bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pitfalls of the most commonly used models of context dependent substitution
Authors: Lindsay Helen , Yap Von Bing , Ying Hua , Huttley Gavin A 
Published: December 2008

AbstractBackgroundNeighboring nucleotides exert a striking influence on mutation, with the hypermutability of CpG dinucleotides in many genomes being an exemplar. Among the approaches employed to measure the relative importance of sequence neighbors on molecular evolution have been continuous-time Markov process models for substitutions that treat sequences as a series of independent tuples. The most widely used examples are the codon substitution models. We evaluated the suitability of derivatives of the nucleotide frequency weighted (hereafter NF) and tuple frequency weighted (hereafter TF) models for measuring sequence context dependent substitution. Critical properties we address are their relationships to an independent nucleotide process and the robustness of parameter estimation to changes in sequence composition. We then consider the impact on inference concerning dinucleotide substitution processes from application of these two forms to intron sequence alignments from primates.ResultsWe prove that the NF form always nests the independent nucleotide process and that this is not true for the TF form. As a consequence, using TF to study context effects can be misleading, which is shown by both theoretical calculations and simulations. We describe a simple example where a context parameter estimated under TF is confounded with composition terms unless all sequence states are equi-frequent. We illustrate this for the dinucleotide case by simulation under a nucleotide model, showing that the TF form identifies a CpG effect when none exists. Our analysis of primate introns revealed that the effect of nucleotide neighbors is over-estimated under TF compared with NF. Parameter estimates for a number of contexts are also strikingly discordant between the two model forms.ConclusionOur results establish that the NF form should be used for analysis of independent-tuple context dependent processes. Although neighboring effects in general are still important, prominent influences such as the elevated CpG transversion rate previously identified using the TF form are an artifact. Our results further suggest as few as 5 parameters may account for ~85% of neighboring nucleotide influence.ReviewersThis article was reviewed by Dr Rob Knight, Dr Josh Cherry (nominated by Dr David Lipman) and Dr Stephen Altschul (nominated by Dr David Lipman).
LED-FISH: Fluorescence microscopy based on light emitting diodes for the molecular analysis of Her-2/neu oncogene amplification
Authors: Lang Dagmar S , Zeiser Tobias , Schultz Holger , Stellmacher Florian , Vollmer Ekkehard , Zabel Peter , Goldmann Torsten 
Published: December 2008

Abstract
Light emitting diodes (LED), which are available as small monochromatic light sources with characteristic features such as maximum illumination power combined with minimum energy consumption and extremely long lifespan have already proved as a highly potential low-cost alternative for specific diagnostic applications in clinical medicine such as tuberculosis fluorescence microscopy. Likewise, the most reliable evaluation of Her-2/neu (c-erbB2) gene amplification, which has been established in the last few years for routine diagnosis in clinical pathology as determinant towards Herceptin-based treatment of patients with breast cancer, is based on fluorescence in situ hybridization (FISH) and corresponding high priced fluorescence equipment. In order to test the possibility to utilize the advantages of low-cost LED technology on FISH analysis of c-erbB2 gene expression for routine diagnostic purposes, the applicability of a standard bright field Carl Zeiss Axiostar Plus microscope equipped with a Fraen AFTER* LED Fluorescence Microscope Kit for the detection of Her-2/neu gene signals was compared to an advanced Nikon Eclipse 80i fluorescence microscope in combination with a conventional 100W mercury vapor lamp. Both microscopes were fitted with the same Quicam FAST CCD digital camera to unequivocally compare the quality of the captured images. C-erbB2 gene expression was analyzed in 30 different human tissue samples of primary invasive breast cancer, following formalin fixation and subsequent paraffin-embedding. The Her2/neu gene signals (green) were identifiable in the tumor cells in all cases and images of equal quality were captured under almost identical conditions by 480 nm (blue) LED module equipped standard Axiostar microscope as compared to conventional fluorescence microscopy. In this first attempt, these monochromatic LED elements proved in principle to be suitable for the detection of Her-2/neu gene expression by FISH. Thus, our own experiences emphasize the high potential of this technology to provide a serious alternative to conventional fluorescence microscopy in routine pathology; representing a sustainable technological progress, this low-cost technology will clearly give direction also to the growing field of molecular pathology.
* AFTER = Amplified Fluorescence by transmitted Excitation of Radiation
Neural tube derived Wnt signals cooperate with FGF signaling in the formation and differentiation of the trigeminal placodes
Authors: Canning Claire A , Lee Lily , Luo Sarah Xinwei , Graham Anthony , Jones C Michael 
Published: December 2008

Abstract
Background
Neurogenic placodes are focal thickenings of the embryonic ectoderm that form in the vertebrate head. It is within these structures that the precursors of the majority of the sensory neurons of the cranial ganglia are specified. The trigeminal placodes, the ophthalmic and maxillomandibular, form close to the midbrain-hindbrain boundary and many lines of evidence have shown that signals emanating from this level of the neuraxis are important for the development of the ophthalmic placode.

Results
Here, we provide the first evidence that both the ophthalmic and maxillomandibular placodes form under the influence of isthmic Wnt and FGF signals. Activated Wnt signals direct development of the Pax3 expressing ophthalmic placodal field and induce premature differentiation of both the ophthalmic and the maxillomandibular placodes. Similarly, overexpression of Fgf8 directs premature differentiation of the trigeminal placodes. Wnt signals require FGF receptor activity to initiate Pax3 expression and, subsequently, the expression of neural markers, such as Brn3a, within the cranial ectoderm. Furthermore, fibroblast growth factor signaling via the mitogen activated protein kinase pathway is required to maintain early neuronal differentiation within the trigeminal placodes.

Conclusion
We demonstrate the identity of inductive signals that are necessary for trigeminal ganglion formation. This is the first report that describes how isthmic derived Wnt signals act in concert with fibroblast growth factor signaling. Together, both are necessary and sufficient for the establishment and differentiation of the ophthalmic and maxillomandibular placodes and, consequently, the trigeminal ganglion.
Guidelines of the Italian Society for Virology on HPV testing and vaccination for cervical cancer prevention
Authors: Barzon Luisa , Giorgi Colomba , Buonaguro Franco M , Palù Giorgio ,   the Italian Society for Virology
Published: December 2008

AbstractObjectiveTo provide guidelines for health-care providers on strategies for cervical cancer prevention based on HPV testing and anti-HPV vaccination.OutcomesOverall efficacy of different preventive strategies, assessing reduction in the incidence of invasive cervical cancer and precancerous lesions.EvidenceMedline and the Cochrane Database were searched for articles in English on subjects related to HPVs, HPV diagnosis, HPV anogenital lesions, cervical cancer, HPV testing, and HPV vaccines, in order to elaborate an up-dated document. Relevant Italian Government publications and position papers from appropriate health and family planning organizations were also reviewed.ValuesThe quality of the evidence and ranking of recommendations for practice were rated using criteria defined by SIV, which were adapted from the Canadian Task Force on Preventive Health Care.
An unusual case of frost bite autoamputation of toes
Authors: Wani Adil Hafeez , Mohsin Mir , Darzi Mohammed Ashraf , Zaroo Mohammed Inam , Bashir Sheikh Adil , Zargar Haroon Rashid , Rasool Altaf , Bijli Mohammed Akram , Dar Hameedullah , Farooq Peerzada Omar , Ahmed Sheikh Tariq 
Published: December 2008

Abstract

Background
We report a case of a 15 year old young female who suffered autoamputation of left mid foot and four digits of right foot following repeated application of snow to relieve the pain in her frost bitten feet.

Case presentation
The sociodemographic background, cause, resulting injury and subsequent management are discussed.

Conclusion
Such injuries are relatively rare but awareness of the risk of this type of injury is important.
Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide
Authors: Krishnamurthy Kannan , Wang Guanghu , Rokhfeld Dmitriy , Bieberich Erhard 
Published: December 2008

Abstract
Introduction
At physiologic concentration in serum, the bile acid sodium deoxycholate (DC) induces survival and migration of breast cancer cells. Here we provide evidence of a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells.

Methods
Murine mammacarcinoma 4T1 cells were used in vitro to determine apoptosis and alteration of sphingolipid metabolism by DC, and in vivo to quantify the effect of DC on metastasis.

Results
We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. The metastatic nodes contained slowly dividing cancer cells in immediate vicinity of newly formed blood vessels. These cells were positive for CD44, a marker that has been suggested to be expressed on breast cancer stem cells. In culture, a subpopulation (3 ± 1%) of slowly dividing, CD44+ cells gave rise to rapidly dividing, CD44- cells. DC promoted survival of CD44+ cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. Z-guggulsterone, an antagonist of the farnesoid-X-receptor, obliterated this anti-apoptotic effect, indicating that DC increased cell survival via farnesoid-X-receptor. DC also increased the gene expression of the vascular endothelial growth factor receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. The Flk-1 antagonist SU5416 obliterated the reduction of ceramide and apoptosis by DC, indicating that enhanced cell survival is due to Flk-1-induced reduction in ceramide.

Conclusions
Our findings show, for the first time, that DC is a natural tumor promoter by elevating Flk-1 and decreasing ceramide-mediated apoptosis of breast cancer progenitor cells. Reducing the level or effect of serum DC and elevating ceramide in breast cancer progenitor cells by treatment with Z-guggulsterone and/or vascular endothelial growth factor receptor 2/Flk-1 antagonists may thus be a promising strategy to reduce breast cancer metastasis.
Prioritizing functional modules mediating genetic perturbations and their phenotypic effects: a global strategy
Authors: Wang Li , Sun Fengzhu , Chen Ting 
Published: December 2008

AbstractWe have developed a global strategy based on the Bayesian network framework to prioritize the functional modules mediating genetic perturbations and their phenotypic effects among a set of overlapping candidate modules. We take lethality in Saccharomyces cerevisiae and human cancer as two examples to show the effectiveness of this approach. We discovered that lethality is more conserved at the module level than at the gene level and we identified several potentially 'new' cancer-related biological processes.
Phase II Genomics Study of Ixabepilone as Neoadjuvant Treatment for Breast Cancer
Authors: Baselga José , Zambetti Milvia , Llombart-Cussac Antoni , Manikhas Georgy , Kubista Ernst , Steger Günther G. , Makhson Anatoly , Tjulandin Sergei , Ludwig Heinz , Verrill Mark , Ciruelos Eva , Egyhazi Suzanne , Xu Li-An , Zerba Kim E. , Lee Hyerim , Clark Edwin , Galbraith Susan 
Published: December 2008

Purpose This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations. Patients and Methods Patients with invasive breast cancer ≥ 3 cm were eligible. Ixabepilone 40 mg/m2 was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles. Results One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) –negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in ≤ 3% of patients. Reversible peripheral neuropathy was experienced by 3% of patients. Conclusion ER, microtubule-associated protein tau, and a 10-gene PLR model that included ER were identified as predictors of ixabepilone-induced pCR. Results indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors.
Dietary Pattern Influences Breast Cancer Prognosis in Women Without Hot Flashes: The Women's Healthy Eating and Living Trial
Authors: Gold Ellen B. , Pierce John P. , Natarajan Loki , Stefanick Marcia L. , Laughlin Gail A. , Caan Bette J. , Flatt Shirley W. , Emond Jennifer A. , Saquib Nazmus , Madlensky Lisa , Kealey Sheila , Wasserman Linda , Thomson Cynthia A. , Rock Cheryl L. , Parker Barbara A. , Karanja Njeri , Jones Vicky , Hajek Richard A. , Pu Minya , Mortimer Joanne E. 
Published: December 2008

Purpose To determine whether a low-fat diet high in vegetables, fruit, and fiber differentially affects prognosis in breast cancer survivors with hot flashes (HF) or without HF after treatment. Patients and Methods A secondary analysis was conducted on 2,967 breast cancer survivors, age 18 to 70 years, who were randomly assigned between 1995 and 2000 in a multicenter, controlled trial of a dietary intervention to prevent additional breast cancer events and observed through June 1, 2006. We compared the dietary intervention group with a group who received five-a-day dietary guidelines. Results Independent of HF status, a substantial between-group difference among those who did and did not receive dietary guidelines was achieved and maintained at 4 years in intake of vegetable/fruit servings per day (54% higher; 10 v 6.5 servings/d, respectively), fiber (31% higher; 25.5 v 19.4 g/d, respectively), and percent energy from fat (14% lower; 26.9% v 31.3%, respectively). Adjusting for tumor characteristics and antiestrogen treatment, HF-negative women assigned to the intervention had 31% fewer events than HF-negative women assigned to the comparison group (hazard ratio [HR] = 0.69; 95% CI, 0.51 to 0.93; P = .02). The intervention did not affect prognosis in the women with baseline HFs. Furthermore, compared with HF-negative women assigned to the comparison group, HF-positive women had significantly fewer events in both the intervention (HR = 0.77; 95% CI, 0.59 to 1.00; P = .05) and comparison groups (HR = 0.65; 95% CI, 0.49 to 0.85; P = .002). Conclusion A diet with higher vegetable, fruit, and fiber and lower fat intakes than the five-a-day diet may reduce risk of additional events in HF-negative breast cancer survivors. This suggestive finding needs confirmation in a trial in which it is the primary hypothesis.
Role for Genetic Anticipation in Lynch Syndrome
Authors: Nilbert Mef , Timshel Susanne , Bernstein Inge , Larsen Klaus 
Published: December 2008

Purpose Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. Patients and Methods In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation. Results Both methods revealed anticipation with children developing cancer mean 9.8 years (P < .001) earlier than parents using the paired t-test and 5.5 years (P < .001) earlier using the bivariate model. Birth cohort effects were excluded since anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years. The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated. Conclusion The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation.
Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients
Authors: Bielack Stefan S. , Kempf-Bielack Beate , Branscheid Detlev , Carrle Dorothe , Friedel Godehard , Helmke Knut , Kevric Matthias , Jundt Gernot , Kühne Thomas , Maas Rainer , Schwarz Rudolf , Zoubek Andreas , Jürgens Heribert 
Published: December 2008

PurposeTo evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma.Patients and MethodsTwo hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes.ResultsFive-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions.ConclusionTo our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.
Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia
Authors: Foon Kenneth A. , Boyiadzis Michael , Land Stephanie R. , Marks Stanley , Raptis Anastasios , Pietragallo Louis , Meisner Dennis , Laman Andrew , Sulecki Mathew , Butchko Allyson , Schaefer Patricia , Lenzer Diana , Tarhini Ahmad 
Published: December 2008

Purpose Chemoimmunotherapy combining fludarabine, cyclophosphamide, and rituximab (FCR) is an active regimen for untreated patients with chronic lymphocytic leukemia (CLL) with 70% complete responses (CRs) and 95% overall responses (ORs). However, grade 3/4 neutropenia was reported in 52% of cycles of treatment. The purpose of this trial was to maintain the high responses but reduce the toxicity of FCR by decreasing the fludarabine and cyclophosphamide (FCR-Lite). Patients and Methods We conducted a single arm study of FCR-Lite which includes maintenance rituximab in 50 untreated CLL patients. Patients were evaluated for response using both the 1996 National Cancer Institute Working Group (NCIWG) guidelines and the 2008 guidelines. Two thirds of patients were treated by community physicians. Results The median age was 58 years (range, 36 to 85 years); 20 patients had Rai stage 1, 22 had Rai stage 2, and eight had Rai stage 3 and 4. The OR and CR rates were 100% and 79%, respectively, using the 1996 NCIWG guidelines and 100% and 77% using the 2008 guidelines. Median duration of complete response was 22.3 months (range, 5.2 to 42.5 months) and none of the complete responders have relapsed. Grade 3/4 neutropenia was noted in 13% of the cycles of therapy. Conclusion FCR-Lite is highly effective in previously untreated CLL patients. Grade 3/4 neutropenia was dramatically reduced compared to standard FCR and our data demonstrated FCR-Lite can be safely administered in the community setting.