Changes in resting state networks in high school football athletes across a single season.

OBJECTIVE: The aim of this pilot cohort study was to examine changes in the organization of resting-state brain networks in high school football athletes and its relationship to exposure to on-field head impacts over the course of a single season. METHODS: Seventeen male high school football players underwent functional magnetic resonance imaging and computerized neurocognitive testing (CNS Vital Signs) before the start of contact practices and again after the conclusion of the season. The players were equipped with helmet accelerometer systems (Head Impact Telemetry System) to record head impacts in practices and games. Graph theory analysis was applied to study intranetwork local efficiency and strength of connectivity within six anatomically defined brain networks. RESULTS: We observed a significant decrease in the local efficiency (-24.9 ± 51.4%, r = 0.7, p < 0.01) and strength (-14.5 ± 26.8%, r = 0.5, p < 0.01) of functional connectivity within the frontal lobe resting-state network and strength within the parietal lobe resting-state network (-7.5 ± 17.3%, r = 0.1, p < 0.01), as well as a concomitant increase in the local efficiency (+55.0 +/- 59.8%, r = 0.5, p < 0.01) and strength (+47.4 +/- 47.3%, r = 0.5, p < 0.01) within the mediotemporal networks. These alterations in network organization were associated with changes in performance on verbal memory (p < 0.05) and executive function (p < 0.05). We did not observe a significant relationship between the frequency or cumulative magnitude of impacts sustained during the season and neurocognitive or imaging outcomes (p > 0.05). CONCLUSION: Our findings suggest the efficiency and strength of resting-state networks are altered across a season of high school football, but the association of exposure levels to subconcussive impacts is unclear. ADVANCES IN KNOWLEDGE: The efficiency of resting-state networks is dynamic in high school football athletes; such changes may be related to impacts sustained during the season, though further study is needed.

Evidence to Eliminate Double-Leg Conditions From the Modified Balance Error Scoring System and Balance Error Scoring System.

OBJECTIVE: The purpose of our study was to assess the differences between the Balance Error Scoring System (BESS), modified BESS (mBESS), and both measures with the double-leg (DL) stances removed [BESS-revised (BESS-R) and mBESS-revised (mBESS-R)] among healthy and concussed collegiate student-athletes. DESIGN: Retrospective, repeated-measures cohort study. SETTING: Clinical. PATIENTS OR OTHER PARTICIPANTS: Healthy and concussed collegiate athletes (baseline n = 622, postinjury n = 41) from 12 National Collegiate Athletic Association Division I sports cheer and dance at a single university. INTERVENTION OR INDEPENDENT VARIABLES: Balance Error Scoring System, mBESS, BESS-R, and mBESS-R test versions from baseline and postinjury testing. MAIN OUTCOME MEASURES: The mBESS and BESS and their revised versions with DL stances removed (mBESS-R and BESS-R) scores were compared at baseline. Baseline and postinjury scores for all 4 BESS variations and the 6 BESS conditions were compared for those who sustained a concussion. RESULTS: The BESS and BESS-R were statistically different at baseline for the entire sample (99.6% confidence interval 0.32, 0.38, P > 0.0001). None of the other comparisons were significantly different ( P > 0.004). CONCLUSION: Although our results do suggest statistically significant differences between the BESS and BESS-R test versions, they do not represent clinically meaningful differences. The greatest mean difference between all test versions was <1 error; therefore, these BESS versions may not be specific enough to identify balance deficits at baseline or postinjury. Elimination of the time intensive DL measures in the revised BESS variations may be a more clinically practical alternative.

Concussion Baseline Retesting Is Necessary When Initial Scores Are Low.

OBJECTIVE: To determine whether (1) initial baseline scores are significantly better for those who have valid (initial valid) versus invalid scores (initial invalid) on their concussion baseline testing, (2) retesting results in significantly improved baseline scores, and (3) there is a significant difference in scores between those who have valid scores on their initial attempt and those who retook baseline tests (retest valid). DESIGN: Prospective, repeated-measures. SETTING: Two years of collegiate preparticipation concussion baseline testing. PARTICIPANTS: Five hundred forty-seven male and female Division I collegiate athletes (19.02 ± 1.31 years, female = 217). INDEPENDENT VARIABLES: Participants were divided into initial valid and initial invalid. The retest group was further divided into their initial (initial invalid) and final valid attempt (retest valid). MAIN OUTCOME MEASURES: Data were analyzed to determine the relationship between the 3 groups and overall initial and final scores on 28 individual items: total symptoms score, coordination, near-point convergence, CNS Vital Signs (CNSVS), Senaptec Sensory Station, and Neurocom Sensory Organization Test (SOT). RESULTS: The initial valid group scored significantly better than the initial invalid group on 8 CNSVS items and 5 Senaptec items (P < 0.002). The retest valid scores were significantly better compared with the initial invalid scores on 17 items (P < 0.002). CONCLUSIONS: Retesting is recommended for individuals who score below acceptable ranges. This is important because athletes may experience a learning effect and are highly motivated during postinjury testing, so accurate baseline scores are imperative for athlete safety. Completion time for the coordination test may be a more informative option.

Screening Emergency Admissions at Risk of Chronic Hepatitis C (SEARCH) to diagnose or 're-diagnose' infections is effective in Australia.

The World Health Organization has set ambitious viral hepatitis elimination targets; however, difficulties in identifying and engaging patients remain. The emergency visit is an opportunity for enhanced linkage to care (LTC). We assessed the effectiveness of an automated Emergency Department (ED) screening service in identifying patients with hepatitis C (HCV) and achieving LTC. A retrospective evaluation was undertaken, analysing the first 5000 patients screened through an automatic Australian service termed 'Screening Emergency Admissions at Risk of Chronic Hepatitis' (SEARCH). Screening was performed for those recommended in the Australian national testing policy, specifically overseas born (OB) and Aboriginal or Torres Strait Islanders (ATSI). Healthcare worker education, patient information materials and opt-out informed consent were used to test sera already collected for biochemistry assays. 5000 of 5801 (86.2%) consecutive eligible patients were screened (OB: 4778, ATSI: 222) from 14 093 ED presentations. HCV antibody was positive in 181 patients (3.6%); 51 (1.0%) were HCV RNA positive. Of 51 HCV RNA-positive patients, 12 were new diagnoses, 32 were 're-diagnoses' (aware but lost to follow-up [LTFU]), and 7 were previously known but treatment contraindicated. LTC was successful in 38 viraemic patients (7 deceased, 4 LTFU, 1 treatment ineligible and 1 declined). Of RNA-negative patients, 75 were previously treated and 49 had presumed spontaneous clearance. Opt-out consent was acceptable to all patients and staff involved. ED screening can lead to additional diagnosing and 're-diagnosing' of HCV, with high rates of LTC. Opt-out consent and automation removed major obstacles to testing.

Head Impact Locations in U.S. High School Boys' and Girls' Soccer Concussions, 2012/13-2015/16.

This study describes concussions and concussion-related outcomes sustained by high school soccer players by head impact location, sex, and injury mechanism. Data were obtained for the 2012/13-2015/16 school years from the National High School Sports-Related Injury Surveillance System, High School RIO™. This Internet-based sports injury surveillance system captures data reported by athletic trainers from an annual average of 162 U.S. high schools. Data were analyzed to describe circumstances of soccer concussion (e.g., symptomology, symptom resolution, and return-to-play time) by impact location (i.e., front- [face included], back-, side-, and top-of-the-head) and sex. Most concussions were from front-of-the-head impacts (boys, 30.5%; girls, 34.0%). Overall, 4.1 ± 2.2 and 4.6 ± 2.3 symptoms were reported in boys and girls, respectively. In boys, symptom frequency was not associated with head impact location (p = 0.66); an association was found in girls (p = 0.02), with the highest symptom frequency reported in top-of-the-head impacts (5.4 ± 2.2). Head impact location was not associated with symptom resolution time (boys, p = 0.21; girls, p = 0.19) or return-to-play time (boys, p = 0.18; girls, p = 0.07). Heading was associated with 28.0% and 26.5% of concussions in boys and girls, respectively. Most player-player contact concussions during heading occurred from side-of-the-head impacts (boys, 49.4%; girls, 43.2%); most heading-related ball contact concussions occurred from front-of-the-head (boys, 41.4%; girls, 42.6%) and top-of-the-head (boys, 34.5%; girls, 36.9%) impacts. Head impact location was generally independent of symptom resolution time, return-to-play time, and recurrence among high school soccer concussions. However, impact location may be associated with reported symptom frequency. Further, many of these clinical concussion descriptors were associated with sex.

Microstructural alterations of cortical and deep gray matter over a season of high school football revealed by diffusion kurtosis imaging.

OBJECTIVES: To probe microstructural changes that are associated with subconcussive head impact exposure in deep and cortical gray matter of high school football players over a single season. METHODS: Players underwent diffusion kurtosis imaging (DKI) and quantitative susceptibility mapping (QSM) scans. Head impact data was recorded. Association between parametric changes and frequency of frontal head impact was assessed. RESULTS: In deep gray matter, significant decreases in mean kurtosis (MK) and increases in mean diffusivity (MD) over the season were observed in the thalamus and putamen. Correlations between changes in DKI metrics and frequency of frontal impacts were observed in the putamen and caudate. In cortical gray matter, decreases in MK were observed in regions including the pars triangularis and inferior parietal. In addition, increases in MD were observed in the rostral middle frontal cortices. Negative correlations between MK and frequency of frontal impacts were observed in the posterior part of the brain including the pericalcarine, lingual and middle temporal cortices. Magnetic susceptibility values exhibited no significant difference or correlation, suggesting these diffusion changes common within the group may not be associated with iron-related mechanisms. CONCLUSION: Microstructural alterations over the season and correlations with head impacts were captured by DKI metrics, which suggested that DKI imaging of gray matter may yield valuable biomarkers for evaluating brain injuries associated with subconcussive head impact. Findings of associations between frontal impacts and changes in posterior cortical gray matter also indicated that contrecoup injury rather than coup injury might be the dominant mechanism underlying the observed microstructural alterations. ADVANCES IN KNOWLEDGE: Significant microstructural changes, as reflected by DKI metrics, in cortical gray matter such as the rostral middle frontal cortices, and in deep gray matter such as the thalamus were observed in high school football players over the course of a single season without clinically diagnosed concussion. QSM showed no evidence of iron-related changes in the observed subconcussive brain injuries. The detected microstructural changes in cortical and deep gray matter correlated with frequency of subconcussive head impacts. IMPLICATIONS FOR PATIENT CARE: DKI may yield valuable biomarkers for evaluating the severity of brain injuries associated with subconcussive head impacts in contact sport athletes.

Ball-Contact Injuries in 11 National Collegiate Athletic Association Sports: The Injury Surveillance Program, 2009-2010 Through 2014-2015.

CONTEXT: Surveillance data regarding injuries caused by ball contact in collegiate athletes have not been well examined and are mostly limited to discussions of concussions and catastrophic injuries. OBJECTIVE: To describe the epidemiology of ball-contact injuries in 11 National Collegiate Athletic Association (NCAA) sports during the 2009-2010 through 2014-2015 academic years. DESIGN: Descriptive epidemiology study. SETTING: Convenience sample of NCAA programs in 11 sports (men's football, women's field hockey, women's volleyball, men's baseball, women's softball, men's and women's basketball, men's and women's lacrosse, and men's and women's soccer) during the 2009-2010 through 2014-2015 academic years. PATIENTS OR OTHER PARTICIPANTS: Collegiate student-athletes participating in 11 sports. MAIN OUTCOME MEASURE(S): Ball-contact-injury rates, proportions, rate ratios, and proportion ratios with 95% confidence intervals were based on data from the NCAA Injury Surveillance Program during the 2009-2010 through 2014-2015 academic years. RESULTS: During the 2009-2010 through 2014-2015 academic years, 1123 ball-contact injuries were reported, for an overall rate of 3.54/10 000 AEs. The sports with the highest rates were women's softball (8.82/10 000 AEs), women's field hockey (7.71/10 000 AEs), and men's baseball (7.20/10 000 AEs). Most ball-contact injuries were to the hand/wrist (32.7%) and head/face (27.0%) and were diagnosed as contusions (30.5%), sprains (23.1%), and concussions (16.1%). Among sex-comparable sports (ie, baseball/softball, basketball, and soccer), women had a larger proportion of ball-contact injuries diagnosed as concussions than men (injury proportion ratio = 2.33; 95% confidence interval = 1.63, 3.33). More than half (51.0%) of ball-contact injuries were non-time loss (ie, participation-restriction time <24 hours), and 6.6% were severe (ie, participation-restriction time ≥21 days). The most common severe ball-contact injuries were concussions (n = 18) and finger fractures (n = 10). CONCLUSION: Ball-contact-injury rates were the highest in women's softball, women's field hockey, and men's baseball. Although more than half were non-time-loss injuries, severe injuries such as concussions and fractures were reported.

Epidemiology of Skin Infections in Men's Wrestling: Analysis of 2009-2010 Through 2013-2014 National Collegiate Athletic Association Surveillance Data.

CONTEXT: Our knowledge of the current epidemiology of skin infections among wrestlers is limited. OBJECTIVE: To analyze and report the epidemiology of skin infections among National Collegiate Athletic Association (NCAA) men's wrestling student-athletes during the 2009-2010 through 2013-2014 academic years. DESIGN: Descriptive epidemiology study. SETTING: Aggregate skin infection and exposure data collected by the NCAA Injury Surveillance Program. PATIENTS OR OTHER PARTICIPANTS: Collegiate men's wrestling student-athletes. MAIN OUTCOME MEASURE(S): All viral, bacterial, or fungal skin infections reported by athletic trainers at 17 NCAA programs were analyzed, providing 35 team-seasons of data. Skin infection rates per 10 000 athlete-exposures (AEs), rate ratios, skin infection proportions, and skin infection proportion ratios were calculated. RESULTS: The athletic trainers reported 112 skin infections contracted by 87 student-athletes across 78 720 AEs. The overall skin infection rate was 14.23/10 000 AEs (95% confidence interval [CI] = 11.59, 16.86). Of the skin infections identified, 22.3% (n = 25) were recurrent skin infections. Most skin infections (65.2%) were attributable to 5 team-seasons (range, 11-19 infections). Most skin infections occurred during the regular season (n = 76, 67.9%), were identified during practice (n = 100, 89.3%), and resulted in ≥24 hours' time loss (n = 83, 74.1%). The rate for viral skin infections was 1.72 times the rate for bacterial skin infections (95% CI = 1.09, 2.72) and 2.08 times the rate for fungal skin infections (95% CI = 1.28, 3.39). Fungal skin infections more often resulted in time loss <24 hours compared with all other skin infections (75.0% versus 12.5%; infection proportion ratio = 6.00; 95% CI = 3.30, 10.92). CONCLUSIONS: Our findings highlight the contagiousness of skin infections and suggest that skin infection rates may be attributable to high incidences among particular teams.

Football Equipment Removal Improves Chest Compression and Ventilation Efficacy.

OBJECTIVE: Airway access recommendations in potential catastrophic spine injury scenarios advocate for facemask removal, while keeping the helmet and shoulder pads in place for ensuing emergency transport. The anecdotal evidence to support these recommendations assumes that maintaining the helmet and shoulder pads assists inline cervical stabilization and that facial access guarantees adequate airway access. Our objective was to determine the effect of football equipment interference on performing chest compressions and delivering adequate ventilations on patient simulators. We hypothesized that conditions with more football equipment would decrease chest compression and ventilation efficacy. METHODS: Thirty-two certified athletic trainers were block randomized to participate in six different compression conditions and six different ventilation conditions using human patient simulators. Data for chest compression (mean compression depth, compression rate, percentage of correctly released compressions, and percentage of adequate compressions) and ventilation (total ventilations, mean ventilation volume, and percentage of ventilations delivering adequate volume) conditions were analyzed across all conditions. RESULTS: The fully equipped athlete resulted in the lowest mean compression depth (F5,154 = 22.82; P < 0.001; Effect Size = 0.98) and delivery of adequate compressions (F5,154 = 15.06; P < 0.001; Effect Size = 1.09) compared to all other conditions. Bag-valve mask conditions resulted in delivery of significantly higher mean ventilation volumes compared to all 1- or 2-person pocketmask conditions (F5,150 = 40.05; P < 0.001; Effect Size = 1.47). Two-responder ventilation scenarios resulted in delivery of a greater number of total ventilations (F5,153 = 3.99; P = 0.002; Effect Size = 0.26) and percentage of adequate ventilations (F5,150 = 5.44; P < 0.001; Effect Size = 0.89) compared to one-responder scenarios. Non-chinstrap conditions permitted greater ventilation volumes (F3,28 = 35.17; P < 0.001; Effect Size = 1.78) and a greater percentage of adequate volume (F3,28 = 4.85; P = 0.008; Effect Size = 1.12) compared to conditions with the chinstrap buckled or with the chinstrap in place but not buckled. CONCLUSIONS: Chest compression and ventilation delivery are compromised in equipment-intense conditions when compared to conditions whereby equipment was mostly or entirely removed. Emergency medical personnel should remove the helmet and shoulder pads from all football athletes who require cardiopulmonary resuscitation, while maintaining appropriate cervical spine stabilization when injury is suspected. Further research is needed to confirm our findings supporting full equipment removal for chest compression and ventilation delivery.

Perinatal transmission of hepatitis B virus: an Australian experience.

OBJECTIVE: To determine the rate of perinatal hepatitis B virus (HBV) transmission in an Australian setting and to identify maternal virological factors associated with highest risk of transmission. DESIGN, PARTICIPANTS AND SETTING: A prospective, observational study of perinatal transmission of HBV. Participants were pregnant women attending Sydney South West Area Health Service antenatal clinics who tested positive for hepatitis B surface antigen (HBsAg), and their babies. All babies were routinely offered hepatitis B immunoglobulin (HBIG) and HBV vaccination. Babies positive for HBsAg at 9-month follow-up underwent further virological testing, including HBV DNA sequencing. The study was conducted between August 2002 and May 2008. MAIN OUTCOME MEASURES: HBV DNA levels and demographic characteristics of HBsAg-positive pregnant women; proportion of their infants with active HBV infection at 9-month follow-up; maternal characteristics affecting transmission rate; HBV DNA sequencing of infected infants and their mothers. RESULTS: Of 313 HBsAg-positive pregnant women, 213 (68%) were HBV DNA-positive and 92 (29%) were positive for hepatitis B "e" antigen (HBeAg); 138 babies born to HBV DNA-positive mothers were tested for HBV infection (HBsAg positivity) at about 9 months of age. Four cases of transmission were identified. All four mothers had very high HBV DNA levels (> 10(8) copies/mL) and were HBeAg-positive. Three of the four infants were infected with wild-type HBV strains, with identical maternal/infant isolates. The fourth mother-infant pair had an S gene variant, HBV D144E, which has been previously reported in association with vaccine/HBIG escape. (Unfortunately, HBIG was inadvertently omitted from the immunisation schedule of this infant.) Transmission rates were 4/138 (3%) from HBV DNA-positive mothers overall, 4/61 (7%) from HBeAg-positive mothers, and 4/47 (9%) from mothers with very high HBV DNA levels. No transmission was seen in 91 babies of mothers with HBV DNA levels < 10(8) copies/mL. CONCLUSION: In this cohort, HBV perinatal transmission was restricted to HBeAg-positive mothers with very high viral loads.

Clinical and molecular characteristics of malignant transformation of low-grade glioma in children.

PURPOSE: To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children. PATIENTS AND METHODS: The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval. RESULTS: Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% +/- 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient. CONCLUSION: The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.

CaSm-mediated cellular transformation is associated with altered gene expression and messenger RNA stability.

CaSm (cancer-associated Sm-like) was originally identified based on elevated expression in pancreatic cancer and in several cancer-derived cell lines. CaSm encodes a 133 amino acid protein that contains two Sm motifs found in the common small nuclear RNA proteins and the LSm (like-Sm) family of proteins. Compared with normal human prostate tissue and primary prostate epithelial cells, some primary prostate tumors and prostate cancer-derived cell lines have elevated CaSm expression. Expression of antisense CaSm RNA in DU145 cells results in reduced CaSm protein levels and less transformed phenotype, measured by anchorage-independent growth in vitro and tumor formation in severe combined immunodeficient mice in vivo. Additional data shows that adenoviral delivery of antisense CaSm inhibits the growth of prostate cancer cell lines by altering cell cycle progression, and is associated with reduced expression of cyclin B1 and CDK1 proteins. Consistent with failure of antisense-treated cells to enter mitosis, microarray analysis identified altered expression of NEK2 and nucleophosmin/B23. Although the mechanisms by which CaSm contributes to neoplastic transformation and cellular proliferation are unknown, it has been shown that the yeast homologue (spb8/LSm1) of CaSm is required for 5' to 3' degradation of specific mRNAs. We provide data consistent with a similar role for CaSm in human cells, supporting the hypothesis that elevated CaSm expression observed in cancer leads to destabilization of multiple gene transcripts, contributing to the mutator phenotype of cancer cells.

Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway.

Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions. Four patients met diagnostic criteria for CD, and many of the remaining patients had some clinical features of CD. Immunohistochemical analysis showed high levels of phospho-AKT and phospho-S6 in the large ganglionic cells forming the lesions, indicating activation of the PTEN/AKT/mTOR pathway and suggesting a central role for mTOR in the pathogenesis of LDD. These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR.

Establishing a murine pancreatic cancer CaSm model: up-regulation of CaSm is required for the transformed phenotype of murine pancreatic adenocarcinoma.

We have recently shown that the cancer-associated Sm-like protein (CaSm) is overexpressed in human pancreatic adenocarcinoma (PC). However, the role of CaSm in the process of neoplastic transformation remains unclear. To define further the role of CaSm in PC transformation, we have established a murine model based on the murine pancreatic cancer cell lines Panc02 and Panc03. CaSm is overexpressed in the aggressive Panc02 cells and expressed at much lower levels in the more indolent Panc03 cells. Up-regulation of CaSm in Panc03 cells increased in vitro proliferation and anchorage-independent growth and promoted subcutaneous tumor establishment and growth in syngeneic mice. Conversely, adenoviral down-regulation of CaSm in Panc02 led to significant inhibition of cellular proliferation and anchorage-independent growth in vitro and complete abolition of tumor growth and metastasis in vivo. Up-regulation of CaSm in NIH3T3 resulted in loss of contact inhibition and increased soft agar colony formation in vitro. The requirement for CaSm overexpression for neoplastic transformation confirms the concept that CaSm is a critical oncogene and potential target for molecular intervention. Furthermore, establishment of the murine clinically relevant model of pancreatic metastases provides a framework for the generation of preclinical data to support the development of novel molecular therapies targeting CaSm.

Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo.

Somatic mutations of PTEN are found in many types of cancers including glioblastoma, the most malignant astrocytic tumor. PTEN mutation occurs in 25 to 40% of glioblastomas but is rarely observed in low-grade glial neoplasms. To determine the role of Pten in astrocytes and glial tumor formation, we inactivated Pten by a Cre-loxP approach with a GFAP-cre transgenic mouse that induced Cre-mediated recombination in astrocytes. Pten conditional knockout mice showed a striking progressive enlargement of the entire brain. Increased nuclear and soma size was observed in both astrocytes and neurons, which contributed in part to the increase in brain size. Pten-deficient astrocytes showed accelerated proliferation in vitro and aberrant ongoing proliferation in adult brains in vivo. In contrast, neurons lacking Pten did not show alterations in proliferation. This study shows cell-type dependent effects of Pten loss in the adult brain, including increased astrocyte proliferation that may render astroglial cells susceptible to neoplastic transformation or malignant progression.

CaSm antisense gene therapy: a novel approach for the treatment of pancreatic cancer.

Pancreatic adenocarcinoma is a major clinical problem with few effective treatment options. In the United States 29,000 cases are diagnosed annually with an associated mortality rate greater than 90%. Given this dismal prognosis, a better understanding of the molecular controls that govern pancreatic cancer is clearly needed in order to develop more effective therapies. As such, our group has been actively investigating the identification and potential application of novel gene targets for this disease. We have recently identified the cancer-associated Sm-like (CaSm) oncogene, shown that it is overexpressed in 87% of human pancreatic cancer samples, and clearly demonstrated that it functions as a classic oncogene. We have also been able to show that an adenovirus expressing antisense RNA to the CaSm gene (Ad-alpha CaSm) is able to reduce endogenous CaSm mRNA expression and decrease anchorage-independent growth. A single intratumor injection of Ad-alpha CaSm extended survival in an in vivo SCID mouse model of human pancreatic cancer. To gain insight into the mechanism of Ad-alpha CaSm's anti-tumor effect, cell cycle studies were performed. Ad-alpha CaSm treatment of pancreatic cancer cells resulted in a cytostatic block with decreased G1-phase and increased DNA content in vitro. Importantly, the combination of Ad-alpha CaSm with gemcitabine (an S-phase active chemotherapy) significantly extended survival time beyond either therapy alone. These studies have defined the CaSm oncogene as a novel gene target for therapy and have begun to define its potential role in the pathogenesis of pancreatic cancer.