Recent Research Articles from UNTHSC

Challenges in the development of glaucoma neuroprotection therapy.

Cell Tissue Res. 2013 Mar 10;

Authors: Liu Y, Pang IH

Abstract
Glaucoma, a disease of the optic nerve and retina, causes blindness in millions of people worldwide. Currently available therapies for this disease only attempt to reduce intraocular pressure, the major risk factor, without addressing the associated optic neuropathy and retinopathy. Development of glaucoma neuroprotective treatment is therefore a pressing unmet medical need. Unfortunately, many challenges hinder this effort, including an incomplete understanding of the mechanism of pathogenesis, leading to uncertain therapeutic targets and confounded by not yet validated preclinical models. Most importantly, with slow disease progression and a less than ideal endpoint measurement method, clinical trials are necessarily large, lengthy, expensive and, to many, prohibitive. No easy solution is available to overcome these challenges. Increased commitment to basic mechanistic research is an essential foundation for dealing with this problem. Innovations in clinical trials with novel surrogate endpoints, nontraditional study designs and the use of surrogate diseases might shorten the study time, reduce the patient sample size and consequently lower the budgetary hurdle for the development of new therapies.

PMID: 23474740 [PubMed - as supplied by publisher]

Polarization properties of fluorescent BSA protected Au25 nanoclusters.

Nanoscale. 2013 Mar 8;

Authors: Raut S, Chib R, Rich R, Shumilov D, Gryczynski Z, Gryczynski I

Abstract
BSA protected gold nanoclusters (Au25) are attracting a great deal of attention due to their unique spectroscopic properties and possible use in biophysical applications. Although there are reports on synthetic strategies, spectroscopy and applications, little is known about their polarization behavior. In this study, we synthesized the BSA protected Au25 nanoclusters and studied their steady state and time resolved fluorescence properties including polarization behavior in different solvents: glycerol, propylene glycol and water. We demonstrated that the nanocluster absorption spectrum can be separated from the extinction spectrum by subtraction of Rayleigh scattering. The nanocluster absorption spectrum is well approximated by three Gaussian components. By a comparison of the emissions from BSA Au25 clusters and rhodamine B in water, we estimated the quantum yield of nanoclusters to be higher than 0.06. The fluorescence lifetime of BSA Au25 clusters is long and heterogeneous with an average value of 1.84 μs. In glycerol at -20 °C the anisotropy is high, reaching a value of 0.35. However, the excitation anisotropy strongly depends on the excitation wavelengths indicating a significant overlap of the different transition moments. The anisotropy decay in water reveals a correlation time below 0.2 μs. In propylene glycol the measured correlation time is longer and the initial anisotropy depends on the excitation wavelength. BSA Au25 clusters, due to long lifetime and high polarization, can potentially be used in studying large macromolecules such as protein complexes with large molecular weight.

PMID: 23474596 [PubMed - as supplied by publisher]

Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration.

Cell Death Dis. 2013;4:e528

Authors: Choudhury S, Bhootada Y, Gorbatyuk O, Gorbatyuk M

Abstract
The UPR is activated in the mouse retina expressing misfolded T17M rhodopsin (RHO) during autosomal dominant retinitis pigmentosa (ADRP) progression. Therefore, the goal of this study is to validate the UPR-induced caspase-7 as a new therapeutic target that modulates the UPR, reduces the level of apoptosis and protects the ADRP retina from retinal degeneration and light-induced damage. Mice were analyzed using ERG, SD-OCT and histology to determine the role of caspase-7 ablation. The results of these experiments demonstrate the significant preservation of photoreceptors and their function in T17M RHO CASP-7 retinas from P30 to P90 compared with control mice. These mice were also protected from the light-induced decline in the ERG responses and apoptosis. The RNA and protein analyses of T17M RHO+Csp7-siRNA, Tn+Csp7-siRNA 661W cells and T17M RHO CASP-7 retinas revealed that caspase-7 ablation reprograms the UPR and reduces JNK-induced apoptosis. This reduction is believed to occur through the downregulation of the mTOR and Hif1a proteins. In addition, decline in activated PARP1 was detected in T17M RHO CASP-7 retina. Altogether, our findings indicate that the targeting of caspase-7 in T17M RHO mice could be a feasible therapeutic strategy for advanced stages of ADRP.

PMID: 23470535 [PubMed - in process]

Extracellular regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metalloproteinase-1 expression.

PLoS One. 2013;8(2):e56891

Authors: Fields J, Cisneros IE, Borgmann K, Ghorpade A

Abstract
Astrocytes are essential for proper central nervous system (CNS) function and are intricately involved in neuroinflammation. Despite evidence that immune-activated astrocytes contribute to many CNS pathologies, little is known about the inflammatory pathways controlling gene expression. Our laboratory identified altered levels of tissue inhibitor of metalloproteinase (TIMP)-1 in brain lysates from human immunodeficiency virus (HIV)-1 infected patients, compared to age-matched controls, and interleukin (IL)-1β as a key regulator of astrocyte TIMP-1. Additionally, CCAAT enhancer binding protein (C/EBP)β levels are elevated in brain specimens from HIV-1 patients and the transcription factor contributes to astrocyte TIMP-1 expression. In this report we sought to identify key signaling pathways necessary for IL-1β-mediated astrocyte TIMP-1 expression and their interaction with C/EBPβ. Primary human astrocytes were cultured and treated with mitogen activated protein kinase-selective small molecule inhibitors, and IL-1β. TIMP-1 and C/EBPβ mRNA and protein expression were evaluated at 12 and 24 h post-treatment, respectively. TIMP-1 promoter-driven luciferase plasmids were used to evaluate TIMP-1 promoter activity in inhibitor-treated astrocytes. These data show that extracellular regulated kinase (ERK) 1/2-selective inhibitors block IL-1β-induced astrocyte TIMP-1 expression, but did not decrease C/EBPβ expression in parallel. The p38 kinase (p38K) inhibitors partially blocked both IL-1β-induced astrocyte TIMP-1 expression and C/EBPβ expression. The ERK1/2-selective inhibitor abrogated IL-1β-mediated increases in TIMP-1 promoter activity. Our data demonstrate that ERK1/2 activation is critical for IL-1β-mediated astrocyte TIMP-1 expression. ERK1/2-selective inhibition may elicit a compensatory response in the form of enhanced IL-1β-mediated astrocyte C/EBPβ expression, or, alternatively, ERK1/2 signaling may function to moderate IL-1β-mediated astrocyte C/EBPβ expression. Furthermore, p38K activation contributes to IL-1β-induced astrocyte TIMP-1 and C/EBPβ expression. These data suggest that ERK1/2 signals downstream of C/EBPβ to facilitate IL-1β-induced astrocyte TIMP-1 expression. Astrocyte ERK1/2 and p38K signaling may serve as therapeutic targets for manipulating CNS TIMP-1 and C/EBPβ levels, respectively.

PMID: 23457635 [PubMed - in process]

Race- and gender-related differences in clinical characteristics and quality of life among outpatients with psychotic disorders.

J Psychiatr Pract. 2012 Sep;18(5):329-37

Authors: Nejtek VA, Allison N, Hilburn C

Abstract
BACKGROUND: Historically, the literature suggests that African Americans with mental illness are diagnosed with psychotic disorders at a higher rate and receive higher doses of antipsychotic medications than other racial groups. However, few studies have compared clinical characteristics and quality of life among African-American (AA) and white men and women. Thus, research is needed to examine potential race and gender differences in clinical characteristics, prescribing practices, and quality of life.
METHODS: This exploratory, hypothesis-generating study examined current and past diagnoses, current pharmacotherapy, failed psychotropic medications, and quality of life among 23 AA and 31 white men and women receiving outpatient treatment for psychosis.
RESULTS: Depression and psychotic depression were common complaints in the sample, yet only a third of the patients received antidepressants. We found that AA men received an antidepressant for depression symptoms less often, received higher antipsychotic doses, and rated their overall quality of life as poorer than any other group. White men and AA women had a history of more years of mental illness and had experienced 57% and 69% more psychotropic medication failures, respectively, than AA men or white women. Quality of life scores were significantly related to years of mental illness, number of past diagnoses, and number of failed medications.
CONCLUSIONS: Our data suggest that clinicians could significantly enhance prognostic outcomes in outpatients with psychotic disorders by routinely re-evaluating depressive symptomatology and prescribing practices and considering adding psychosocial interventions to avert deterioration in quality of life. Further investigation of race and gender differences in quality of life and satisfaction as a function of diagnoses and treatment is warranted.

PMID: 22995960 [PubMed - indexed for MEDLINE]

Neuroprotection and estrogen receptors.

Neuroendocrinology. 2012;96(2):119-30

Authors: Simpkins JW, Singh M, Brock C, Etgen AM

Abstract
This review is intended to assess the state of current knowledge on the role of estrogen receptors (ERs) in the neuroprotective effects of estrogens in models for acute neuronal injury and death. We evaluate the overall evidence that estrogens are neuroprotective in acute injury and critically assess the role of ERα, ERβ, GPR 30, and nonreceptor-mediated mechanisms in these robust neuroprotective effects of this ovarian steroid hormone. We conclude that all three receptors, as well as nonreceptor-mediated mechanisms can be involved in neuroprotection, depending on the model used, the level of estrogen administrated, and the mode of administration of the steroid. Also, the signaling pathways used by both ER-dependent and ER-independent mechanisms to exert neuroprotection are considered. Finally, further studies that are needed to parse out the relative contribution of receptor versus nonreceptor-mediated signaling are discussed.

PMID: 22538356 [PubMed - indexed for MEDLINE]

Detection of hyaluronidase activity using fluorescein labeled hyaluronic acid and Fluorescence Correlation Spectroscopy.

J Photochem Photobiol B. 2012 Nov 5;116:7-12

Authors: Rich RM, Mummert M, Foldes-Papp Z, Gryczynski Z, Borejdo J, Gryczynski I, Fudala R

Abstract
The over-expression of hyaluronidase has been observed in many types of cancer, suggesting that it may have utility for diagnosis. Here we present a technique for the detection of hyaluronidase using Fluorescence Correlation Spectroscopy (FCS). Hyaluronan macromolecules (HAs) have been heavily labeled with fluorescein amine resulting in strong self-quenching. In the presence of hyaluronidase, HA is cleaved into smaller, fluorescein-labeled fragments and the self-quenching is released. Such cleavage is manifested by the increased average diffusion rate of the HA fragments, increased concentration of individual, fluorescent HA fragments, and increased intensity. All three of these properties are monitored simultaneously throughout FCS measurements, both as a function of time and hyaluronidase concentration. The method we present provides a sensitive measure of hyaluronidase activity and requires extremely small amounts of the HA substrate.

PMID: 23018154 [PubMed - indexed for MEDLINE]

Prediction of ligament length and carpal diastasis during wrist flexion-extension and after simulated scapholunate instability.

J Hand Surg Am. 2013 Mar;38(3):509-18

Authors: Patterson RM, Yazaki N, Andersen CR, Viegas SF

Abstract
PURPOSE: To determine the role of the carpal ligaments during wrist flexion-extension and to understand whether maintaining integrity of only the dorsal scapholunate ligament (SLL) is adequate for maintaining stability of the scapholunate joint.
METHODS: This study combined motion analysis and manual digitization of ligament attachment regions to generate predictions of carpal ligament length and implied strain during wrist motion and length changes after simulated ligamentous injury.
RESULTS: We modeled 13 ligaments and 22 ligament segments (subportions). We measured ligament length change with respect to wrist angle. A total of 11 segments had minimum stretch or elongation from neutral wrist position over the entire wrist range of motion for any ligament cut condition. The remaining 11 segments had more than 10% stretch in some portion of flexion-extension. In general, ligaments had increased stretch during wrist flexion and after cutting the entire SLL and the dorsal intercarpal ligaments off the scaphoid.
CONCLUSIONS: Disruption of the membranous and palmar portions of the SLL and the dorsal intercarpal ligament off the scaphoid did not result in the development of an increased 3-dimensional scapholunate gap, as measured by differences in ligament length calculations between the scaphoid and lunate. This may indicate a predynamic instability condition (before clinical signs and x-ray findings) that is stabilized by the dorsal SLL, preventing the increase in the 3-dimensional scapholunate gap. This may also support surgical treatment recommendations, which suggest that repair of the dorsal component only of the SLL will be effective. Disruption of the dorsal intercarpal ligament off the scaphoid or lunate did not result in further significant changes. Therefore, the dorsal SLL has an important role in preventing scapholunate ligament instability.
CLINICAL RELEVANCE: These results provide insight into the abnormal kinematics as various ligaments are compromised.

PMID: 23428189 [PubMed - in process]

Nutlin-3 enhances sorafenib efficacy in renal cell carcinoma.

Mol Carcinog. 2013 Jan;52(1):39-48

Authors: Vatsyayan R, Singhal J, Nagaprashantha LD, Awasthi S, Singhal SS

Abstract
The renal cell carcinoma (RCC) is one of the top 10 cancers in USA. The renal tumors are highly angiogenic and are resistant to conventional interventions, particularly radiotherapy. The advent of multi-specific tyrosine kinase inhibitor sorafenib has improved the progression-free survival in RCC, but overall survival in recurrent and metastatic RCC is still a concern that has lead to characterization of combinatorial regimens. Hence, we studied the effect of combination of nutlin-3, an MDM2 inhibitor, which increases p53 levels, and sorafenib in RCC. Sorafenib along with nutlin-3 synergistically inhibited the cell survival and enhanced caspase-3 cleavage leading to apoptosis in RCC. Nutlin-3 and sorafenib were more effective in reducing the migration of RCC, in combination than as single agents. Sorafenib and nutlin-3 decreased the phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) and ERK along with inducing p53 activity. The sorafenib and nutlin-3 co-treatment lead to enhanced levels of p53, p-p53, and increase in the levels of p53 pro-apoptotic effector PUMA, Bax, and decrease in the anti-apoptotic Bcl-2 levels. Importantly, our studies revealed that sorafenib alone can activate p53 in a concentration dependent manner. Thus, co-treatment of nutlin-3 with sorafenib leads to increased half-life of p53, which in turn can be activated by sorafenib, to induce downstream pro-apoptotic and anti-proliferative effects. This is the first report showing the synergistic effect of sorafenib and nutlin-3 while providing a strong clinical-translational rationale for further testing of sorafenib and nutlin-3 combinatorial regimen in human RCC.

PMID: 22006587 [PubMed - indexed for MEDLINE]

Does phytoestrogen supplementation affect cognition differentially in males and females?

Brain Res. 2013 Feb 13;

Authors: Sumien N, Chaudhari K, Sidhu A, Forster MJ

Abstract
Phytoestrogens are plant-derived compounds found mainly in soy with known estrogenic properties and a potential for benefits to human health. Increased intake in phytoestrogens stemmed from the search for safe alternatives to hormone replacement therapies. Based on epidemiologic evidence comparing Western and Asian population and clinical studies, phytoestrogens show promise to improve health and brain function. This review will focus on the effects of phytoestrogens on cognition by examining clinical and animals studies, with special attention placed on (1) a window of therapeutic opportunity which may explains the discrepancy amongst studies, and (2) whether a sex/gender difference exists in response to phytoestrogen intake and what the possible underlying mechanisms may be.

PMID: 23415935 [PubMed - as supplied by publisher]

Obesity-Related Increased γ' Fibrinogen Concentration in Children and Its Reduction by a Physical Activity-Based Lifestyle Intervention: A Randomized Controlled Study.

J Pediatr. 2013 Feb 14;

Authors: Lovely R, Hossain J, Ramsey JP, Komakula V, George D, Farrell DH, Balagopal PB

Abstract
OBJECTIVE: To determine if elevated plasma γ'-fibrinogen, typically involved in the formation of fibrinolysis-resistant clots, confers an increased risk for cardiovascular disease (CVD) and thrombosis in children as it does in adults. Although obesity-related hyperfibrinogenemia is frequently reported in children, the role of γ' fibrinogen and its response to physical activity-based lifestyle are less clear in this population. STUDY DESIGN: In a randomized controlled 3-month physical activity-based lifestyle intervention, γ' fibrinogen concentration was measured in 21 children (aged 14-18 years; Tanner stage > IV), including 15 in the obese group and 6 in the normal weight group, with body mass index percentiles for age and sex of >95 and <85, respectively. RESULTS: The relationships between γ' fibrinogen and other risk factors for CVD, such as markers of insulin resistance and subclinical inflammation, along with body composition (as measured by dual-energy X-ray absortiometry), were assessed before and after the intervention. γ' fibrinogen concentration was higher in the obese group compared with the normal weight group (P < .05) and was correlated with other risk factors for CVD (adjusted R(2) = 0.9; P < .05), and insulin emerged as the major predictor of γ' fibrinogen. The intervention reduced γ'-fibrinogen concentration (P < .05). CONCLUSION: Our data reveal: (1) elevated γ' fibrinogen concentrations in obese insulin-resistant children compared with normal lean controls; (2) a relationship between γ' fibrinogen and other CVD risk factors; and (3) physical activity-induced reduction in γ' fibrinogen in obese children.

PMID: 23415619 [PubMed - as supplied by publisher]

Reversing the Warburg Effect as a Treatment for Glioblastoma.

J Biol Chem. 2013 Feb 13;

Authors: Poteet E, Choudhury GR, Winters A, Li W, Ryou MG, Liu R, Tang L, Ghorpade A, Wen Y, Yuan F, Keir ST, Yan H, Bigner DD, Simpkins JW, Yang SH

Abstract
Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg Effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP- activated protein kinase (AMPK), MB inactivates downstream acetyl-CoA carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide sensitive and insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not activate AMPK signaling and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM.

PMID: 23408428 [PubMed - as supplied by publisher]

Pulmonary impairment after tuberculosis and its contribution to TB burden.

BMC Public Health. 2010;10:259

Authors: Pasipanodya JG, McNabb SJ, Hilsenrath P, Bae S, Lykens K, Vecino E, Munguia G, Miller TL, Drewyer G, Weis SE

Abstract
BACKGROUND: The health impacts of pulmonary impairment after tuberculosis (TB) treatment have not been included in assessments of TB burden. Therefore, previous global and national TB burden estimates do not reflect the full consequences of surviving TB. We assessed the burden of TB including pulmonary impairment after tuberculosis in Tarrant County, Texas using Disability-adjusted Life Years (DALYs).
METHODS: TB burden was calculated for all culture-confirmed TB patients treated at Tarrant County Public Health between January 2005 and December 2006 using identical methods and life tables as the Global Burden of Disease Study. Years of life-lost were calculated as the difference between life expectancy using standardized life tables and age-at-death from TB. Years lived-with-disability were calculated from age and gender-specific TB disease incidence using published disability weights. Non-fatal health impacts of TB were divided into years lived-with-disability-acute and years lived-with-disability-chronic. Years lived-with-disability-acute was defined as TB burden resulting from illness prior to completion of treatment including the burden from treatment-related side effects. Years lived-with-disability-chronic was defined as TB burden from disability resulting from pulmonary impairment after tuberculosis.
RESULTS: There were 224 TB cases in the time period, of these 177 were culture confirmed. These 177 subjects lost a total of 1189 DALYs. Of these 1189 DALYs 23% were from years of life-lost, 2% were from years lived-with-disability-acute and 75% were from years lived-with-disability-chronic.
CONCLUSIONS: Our findings demonstrate that the disease burden from TB is greater than previously estimated. Pulmonary impairment after tuberculosis was responsible for the majority of the burden. These data demonstrate that successful TB control efforts may reduce the health burden more than previously recognized.

PMID: 20482835 [PubMed - indexed for MEDLINE]

Biomarkers of Vascular Risk, Systemic Inflammation, and Microvascular Pathology and Neuropsychiatric Symptoms in Alzheimer's Disease.

J Alzheimers Dis. 2013 Feb 12;

Authors: Hall JR, Wiechmann AR, Johnson LA, Edwards M, Barber RC, Winter AS, Singh M, O'Bryant SE

Abstract
Numerous serum and plasma based biomarkers of systemic inflammation have been linked to both neuropsychiatric disorders and Alzheimer's disease (AD). The present study investigated the relationship of clinical biomarkers of cardiovascular risk (cholesterol, triglycerides, and homocysteine) and a panel of markers of systemic inflammation (CRP, TNF-α, IL1-ra, IL-7, IL-10, IL-15, IL-18) and microvascular pathology (ICAM-1, VCAM-1) to neuropsychiatric symptoms in a sample with mild AD. Biomarker data was analyzed on a sample of 194 diagnosed with mild to moderate probable AD. The sample was composed of 127 females and 67 males. The presence of neuropsychiatric symptoms was gathered from interview with caretakers/family members using the Neuropsychiatric Inventory. For the total sample, IL-15, VCAM (vascular adhesion molecule), and triglycerides were significantly and negatively related to number of neuropsychiatric symptoms, and total cholesterol and homocysteine were positively related and as a group accounted for 16.1% of the variance. When stratified by gender, different patterns of significant biomarkers were found with relationships more robust for males for both total symptoms and symptom clusters. A combination of biomarkers of systemic inflammation, microvascular pathology, and clinical biomarkers of cardiovascular risk can account for a significant portion of the variance in the occurrence of neuropsychiatric symptoms in AD supporting a vascular and inflammatory component of psychiatric disorders found in AD. Gender differences suggest distinct impact of specific risks with total cholesterol, a measure of cardiovascular risk, being the strongest marker for males and IL-15, a marker of inflammation, being the strongest for females.

PMID: 23403534 [PubMed - as supplied by publisher]

Involvement of estrogen receptor β 5 in the progression of glioma.

Brain Res. 2013 Feb 8;

Authors: Li W, Winters A, Poteet E, Ryou MG, Lin S, Hao S, Wu Z, Yuan F, Hatanpaa KJ, Simpkins JW, Yang SH

Abstract
Emerging evidence suggests a decline of ERβ expression in various peripheral cancers. ERβ has been proposed as a cancer brake that inhibits tumor proliferation. In the current study, we have identified ERβ5 as the predominant isoform of ERβ in human glioma and its expression was significantly increased in human glioma as compared with non-neoplastic brain tissue. Hypoxia and activation of hypoxia inducible factor (HIF) increased ERβ transcription in U87 cells, suggesting elevated ERβ expression in glioma might be induced by the hypoxic stress in the tumor. Over-expression of either ERβ1 or ERβ5 increased PTEN expression and inhibited activation of the PI3K/AKT/mTOR pathway. In addition, ERβ5 inhibited the MAPK/ERK pathway. In U87 cells, ERβ1 and ERβ5 inhibit cell proliferation and reduced cells in the S+G2/M phase. Our findings suggest hypoxia induced ERβ5 expression in glioma as a self-protective mechanism against tumor proliferation and that ERβ5 might serve as a therapeutic target for the treatment of glioma.

PMID: 23399685 [PubMed - as supplied by publisher]

Recursive SVM biomarker selection for early detection of breast cancer in peripheral blood.

BMC Med Genomics. 2013;6 Suppl 1:S4

Authors: Zhang F, Kaufman HL, Deng Y, Drabier R

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.

PMID: 23369435 [PubMed - in process]

Associations of cytokine concentrations with key osteopathic lesions and clinical outcomes in patients with nonspecific chronic low back pain: results from the OSTEOPATHIC Trial.

J Am Osteopath Assoc. 2012 Sep;112(9):596-605

Authors: Licciardone JC, Kearns CM, Hodge LM, Bergamini MV

Abstract
CONTEXT: Little is known about the role that cytokines play in osteopathic manual treatment (OMT) of patients with chronic low back pain (LBP).
OBJECTIVE: To measure the baseline concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α in patients with chronic LBP; the correlations of these cytokine concentrations with clinical measures, including the number of key osteopathic lesions; the changes in cytokine concentrations with OMT; and the association of such changes with clinical outcomes.
DESIGN: Substudy nested within a randomized controlled trial of OMT for nonspecific chronic LBP.
SETTING: University-based study in Dallas-Fort Worth, Texas.
PATIENTS: Seventy adult research patients with nonspecific chronic LBP.
MAIN OUTCOME MEASURES: A 10-cm visual analog scale, the Roland-Morris Disability Questionnaire, and the Medical Outcomes Study Short Form-36 Health Survey were used to measure LBP severity, back-specific functioning, and general health, respectively.
RESULTS: At baseline, IL-1β (ρ = 0.33; P = .005) and IL-6 (ρ = 0.32; P = .006) were each correlated with the number of key osteopathic lesions; however, only IL-6 was correlated with LBP severity (ρ = 0.28; P = .02). There was a significantly greater reduction of TNF-α concentration after 12 weeks in patients who received OMT compared with patients who received sham OMT (Mann-Whitney U = 251.5; P = .03). Significant associations were found between OMT and a reduced TNF-α concentration response at week 12 among patients who achieved moderate (response ratio, 2.13; 95% confidence interval [CI], 1.11-4.06; P = .006) and substantial (response ratio, 2.13; 95% CI, 1.07-4.25; P = .01) LBP improvements, and improvement in back-specific functioning (response ratio, 1.68; 95% CI, 1.04-2.71; P = .03).
CONCLUSIONS: This study found associations between IL-1β and IL-6 concentrations and the number of key osteopathic lesions and between IL-6 and LBP severity at baseline. However, only TNF-α concentration changed significantly after 12 weeks in response to OMT. These discordant findings indicate that additional research is needed to elucidate the underlying mechanisms of action of OMT in patients with nonspecific chronic LBP.

PMID: 22984233 [PubMed - indexed for MEDLINE]

Using manual and conventional therapies to enhance musculoskeletal health: highlights of the Osteopathic Research Center's 10th Anniversary Conference.

J Am Osteopath Assoc. 2012 Sep;112(9):591-5

Authors: Licciardone JC

PMID: 22984232 [PubMed - indexed for MEDLINE]

Intensive care unit-acquired weakness: implications for physical therapist management.

Phys Ther. 2012 Dec;92(12):1494-506

Authors: Nordon-Craft A, Moss M, Quan D, Schenkman M

Abstract
Patients admitted to the intensive care unit (ICU) can develop a condition referred to as "ICU-acquired weakness." This condition is characterized by profound weakness that is greater than might be expected to result from prolonged bed rest. Intensive care unit-acquired weakness often is accompanied by dysfunction of multiple organ systems. Individuals with ICU-acquired weakness typically have significant activity limitations, often requiring physical assistance for even the most basic activities associated with bed mobility. Many of these individuals have activity limitations months to years after hospitalization. The purpose of this article is to review evidence that guides physical rehabilitation of people with ICU-acquired weakness. Included are diagnostic criteria, medical management, and prognostic indicators, as well as criteria for beginning physical rehabilitation, with an emphasis on patient safety. Data are presented indicating that rehabilitation can be implemented with very few adverse effects. Evidence is provided for appropriate measurement approaches and for physical intervention strategies. Finally, some of the key issues are summarized that should be investigated to determine the best intervention guidelines for individuals with ICU-acquired weakness.

PMID: 22282769 [PubMed - indexed for MEDLINE]

Treatment of high-grade anal intraepithelial neoplasia with infrared coagulation in a primary care population of HIV-infected men and women.

Dis Colon Rectum. 2012 Dec;55(12):1236-43

Authors: Weis SE, Vecino I, Pogoda JM, Susa JS

Abstract
BACKGROUND: High-grade anal intraepithelial neoplasia, the putative anal carcinoma precursor, is more common in HIV-infected persons. The ideal treatment for these lesions has not been established.
OBJECTIVE: The aim of this study was to evaluate the effectiveness of infrared coagulation treatment for high-grade anal intraepithelial neoplasia.
DESIGN: This is a prospective cohort study. Patients with high-grade anal intraepithelial neoplasia either received infrared coagulation treatment or voluntarily did not receive treatment and were reevaluated at a subsequent time point.
SETTING: This investigation was performed at a Ryan White-funded clinic located in the United States.
PATIENTS: HIV-infected men and women with biopsy-confirmed high-grade anal intraepithelial neoplasia were included.
MAIN OUTCOME MEASURES: The primary outcome measured was the histology collected by high-resolution anoscopy-directed biopsy.
RESULTS: The study included 124 patients. Of 42 patients who either delayed treatment or were not treated, 37 (88%; 95% CI = 74%-96%) still had high-grade anal intraepithelial neoplasia on reevaluation and 2 (5%; 95%CI = 1%-16%) had squamous-cell carcinoma. Of 98 patients who received infrared coagulation treatment, 73 (74%; 95% CI = 65%-83%) patients had no evidence of high-grade anal intraepithelial neoplasia on their first posttreatment evaluation, and none had progressed to squamous-cell carcinoma (p < 0.0001 in comparison with untreated). Upon completing all initial and, if necessary, follow-up treatment, 85 (87%; 95% CI = 78%-93%) patients treated by infrared coagulation had no evidence of high-grade anal intraepithelial neoplasia and none had progressed to squamous-cell carcinoma.
LIMITATIONS: The study population may not be representative of the general population, the study environment was uncontrolled, and patients were not randomly assigned to treatment.
CONCLUSIONS: Infrared coagulation is an effective treatment for high-grade anal intraepithelial neoplasia.

PMID: 23135581 [PubMed - indexed for MEDLINE]