bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hybrid metabolic flux analysis: combining stoichiometric and statistical constraints to model the formation of complex recombinant products
Authors: Carinhas Nuno , Bernal Vicente , Teixeira Ana P , Carrondo Manuel JT , Alves Paula M , Oliveira Rui 
Published: February 2011

Abstract

Background
Stoichiometric models constitute the basic framework for fluxome quantification in the realm of metabolic engineering. A recurrent bottleneck, however, is the establishment of consistent stoichiometric models for the synthesis of recombinant proteins or viruses. Although optimization algorithms for in silico metabolic redesign have been developed in the context of genome-scale stoichiometric models for small molecule production, still rudimentary knowledge of how different cellular levels are regulated and phenotypically expressed prevents their full applicability for complex product optimization.

Results
A hybrid framework is presented combining classical metabolic flux analysis with projection to latent structures to further link estimated metabolic fluxes with measured productivities. We first explore the functional metabolic decomposition of a baculovirus-producing insect cell line from experimental data, highlighting the TCA cycle and mitochondrial respiration as pathways strongly associated with viral replication. To reduce uncertainty in metabolic target identification, a Monte Carlo sampling method was used to select meaningful associations with the target, from which 66% of the estimated fluxome had to be screened out due to weak correlations and/or high estimation errors. The proposed hybrid model was then validated using a subset of preliminary experiments to pinpoint the same determinant pathways, while predicting the productivity of independent cultures.

Conclusions
Overall, the results indicate our hybrid metabolic flux analysis framework is an advantageous tool for metabolic identification and quantification in incomplete or ill-defined metabolic networks. As experimental and computational solutions for constructing comprehensive global cellular models are in development, the contribution of hybrid metabolic flux analysis should constitute a valuable complement to current computational platforms in bridging the metabolic state with improved cell culture performance.
New-onset headache in an elderly man with uremia that improved only after correction of hyperphosphatemia ("uremic headache"): a case report
Authors: Razdan Sushil , Pandita KK , Chopra Vanilla , Koul Sanjay 
Published: February 2011

Abstract

Introduction
New-onset headaches in the elderly are usually secondary and rarely primary. We present the case of an elderly man with recent-onset headache due to uremic hyperphosphatemia and hypocalcemia. To the best of our knowledge, this is the first case report of its kind in the literature.

Case presentation
We present the case of a 70-year-old Indian man with chronic kidney disease whose new-onset headache improved only when his hyperphosphatemia and hypocalcemia were corrected. He had diffuse, dense calcification of tentorium cerebelli and falx due to hyperphosphatemia.

Conclusions
This case report reinforces the importance of identifying the cause of a new-onset headache, particularly in the elderly, and treating it before blaming a tension headache or primary headache as the cause.
Evaluation of chronic lymphocytic leukemia by BAC-based microarray analysis
Authors: Schultz Roger A , Delioukina Maria , Gaal Karl , Bedell Victoria , Smith David D , Forman Stephen J , McDaniel Lisa D , Ballif Blake C , Shaffer Lisa G , Slovak Marilyn L 
Published: February 2011

AbstractBackgroundChronic lymphocytic leukemia (CLL) is a highly variable disease with life expectancies ranging from months to decades. Cytogenetic findings play an integral role in defining the prognostic significance and treatment for individual patients.ResultsWe have evaluated 25 clinical cases from a tertiary cancer center that have an established diagnosis of CLL and for which there was prior cytogenetic and/or fluorescencein situhybridization (FISH) data. We performed microarray-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome (BAC)-based microarray designed for the detection of known constitutional genetic syndromes. In 15 of the 25 cases, aCGH detected all copy number imbalances identified by prior cytogenetic and/or FISH studies. For the majority of those not detected, the aberrations were present at low levels of mosaicism. Furthermore, for 15 of the 25 cases, additional abnormalities were detected. Four of those cases had deletions that mapped to intervals implicated in inherited predisposition to CLL. For most cases, aCGH was able to detect abnormalities present in as few as 10% of cells. Although changes in ploidy are not easily discernable by aCGH, results for two cases illustrate the detection of additional copy gains and losses present within a mosaic tetraploid cell population.ConclusionsOur results illustrate the successful evaluation of CLL using a microarray optimized for the interrogation of inherited disorders and the identification of alterations with possible relevance to CLL susceptibility.
Distinct influences of tandem repeats and retrotransposons on CENH3 nucleosome positioning
Authors: Gent Jonathan I , Schneider Kevin L , Topp Christopher N , Rodriguez Carmen , Presting Gernot G , Dawe R Kelly 
Published: February 2011

Abstract

Background
Unique structural characteristics of centromere chromatin enable it to support assembly of the kinetochore and its associated tensions. The histone H3 variant CENH3 (centromeric histone H3) is viewed as the key element of centromere chromatin and its interaction with centromere DNA is epigenetic in that its localization to centromeres is not sequence-dependent.

Results
In order to investigate what influence the DNA sequence exerts on CENH3 chromatin structure, we examined CENH3 nucleosome footprints on maize centromere DNA. We found a predominant average nucleosome spacing pattern of roughly 190-bp intervals, which was also the dominant arrangement for nucleosomes genome-wide. For CENH3-containing nucleosomes, distinct modes of nucleosome positioning were evident within that general spacing constraint. Over arrays of the major ~156-bp centromeric satellite sequence (tandem repeat) CentC, nucleosomes were not positioned in register with CentC monomers but in conformity with a striking ~10-bp periodicity of AA/TT dimers within the sequence. In contrast, nucleosomes on a class of centromeric retrotransposon (CRM2) lacked a detectable AA/TT periodicity but exhibited tightly phased positioning.

Conclusions
These data support a model in which general chromatin factors independent of both DNA sequence and CENH3 enforce roughly uniform centromeric nucleosome spacing while allowing flexibility in the mode in which nucleosomes are positioned. In the case of tandem repeat DNA, the natural bending effects related to AA/TT periodicity produce an energetically-favourable arrangement consistent with conformationally rigid nucleosomes and stable chromatin at centromeres.
Protecting HIV information in countries scaling up HIV services: a baseline study
Authors: Beck Eduard J , Mandalia Sundhiya , Harling Guy , Santas Xenophon M , Mosure Debra , Delay Paul R 
Published: February 2011

BackgroundIndividual‐level data are needed to optimize clinical care and monitor and evaluate HIV services. Confidentiality and security of such data must be safeguarded to avoid stigmatization and discrimination of people living with HIV. We set out to assess the extent that countries scaling up HIV services have developed and implemented guidelines to protect the confidentiality and security of HIV information.MethodsQuestionnaires were sent to UNAIDS field staff in 98 middle‐ and lower‐income countries, some reportedly with guidelines (G‐countries) and others intending to develop them (NG‐countries). Responses were scored, aggregated and weighted to produce standard scores for six categories: information governance, country policies, data collection, data storage, data transfer and data access. Responses were analyzed using regression analyses for associations with national HIV prevalence, gross national income per capita, OECD income, receiving US PEPFAR funding, and being a G‐ or NG‐country. Differences between G‐ and NG‐countries were investigated using non‐parametric methods.ResultsHigher information governance scores were observed for G‐countries compared with NG‐countries; no differences were observed between country policies or data collection categories. However, for data storage, data transfer and data access, G‐countries had lower scores compared with NG‐countries. No significant associations were observed between country score and HIV prevalence, per capita gross national income, OECD economic category, and whether countries had received PEPFAR funding.ConclusionsFew countries, including G‐countries, had developed comprehensive guidelines on protecting the confidentiality and security of HIV information. Countries must develop their own guidelines, using established frameworks to guide their efforts, and may require assistance in adapting, adopting and implementing them.
Successful Multifold Dose Escalation of Anti-GD2 Monoclonal Antibody 3F8 in Patients With Neuroblastoma: A Phase I Study
Authors: Kushner Brian H. , Kramer Kim , Modak Shakeel , Cheung Nai-Kong V. 
Published: February 2011

Purpose Pain can hinder immunotherapy with anti-GD2 monoclonal antibodies (MoAbs) like 3F8. Heat-modified 3F8 (HM3F8) lacks effector functions and could mask GD2 or cross-reactive epitopes on nerves, thereby preventing a subsequent dose of unmodified 3F8 from activating pain fibers. We hypothesized that 3F8 dose escalation is possible without increased analgesic requirements in patients pretreated with HM3F8. Patients and Methods Thirty patients with resistant neuroblastoma (NB) received one to two cycles of 3F8 plus granulocyte-macrophage colony-stimulating factor. 3F8 dosing began at 20 mg/m2/d and increased by 20 mg/m2/d in the absence of dose-limiting toxicity (DLT). Premedication included analgesics, antihistamines, and 5-minute infusions of HM3F8. On the basis of experience with 3F8 10 mg/m2/d in prior protocols, the DLT of pain was defined as more than seven doses of opioids administered within 2 hours. Opioid use was compared with a contemporary control group treated with 3F8 20 mg/m2/d but no HM3F8. Disease response was assessed. Results Treatment was administered in the outpatient setting. Dose escalation stopped at 160 mg/m2/d because of drug supply limitations; even through this dosage level, analgesic requirements were similar to historical controls, and there were no DLTs. Analgesic requirements at 3F8 dosage levels through 80 mg/m2/d were significantly less compared with controls. Anti-NB activity occurred at all dosages. Conclusion Multifold dose escalation of 3F8 is feasible. The findings can be interpreted as compatible with the possibility that HM3F8 can modify toxicity without blunting anti-NB activity. This pain control strategy may help achieve dose escalation with other anti-GD2 MoAbs.
Can This Patient Be Discharged Home? Factors Associated With At-Home Death Among Patients With Cancer
Authors: Alonso-Babarro Alberto , Bruera Eduardo , Varela-Cerdeira María , Boya-Cristia María Jesús , Madero Rosario , Torres-Vigil Isabel , De Castro Javier , González-Barón Manuel 
Published: February 2011

Purpose The purpose of this study was to identify factors associated with at-home death among patients with advanced cancer and create a decision-making model for discharging patients from an acute-care hospital. Patients and Methods We conducted an observational cohort study to identify the association between place of death and the clinical and demographic characteristics of patients with advanced cancer who received care from a palliative home care team (PHCT) and of their primary caregivers. We used logistic regression analysis to identify the predictors of at-home death. Results We identified 380 patients who met the study inclusion criteria; of these, 245 patients (64%) died at home, 72 (19%) died in an acute-care hospital, 60 (16%) died in a palliative care unit, and three (1%) died in a nursing home. Median follow-up was 48 days. We included the 16 variables that were significant in univariate analysis in our decision-making model. Five variables predictive of at-home death were retained in the multivariate analysis: caregiver's preferred place of death, patients' preferred place of death, caregiver's perceived social support, number of hospital admission days, and number of PHCT visits. A subsequent reduced model including only those variables that were known at the time of discharge (caregivers' preferred place of death, patients' preferred place of death, and caregivers' perceived social support) had a sensitivity of 96% and a specificity of 81% in predicting place of death. Conclusion Asking a few simple patient- and family-centered questions may help to inform the decision regarding the best place for end-of-life care and death.
Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma
Authors: Beasley Georgia M. , Riboh Jonathan C. , Augustine Christina K. , Zager Jonathan S. , Hochwald Steven N. , Grobmyer Stephen R. , Peterson Bercedis , Royal Richard , Ross Merrick I. , Tyler Douglas S. 
Published: February 2011

Purpose Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. Patients and Methods Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). Conclusion To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.
American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer
Authors: Van Poznak Catherine H. , Temin Sarah , Yee Gary C. , Janjan Nora A. , Barlow William E. , Biermann J. Sybil , Bosserman Linda D. , Geoghegan Cindy , Hillner Bruce E. , Theriault Richard L. , Zuckerman Dan S. , Von Roenn Jamie H. 
Published: February 2011

Purpose To update the recommendations on the role of bone-modifying agents in the prevention and treatment of skeletal-related events (SREs) for patients with metastatic breast cancer with bone metastases. Methods A literature search using MEDLINE and the Cochrane Collaboration Library identified relevant studies published between January 2003 and November 2010. The primary outcomes of interest were SREs and time to SRE. Secondary outcomes included adverse events and pain. An Update Committee reviewed the literature and re-evaluated previous recommendations. Results Recommendations were modified to include a new agent. A recommendation regarding osteonecrosis of the jaw was added. Recommendations Bone-modifying agent therapy is only recommended for patients with breast cancer with evidence of bone metastases; denosumab 120 mg subcutaneously every 4 weeks, intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence to demonstrate greater efficacy of one bone-modifying agent over another. In patients with a calculated serum creatinine clearance of more than 60 mg/min, no change in dosage, infusion time, or interval of bisphosphonate administration is required. Serum creatinine should be monitored before each dose. All patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health. Current standards of care for cancer bone pain management should be applied at the onset of pain, in concert with the initiation of bone-modifying agent therapy. The use of biochemical markers to monitor bone-modifying agent use is not recommended.
TET2 Mutations Improve the New European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Metzeler Klaus H. , Maharry Kati , Radmacher Michael D. , Mrózek Krzysztof , Margeson Dean , Becker Heiko , Curfman John , Holland Kelsi B. , Schwind Sebastian , Whitman Susan P. , Wu Yue-Zhong , Blum William , Powell Bayard L. , Carter Thomas H. , Wetzler Meir , Moore Joseph O. , Kolitz Jonathan E. , Baer Maria R. , Carroll Andrew J. , Larson Richard A. , Caligiuri Michael A. , Marcucci Guido , Bloomfield Clara D. 
Published: February 2011

Purpose To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays. Results TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I–risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AML patients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I–risk patients and found distinct mutation-associated microRNA signatures in both ELN groups. Conclusion TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.
Phase II Trial of Pemetrexed and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer
Authors: Argiris Athanassios , Karamouzis Michalis V. , Gooding William E. , Branstetter Barton F. , Zhong Shilong , Raez Luis E. , Savvides Panayiotis , Romkes Marjorie 
Published: February 2011

Purpose We hypothesized that bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), will potentiate the activity of pemetrexed, a multitargeted antifolate, in squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B12 supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF. Results Forty patients were enrolled. The median TTP was 5 months, and the median overall survival (OS) was 11.3 months. In 37 evaluable patients, the overall response rate was 30%, including a complete response rate of 5%, and the disease control rate was 86%. Grade 3 to 5 bleeding events occurred in six patients (15%): four were grade 3, and two were fatal. Other serious toxicities in 10% or more of patients included neutropenia (10%) and infection (12.5%). One patient died of sepsis after receiving eight cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (P = .034). Conclusion The addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization.
Development of a Practical Synthetic Method for N-tert-Butoxycarbonyl α-Ketimino Esters
Authors: Hashimoto Takuya , Yamamoto Kumiko , Maruoka Keiji 
Published: February 2011

Abstract
Despite the potential synthetic utility of N-Boc α-ketimino esters as prochiral ketimines to give chiral α-tertiary amines, there has been no general method to access these molecules in a practical fashion. We report herein a procedure for the one-step synthesis of N-Boc α-ketimino esters starting from the corresponding α-keto esters.