Chemokine-derived oncolytic peptide induces immunogenic cancer cell death and significantly suppresses tumor growth.

Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic peptide derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only as an anti-angiogenic peptide but also as an oncolytic peptide due to its structural and physical properties. CKS1 induced both necrotic and apoptotic cell death specifically in cancer cells while showing minimal toxicity in non-cancerous cells. Mechanistically, CKS1 disrupted the cell membrane of cancer cells quickly after treatment and activated the apoptotic pathway at later time points. Furthermore, immunogenic molecules were released from CKS1-treated cells, indicating that CKS1 induces immunogenic cell death. CKS1 effectively suppressed tumor growth in vivo. Collectively, these data demonstrate that CKS1 functions as an oncolytic peptide and has a therapeutic potential to treat cancer.

Enteric neurospheres retain the capacity to assemble neural networks with motile and metamorphic gliocytes and ganglia.

BACKGROUND: Neurosphere medium (NSM) and self-renewal medium (SRM) were widely used to isolate enteric neural stem cells (ENSCs) in the form of neurospheres. ENSCs or their neurosphere forms were neurogenic and gliogenic, but the compelling evidence for their capacity of assembling enteric neural networks remained lacking, raising the question of their aptitude for rebuilding the enteric nervous system (ENS) in ENSC therapeutics. It prompted us to explore an effective culture protocol or strategy for assembling ENS networks, which might also be employed as an in vitro model to simplify the biological complexity of ENS embedded in gut walls. METHODS: NSM and SRM were examined for their capacity to generate neurospheres in mass culture of dispersed murine fetal enterocytes at serially diluted doses and assemble enteric neural networks in two- and three-dimensional cell culture systems and ex vivo on gut explants. Time-lapse microphotography was employed to capture cell activities of assembled neural networks. Neurosphere transplantation was performed via rectal submucosal injection. RESULTS: In mass culture of dispersed enterocytes, NSM generated discrete units of neurospheres, whereas SRM promoted neural network assembly with neurospheres akin to enteric ganglia. Both were highly affected by seeding cell doses. SRM had similar ENSC mitosis-driving capacity to NSM, but was superior in driving ENSC differentiation in company with heightened ENSC apoptosis. Enteric neurospheres were motile, capable of merging together. It argued against their clonal entities. When nurtured in SRM, enteric neurospheres proved competent to assemble neural networks on two-dimensional coverslips, in three-dimensional hydrogels and on gut explants. In the course of neural network assembly from enteric neurospheres, neurite extension was preceded by migratory expansion of gliocytes. Assembled neural networks contained motile ganglia and gliocytes that constantly underwent shapeshift. Neurospheres transplanted into rectal submucosa might reconstitute myenteric plexuses of recipients' rectum. CONCLUSION: Enteric neurospheres mass-produced in NSM might assemble neural networks in SRM-immersed two- or three-dimensional environments and on gut explants, and reconstitute myenteric plexuses of the colon after rectal submucosal transplantation. Our results also shed first light on the dynamic entity of ENS and open the experimental avenues to explore cellular activities of ENS and facilitate ENS demystification.

Chemokine-derived oncolytic peptide induces immunogenic cancer cell death and significantly suppresses tumor growth.

Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic peptide derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only as an anti-angiogenic peptide but also as an oncolytic peptide due to its structural and physical properties. CKS1 induced both necrotic and apoptotic cell death specifically in cancer cells while showing minimal toxicity in non-cancerous cells. Mechanistically, CKS1 disrupted the cell membrane of cancer cells quickly after treatment and activated the apoptotic pathway at later time points. Furthermore, immunogenic molecules were released from CKS1 treated cells, indicating that CKS1 induces immunogenic cell death. CKS1 effectively suppressed tumor growth in vivo. Collectively, these data demonstrate that CKS1 is a unique peptide that functions both as an anti-angiogenic peptide and as an oncolytic peptide and has a therapeutic potential to treat cancer.

Precision Medicine-A Demand Signal for Genomics Education.

Pressed by the accumulating knowledge in genomics and the proven success of the translation of cancer genomics to clinical practice in oncology, the Obama administration unveiled a $215 million commitment for the Precision Medicine Initiative (PMI) in 2016, a pioneering research effort to improve health and treat disease using a new model of patient-powered research. The objectives of the initiative include more effective treatments for cancer and other diseases, creation of a voluntary national research cohort, adherence to privacy protections for maintaining data sharing and use, modernization of the regulatory framework, and forging public-private partnerships to facilitate these objectives. Specifically, the DoD Military Health System joined other agencies to execute a comprehensive effort for PMI. Of the many challenges to consider that may contribute to the implementation of genomics-lack of familiarity and understanding, poor access to genomic medicine expertise, needs for extensive informatics and infrastructure to integrate genomic results, privacy and security, and policy development to address the unique requirements of military medical practice-we will focus on the need to establish education in genomics appropriate to the provider's responsibilities. Our hypothesis is that there is a growing urgency for the development of educational experiences, formal and informal, to enable clinicians to acquire competency in genomics commensurate with their level of practice. Several educational approaches, both in practice and in development, are presented to inform decision-makers and empower military providers to pursue courses of action that respond to this need.

The unborn fetus: The unrecognized victim of trauma during pregnancy.

BACKGROUND: Trauma is the leading cause of non-obstetric death in pregnancy. While maternal management is defined, few studies have examined the effects on the fetus. METHODS: Following IRB approval, all pregnant females (2010-2017) at a level-1 trauma center were retrospectively reviewed. Maternal and fetal demographics, interventions, and clinical outcomes were analyzed. RESULTS: There were 188 pregnancies in 5654 females. Maternal demographics were 26 ±â€¯7 years old, gestational age at trauma 21 ±â€¯12 weeks, 81% blunt mechanism, and maternal mortality 6%. Forty-one (22%) fetuses were immediately affected by the trauma including 20 (11%) born alive, 12 (7%) fetal demise, and 9 (5%) stillbirths. Of those that initially survived (n = 20), 5 (25%) expired during neonatal hospitalization. Two mothers returned immediately after trauma discharge with stillbirths for an overall infant mortality of 14% (n = 26). There were 84 patients with complete data to delivery including the 41 born at trauma and 43 born on a subsequent hospitalization. Those born at the time of trauma had significantly more delivery/neonatal complications and worse outcomes. Overall trauma burden to the fetus (preterm delivery, stillbirth, delivery/neonatal complication, or long-term disability) was 66% (56/84). CONCLUSIONS: Trauma during pregnancy has significant immediate mortality and delayed effects on the unborn fetus. This study has uncovered a previously hidden burden and mortality of trauma during pregnancy. LEVEL OF EVIDENCE: Level III.

Fixation of lung apex in spontaneous pneumothorax is safe and efficient in decrease recurrences.

BACKGROUND: Video-assisted thoracoscopic bullectomy with pleurodesis is widely used to treat spontaneous pneumothorax. However, 1%-3% of patients experience postoperative complications that may require reoperation, such as bleeding or prolonged air leaks, and 3%-7% of patients require a repeat thoracoscopic bullectomy due to recurrence. Therefore, a modified procedure with improved outcomes is required. METHODS: Between January 1, 2011 and December 31, 2015, 196 patients with spontaneous pneumothorax underwent thoracoscopic bullectomy and pleurodesis with or without fixation of the lung apex to the chest wall. In patients in the fixation group, the lung apex was fixed to the chest wall with two non-absorbable sutures after bullectomy and pleurodesis. The treatment of each lung was considered an independent operation in patients with bilateral spontaneous pneumothorax. RESULTS: The patients in each group had comparable backgrounds. In the fixation group, 67 patients underwent 87 operations, four of which (in three patients) led to recurrences (recurrence rate, 4.60%). There were no readmissions or reoperations within 30 days in this group. In the non-fixation group, 128 patients underwent 161 operations, 14 of which (in nine patients) led to recurrences (recurrence rate, 8.7%). In addition, three patients in this group required reoperation and two were readmitted within 30 days. CONCLUSIONS: Modified thoracoscopic bullectomy with fixation of the lung apex is a safe procedure that provides better outcomes with lower complication rates.

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML.

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγnull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34+ cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n = 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34+ cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34+ cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n = 4 patients, n = 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.

Maternal diabetes and high glucose in vitro trigger Sca1+ cardiac progenitor cell apoptosis through FoxO3a.

Recent controversies surrounding the authenticity of c-kit+ cardiac progenitor cells significantly push back the advance in regenerative therapies for cardiovascular diseases. There is an urgent need for research in characterizing alternative types of cardiac progenitor cells. Towards this goal, in the present study, we determined the effect of maternal diabetes on Sca1+ cardiac progenitor cells. Maternal diabetes induced caspase 3-dependent apoptosis in Sca1+ cardiac progenitor cells derived from embryonic day 17.5 (E17.5). Similarly, high glucose in vitro but not the glucose osmotic control mannitol triggered Sca1+ cardiac progenitor cell apoptosis in a dose- and time-dependent manner. Both maternal diabetes and high glucose in vitro activated the pro-apoptotic transcription factor, Forkhead O 3a (FoxO3a) via dephosphorylation at threonine 32 (Thr-32) residue. foxo3a gene deletion abolished maternal diabetes-induced Sca1+ cardiac progenitor cell apoptosis. The dominant negative FoxO3a mutant without the transactivation domain from the C terminus blocked high glucose-induced Sca1+ cardiac progenitor cell apoptosis, whereas the constitutively active FoxO3a mutant with the three phosphorylation sites, Thr-32, Ser-253, and Ser-315, being replaced by alanine residues mimicked the pro-apoptotic effect of high glucose. Thus, maternal diabetes and high glucose in vitro may limit the regenerative potential of Sca1+ cardiac progenitor cells by inducing apoptosis through FoxO3a activation. These findings will serve as the guide in optimizing the autologous therapy using Sca1+ cardiac progenitor cells in cardiac defect babies born exposed to maternal diabetes.

Surgical Management of Complicated Necrotizing Pneumonia in Children.

BACKGROUND: There are no well-established indications for the surgical management of acute necrotizing pneumonitis in children. This study presents our experience regarding this challenging topic. METHODS: Between 2002 and 2009, 56 necrotizing pneumonitis patients with empyema were treated surgically. The outcomes were analyzed retrospectively. Computed tomography findings of massive lung necrosis or large cavities involving more than 50% of the involved lobe were deemed to be complicated necrotizing pneumonitis. Patients without the above indications were considered uncomplicated. RESULTS: Thirty-one cases were uncomplicated and 25 were complicated. Operative procedures included 38 decortications (31 uncomplicated and seven complicated), 14 wedge resections, and four lobectomies (complicated only). Preoperatively, patients with complicated necrotizing pneumonia had a higher incidence of pneumothorax (32% vs. 14.3%; p = 0.001), endotracheal intubation (44% vs. 9.7%; p = 0.008), and hemolytic uremic syndrome (20% vs. 3.2%; p = 0.01). These patients also had higher incidences of intraoperative transfusion (68% vs. 9.7%; p = 0.03), major postoperative complications (16% vs. 0%; p = 0.02), reoperations (16% vs. 0%; p = 0.02), and longer postoperative stay (19.8 ± 24.2 days vs. 11.2 ± 5.8 days; p = 0.03). Four complicated patients, who initially had decortications and limited resections, underwent reoperations. Compared with uncomplicated patients, those who underwent decortications and wedge resection required longer postoperative stays (23.6 ± 9.9 days, p < 0.01 and 21.1 ± 30.7 days, p = 0.04, respectively), whereas patients who had lobectomy had a similar duration of recovery (9.0 ± 2.1 days, p = 0.23). All patients improved significantly at follow-up. CONCLUSION: Children with complicated necrotizing pneumonitis have more preoperative morbidities, more major postoperative complications, and require longer postoperative stays. Aggressive surgical treatment results in significant clinical improvement. Lobectomy in patients with complicated necrotizing pneumonitis may shorten the postoperative course and avoid subsequent surgery.

PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment.

The scavenging of extracellular macromolecules by engulfment can sustain cell growth in a nutrient-depleted environment. Engulfed macromolecules are contained within vacuoles that are targeted for lysosome fusion to initiate degradation and nutrient export. We have shown that vacuoles containing engulfed material undergo mTORC1-dependent fission that redistributes degraded cargo back into the endosomal network. Here we identify the lipid kinase PIKfyve as a regulator of an alternative pathway that distributes engulfed contents in support of intracellular macromolecular synthesis during macropinocytosis, entosis, and phagocytosis. We find that PIKfyve regulates vacuole size in part through its downstream effector, the cationic transporter TRPML1. Furthermore, PIKfyve promotes recovery of nutrients from vacuoles, suggesting a potential link between PIKfyve activity and lysosomal nutrient export. During nutrient depletion, PIKfyve activity protects Ras-mutant cells from starvation-induced cell death and supports their proliferation. These data identify PIKfyve as a critical regulator of vacuole maturation and nutrient recovery during engulfment.

Experience of single-incision laparoscopy in children.

CONTEXT: Laparoscopic surgery is commonly used for the treatment of many pediatric surgical diseases at our department. Single-incision laparoscopic surgery (SILS) is well-known for its cosmetic benefit. We, hereby, present our experience of SILS and evaluate its efficacy. MATERIALS AND METHODS: From July 2012 to June 2014, 78 patients aged less than 18 years who underwent SILS were retrospectively evaluated. There were 44 males and 34 females, with a mean age of 10.3 years. The procedures included appendectomy (n = 64), reduction of intussusception (n = 8), removal of an intestinal foreign body (n = 3), and Meckel's diverticulectomy (n = 3). We compared the patients who underwent SILS with those who underwent conventional laparoscopic surgery (CLS), regarding these procedures. The parameters for analysis included the patient's demographic data, surgical indication, complications, operative time, and length of hospital stay. CONCLUSION: SILS is comparable to CLS regarding two major procedures, namely, appendectomy and reduction of intussusception. There were no significant differences between the two groups regarding the patients' demographic data, complications, and length of hospital stay. According to our experience of SILS, it could be a feasible and safe procedure for the treatment of various pediatric surgical diseases. However, large prospective randomized studies are needed to identify the differences between SIL and CLS.

Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice.

Low-grade chronic inflammation plays an important role in the pathogenesis of obesity-induced insulin resistance. ABCA1 is essential for reverse cholesterol transport and HDL synthesis, and protects against macrophage inflammation. In the present study, the effects of ABCA1 deficiency in hematopoietic cells on diet-induced inflammation and insulin resistance were tested in vivo using bone marrow transplanted (BMT)-WT and BMT-ABCA1(-/-) mice. When challenged with a high-fat high-carbohydrate diabetogenic diet with added cholesterol (HFHSC), BMT-ABCA1(-/-) mice displayed enhanced insulin resistance and impaired glucose tolerance as compared with BMT-WT mice. The worsened insulin resistance and impaired glucose tolerance in BMT-ABCA1(-/-) mice were accompanied by increased macrophage accumulation and inflammation in adipose tissue and liver. Moreover, BMT-ABCA1(-/-) mice had significantly higher hematopoietic stem cell proliferation, myeloid cell expansion, and monocytosis when challenged with the HFHSC diet. In vitro studies indicated that macrophages from ABCA1(-/-) mice showed significantly increased inflammatory responses induced by saturated fatty acids. Taken together, these studies point to an important role for hematopoietic ABCA1 in modulating a feed-forward mechanism in obesity such that inflamed tissue macrophages stimulate the production of more monocytes, leading to an exacerbation of inflammation and associated disease processes.

High potential for iron reduction in upland soils.

Changes in the redox state of iron (Fe) can be coupled to the biogeochemical cycling of carbon (C), nitrogen, and phosphorus, and thus regulate soil C, ecosystem nutrient availability, and greenhouse gas production. However, its importance broadly in non-flooded upland terrestrial ecosystems is unknown. We measured Fe reduction in soil samples from an annual grassland, a drained peatland, and a humid tropical forest We incubated soil slurries in an anoxic glovebox for 5.5 days and added sodium acetate daily at rates up to 0.4 mg C x (g soil)(-1) x d(-1). Soil moisture, poorly crystalline Fe oxide concentrations, and Fe(II) concentrations differed among study sites in the following order: annual grassland < drained peatland < tropical forest (P < 0.001 for all characteristics). All of the soil samples demonstrated high Fe reduction potential with maximum rates over the course of the incubation averaging 1706 ± 66, 2016 ± 12, and 2973 ± 115 µg Fe x (g soil)(-1) x d(-1) (mean ± SE) for the tropical forest, annual grassland, and drained peatland, respectively. Our results suggest that upland soils from diverse ecosystems have the potential to exhibit high short-term rates of Fe reduction that may play an important role in driving soil biogeochemical processes during periods of anaerobiosis.

A comparison of parecoxib and thoracic epidural analgesia for postoperative analgesia following Nuss procedure.

BACKGROUND: The purpose of this study was to compare the results of thoracic epidural analgesia (TEA) and parecoxib in controlling postoperative pain after the Nuss procedure. METHODS: Between August 2005 and July 2014, 120 adolescents and adults underwent Nuss procedures and received either TEA or parecoxib for postoperative pain control. Demographic data, preoperative preparation times, visual analog scale (VAS) pain scores from postoperative day 1 to day 5, medical costs of pain control, days to Foley catheter removal, days to being able to sit up, days to being able to walk, days of hospital stay, nausea/vomiting scores, and complications related to pain control were compared. RESULTS: A total of 106 patients received TEA, and 14 received parecoxib. No between-group differences in demographics were observed. Patients in the parecoxib group had shorter preparation times (p<0.001), lower VAS pain scores from postoperative day 2 to day 5 (day 2, p=0.006; day 3, p=0.006; day 4, p<0.001; day 5, p<0.001), shorter hospital stays (p<0.001), lower pain control costs (p<0.001), and lower nausea/vomiting scores (p=0.046). CONCLUSIONS: For adolescents and adults undergoing the Nuss procedure, parecoxib affords better pain control efficacy, a shorter hospital stay, lower medical pain control costs, and fewer side effects compared with TEA.

MMTV/LTR Promoter-Driven Transgenic Expression of EpCAM Leads to the Development of Large Pancreatic Islets.

Our previous work demonstrated an important role of EpCAM in the regulation of pancreatic cell adhesion, growth and differentiation. Here we investigated the consequences of human EpCAM (hEpCAM) overexpression under the control of the MMTV-LTR promoter, known to drive robust gene expression in a number of ductal epithelia, including the pancreas. In this animal model (MMTV-hEpCAM) we uncovered a striking pancreatic phenotype exhibiting a 12-fold increase in the islet cell mass, with normal expression patterns of insulin and the transcription factor PDX-1. Intriguingly, these large islet clusters revealed an altered architectural organization of α- and δ-cells that appeared interspersed with ß-cells in the islet cores. This suggests an effect of the hEpCAM transgene on the function of other cell adhesion molecules that we have previously shown to regulate islet cell type segregation. Consistent with this finding, we show that the pancreatic epithelium in MMTV-hEpCAM transgenic mice exhibits a redistribution of ß-catenin, a known regulator of E-cadherin-mediated adhesions. Collectively, these results provide an important in vivo validation of hEpCAM signaling properties in normal epithelia and offer unique opportunities to further explore the function of this glycoprotein in select pancreatic cell lineages to elicit islet cell expansion, and/or regeneration in diabetes.

ß1 integrin is a crucial regulator of pancreatic ß-cell expansion.

Development of the endocrine compartment of the pancreas, as represented by the islets of Langerhans, occurs through a series of highly regulated events encompassing branching of the pancreatic epithelium, delamination and differentiation of islet progenitors from ductal domains, followed by expansion and three-dimensional organization into islet clusters. Cellular interactions with the extracellular matrix (ECM) mediated by receptors of the integrin family are postulated to regulate key functions in these processes. Yet, specific events regulated by these receptors in the developing pancreas remain unknown. Here, we show that ablation of the ß1 integrin gene in developing pancreatic ß-cells reduces their ability to expand during embryonic life, during the first week of postnatal life, and thereafter. Mice lacking ß1 integrin in insulin-producing cells exhibit a dramatic reduction of the number of ß-cells to only ∼18% of wild-type levels. Despite the significant reduction in ß-cell mass, these mutant mice are not diabetic. A thorough phenotypic analysis of ß-cells lacking ß1 integrin revealed a normal expression repertoire of ß-cell markers, normal architectural organization within islet clusters, and a normal ultrastructure. Global gene expression analysis revealed that ablation of this ECM receptor in ß-cells inhibits the expression of genes regulating cell cycle progression. Collectively, our results demonstrate that ß1 integrin receptors function as crucial positive regulators of ß-cell expansion.

Splenic hemangiopericytoma in a one-month-old infant.

Hemangiopericytoma is an uncommon tumor that occurs mostly in middle-aged adults. There have been only sporadic case reports of splenic involvement, and in all but one the treatment has been total splenectomy. We present a one-month-old boy with splenic hemangiopericytoma treated with partial splenectomy. This is the youngest case in the literature, and there has been no recurrence noted after two years of follow up.

Denicotinized versus average nicotine tobacco cigarette smoking differentially releases striatal dopamine.

INTRODUCTION: Nicotine has long been recognized as a necessary but insufficient component of tobacco cigarettes to maintain a psychophysiological need to smoke. This study examined venous plasma concentrations effects of nicotine in cigarette smoking after overnight abstinence to release striatal dopamine (DA). METHODS: Twenty-two male smokers smoked either denicotinized (denic) or average nicotine (nic) cigarettes under single blind conditions. Each was given [(11)C]raclopride and scanned in a positron emission tomography (PET) facility. RESULTS: Smoking either denic or nic cigarettes released striatal DA. Denic cigarette smoking released DA primarily in the right striatum, whereas nic cigarette smoking released DA in both striata, but especially in the left. Increases in venous plasma nicotine concentrations correlated positively with increased DA release in the left caudate nucleus. Smoking denic cigarettes reduced craving as much as smoking nic cigarettes. Craving reduction after nic tobacco smoking correlated with increases in plasma nicotine. CONCLUSIONS: Nonnicotine factors in tobacco smoking produce important right brain effects. Nicotine is a pharmacological factor during tobacco smoking that releases bilateral striatal DA, but more in the left brain.

Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a neurological disorder caused by mutations in the huntingtin (HTT) gene, the product of which leads to selective and progressive neuronal cell death in the striatum and cortex. Transcriptional dysregulation has emerged as a core pathologic feature in the CNS of human and animal models of HD. It is still unclear whether perturbations in gene expression are a consequence of the disease or importantly, contribute to the pathogenesis of HD. OBJECTIVE: To examine if transcriptional dysregulation can be ameliorated with antisense oligonucleotides that reduce levels of mutant Htt and provide therapeutic benefit in the YAC128 mouse model of HD. METHODS: Quantitative real-time PCR analysis was used to evaluate dysregulation of a subset of striatal genes in the YAC128 mouse model. Transcripts were then evaluated following ICV delivery of antisense oligonucleotides (ASO). Rota rod and Porsolt swim tests were used to evaluate phenotypic deficits in these mice following ASO treatment. RESULTS: Transcriptional dysregulation was detected in the YAC128 mouse model and appears to progress with age. ICV delivery of ASOs directed against mutant Htt resulted in reduction in mutant Htt levels and amelioration in behavioral deficits in the YAC128 mouse model. These improvements were correlated with improvements in the levels of several dysregulated striatal transcripts. CONCLUSIONS: The role of transcriptional dysregulation in the pathogenesis of Huntington's disease is not well understood, however, a wealth of evidence now strongly suggests that changes in transcriptional signatures are a prominent feature in the brains of both HD patients and animal models of the disease. Our study is the first to show that a therapeutic agent capable of improving an HD disease phenotype is concomitantly correlated with normalization of a subset of dysregulated striatal transcripts. Our data suggests that correction of these disease-altered transcripts may underlie, at least in part, the therapeutic efficacy shown associated with ASO-mediated correction of HD phenotypes and may provide a novel set of early biomarkers for evaluating future therapeutic concepts for HD.