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1.  Invasive Lobular Carcinoma Predicts Micrometastasis in Breast Cancer 
The Journal of surgical research  2012;177(1):93-96.
Invasive lobular carcinomas (ILCs) are almost always estrogen receptor (ER) positive. Most delayed breast cancer recurrences occur in ER positive patients. Disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) have been implicated in recurrence. The study purpose was to determine if DTCs and CTCs are associated with ILCs in stage I-III breast cancer.
Materials and Methods
Clinical stage I-III breast cancer patients consented to participate in an IRB-approved study involving collection of bone marrow and blood at surgery for their primary breast cancer. DTCs were assessed by anti-CK antibody cocktail following cytospin. CTCs were detected using CellSearchTM. CTCs were defined as nucleated cells lacking CD45 but expressing cytokeratin. One or more cells per 5 ml of bone marrow or 7.5 ml of blood was considered positive. Statistical analyses used chi-square and Fischer’s exact tests.
We prospectively enrolled 422 patients, 64 with ILC and 358 with invasive ductal carcinoma (IDC). ER positivity was higher in ILCs (92.2% vs. 66.2%). {P=0.0001} DTCs were identified 43.4% with ILC compared to 28.9% with IDC. {P = 0.03} CTC rates were similar. Either DTCs or CTCs were identified in 75.6% with ILC compared to 51.7% with IDC. {P = 0.002} No correlation was observed between presence of DTCs and CTCs in ILC patients and tumor size, grade, hormone receptor status, stage, lymph node status, or administration of NACT.
ILC independently predicted micrometastatic disease. Since most late recurrences are ER positive, this raises the question of whether DTCs and CTCs are indeed responsible for late breast cancer recurrence.
PMCID: PMC3419792  PMID: 22482764
2.  Amiodarone-Induced Cirrhosis of Liver: What Predicts Mortality? 
ISRN Cardiology  2013;2013:617943.
Introduction. Amiodarone has been used for more than 5 decades for the treatment of various tachyarrhythmias and previously for the treatment of refractory angina. There are multiple well-established side effects of amiodarone. However, amiodarone-induced cirrhosis (AIC) of liver is an underrecognized complication. Methods. A systematic search of Medline from January 1970 to November 2012 by using the following terms, amiodarone and cirrhosis, identified 37 reported cases of which 30 were used in this analysis. Patients were divided into 2 subsets, survivors versus nonsurvivors, at 5 months. Results. Aspartate aminotransferase was significantly lower (P = 0.03) in patients who survived at 5-months (mean 103.33 IU/L) compared to nonsurvivors (mean 216.88 IU/L). There was no statistical difference in the levels of prothrombin time, total bilirubin, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, cumulative dose, and latency period between the two groups. The prevalence of DM, HTN, HLD, CAD, and CHF was similar in the two groups. None of the above-mentioned variables could be identified as a predictor of survival at 5 months. Conclusion. AIC carries a mortality risk of 60% at 5 months once the diagnosis is established. Further prospective studies are needed to identify predictors of AIC and of mortality or survival in cases of AIC.
PMCID: PMC3612472  PMID: 23577267
3.  Utilization of vinasse for production of poly-3-(hydroxybutyrate-co-hydroxyvalerate) by Haloferax mediterranei 
AMB Express  2012;2:34.
Vinasse, a highly polluting waste of the ethanol industry was utilized for the production of polyhydroxyalkanoate (PHA) by the extremely halophilic archaeon, Haloferax mediterranei in shake-flasks. Following pre-treatment through adsorption on activated carbon, 25%-50% (v/v) pre-treated vinasse was utilized leading to 70% maximum accumulation of PHA. Maximum PHA concentration of 19.7 g/l, product yield coefficient (based on total carbohydrates) of 0.87 and 0.21 g/l h volumetric productivity were achieved. Concomitant lowering of BOD5 of pre-treated vinasse by at least 78% and COD by at least 80% was attained at the end of this process. The PHA was recovered by osmotic lysis of the cells and purification by sodium hypochlorite and organic solvents. Through UV–vis spectroscopy, gas chromatography, differential scanning calorimetry and nuclear magnetic resonance spectroscopy, the PHA was identified as poly-3-(hydroxybutyrate-co-hydroxyvalerate). The 3-hydroxyvalerate content was 12.36 mol % (utilizing 25% pre-treated vinasse) and 14.09 mol % (utilizing 50% pre-treated vinasse). High salt concentration in the medium allowed this process without sterile conditions and thus reduction in costs of sterilization can be envisaged. Activated charcoal pre-treatment of vinasse is economical than competing processes such as ultrafiltration of whey, extrusion and enzymatic treatment of rice and corn starch. Without impacting sugar prices, this process can easily be integrated into a distillery that has fermentation equipment and trained personnel. High PHA content, productivity, zero-cost carbon source, low-cost isolation of a high-purity product and potential integration into ethanol manufacturing unit with concomitant wastewater treatment should merit further development of this process to higher scales.
PMCID: PMC3507687  PMID: 22776040
Poly-3-(hydroxybutyrate-co-hydroxyvalerate); Vinasse; Polyphenols; Haloarchaea; Haloferax mediterranei
4.  Peripartum Cardiomyopathy 
Texas Heart Institute Journal  2012;39(1):8-16.
Peripartum cardiomyopathy is idiopathic heart failure occurring in the absence of any determinable heart disease during the last month of pregnancy or the first 5 months postpartum. The incidence varies worldwide but is high in developing nations; the cause of the disease might be a combination of environmental and genetic factors. Diagnostic echocardiographic criteria include left ventricular ejection fraction <0.45 or M-mode fractional shortening <30% (or both) and end-diastolic dimension >2.7 cm/m2. Electrocardiography, magnetic resonance imaging, endomyocardial biopsy, and cardiac catheterization aid in the diagnosis and management of peripartum cardiomyopathy. Cardiac protein assays can also be useful, as suggested by reports of high levels of NT-proBNP, cardiac troponin, tumor necrosis factor-α, interleukin-6, interferon-γ, and C-reactive protein in peripartum cardiomyopathy. The prevalence of mutations associated with familial dilated-cardiomyopathy genes in patients with peripartum cardiomyopathy suggests an overlap in the clinical spectrum of these 2 diseases.
Treatment for peripartum cardiomyopathy includes conventional pharmacologic heart-failure therapies—principally diuretics, angiotensin-converting enzyme inhibitors, vasodilators, digoxin, β-blockers, anticoagulants, and peripartum cardiomyopathy-targeted therapies. Therapeutic decisions are influenced by drug-safety profiles during pregnancy and lactation. Mechanical support and transplantation might be necessary in severe cases. Targeted therapies (such as intravenous immunoglobulin, pentoxifylline, and bromocriptine) have shown promise in small trials but require further evaluation. Fortunately, despite a mortality rate of up to 10% and a high risk of relapse in subsequent pregnancies, many patients with peripartum cardiomyopathy recover within 3 to 6 months of disease onset.
PMCID: PMC3298938  PMID: 22412221
Cardiac output; cardiomyopathies/diagnosis/epidemiology/etiology/therapy; cardiomyopathy, dilated/physiopathology/prevention & control; cardiomyopathy, peripartum; heart failure/diagnosis/etiology/physiopathology/therapy; lactation/blood; postpartum period; pregnancy complications, cardiovascular/diagnosis/epidemiology/etiology/therapy; pregnancy, multiple; pregnancy trimester, third; prognosis; puerperal disorders; ventricular dysfunction, left
5.  MPromDb update 2010: an integrated resource for annotation and visualization of mammalian gene promoters and ChIP-seq experimental data 
Nucleic Acids Research  2010;39(Database issue):D92-D97.
MPromDb (Mammalian Promoter Database) is a curated database that strives to annotate gene promoters identified from ChIP-seq results with the goal of providing an integrated resource for mammalian transcriptional regulation and epigenetics. We analyzed 507 million uniquely aligned RNAP-II ChIP-seq reads from 26 different data sets that include six human cell-types and 10 distinct mouse cell/tissues. The updated MPromDb version consists of computationally predicted (novel) and known active RNAP-II promoters (42 893 human and 48 366 mouse promoters) from various data sets freely available at NCBI GEO database. We found that 36% and 40% of protein-coding genes have alternative promoters in human and mouse genomes and ∼40% of promoters are tissue/cell specific. The identified RNAP-II promoters were annotated using various known and novel gene models. Additionally, for novel promoters we looked into other evidences—GenBank mRNAs, spliced ESTs, CAGE promoter tags and mRNA-seq reads. Users can search the database based on gene id/symbol, or by specific tissue/cell type and filter results based on any combination of tissue/cell specificity, Known/Novel, CpG/NonCpG, and protein-coding/non-coding gene promoters. We have also integrated GBrowse genome browser with MPromDb for visualization of ChIP-seq profiles and to display the annotations. The current release of MPromDb can be accessed at
PMCID: PMC3013732  PMID: 21097880
6.  Genome-wide mapping of RNA Pol-II promoter usage in mouse tissues by ChIP-seq 
Nucleic Acids Research  2010;39(1):190-201.
Alternative promoters that are differentially used in various cellular contexts and tissue types add to the transcriptional complexity in mammalian genome. Identification of alternative promoters and the annotation of their activity in different tissues is one of the major challenges in understanding the transcriptional regulation of the mammalian genes and their isoforms. To determine the use of alternative promoters in different tissues, we performed ChIP-seq experiments using antibody against RNA Pol-II, in five adult mouse tissues (brain, liver, lung, spleen and kidney). Our analysis identified 38 639 Pol-II promoters, including 12 270 novel promoters, for both protein coding and non-coding mouse genes. Of these, 6384 promoters are tissue specific which are CpG poor and we find that only 34% of the novel promoters are located in CpG-rich regions, suggesting that novel promoters are mostly tissue specific. By identifying the Pol-II bound promoter(s) of each annotated gene in a given tissue, we found that 37% of the protein coding genes use alternative promoters in the five mouse tissues. The promoter annotations and ChIP-seq data presented here will aid ongoing efforts of characterizing gene regulatory regions in mammalian genomes.
PMCID: PMC3017616  PMID: 20843783
7.  Annotation of gene promoters by integrative data-mining of ChIP-seq Pol-II enrichment data 
BMC Bioinformatics  2010;11(Suppl 1):S65.
Use of alternative gene promoters that drive widespread cell-type, tissue-type or developmental gene regulation in mammalian genomes is a common phenomenon. Chromatin immunoprecipitation methods coupled with DNA microarray (ChIP-chip) or massive parallel sequencing (ChIP-seq) are enabling genome-wide identification of active promoters in different cellular conditions using antibodies against Pol-II. However, these methods produce enrichment not only near the gene promoters but also inside the genes and other genomic regions due to the non-specificity of the antibodies used in ChIP. Further, the use of these methods is limited by their high cost and strong dependence on cellular type and context.
We trained and tested different state-of-art ensemble and meta classification methods for identification of Pol-II enriched promoter and Pol-II enriched non-promoter sequences, each of length 500 bp. The classification models were trained and tested on a bench-mark dataset, using a set of 39 different feature variables that are based on chromatin modification signatures and various DNA sequence features. The best performing model was applied on seven published ChIP-seq Pol-II datasets to provide genome wide annotation of mouse gene promoters.
We present a novel algorithm based on supervised learning methods to discriminate promoter associated Pol-II enrichment from enrichment elsewhere in the genome in ChIP-chip/seq profiles. We accumulated a dataset of 11,773 promoter and 46,167 non-promoter sequences, each of length 500 bp, generated from RNA Pol-II ChIP-seq data of five tissues (Brain, Kidney, Liver, Lung and Spleen). We evaluated the classification models in building the best predictor and found that Bagging and Random Forest based approaches give the best accuracy. We implemented the algorithm on seven different published ChIP-seq datasets to provide a comprehensive set of promoter annotations for both protein-coding and non-coding genes in the mouse genome. The resulting annotations contain 13,413 (4,747) protein-coding (non-coding) genes with single promoters and 9,929 (1,858) protein-coding (non-coding) genes with two or more alternative promoters, and a significant number of unassigned novel promoters.
Our new algorithm can successfully predict the promoters from the genome wide profile of Pol-II bound regions. In addition, our algorithm performs significantly better than existing promoter prediction methods and can be applied for genome-wide predictions of Pol-II promoters.
PMCID: PMC3009539  PMID: 20122241

Results 1-7 (7)