Showing papers by "Southern Illinois University School of Medicine published in 2013"

LncRNA loc285194 is a p53-regulated tumor suppressor

Abstract: Protein-coding genes account for only a small part of the human genome, whereas the vast majority of transcripts make up the non-coding RNAs including long non-coding RNAs (lncRNAs). Accumulating evidence indicates that lncRNAs could play a critical role in regulation of cellular processes such as cell growth and apoptosis as well as cancer progression and metastasis. LncRNA loc285194 was previously shown to be within a tumor suppressor unit in osteosarcoma and to suppress tumor cell growth. However, it is unknown regarding the regulation of loc285194. Moreover, the underlying mechanism by which loc285194 functions as a potential tumor suppressor is elusive. In this study, we show that loc285194 is a p53 transcription target; ectopic expression of loc285194 inhibits tumor cell growth both in vitro and in vivo. Through deletion analysis, we identify an active region responsible for tumor cell growth inhibition within exon 4, which harbors two miR-211 binding sites. Importantly, this loc285194-mediated growth inhibition is in part due to specific suppression of miR-211. We further demonstrate a reciprocal repression between loc285194 and miR-211; in contrast to loc285194, miR-211 promotes cell growth. Finally, we detect downregulation of loc285194 in colon cancer specimens by quantitative PCR arrays and in situ hybridization of tissue microarrays. Together, these results suggest that loc285194 is a p53-regulated tumor suppressor, which acts in part through repression of miR-211.

The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage

Abstract: It is well known that upon stress, the level of the tumor suppressor p53 is remarkably elevated. However, despite extensive studies, the underlying mechanism involving important inter-players for stress-induced p53 regulation is still not fully understood. We present evidence that the human lincRNA-RoR (RoR) is a strong negative regulator of p53. Unlike MDM2 that causes p53 degradation through the ubiquitin-proteasome pathway, RoR suppresses p53 translation through direct interaction with the heterogeneous nuclear ribonucleoprotein I (hnRNP I). Importantly, a 28-base RoR sequence carrying hnRNP I binding motifs is essential and sufficient for p53 repression. We further show that RoR inhibits p53-mediated cell cycle arrest and apoptosis. Finally, we demonstrate a RoR-p53 autoregulatory feedback loop where p53 transcriptionally induces RoR expression. Together, these results suggest that the RoR-hnRNP I-p53 axis may constitute an additional surveillance network for the cell to better respond to various stresses.

External branch of the superior laryngeal nerve monitoring during thyroid and parathyroid surgery: International Neural Monitoring Study Group standards guideline statement

Abstract: Intraoperative neural monitoring (IONM) during thyroid surgery has gained widespread acceptance as an adjunct to the gold standard of visual identification of the recurrent laryngeal nerve (RLN). Contrary to routine dissection of the RLN, most surgeons tend to avoid rather than routinely expose and identify the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy or parathyroidectomy. IONM has the potential to be utilized for identification of the EBSLN and functional assessment of its integrity; therefore, IONM might contribute to voice preservation following thyroidectomy or parathyroidectomy. We reviewed the literature and the cumulative experience of the multidisciplinary International Neural Monitoring Study Group (INMSG) with IONM of the EBSLN. A systematic search of the MEDLINE database (from 1950 to the present) with predefined search terms (EBSLN, superior laryngeal nerve, stimulation, neuromonitoring, identification) was undertaken and supplemented by personal communication between members of the INMSG to identify relevant publications in the field. The hypothesis explored in this review is that the use of a standardized approach to the functional preservation of the EBSLN can be facilitated by application of IONM resulting in improved preservation of voice following thyroidectomy or parathyroidectomy. These guidelines are intended to improve the practice of neural monitoring of the EBSLN during thyroidectomy or parathyroidectomy and to optimize clinical utility of this technique based on available evidence and consensus of experts. Level of Evidence 5 Laryngoscope, 123:S1–S14, 2013

miR-7 Suppresses Brain Metastasis of Breast Cancer Stem-Like Cells By Modulating KLF4

Abstract: Despite significant improvement in survival rates of patients with breast cancer, prognosis of metastatic disease is still dismal. Cancer stem-like cells (CSC) are considered to play a role in metastatic progression of breast cancer; however, the exact pathologic role of CSCs is yet to be elucidated. In this report, we found that CSCs (CD24(-)/CD44(+)/ESA(+)) isolated from metastatic breast cell lines are significantly more metastatic than non-CSC populations in an organ-specific manner. The results of our microRNA (miRNA) profile analysis for these cells revealed that CSCs that are highly metastatic to bone and brain expressed significantly lower level of miR-7 and that this miRNA was capable of modulating one of the essential genes for induced pluripotent stem cell, KLF4. Interestingly, high expression of KLF4 was significantly and inversely correlated to brain but not bone metastasis-free survival of patients with breast cancer, and we indeed found that the expression of miR-7 significantly suppressed the ability of CSCs to metastasize to brain but not to bone in our animal model. We also examined the expression of miR-7 and KLF4 in brain-metastatic lesions and found that these genes were significantly down- or upregulated, respectively, in the tumor cells in brain. Furthermore, the results of our in vitro experiments indicate that miR-7 attenuates the abilities of invasion and self-renewal of CSCs by modulating KLF4 expression. These results suggest that miR-7 and KLF4 may serve as biomarkers or therapeutic targets for brain metastasis of breast cancer.

Somatotropic Signaling: Trade-Offs Between Growth, Reproductive Development, and Longevity

Abstract: Growth hormone (GH) is a key determinant of postnatal growth and plays an important role in the control of metabolism and body composition. Surprisingly, deficiency in GH signaling delays aging and...

The key role of growth hormone–insulin–IGF-1 signaling in aging and cancer

Abstract: Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. GH/Insulin/insulin-like growth factor-1 (IGF-1) signaling molecules that have been linked to longevity include daf-2 and InR and their homologues in mammals, and inactivation of the corresponding genes increases lifespan in nematodes, fruit flies and mice. The life-prolonging effects of caloric restriction are likely related to decreasing IGF-1 levels. Evidence has emerged that antidiabetic drugs are promising candidates for both lifespan extension and prevention of cancer. Thus, antidiabetic drugs postpone spontaneous carcinogenesis in mice and rats, as well as chemical and radiation carcinogenesis in mice, rats and hamsters. Furthermore, metformin seems to decrease the risk for cancer in diabetic patients.

Surgical site infection following spinal instrumentation for scoliosis: a multicenter analysis of rates, risk factors, and pathogens.

Abstract: Background: Surgical site infection following correction of pediatric scoliosis is well described However, we are aware of no recent multicenter study describing the rates of surgical site infection, and associated pathogens, among patients with different etiologies for scoliosis Methods: A multicenter, retrospective review of surgical site infections among pediatric patients undergoing spinal instrumentation to correct scoliosis was performed at three children’s hospitals in the United States Study subjects included all patients undergoing posterior spinal instrumentation from January 2006 to December 2008 Surgical site infections were defined according to the Centers for Disease Control and Prevention’s National Healthcare Safety Network case definition, with infections occurring within one year after surgery Results: Following the analysis of 1347 procedures performed in 946 patients, surgical site infection rates varied among procedures performed in patients with different scoliosis etiologies Procedures performed in patients with neuromuscular scoliosis had the highest surgical site infection rates (92%), followed by those performed in patients with syndromic scoliosis (88%), those performed in patients with other scoliosis (84%), those performed in patients with congenital scoliosis (39%), and those performed in patients with idiopathic scoliosis (26%) Surgical site infection rates varied among procedures in patients undergoing primary spinal arthrodesis based on etiology, ranging from 12% (95% confidence interval, 01% to 13%) in patients with idiopathic scoliosis to 131% (95% confidence interval, 84% to 178%) in patients with neuromuscular scoliosis Surgical site infection rates following primary and revision procedures were similar among patients with different etiologies In distraction-based growing constructs, rates were significantly lower for lengthening procedures than for revision procedures (p = 0012) Multivariate analysis demonstrated that non-idiopathic scoliosis and extension of instrumentation to the pelvis were risk factors for surgical site infections The three most common pathogens were Staphylococcus aureus (250% [95% confidence interval, 178% to 322%]), coagulase-negative staphylococci (171% [95% confidence interval, 109% to 233%]), and Pseudomonas aeruginosa (107% [95% confidence interval, 56% to 158%]) Overall, 465% (95% confidence interval, 355% to 575%) of surgical site infections contained at least one gram-negative organism; 970% (95% confidence interval, 908% to 1000%) of these infections were in patients with non-idiopathic scoliosis Conclusions: Surgical site infection rates were significantly higher following procedures in patients with non-idiopathic scoliosis (p < 0001) Lengthening procedures had the lowest rate of surgical site infection among patients with early onset scoliosis who had undergone instrumentation with growing constructs Gram-negative pathogens were common and were most common following procedures in patients with non-idiopathic scoliosis These findings suggest a role for targeted perioperative antibiotic prophylaxis to prevent surgical site infection following pediatric scoliosis instrumentation procedures Level of Evidence: Prognostic Level II See Instructions for Authors for a complete description of levels of evidence

Uterine glands: development, function and experimental model systems

Abstract: Development of uterine glands (adenogenesis) in mammals typically begins during the early post-natal period and involves budding of nascent glands from the luminal epithelium and extensive cell proliferation in these structures as they grow into the surrounding stroma, elongate and mature. Uterine glands are essential for pregnancy, as demonstrated by the infertility that results from inhibiting the development of these glands through gene mutation or epigenetic strategies. Several genes, including forkhead box A2, beta-catenin and members of the Wnt and Hox gene families, are implicated in uterine gland development. Progestins inhibit uterine epithelial proliferation, and this has been employed as a strategy to develop a model in which progestin treatment of ewes for 8 weeks from birth produces infertile adults lacking uterine glands. More recently, mouse models have been developed in which neonatal progestin treatment was used to permanently inhibit adenogenesis and adult fertility. These studies revealed a narrow and well-defined window in which progestin treatments induced permanent infertility by impairing neonatal gland development and establishing endometrial changes that result in implantation defects. These model systems are being utilized to better understand the molecular mechanisms underlying uterine adenogenesis and endometrial function. The ability of neonatal progestin treatment in sheep and mice to produce infertility suggests that an approach of this kind may provide a contraceptive strategy with application in other species. Recent studies have defined the temporal patterns of adenogenesis in uteri of neonatal and juvenile dogs and work is underway to determine whether neonatal progestin or other steroid hormone treatments might be a viable contraceptive approach in this species.

Reactive astrocytes promote the metastatic growth of breast cancer stem‐like cells by activating Notch signalling in brain

Abstract: Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.

The Role of GH in Adipose Tissue: Lessons from Adipose-Specific GH Receptor Gene-Disrupted Mice

Abstract: GH receptor (GHR) gene-disrupted mice (GHR−/−) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR−/− mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR−/− mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHR Knockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR−/− mice. Like the GHR−/− mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR−/− mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism.

Animal models of sleep disorders.

Abstract: Problems with sleep affect a large part of the general population, with more than half of all people in the United States reporting difficulties with sleep or insufficient sleep at various times and about 40 million affected chronically. Sleep is a complex physiologic process that is influenced by many internal and environmental factors, and problems with sleep are often related to specific personal circumstances or are based on subjective reports from the affected person. Although human subjects are used widely in the study of sleep and sleep disorders, the study of animals has been invaluable in developing our understanding about the physiology of sleep and the underlying mechanisms of sleep disorders. Historically, the use of animals for the study of sleep disorders has arguably been most fruitful for the condition of narcolepsy, in which studies of dogs and mice revealed previously unsuspected mechanisms for this condition. The current overview considers animal models that have been used to study 4 of the most common human sleep disorders—insomnia, narcolepsy, restless legs syndrome, and sleep apnea—and summarizes considerations relevant to the use of animals for the study of sleep and sleep disorders. Animal-based research has been vital to the elucidation of mechanisms that underlie sleep, its regulation, and its disorders and undoubtedly will remain crucial for discovering and validating sleep mechanisms and testing interventions for sleep disorders.

Long-Term Survival of Patients Undergoing Mitral Valve Repair and Replacement A Longitudinal Analysis of Medicare Fee-for-Service Beneficiaries

Abstract: Background—Despite the established superiority of mitral repair over replacement, its adoption in the treatment of elderly patients has not been uniform, partly because of a lack of robust long-term survival data. We present the long-term survival of Medicare fee-for-service beneficiaries undergoing mitral valve repair and replacement over a 10-year period. Methods and Results—We used the Medicare database to identify 47 279 fee-for-service beneficiaries ≥65 years of age undergoing primary isolated mitral valve repair or replacement from 2000 to 2009. Operative mortality and long-term survival are presented for repair and replacement. Operative mortality was 3.9% for patients undergoing repair and 8.9% for patients undergoing replacement. The 1-, 5-, and 10-year Kaplan-Meier survival estimates for patients undergoing repair were 90.9%, 77.1%, and 53.6%. The 1-, 5-, and 10-year Kaplan-Meier survival estimates for patients undergoing replacement were 82.6%, 64.7%, and 37.2%. Important predictors of mitral r...

Mortality and major morbidity after tonsillectomy: etiologic factors and strategies for prevention.

Abstract: Objective/Hypothesis To report data on death or permanent disability after tonsillectomy. Study Design Electronic mail survey. Methods A 32-question survey was disseminated via the American Academy of Otolaryngology–Head and Neck Surgery electronic newsletter. Recipients were queried regarding adverse events after tonsillectomy, capturing demographic data, risk factors, and detailed descriptions. Events were classified using a hierarchical taxonomy. Results A group of 552 respondents reported 51 instances of post-tonsillectomy mortality, and four instances of anoxic brain injury. These events occurred in 38 children (71%), 15 adults (25%), and two patients of unstated age (4%). The events were classified as related to medication (22%), pulmonary/cardiorespiratory factors (20%), hemorrhage (16%), perioperative events (7%), progression of underlying disease (5%), or unexplained (31%). Of unexplained events, all but one occurred outside the hospital. One or more comorbidities were identified in 58% of patients, most often neurologic impairment (24%), obesity (18%), or cardiopulmonary compromise (15%). A preoperative diagnosis of obstructive sleep apnea was not associated with increased risk of death or anoxic brain injury. Most events (55%) occurred within the first 2 postoperative days. Otolaryngologists who reported performing <200 tonsillectomies per year were more likely to report an event (P < .001). Conclusions This study, the largest collection of original reports of post-tonsillectomy mortality to date, found that events unrelated to bleeding accounted for a preponderance of deaths and anoxic brain injury. Further research is needed to establish best practices for patient admission, monitoring, and pain management. Laryngoscope, 123:2544–2553, 2013 Level of Evidence N/A.

Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice

Abstract: There is increasing evidence that the hormonal systems involved in growth, the metabolism of glucose, and the processes that balance energy intake and expenditure might also be involved in the aging process. In rodents, mutations in genes involved in these hormone-signaling pathways can substantially increase lifespan, as can a diet that is low in calories but which avoids malnutrition. As well as living longer, such mice also show reductions in age-related conditions such as diabetes, memory loss and cancer. Many of these effects appear to involve the actions of growth hormone. Mice with mutations that disrupt the development of the pituitary gland, which produces growth hormone, show increased longevity, as do mice that lack the receptor for growth hormone. However, these animals also show changes in a number of other hormones, making it difficult to be sure that the reduction in growth hormone signaling is responsible for their increased lifespan. Now, Sun et al. have studied mutant mice that lack a gene called GHRH, which promotes the release of growth hormone. These mice, which have normal levels of all other pituitary hormones, lived for up to 50% longer than their wild-type littermates. They were more active than normal mice and had more body fat, and showed greatly increased sensitivity to insulin. Some of the changes in these mutant mice resembled those seen in animals with a restricted calorie intake, suggesting that the same mechanisms may be implicated in both. However, Sun et al. found that caloric restriction further increased the lifespans of their GHRH knockout mice, indicating that at least some of the effects of caloric restriction are independent of disrupted growth hormone signaling. The results of this study are an important step forward for understanding how growth hormone signaling and caloric restriction regulate aging, both individually and in combination. The GHRH knockout mice are likely to become an important model system for studying these processes and for understanding the complex interactions between diet and hormonal pathways.

TLR4 Is a Novel Determinant of the Response to Paclitaxel in Breast Cancer

Abstract: Overexpression of Toll-like receptor-4 (TLR4) in human tumors often correlates with chemoresistance and metastasis We found that TLR4 is overexpressed in the majority of clinical breast cancer samples and in 68% of the examined breast cancer lines TLR4 is activated by lipopolysaccharide (LPS) and other ligands including the widely used drug paclitaxel LPS is frequently used to show a tumor-promoting role of TLR4 although this bacterial component is unlikely to be found in the breast cancer environment We reasoned that paclitaxel-dependent activation of TLR4 is more relevant to breast cancer chemoresistance that could be mediated by activation of the NF-κB pathway leading to upregulation of prosurvival genes To test this hypothesis, we correlated TLR4 expression with resistance to paclitaxel in two modified breast cancer lines with either depleted or overexpressed TLR4 protein Depletion of TLR4 in naturally overexpressing MDA-MB-231 cells downregulated prosurvival genes concomitant with 2- to 3-fold reduced IC(50) to paclitaxel in vitro and a 6-fold decrease in recurrence rate in vivo Conversely, TLR4 overexpression in a negative cell line HCC1806 significantly increased expression of inflammatory and prosurvival genes along with a 3-fold increase of IC(50) to paclitaxel in vitro and enhanced tumor resistance to paclitaxel therapy in vivo Importantly, both tumor models showed that many paclitaxel-upregulated inflammatory cytokines were coinduced with their receptors suggesting that this therapy induces autocrine tumor-promoting loops Collectively, these results show that paclitaxel not only kills tumor cells but also enhances their survival by activating TLR4 pathway These findings suggest that blocking TLR4 could significantly improve response to paclitaxel therapy

How to minimize infection and thereby maximize patient outcomes in total joint arthroplasty: A multicenter approach

Abstract: Total joint arthroplasty is one of the most common and most successful orthopaedic procedures. Infection after total joint arthroplasty is a devastating problem that expends patient, surgeon, and hospital resources, and it substantially decreases the chances of a successful patient outcome. Postoperative infection affects approximately 1% to 7% of all total joint arthroplasties, at a cost of approximately $50,000 per infection. Decreasing postoperative periprosthetic joint infection is of the utmost importance for the total joint arthroplasty surgeon. Preoperative, perioperative, intraoperative, and postoperative measures to minimize infection and optimize patient outcomes in total joint arthroplasty are discussed. Preoperative measures include management of patients colonized by Staphylococcus aureus, nutritional optimization, and management of medical comorbidities. Perioperative measures include skin preparation and prophylactic antibiotics. Intraoperative measures include body exhaust suits, laminar flow, ultraviolet light, operating-room traffic control, surgical suite enclosures, anesthesia-related considerations, and antibiotic-loaded bone cement. Postoperative measures include continued antibiotic prophylaxis, blood transfusions, hematoma formation and wound drainage, duration of hospital stay, and antibiotic prophylaxis for future invasive procedures.

Griffithsin Protects Mice from Genital Herpes by Preventing Cell-to-Cell Spread

Abstract: Griffithsin, which binds N-linked glycans on gp120 to prevent HIV entry, has the most potent HIV-1 inhibitory activity described for any antiviral lectin and is being developed for topical preexposure prophylaxis. The current studies were designed to further assess its potential by exploring its activity against herpes simplex virus 2 (HSV-2), a cofactor for HIV acquisition, in vitro and in a murine model. Safety was evaluated by examining its impact on epithelial barrier integrity in polarized cultures and testing whether repeated intravaginal dosing potentiates the susceptibility of mice to genital herpes. Griffithsin displayed modest inhibitory activity against HSV-2 if present during viral entry but completely blocked plaque formation if present postentry, reduced plaque size, and prevented cell-to-cell spread. These in vitro findings translated to significant protection against genital herpes in mice treated with 0.1% griffithsin gel. Griffithsin, but not placebo gel, prevented viral spread (visualized with a luciferase-expressing virus), significantly reduced disease scores, and resulted in greater survival (P < 0.05, log rank test). Protection persisted when HSV-2 was introduced in seminal plasma. Although griffithsin triggered a small decline in transepithelial electrical resistance in polarized cultures, this did not translate to any significant increase in the ability of HIV to migrate from the apical to the basolateral chamber nor to an increase in susceptibility to HSV-2 in mice treated with griffithsin gel for 7 days. These findings demonstrate that griffithsin inhibits HSV-2 by a unique mechanism of blocking cell-to-cell spread and support its further development for HIV and HSV-2 prevention.

Effects of a physical activity behavior change intervention on inflammation and related health outcomes in breast cancer survivors: pilot randomized trial

Abstract: Background. The goal of this pilot study was to determine the magnitude and direction of intervention effect sizes for inflammatory-related serum markers and relevant health outcomes among breast c...

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease.

Abstract: With aging and Alzheimer’s disease (AD), there is an increased sensitivity to stress along with declines in the memory-associated neurotrophin brain-derived neurotrophic factor in AD. We have replicated this aging phenotype in cultured neurons from aged mice despite being grown in the same environmental conditions as young neurons. This led us to hypothesize that age-related differences in epigenetic acetylation and methylation of histones are associated with age-related gene regulation. We cultured hippocampal/cortical neurons from the 3xTg-AD mouse model and from non-transgenic mice to quantify single cell acetylation and methylation levels across the life span. In non-transgenic neurons, H3 acetylation was unchanged with age, while H4 acetylation decreased with age of the donor. Compared to non-transgenic neurons, 3xTg-AD neurons had higher levels of H3 and H4 acetylation beginning at 4 months of age. In contrast to non-transgenic neurons, 3xTg-AD neurons increased acetylation with age; 3xTg-AD neurons also responded differently to inhibition of histone deacetylases at an early age. Importantly, treatment of non-transgenic neurons with the AD peptide Aβ also elevated levels of acetylation. We also examined the repressive function of histone H3 lysine 9 (H3K9) methylation. H3K9 methylation increased with age in non-transgenic neurons, which was amplified further in 3xTg-AD neurons. The dominant effect of higher H3K9 methylation was supported by lower Bdnf gene expression in non-transgenic and 3xTg-AD mice. These data show that the epigenetic states of non-transgenic and 3xTg-AD brain neurons are profoundly different and reversible, beginning at 4 months of age when the first memory deficits are reported.

Identification of Ovarian Cancer Metastatic miRNAs

Abstract: Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2–4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.

Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer.

Abstract: Upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. However, the exact role of lipogenesis in tumor initiation is as yet poorly understood. We examined the expression profile of key lipogenic genes in clinical samples of ductal carcinoma in situ (DCIS) of breast cancer and found that these genes were significantly upregulated in DCIS. We also isolated cancer stem-like cells (CSCs) from DCIS.com cell line using cell surface markers (CS24(-)CD44(+)ESA(+)) and found that this cell population has significantly higher tumor-initiating ability to generate DCIS compared with the non-stem-like population. Furthermore, the CSCs showed significantly higher level of expression of all lipogenic genes than the counterpart population from non-tumorigenic breast cancer cell line, MCF10A. Importantly, ectopic expression of SREBP1, the master regulator of lipogenic genes, in MCF10A significantly enhanced lipogenesis in stem-like cells and promoted cell growth as well as mammosphere formation. Moreover, SREBP1 expression significantly increased the ability of cell survival of CSCs from MCF10AT, another cell line that is capable of generating DCIS, in mouse and in cell culture. These results indicate that upregulation of lipogenesis is a pre-requisite for DCIS formation by endowing the ability of cell survival. We have also shown that resveratrol was capable of blocking the lipogenic gene expression in CSCs and significantly suppressed their ability to generate DCIS in animals, which provides us with a strong rationale to use this agent for chemoprevention against DCIS.

What is essential tremor

Abstract: Classic essential tremor is a clinical syndrome of action tremor in the upper limbs (at least 95 % of patients) and less commonly the head, face/jaw, voice, tongue, trunk, and lower limbs, in the absence of other neurologic signs. However, the longstanding notion that essential tremor is a monosymptomatic tremor disorder is being challenged by a growing literature describing associated disturbances of tandem walking, personality, mood, hearing, and cognition. There is also epidemiologic, pathologic, and genetic evidence that essential tremor is pathophysiologically heterogeneous. Misdiagnosis of essential tremor is common because clinicians frequently overlook other neurologic signs and because action tremor in the hands is caused by many conditions, including dystonia, Parkinson disease, and drug-induced tremor. Thus, essential tremor is nothing more than a syndrome of idiopathic tremulousness, and the challenge for researchers and clinicians is to find specific etiologies of this syndrome.

Pilot, randomized trial of resistance exercise during radiation therapy for head and neck cancer

Abstract: Background The purpose of this study was to determine the feasibility of a randomized trial of resistance exercise in patients with head and neck cancer receiving radiation. Methods Fifteen patients with head and neck cancer receiving radiation were randomized to resistance exercise (using resistance bands) or control group. Resistance exercise occurred at the radiation therapy site (weeks 1–6) and home (weeks 7–12). Results No serious adverse events occurred related to resistance exercise. Medium to large effect size differences favoring resistance exercise versus control group were noted for perceived fatigue at 6 weeks (smaller increase in fatigue for resistance exercise group; 7.4 vs 15.4, effect size [d] = −0.64), quality of life at 6 weeks (−7.0 vs −14.4, d = 0.52), and chair rise time (seconds) at 6 and 12 weeks (−1.6 vs 0.4, d = −.63 and −1.9 vs 0.1, d = −0.60, respectively). Conclusions Resistance exercise is safe and feasible in patients with head and neck cancer receiving radiation; a definitive trial is warranted. © 2012 Wiley Periodicals, Inc. Head Neck, 2013

Nucleosome mobilization by ISW2 requires the concerted action of the ATPase and SLIDE domains

Abstract: The ISWI family of ATP-dependent chromatin remodelers represses transcription by changing nucleosome positions. ISWI regulates nucleosome positioning by requiring a minimal length of extranucleosomal DNA for moving nucleosomes. ISW2 from Saccharomyces cerevisiae, a member of the ISWI family, has a conserved domain called SLIDE (SANT-like ISWI domain) that binds to extranucleosomal DNA ~19 base pairs from the edge of nucleosomes. Loss of SLIDE binding does not perturb binding of the ATPase domain or the initial movement of DNA inside of nucleosomes. Not only is extranucleosomal DNA required to help recruit ISW2, but also the interactions of the SLIDE domain with extranucleosomal DNA are functionally required to move nucleosomes.