic parameters for OS were prior gastrectomy, peritoneal dissemination, performance status and hemoglobin level

Conclusion

All of the cisplatin-based doublet chemotherapy regimens appear to be active as first-line chemotherapy for AGC. With better patient selection according to clinical parameters and molecular markers, clinical outcomes of AGC patients in first-line setting can be improved.
Physician's manual reporting underestimates mortality: evidence from a population-based HIV/AIDS treatment program
Authors: Au-Yeung Christopher G , Anema Aranka , Chan Keith , Yip Benita , Montaner Julio SG , Hogg Robert S
Published: October 2010

Background

In clinical and cohort research, mortality estimates are often derived from manual reports generated by physicians or electronic reports from vital event registries. We examined the rate of underreporting of deaths by manual methods as compared with electronic reports from a vital event registry.

Methods

The retrospective analyses included deaths among participants registered in an observational cohort who initiated highly-active antiretroviral therapy (HAART) between August 1, 1996 and June 30, 2006. Deaths were routinely reported manually by physicians and through annual electronic record linkages with a population-based vital event registry. Multivariate logistic regression was carried out to assess independent predictors of death reporting by manual methods.

Results

Of the 3,116 individuals included in the analyses, 622 (20.0%) died during follow-up. Manual reporting by physicians only identified 377 (60.6%), while electronic linkages captured 598 (96.1%) of all deaths. Multivariate analysis indicated that deaths among individuals with lower CD4 cell count, higher HIV plasma viral load, a history of injection drug use, and under the care of an HIV-experienced physicians were more likely to be reported manually. Furthermore, non-accidental deaths were more likely to be reported manually, and manual reporting of deaths increased over time.

Conclusions

Relying only on manual reports to ascertain deaths significantly underestimates the total number of deaths in the population. This can generate important biases when evaluating the impact of therapeutic interventions in the populational setting.
Patterns of physical activity in different domains and implications for intervention in a multi-ethnic Asian population: a cross-sectional study
Authors: Khaing Nang Ei Ei , Khoo Eric YH , Salim Agus , Tai E Shyong , Lee Jeannette , Van Dam Rob M
Published: October 2010

Background

The benefits of regular physical activity for quality of life and disease prevention have been well documented. Identification of low activity groups would facilitate interventional programs. Many studies have focussed on leisure time activity, which may not capture the spectrum of physical activity relevant to disease prevention. Furthermore, few studies have been conducted in urban Asian settings.

Methods

We evaluated physical activity in different domains (leisure time, occupational, household and transportation) and its sociodemographic determinants in 4750 adult Chinese, Malay, and Asian Indian Singaporeans. Physical activity was assessed using locally validated questionnaires.

Results

Occupational and household activity contributed substantially more to total physical activity than leisure time or transportation activity. However, when only activity of at least moderate intensity was considered leisure time activity contributed most to total physical activity. Higher socio-economic status was associated with more leisure time activity, but less total physical activity due to reduced activity in the other domains. Chinese ethnicity was also associated with less total physical activity as a result of less activity in non-leisure time domains.

Conclusions

In assessing levels of physical activity and recommending changes, it is important to consider physical activity in different domains. Focus on leisure-time physical activity alone could identify the wrong groups for intervention and miss opportunities for increasing physical activity in populations.
Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption
Authors: Sørensen Mette G , Karsdal Morten A , Dziegiel Morten H , Boutin Jean A , Nosjean Olivier , Henriksen Kim
Published: October 2010

Background

Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts.

Methods

Human osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours). The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue.

Results

Of the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently.

Conclusions

In conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.
α-TEA-induced death receptor dependent apoptosis involves activation of acid sphingomyelinase and elevated ceramide-enriched cell surface membranes
Authors: Li Jing , Yu Weiping , Tiwary Richa , Park Sook-Kyung , Xiong Ailian , Sanders Bob G , Kline Kimberly
Published: October 2010

Background

Alpha-tocopherol ether-linked acetic acid (α-TEA), an analog of vitamin E (RRR-alpha-tocopherol), is a potent and selective apoptosis-inducing agent for human cancer cells in vivo and in vitro. α-TEA induces apoptosis via activation of extrinsic death receptors Fas (CD95) and DR5, JNK/p73/Noxa pathways, and suppression of anti-apoptotic mediators Akt, ERK, c-FLIP and survivin in breast, ovarian and prostate cancer cells.

Results

In this study, we demonstrate that α-TEA induces the accumulation of cell surface membrane ceramide, leading to co-localization with Fas, DR5, and FADD, followed by activation of caspases-8 and -9 and apoptosis in human MDA-MB-231 breast cancer cells. α-TEA treatment leads to increased acid sphingomyelinase (ASMase) activity by 30 min, peaking at 4 hrs, which is correlated with ASMase translocation from cytosol to the cell surface membrane. Functional knockdown of ASMase with either the chemical inhibitor, desipramine, or siRNA markedly reduces α-TEA-induced cell surface membrane accumulation of ceramide and its co-localization with Fas, DR5, and FADD, cleavage of caspases-8 and -9 and apoptosis, suggesting an early and critical role for ASMase in α-TEA-induced apoptosis. Consistent with cell culture data, immunohistochemical analyses of tumor tissues taken from α-TEA treated nude mice bearing MDA-MB-231 xenografts show increased levels of cell surface membrane ceramide in comparison to tumor tissues from control animals.

Conclusion

Taken together, these studies demonstrate that ASMase activation and membrane ceramide accumulation are early events contributing to α-TEA-induced apoptosis in vitro and perhaps in vivo.
Colonization, mouse-style
Authors: Gabriel Sofia I , Jóhannesdóttir Fríða , Jones Eleanor P , Searle Jeremy B
Published: October 2010

Several recent papers, including one in BMC Evolutionary Biology, examine the colonization history of house mice. As well as background for the analysis of mouse adaptation, such studies offer a perspective on the history of movements of the humans that accidentally transported the mice.

See research article: http://www.biomedcentral.com/1471-2148/10/325
Thermodynamic modeling of transcription: sensitivity analysis differentiates biological mechanism from mathematical model-induced effects
Authors: Dresch Jacqueline M , Liu Xiaozhou , Arnosti David N , Ay Ahmet
Published: October 2010

Background

Quantitative models of gene expression generate parameter values that can shed light on biological features such as transcription factor activity, cooperativity, and local effects of repressors. An important element in such investigations is sensitivity analysis, which determines how strongly a model's output reacts to variations in parameter values. Parameters of low sensitivity may not be accurately estimated, leading to unwarranted conclusions. Low sensitivity may reflect the nature of the biological data, or it may be a result of the model structure. Here, we focus on the analysis of thermodynamic models, which have been used extensively to analyze gene transcription. Extracted parameter values have been interpreted biologically, but until now little attention has been given to parameter sensitivity in this context.

Results

We apply local and global sensitivity analyses to two recent transcriptional models to determine the sensitivity of individual parameters. We show that in one case, values for repressor efficiencies are very sensitive, while values for protein cooperativities are not, and provide insights on why these differential sensitivities stem from both biological effects and the structure of the applied models. In a second case, we demonstrate that parameters that were thought to prove the system's dependence on activator-activator cooperativity are relatively insensitive. We show that there are numerous parameter sets that do not satisfy the relationships proferred as the optimal solutions, indicating that structural differences between the two types of transcriptional enhancers analyzed may not be as simple as altered activator cooperativity.

Conclusions

Our results emphasize the need for sensitivity analysis to examine model construction and forms of biological data used for modeling transcriptional processes, in order to determine the significance of estimated parameter values for thermodynamic models. Knowledge of parameter sensitivities can provide the necessary context to determine how modeling results should be interpreted in biological systems.
Continuous glucose monitors prove highly accurate in critically ill children
Authors: Bridges Brian C , Preissig Catherine M , Maher Kevin O , Rigby Mark R
Published: October 2010

Introduction

Hyperglycemia is associated with increased morbidity and mortality in critically ill patients and strict glycemic control has become standard care for adults. Recent studies have questioned the optimal targets for such management and reported increased rates of iatrogenic hypoglycemia in both critically ill children and adults. The ability to provide accurate, real-time continuous glucose monitoring would improve the efficacy and safety of this practice in critically ill patients. The aim of our study is to determine if a continuous, interstitial glucose monitor will correlate with blood glucose values in critically ill children.

Methods

We evaluated 50 critically ill children age 6 weeks to 16 years old with a commercially available continuous glucose monitor (CGM; Medtronic Guardian®). CGM values and standard blood glucose (BG) values were compared. During the study, no changes in patient management were made based on CGM readings alone.

Results

Forty-seven patients had analyzable CGM data. A total of 1,555 CGM and routine BG measurements were compared using Clarke error grid and Bland-Altman analysis. For all readings, 97.9% were within clinically acceptable agreement. The mean absolute relative difference between CGM and BG readings was 15.3%. For the 1,555 paired CGM and BG measurements, there is a statistically significant linear relationship between CGM values and BG (P <.0001). A high degree of clinical agreement existed in three subpopulation analyses based on age, illness severity, and support measures. This included some of our smallest patients (that is, <12 months old), those who required vasopressors, and those who were treated for critical illness hyperglycemia.

Conclusions

In one of the largest studies to date, in a highly vulnerable ICU population, CGM values have a clinically acceptable correlation with the BG values now used diagnostically and therapeutically. Our data contest the theoretical concerns posed by some regarding CGM use in the ICU. The existing medical evidence may now support a role for CGM devices in the identification and management of hyperglycemia in diverse ICU settings.
Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer
Authors: Maki Robert G.
Published: October 2010

Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non–small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed.
Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab
Authors: Andre Fabrice , Campone Mario , O'Regan Ruth , Manlius Corinne , Massacesi Cristian , Tarek Sahmoud , Mukhopadhyay Pabak , Soria Jean-Charles , Naughton Michael , Hurvitz Sara A.
Published: October 2010

Purpose

To determine the recommended dose of everolimus, a mammalian target of rapamycin inhibitor, combined with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) –overexpressing metastatic breast cancer pretreated with trastuzumab.

Methods

In this phase Ib, multicenter, dose-escalation study, patients were treated with everolimus 5 mg/d, 10 mg/d, or 30 mg/wk in combination with paclitaxel (80 mg/m2 days 1, 8, and 15 every 4 weeks) and trastuzumab (2 mg/kg weekly). End points included end-of–cycle 1 dose-limiting toxicity (DLT) rate (primary end point), safety, relative dose intensity of study drugs, overall response rate (ORR), and pharmacokinetics.

Results

Of 33 patients enrolled, 31 were pretreated with taxanes, and 32 were resistant to trastuzumab. Patients received a median of two lines of chemotherapy in the metastatic setting (range, 0 to 17 lines). Three patients experienced cycle 1 DLTs: febrile neutropenia (5 mg/d), stomatitis (10 mg/d), and confusion (30 mg/wk). Grade 3 to 4 neutropenia was the most common toxicity observed (n = 17 patients [52%]). On the basis of observed DLTs and overall safety, 10 mg/d was recommended for additional development. Twenty-seven patients had measurable disease and were evaluable for efficacy. Among these patients, ORR was 44%. Overall disease was controlled for 6 months or more in 74%. Median progression-free survival was 34 weeks (95% CI, 29.1 to 40.7 weeks). Among 11 patients who were resistant to both trastuzumab and taxane, a similar level of antitumor activity was observed (ORR, 55%).

Conclusion

Everolimus combined with weekly paclitaxel and trastuzumab was generally well tolerated and had encouraging antitumor activity in patients with trastuzumab-pretreated and -resistant metastatic HER2-overexpressing breast cancer.
Multicenter Phase II Trial of S-1 in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma
Authors: Naito Seiji , Eto Masatoshi , Shinohara Nobuo , Tomita Yoshihiko , Fujisawa Masato , Namiki Mikio , Nishikido Masaharu , Usami Michiyuki , Tsukamoto Taiji , Akaza Hideyuki
Published: October 2010

Purpose

This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU).

Methods

Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse-transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy.

Results

A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S-1, and 28 (62.2%) had stable disease. Median progression-free survival was 9.2 months. The severity of most adverse events was mild to moderate. The most common grade 3/4 drug-related adverse events were neutropenia (8.9%) and anorexia (8.9%). The expression level of thymidylate synthase (TS) mRNA was significantly lower in patients who responded to treatment (t-test, P = .048), and progression-free survival was significantly longer in patients whose TS mRNA expression levels were below the median value, as compared with those with higher levels (log-rank test, P = .006).

Conclusion

S-1 is active against cytokine-refractory mRCC. Quantification of TS mRNA levels in tumors before treatment may facilitate prediction of the response of mRCC to S-1.
Testosterone Levels and Quality of Life in Diverse Male Patients With Cancers Unrelated to Androgens
Authors: Fleishman Stewart B. , Khan Hina , Homel Peter , Suhail Mohammad F. , Strebel-Amrhein Rotraud , Mohammad Farhan , Mahajan Divya , Rosenwald Victoria , Guarino Michael J. , Mirzoyev Tahir , Wozniak Timothy F. , Suppiah Kathiresan
Published: October 2010

Purpose

Symptoms secondary to hormonal changes significantly impact quality of life (QoL) in patients with cancer. This cross-sectional study examines prevalence of hypogonadism and its correlation with QoL and sexual dysfunction.

Patients and Methods

We collected blood and medical histories from 428 male patients with non–testosterone-related cancer at three cancer centers. Serum was analyzed for total testosterone (TT), free testosterone (FT), bioavailable testosterone (BAT), and sex hormone binding globulin (SHBG). The Functional Assessment of Cancer Therapy-Prostate (FACT-P) QoL questionnaire measured physical, social, emotional, and functional domains as well as sexual function. Exclusion criteria were prostate, testicular, or male breast cancer; known hypogonadism; and HIV.

Results

Mean and median TTs were 337.46 and 310 ng/dL, respectively. The mean age of patients was 62.05 years. The crude prevalence of hypogonadism (ie, TT < 300 ng/dL) was 48%, and mean TT in hypogonadal patients was 176 ng/dL. The prevalences that were based on FT (ie, hypogonadal < 52 pg/dL) and BAT (ie, hypogonadal < 95 ng/dL) were 78% and 66%, respectively. The mean FT and BAT values in hypogonadal patients were 25 pg/dL and 45 ng/dL, respectively. Hypogonadal patients had decreased total QoL scores on FACT-P (P = .01) and decreased three-item sexual function subset (P = .003).

Conclusion

The prevalence of hypogonadism was unexpectedly high. Measurement of FT or BAT detected a higher prevalence than TT alone, which confirmed previous studies. Correlation of T with FACT-P showed significant reduction of both overall QoL and sexual function for hypogonadal men. BAT and FT levels showed a stronger correlation than TT with overall FACT-P and subscales. The prevalence of symptomatic hypogonadism in male patients with cancer exceeds that found in comparable studies in noncancer populations.
Dose Intensity of Chemotherapy in Patients With Relapsed Hodgkin's Lymphoma
Authors: Josting Andreas , Müller Horst , Borchmann Peter , Baars Joke W. , Metzner Bernd , Döhner Hartmut , Aurer Igor , Smardova Lenka , Fischer Thomas , Niederwieser Dietger , Schäfer-Eckart Kerstin , Schmitz Norbert , Sureda Anna , Glossmann Jan , Diehl Volker , DeJong Daphne , Hansmann Martin-Leo , Raemaekers John , Engert Andreas
Published: October 2010

Purpose

High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy.

Patients and Methods

Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points.

Results

From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001).

Conclusion

Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL.
Environmentalism—Long Live the Politics of Fear
Authors: Gourevitch Alex
Published: October 2010

It is safe to say that the politics of fear, that doomed project of national rejuvenation through fear and emergency, is in the past. But past in what sense? The answer depends on the response to another question: what are the alternatives offered by the Left that could provide an equally overarching and commanding framework to replace the war on terror? Environmentalism is one of the few movements on the left that presents itself in the same totalizing political terms that the war on terror did on the right. Yet the politics of fear is a broad, deeply rooted political phenomenon, of which environmentalism is as much a part as the war on terror. If anything, the politics of fear can renew itself by shedding its association with the discredited war on terror and by attaching itself to the seemingly wholesome and pacific environmentalism standing in the wings. What environmentalism shares with the war on terror is the idea that we ought to organize our political life around the quest for security and that we can even recover a sense of moral purpose through the response to (environmental) emergencies. Here too the aim seems to be to scare us into submission, rather than open up new possibilities.
Spaces Stretch Inward: Intersections between Architecture and Minor Literature
Authors: Feigis Irit Katz
Published: October 2010

This essay offers an analysis of the architectural environment of the Palestinian refugee camps in Gaza, examined through a comparison of Deleuze and Guattari's “minor literature” interpreting Kafka's work.
Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation
Authors: Gordon Emma J. , Rao Sujata , Pollard Jeffrey W. , Nutt Stephen L. , Lang Richard A. , Harvey Natasha L.
Published: October 2010

Macrophages have been suggested to stimulate neo-lymphangiogenesis in settings of inflammation via two potential mechanisms: (1) acting as a source of lymphatic endothelial progenitor cells via the ability to transdifferentiate into lymphatic endothelial cells and be incorporated into growing lymphatic vessels; and (2) providing a crucial source of pro-lymphangiogenic growth factors and proteases. We set out to establish whether cells of the myeloid lineage are important for development of the lymphatic vasculature through either of these mechanisms. Here, we provide lineage tracing evidence to demonstrate that lymphatic endothelial cells arise independently of the myeloid lineage during both embryogenesis and tumour-stimulated lymphangiogenesis in the mouse, thus excluding macrophages as a source of lymphatic endothelial progenitor cells in these settings. In addition, we demonstrate that the dermal lymphatic vasculature of PU.1–/– and Csf1r–/– macrophage-deficient mouse embryos is hyperplastic owing to elevated lymphatic endothelial cell proliferation, suggesting that cells of the myeloid lineage provide signals that act to restrain lymphatic vessel calibre in the skin during development. In contrast to what has been demonstrated in settings of inflammation, macrophages do not comprise the principal source of pro-lymphangiogenic growth factors, including VEGFC and VEGFD, in the embryonic dermal microenvironment, illustrating that the sources of patterning and proliferative signals driving embryonic and disease-stimulated lymphangiogenesis are likely to be distinct.
Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors
Authors: Parsa Sara , Kuremoto Koh-ichi , Seidel Kerstin , Tabatabai Reza , MacKenzie BreAnne , Yamaza Takayoshi , Akiyama Kentaro , Branch Jonathan , Koh Chester J. , Alam Denise Al , Klein Ophir D. , Bellusci Saverio
Published: October 2010

Rodent incisors regenerate throughout the lifetime of the animal owing to the presence of epithelial and mesenchymal stem cells in the proximal region of the tooth. Enamel, the hardest component of the tooth, is continuously deposited by stem cell-derived ameloblasts exclusively on the labial, or outer, surface of the tooth. The epithelial stem cells that are the ameloblast progenitors reside in structures called cervical loops at the base of the incisors. Previous studies have suggested that FGF10, acting mainly through fibroblast growth factor receptor 2b (FGFR2b), is crucial for development of the epithelial stem cell population in mouse incisors. To explore the role of FGFR2b signaling during development and adult life, we used an rtTA transactivator/tetracycline promoter approach that allows inducible and reversible attenuation of FGFR2b signaling. Downregulation of FGFR2b signaling during embryonic stages led to abnormal development of the labial cervical loop and of the inner enamel epithelial layer. In addition, postnatal attenuation of signaling resulted in impaired incisor growth, characterized by failure of enamel formation and degradation of the incisors. At a cellular level, these changes were accompanied by decreased proliferation of the transit-amplifying cells that are progenitors of the ameloblasts. Upon release of the signaling blockade, the incisors resumed growth and reformed an enamel layer, demonstrating that survival of the stem cells was not compromised by transient postnatal attenuation of FGFR2b signaling. Taken together, our results demonstrate that FGFR2b signaling regulates both the establishment of the incisor stem cell niches in the embryo and the regenerative capacity of incisors in the adult.
Diffusion-based DNA target colocalization by thermodynamic mechanisms
Authors: Scialdone Antonio , Nicodemi Mario
Published: October 2010

In eukaryotic cell nuclei, a variety of DNA interactions with nuclear elements occur, which, in combination with intra- and inter-chromosomal cross-talks, shape a functional 3D architecture. In some cases they are organized by active, i.e. actin/myosin, motors. More often, however, they have been related to passive diffusion mechanisms. Yet, the crucial questions on how DNA loci recognize their target and are reliably shuttled to their destination by Brownian diffusion are still open. Here, we complement the current experimental scenario by considering a physics model, in which the interaction between distant loci is mediated by diffusing bridging molecules. We show that, in such a system, the mechanism underlying target recognition and colocalization is a thermodynamic switch-like process (a phase transition) that only occurs if the concentration and affinity of binding molecules is above a threshold, or else stable contacts are not possible. We also briefly discuss the kinetics of this `passive-shuttling' process, as produced by random diffusion of DNA loci and their binders, and derive predictions based on the effects of genomic modifications and deletions.
A dual role for ErbB2 signaling in cardiac trabeculation
Authors: Liu Jiandong , Bressan Michael , Hassel David , Huisken Jan , Staudt David , Kikuchi Kazu , Poss Kenneth D. , Mikawa Takashi , Stainier Didier Y. R.
Published: October 2010

Cardiac trabeculation is a crucial morphogenetic process by which clusters of ventricular cardiomyocytes extrude and expand into the cardiac jelly to form sheet-like projections. Although it has been suggested that cardiac trabeculae enhance cardiac contractility and intra-ventricular conduction, their exact function in heart development has not been directly addressed. We found that in zebrafish erbb2 mutants, which we show completely lack cardiac trabeculae, cardiac function is significantly compromised, with mutant hearts exhibiting decreased fractional shortening and an immature conduction pattern. To begin to elucidate the cellular mechanisms of ErbB2 function in cardiac trabeculation, we analyzed erbb2 mutant hearts more closely and found that loss of ErbB2 activity resulted in a complete absence of cardiomyocyte proliferation during trabeculation stages. In addition, based on data obtained from proliferation, lineage tracing and transplantation studies, we propose that cardiac trabeculation is initiated by directional cardiomyocyte migration rather than oriented cell division, and that ErbB2 cell-autonomously regulates this process.
The CRL2LRR-1 ubiquitin ligase regulates cell cycle progression during C. elegans development
Authors: Merlet Jorge , Burger Julien , Tavernier Nicolas , Richaudeau Bénédicte , Gomes José-Eduardo , Pintard Lionel
Published: October 2010

The molecular mechanisms that regulate cell cycle progression in a developmental context are poorly understood. Here, we show that the leucine-rich repeat protein LRR-1 promotes cell cycle progression during C. elegans development, both in the germ line and in the early embryo. Our results indicate that LRR-1 acts as a nuclear substrate-recognition subunit of a Cullin 2-RING E3 ligase complex (CRL2LRR-1), which ensures DNA replication integrity. LRR-1 contains a typical BC/Cul-2 box and binds CRL2 components in vitro and in vivo in a BC/Cul-2 box-dependent manner. Loss of lrr-1 function causes cell cycle arrest in the mitotic region of the germ line, resulting in sterility due to the depletion of germ cells. Inactivation of the DNA replication checkpoint signaling components ATL-1 and CHK-1 suppresses this cell cycle arrest and, remarkably, restores lrr-1 mutant fertility. Likewise, in the early embryo, loss of lrr-1 function induces CHK-1 phosphorylation and a severe cell cycle delay in P lineage division, causing embryonic lethality. Checkpoint activation is not constitutive in lrr-1 mutants but is induced by DNA damage, which may arise due to re-replication of some regions of the genome as evidenced by the accumulation of single-stranded DNA-replication protein A (ssDNA-RPA-1) nuclear foci and the increase in germ cell ploidy in lrr-1 and lrr-1; atl-1 double mutants, respectively. Collectively, these observations highlight a crucial function of the CRL2LRR-1 complex in genome stability via maintenance of DNA replication integrity during C. elegans development.
Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor
Authors: Seidel Kerstin , Ahn Christina P. , Lyons David , Nee Alexander , Ting Kevin , Brownell Isaac , Cao Tim , Carano Richard A. D. , Curran Tom , Schober Markus , Fuchs Elaine , Joyner Alexandra , Martin Gail R. , de Sauvage Frederic J. , Klein Ophir D.
Published: October 2010

In many organ systems such as the skin, gastrointestinal tract and hematopoietic system, homeostasis is dependent on the continuous generation of differentiated progeny from stem cells. The rodent incisor, unlike human teeth, grows throughout the life of the animal and provides a prime example of an organ that rapidly deteriorates if newly differentiated cells cease to form from adult stem cells. Hedgehog (Hh) signaling has been proposed to regulate self-renewal, survival, proliferation and/or differentiation of stem cells in several systems, but to date there is little evidence supporting a role for Hh signaling in adult stem cells. We used in vivo genetic lineage tracing to identify Hh-responsive stem cells in the mouse incisor and we show that sonic hedgehog (SHH), which is produced by the differentiating progeny of the stem cells, signals to several regions of the incisor. Using a hedgehog pathway inhibitor (HPI), we demonstrate that Hh signaling is not required for stem cell survival but is essential for the generation of ameloblasts, one of the major differentiated cell types in the tooth, from the stem cells. These results therefore reveal the existence of a positive-feedback loop in which differentiating progeny produce the signal that in turn allows them to be generated from stem cells.
An interview with Shinichi Aizawa: President of the Japanese Society of Developmental Biologists
Authors: Amsen Eva
Published: October 2010

This August, the Society for Developmental Biology (SDB) held their annual meeting in Albuquerque, New Mexico, USA, jointly with the Japanese Society of Developmental Biologists (JSDB). The JSDB has recently increased their international profile under the presidency of Dr Shinichi Aizawa from the RIKEN Center for Developmental Biology (CDB). We caught up with him at the SDB/JSDB joint meeting to discuss the projects that the JSDB has been undertaking under his leadership to expand the activities of the society beyond the borders of Japan.
Design for Location? The Impact of Manufacturing Offshore on Technology Competitiveness in the Optoelectronics Industry
Authors: Fuchs Erica , Kirchain Randolph
Published: October 2010

This paper presents a case study of the impact of manufacturing offshore on technology competitiveness in the optoelectronics industry. It examines a critical design/facility location decision being faced by optoelectronic component manufacturers. This paper uses a combination of simulation modeling and empirical data to demonstrate the economic constraints facing these firms. The results show that production location changes the relative production economics of the two competing designs—one emerging, one prevailing—that are currently perfect substitutes for each other on the telecom market, but not necessarily perfect substitutes in other markets in the long term. Specifically, if optoelectronic component firms shift production from the United States to countries in developing East Asia, the emerging designs that were developed in the United States no longer pay. Production characteristics are different abroad, and the prevailing design can be more cost effective in developing country production environments. The emerging designs, however, have performance characteristics that may be valuable in the long term to the larger computing market and to pushing forward Moore's law. This paper concludes by exploring the dilemma this creates for the optoelectronic component manufacturers and recommending a framework based on which the results may be generalized to other industries.
Shaking hands: Priming by social action effects
Authors: Flach Rüdiger. , Press Clare. , Badets Arnaud. , Heyes Cecilia.
Published: October 2010

In a semi‐naturalistic response–effect compatibility paradigm, participants were given the opportunity to learn that hand‐shaking actions would be followed by social effects (human hand‐shaking stimuli from a third‐person perspective) or inanimate effects (block arrow stimuli). Relative to the actions, these effects appeared on the same or the opposite side of the screen (positional compatibility), and pointed towards or away from the response hand (directional compatibility). After learning, response times indicated a positional compatibility effect for both social and inanimate effects, but a directional compatibility effect occurred only for social action effects. These findings indicate that actions can be represented, not only by their effects on the inanimate world, but also by their effects on the actions of others. They are consistent with ideomotor theory, and with the view that actions are represented by bidirectional response–effect associations. They also have implications with respect to the origins and on‐line control of imitation and the systems supporting imitation.
Book Reviews
Authors: Cummings Jorden A.
Published: October 2010

Evidence‐based practice of cognitive‐behavioral therapy Dobson Deborah Dobson Keith S. New York: Guilford Press, 2009. $40.00. ISBN 978‐1‐60623‐020‐6
Nail-Houses, Land Rights, and Frames of Injustice on China's Protest Landscape
Authors: Hess Steve
Published: October 2010

This article highlights the way in which Chinese protestors resisting home eviction and demolition have begun to develop innovative, media-savvy tactics for winning public sympathy for their causes and framing their plights as unjust, and considers the political implications of this trend.
Was 2005 a Critical Election in Taiwan?: Locating the Start of a New Political Era
Authors: Fell Dafydd
Published: October 2010

This study applies the concept of critical elections to Taiwan's recent political history. Instead of 2008, it is argued that 2005 deserves the title of a critical election. Political developments in 2005 laid the foundations for the Kuomintang's return to political dominance.
"You Have Been Very Thoughtful Today": The Significance of Gratitude and Reciprocity in Missionary-Hawaiian Gift Exchange
Authors: Thigpen Jennifer
Published: October 2010

In October 1819 the first company of American missionaries set sail for the Hawaiian Islands with the express intent of converting its inhabitants to Christianity. The missionaries earnestly believed that they might provide Hawaiian Islanders with the dual gifts of civilization and salvation and were eager to set about the work of bestowing them. Missionaries were surprised to discover that Hawaiians had gifts of their own to bestow, interrupting the missionary agenda almost from the moment of their arrival. Exploring the unspoken and often symbolic language of gifts, this article offers a re-examination of early Hawaiian-missionary contact to argue that Hawaiian and missionary women—who situated themselves at the very center of the exchange of things—were powerful figures in this missionary and colonial drama.
Getting Out of a Rut: Decolonizing Western Women's History
Authors: Jacobs Margaret D.
Published: October 2010

For over three decades, western women's historians have been working not just to challenge male biases within western history scholarship but also to create a more multicultural inclusive narrative. Paradoxically, however, the overarching narrative of western women's history continues to sideline women of color and to advance a triumphalist interpretation of white women in the West. This essay argues that a multicultural approach has not provided an adequate framework for understanding women and gender in the American West. Instead, western women historians must "decolonize" our narrative and our field through seriously considering the West as a colonial site. To do so, we must employ the tools and theories that scholars of gender and colonialism worldwide have developed to analyze other comparable colonial contexts and projects.