bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recursive SVM biomarker selection for early detection of breast cancer in peripheral blood
Authors: Zhang Fan , Kaufman Howard L , Deng Youping , Drabier Renee 
Published: January 2013

Abstract

Background
Breast cancer is worldwide the second most common type of cancer after lung cancer. Traditional mammography and Tissue Microarray has been studied for early cancer detection and cancer prediction. However, there is a need for more reliable diagnostic tools for early detection of breast cancer. This can be a challenge due to a number of factors and logistics. First, obtaining tissue biopsies can be difficult. Second, mammography may not detect small tumors, and is often unsatisfactory for younger women who typically have dense breast tissue. Lastly, breast cancer is not a single homogeneous disease but consists of multiple disease states, each arising from a distinct molecular mechanism and having a distinct clinical progression path which makes the disease difficult to detect and predict in early stages.

Results
In the paper, we present a Support Vector Machine based on Recursive Feature Elimination and Cross Validation (SVM-RFE-CV) algorithm for early detection of breast cancer in peripheral blood and show how to use SVM-RFE-CV to model the classification and prediction problem of early detection of breast cancer in peripheral blood.
The training set which consists of 32 health and 33 cancer samples and the testing set consisting of 31 health and 34 cancer samples were randomly separated from a dataset of peripheral blood of breast cancer that is downloaded from Gene Express Omnibus. First, we identified the 42 differentially expressed biomarkers between "normal" and "cancer". Then, with the SVM-RFE-CV we extracted 15 biomarkers that yield zero cross validation score. Lastly, we compared the classification and prediction performance of SVM-RFE-CV with that of SVM and SVM Recursive Feature Elimination (SVM-RFE).

Conclusions
We found that 1) the SVM-RFE-CV is suitable for analyzing noisy high-throughput microarray data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance (Area Under Curve) in the testing data set from 0.5826 to 0.7879. Further pathway analysis showed that the biomarkers are associated with Signaling, Hemostasis, Hormones, and Immune System, which are consistent with previous findings. Our prediction model can serve as a general model for biomarker discovery in early detection of other cancers. In the future, Polymerase Chain Reaction (PCR) is planned for validation of the ability of these potential biomarkers for early detection of breast cancer.
Assessment of gene order computing methods for Alzheimer's disease
Authors: Hu Benqiong , Jiang Gang , Pang Chaoyang , Wang Shipeng , Liu Qingzhong , Chen Zhongxue , Vanderburg Charles R , Rogers Jack T , Deng Youping , Huang Xudong 
Published: January 2013

Abstract

Background
Computational genomics of Alzheimer disease (AD), the most common form of senile dementia, is a nascent field in AD research. The field includes AD gene clustering by computing gene order which generates higher quality gene clustering patterns than most other clustering methods. However, there are few available gene order computing methods such as Genetic Algorithm (GA) and Ant Colony Optimization (ACO). Further, their performance in gene order computation using AD microarray data is not known. We thus set forth to evaluate the performances of current gene order computing methods with different distance formulas, and to identify additional features associated with gene order computation.

Methods
Using different distance formulas- Pearson distance and Euclidean distance, the squared Euclidean distance, and other conditions, gene orders were calculated by ACO and GA (including standard GA and improved GA) methods, respectively. The qualities of the gene orders were compared, and new features from the calculated gene orders were identified.

Results
Compared to the GA methods tested in this study, ACO fits the AD microarray data the best when calculating gene order. In addition, the following features were revealed: different distance formulas generated a different quality of gene order, and the commonly used Pearson distance was not the best distance formula when used with both GA and ACO methods for AD microarray data.

Conclusion
Compared with Pearson distance and Euclidean distance, the squared Euclidean distance generated the best quality gene order computed by GA and ACO methods.
Cytomegalovirus-induced salivary gland pathology: resistance to kinase inhibitors of the upregulated host cell EGFR/ERK pathway is associated with CMV-dependent stromal overexpression of IL-6 and fibronectin
Authors: Melnick Michael , Sedghizadeh Parish P , Deluca Krysta A , Jaskoll Tina 
Published: January 2013

Abstract

Background
Recently we identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway. Our previously characterized, novel mouse organ culture model of mouse CMV (mCMV)-induced tumorigenesis displays a number of histologic and molecular characteristics similar to human MEC.

Methods
Newborn mouse submandibular glands (SMGs) were incubated with 1 × 105 PFU/ml of lacZ-tagged mCMV RM427+ on day 0 for 24 hours and then cultured in virus-free media for a total of 6 or 12 days with or without EGFR/ERK inhibitors and/or aciclovir. SMGs were collected for histology, immunolocalization (pERK, FN, IL-6), viral distribution, or Western blot analysis (pERK).

Results
Here we report: (1) mouse SMG tumors soon exhibit an acquired resistance to EGFR/ERK pathway kinase inhibitors, alone or in combination; (2) long term tumor regression can only be sustained by concurrent inhibitor and antiviral treatment; (3) CMV-dependent, kinase inhibitor resistance is associated with overexpression of fibronectin and IL-6 proteins in abnormal stromal cells.

Conclusions
Acquired resistance to kinase inhibitors is dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway, a phenomenon with important therapeutic implications for human MEC of salivary glands.
Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness
Authors: Hémont Caroline , Neel Antoine , Heslan Michèle , Braudeau Cécile , Josien Régis 
Published: January 2013

Abstract
TLR repertoire and in vitro responsiveness of blood classical DC subsets.
Human blood DCs encompass pDCs and two subsets of mDCs: CD1c+ mDCs and CD141+ mDCs. The rare CD141+ DC population is thought to be the equivalent of mouse CD8α+ cDCs that play a significant role in antigen cross-presentation. Here, we analyzed by Q-PCR TLR1–10 expression in blood DC subsets. Whereas CD1c+ DCs express all TLR except TLR9, CD141+ DCs present a more restricted pattern with high expression of TLR3 and -10, expression of TLR1,-2, -6, and -8, and lack of TLR4, -5, -7, and -9. The in vitro analysis of isolated mDC subset reponsiveness to an extensive panel of TLR ligands confirmed these results, with CD141+ DCs responding only to TLR1/2, -3, and -7/8. The cytokine/chemokine production profile of isolated CD141+ DCs was also more restricted, as they produced mainly proinflammatory cytokines but no IL-12 and to a lower level, in comparison with CD1c+ DCs, except for CXCL10, CCL5, and IFN-β. In contrast, with the use of a whole blood assay, we found that CD141+ DCs produce IL-12 in response to TLR1/2, -3, and more surprisingly, -9. Finally, both mDC subsets are potent inducers of Th1 response, particularly after TLR3 triggering. Taken together, these data confirmed functional differences between blood mDC subsets. The major response of CD141+ mDCs to TLR3 ligand and their cytokine production pattern suggest a role for these cells in antiviral immunity.
Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer
Authors: Welsh James W. , Komaki Ritsuko , Amini Arya , Munsell Mark F. , Unger Wyatt , Allen Pamela K. , Chang Joe Y. , Wefel Jeffrey S. , McGovern Susan L. , Garland Linda L. , Chen Su S. , Holt Jamie , Liao Zhongxing , Brown Paul , Sulman Erik , Heymach John V. , Kim Edward S. , Stea Baldassarre 
Published: January 2013

Purpose Brain metastasis (BM) is a leading cause of death from non–small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety. Patients and Methods Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility. Results Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations. Conclusion Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
Overall and Cancer-Specific Survival of Patients With Breast, Colon, Kidney, and Lung Cancers With and Without Chronic Lymphocytic Leukemia: A SEER Population-Based Study
Authors: Solomon Benjamin M. , Rabe Kari G. , Slager Susan L. , Brewer Jerry D. , Cerhan James R. , Shanafelt Tait D. 
Published: January 2013

Purpose Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the disease course of these cancers once they occur. Patients and Methods All patients with cancers of the breast (n = 579,164), colorectum (n = 412,366), prostate (n = 631,616), lung (n = 489,053), kidney (n = 95,795), pancreas (n = 82,116), and ovary (n = 61,937) reported to the SEER program from 1990 to 2007 were identified. Overall survival (OS; death resulting from any cause) and cancer-specific survival were examined, comparing patients with and without pre-existing CLL. Cancer-specific survival was evaluated for each tumor type in a site-specific manner (eg, death resulting from breast cancer in a patient with breast cancer). Results Patients with cancers of the breast (hazard ratio [HR], 1.70; P < .001), colorectum (HR, 1.65; P < .001), kidney (HR, 1.54; P < .001), prostate (HR, 1.92; P < .001), or lung (HR, 1.19; P < .001) had inferior OS if they had a pre-existing diagnosis of CLL after adjusting for age, sex, race, and disease stage. These results for OS remained significant for patients with cancers of the breast, colorectum, and prostate after excluding or censoring CLL-related deaths. Cancer-specific survival was also inferior for patients with cancers of the breast (HR, 1.41; P = .005) and colorectum (HR, 1.46; P < .001) who had pre-existing CLL after adjusting for age, sex, race, and disease stage. Conclusion Inferior OS and cancer-specific survival was observed for several common cancers in patients with pre-existing CLL. Additional studies are needed to determine the optimal management of these malignancies in patients with CLL and whether more aggressive screening or alternative approaches to adjuvant therapy are needed.
Where Polarity Meets Fusion: Role of Par6 in Trophoblast Differentiation during Placental Development and Preeclampsia
Authors: Sivasubramaniyam Tharini , Garcia Julia , Tagliaferro Andrea , Melland-Smith Megan , Chauvin Sarah , Post Martin , Todros Tullia , Caniggia Isabella 
Published: January 2013

AbstractTrophoblast cell fusion is a prerequisite for proper human placental development. Herein we examined the contribution of Par6 (Partitioning defective protein 6), a key regulator of cell polarity, to trophoblast cell fusion in human placental development. During early placentation, Par6 localized to nuclei of cytotrophoblast cells but with advancing gestation Par6 shifted its localization to the cytoplasm and apical brush border of the syncytium. Exposure of primary isolated trophoblasts to 3% O2 resulted in elevated Par6 expression, maintenance of tight junction marker ZO-1 at cell boundaries, and decreased fusogenic syncytin 1 expression compared with cells cultured at 20% O2. Treatment of choriocarcinoma BeWo cells with forskolin, a known inducer of fusion, increased syncytin 1 expression but decreased that of Par6 and ZO-1. Par6 overexpression in the presence of forskolin maintained ZO-1 at cell boundaries while decreasing syncytin 1 levels. In contrast, silencing of Par6 disrupted ZO-1 localization at cell boundaries and altered the expression and distribution of acetylated α-tubulin. Par6 expression was elevated in preeclamptic placentas relative to normotensive preterm controls and Par6 located to trophoblast cells expressing ZO-1. Together, our data indicate that Par6 negatively regulates trophoblast fusion via its roles on tight junctions and cytoskeleton dynamics and provide novel insight into the contribution of this polarity marker in altered trophoblast cell fusion typical of preeclampsia.
IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells
Authors: Zhou Ping , Baumgarten Sarah C. , Wu Yanguang , Bennett Jill , Winston Nicola , Hirshfeld-Cytron Jennifer , Stocco Carlos 
Published: January 2013

Abstract
FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR.
Nitrofurantoin Contraindication in Patients with a Creatinine Clearance Below 60 mL/min: Looking for the Evidence
Authors: Oplinger Mandy , Andrews Carlota O 
Published: January 2013

OBJECTIVE To investigate the evidence leading to nitrofurantoin contraindication in patients with a creatinine clearance (CrCl) below 60 mL/min. DATA SOURCES Literature was searched in PubMed (1965-June 2012) by using the key words and MeSH terms urinary tract infections-drug therapy, chronic kidney insufficiency, kidney diseases, pharmacokinetics, safety, and efficacy, combined with nitrofurantoin. Articles were limited to the English language. References from the identified studies, Food and Drug Administration–approved product information packets, drug information resources, and pharmacology books were also reviewed. DATA SYNTHESIS The contraindication of nitrofurantoin in patients with a CrCl below 60 mL/min was included in the product information packets sometime between 1988 and 2003. The 1988 Macrodantin product information indicated a CrCl cutoff level of 40 mL/min, but the current contraindication of less than 60 mL/min is found in the 2003 Macrobid product information. It is unclear when and why this change occurred, but it may have followed the work of Sachs and colleagues in 1968, who reported very little drug recovery in the urine of patients with a CrCl below 60 mL/min. This and previous studies have several and severe limitations, such as the inclusion of a small number of patients, an undefined or poorly defined method to determine CrCl and renal impairment, measurement of amounts of nitrofurantoin excreted in the urine instead of urinary concentrations, and most importantly, a lack of clinical efficacy end points. More recently, a chart review on clinical cure of urinary tract infections treated with nitrofurantoin provided grounds for further investigations on the utility of this drug for patients with a CrCl of 60 mL/min or lower. Concerns of increased risks of serious adverse reactions in patients with reduced renal function have further limited the use of nitrofurantoin. However, although not completely clear, these complications seem to be linked most often to prolonged treatment, genetic variability, and predisposition to hypersensitivity. CONCLUSIONS Data supporting the contraindication of nitrofurantoin for patients with a CrCl less than 60 mL/min are nonexistent. Well-designed clinical trials with urinary concentration information and clinical end points on patients with various degrees of renal impairment are much needed. Until such a study becomes available, the limited data available would support considering using this drug in patients with a CrCl of 40 mL/min or higher.
Low malignancy risk of thyroid follicular lesion of undetermined significance in patients from post-endemic areas
Authors: Słowińska-Klencka Dorota , Woźniak Ewa , Wojtaszek Martyna , Popowicz Bożena , Sporny Stanisław , Klencki Mariusz 
Published: January 2013

ObjectiveNew classification of the thyroid fine-needle aspiration biopsy (FNAB) results tries to stratify the risk of malignancy of thyroid follicular lesions using ‘follicular lesion of undetermined significance’ (FLUS) subcategory. Clinical significance of this category in the endemic (or post-endemic) areas has not been clearly established.DesignThe aim of the study was to determine the risk of malignancy for FLUS as well as to evaluate ultrasound (US) malignancy risk features (MRF) in such nodules in comparison with ‘suspicious for neoplasm’ (SFN) and ‘benign lesions’ (BL).MethodsThe US images and cytological diagnoses of 589 thyroid follicular lesions were analysed from January 2010 to July 2012. Cytological follow-up was assessed in 110 cases and surgical one in 100 cases.ResultsFLUS was diagnosed in 340 cases (3.8% of all cytological diagnoses and 57% of thyroid follicular lesions). Altogether, clinical and/or surgical follow-up revealed thyroid cancer in 3.2% patients with FLUS nodules. Repeat FNAB led to more specific diagnosis in 74.4% of FLUS (3.5%, papillary cancers or their suspicion; 2.3%, SFN; 68.6%, BL). The histopathological examination showed thyroid cancer in 6.4% cases of FLUS and 7.0% of SFN and follicular adenoma in 8.5% of FLUS and 11.6% of SFN (NS, FLUS vs SFN). FLUS showed MRF of intermediate values between BL and SFN; SFN more often than FLUS showed at least two MRF (53 vs 30%,P<0.0001).ConclusionsThe risk of cancer in FLUS in areas with recently corrected iodine supply is low. In such areas, repeated biopsy leads to more precise cytological diagnosis in about 3/4 cases.
A Comparison of Models to Infer the Distribution of Fitness Effects of New Mutations
Authors: Kousathanas Athanasios , Keightley Peter D 
Published: January 2013

Abstract
Knowing the distribution of fitness effects (DFE) of new mutations is important for several topics in evolutionary genetics. Existing computational methods with which to infer the DFE based on DNA polymorphism data have frequently assumed that the DFE can be approximated by a unimodal distribution, such as a lognormal or a gamma distribution. However, if the true DFE departs substantially from the assumed distribution (e.g., if the DFE is multimodal), this could lead to misleading inferences about its properties. We conducted simulations to test the performance of parametric and nonparametric discretized distribution models to infer the properties of the DFE for cases in which the true DFE is unimodal, bimodal, or multimodal. We found that lognormal and gamma distribution models can perform poorly in recovering the properties of the distribution if the true DFE is bimodal or multimodal, whereas discretized distribution models perform better. If there is a sufficient amount of data, the discretized models can detect a multimodal DFE and can accurately infer the mean effect and the average fixation probability of a new deleterious mutation. We fitted several models for the DFE of amino acid-changing mutations using whole-genome polymorphism data from Drosophila melanogaster and the house mouse subspecies Mus musculus castaneus. A lognormal DFE best explains the data for D. melanogaster, whereas we find evidence for a bimodal DFE in M. m. castaneus.