Gene therapy of ovarian cancer with IFN-alpha-producing fibroblasts: comparison of constitutive and inducible vectors

Ovarian cancer represents a malignancy suitable for cell and gene therapy approaches owing to its containment within the peritoneal cavity, even at advanced tumor stages. As regulation of transgene expression would be preferable for conducting clinical trials for reasons of safety, we investigated whether intraperitoneal (i.p.) administration of retroviral vector-transduced fibroblasts encoding murine interferon-alpha (IFN-alpha) could have therapeutic activity, and compared its effect with the antitumor effects of fibroblasts producing IFN-alpha under a rapamycin analogue (AP21967)-inducible promoter. Human and murine fibroblasts were recruited into the solid component of transplantable ovarian cancer-grown i.p. in severe combined immunodeficiency mice. Multiple administrations of fibroblasts producing IFN-alpha in a constitutive manner showed therapeutic efficacy, leading to significant prolongation of survival in the majority of animals, associated with inhibition of tumor angiogenesis. Compared to cells transduced by the constitutive vector, fibroblasts transduced by the inducible vector released twofold higher IFN-alpha levels in vitro, following induction by AP21967, and production of the cytokine was under pharmacologic control both in vitro and in vivo. However, these cells elicited only modest therapeutic effects in vivo. Overall, these findings indicate that intracavitary IFN-alpha gene therapy using engineered fibroblasts requires sustained production of IFN-alpha to achieve durable antitumor effects.     

Peak Flow Measurements in Children with Asthma: What Happens at School?

Background. Self-monitoring of symptoms or peak flow monitoring (PFM) is recommended for all asthma patients and is commonly included in asthma management plans. Limited data are available documenting PFM outcomes in school settings. Method. Three hundred twenty-three urban children with persistent asthma were enrolled in a school-based study that implemented an internet-based asthma monitoring and data collection system. The mean age of the children was 10.0 (SD 2.1) years; 57% were male and 91% were African American. Children logged in daily to an internet-based program to record their asthma symptoms and PFM reading. Teachers logged in daily to confirm the PFM readings. School staff responsible for student health reported actions taken for low PFM readings. Results. A total of 12,245 child reports were completed; 98% (n = 11,974) had corresponding teacher reports, confirming the peak flow meter readings reported by the children. The prevalence of reported asthma symptoms varied across PFM readings; the highest prevalence occurred in the setting of red zone readings, with intermediate prevalence in the setting of yellow zone readings, and lowest prevalence in the setting of green zone readings. The actions reported in response to children's symptoms and peak flow results similarly varied; however, instances of no action were reported in the setting of yellow and red zone readings. When comparing the “worst days” of children who had ever had a red or yellow PFM reading with those of children who only had exhibited green, there was a nonsignificant trend toward fewer symptoms in the green-only group. Additionally, there was a nonsignificant trend toward a greater likelihood of being sent to the office or school nurse with greater symptoms in the setting of a yellow or red zone reading. Conclusions. On the whole, peak flow readings tended to correspond to asthma disease activity. However, the data indicate that school staff may be more inclined to take action based on their own perceptions of a child's asthma or respond to children's subjective reports of asthma symptoms rather than using a more objective measure of disease activity provided by a peak flow meter.     

Role of Attachment in Response to Pet Loss

This study examined the impact of attachment on grief severity following the death of a pet. Seventy-one participants who had lost a dog or cat within the past year completed a set of measures that included an attachment measure assessing individual differences in attachment anxiety and avoidance, strength of the past attachment to the pet, the continuing bond with the deceased pet, social support, and complicated grief symptoms. Attachment anxiety and strength of the past attachment to the pet were each uniquely predictive of more severe grief. Furthermore, the continuing bond to the deceased pet partially mediated the impact of strength of the past attachment to the pet on grief severity. No significant mediators of the effect of attachment anxiety on grief were found, however. The results highlight the importance of distinguishing strength of attachment from attachment security in examining the effect of attachment on response to pet loss.     

Genotype–phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene

The aims of our research were to define the genotype–phenotype correlations of mutations in the phenylalanine hydroxylase (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype–phenotype correlations. By using polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/dHPLC) and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes [classic PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia (MHP)]. In 63.2% of patient genotypes, the metabolic phenotype could be predicted, though evidence is also found for both phenotypic inconsistencies among subjects with more than one type of mutation in the PAH gene. Data analysis revealed that about 25% of patients could participate in the future in (6R)-l-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH₄) treatment trials according to their mutation genotypes. This study enables us to construct a national database in Israel that will serve as a valuable tool for genetic counseling and a prognostic evaluation of future cases of PKU.     

Androgen receptor CAG repeat size is associated with stress fracture risk: a pilot study

Background  

Stress fractures commonly affect military recruits during basic training. Several lines of evidence suggest genetic factors are involved in stress fracture predisposition. As gender steroid hormone levels and activity have been implicated in affecting bone strength, one of the candidate genes likely to be involved is the androgen receptor gene.     

Prisoners of Addictive Cues: Biobehavioral Markers of Overweight and Obese Adults with Food Addiction

Obesity is associated with food and eating addiction (FA), but the biobehavioral markers of this condition are poorly understood. To characterize FA, we recruited 18 healthy controls and overweight/obese adults with (n = 31) and without (n = 17) FA (H-C, FAOB, NFAOB, respectively) to assess alpha brain asymmetry at rest using electroencephalogram; event-related potentials following exposure to high-calorie food (HCF), low-calorie food (LCF), and nonfood (NF) images in a Stroop paradigm; reaction time reflective of the Stroop bias; and symptoms of depression and disordered eating behavior. The FAOB group had the greatest emotional and uncontrollable eating, depressive, and binge-eating symptoms. The FAOB group displayed lower resting left alpha brain asymmetry than that of the NFAOB group. Differently from the other groups, the FAOB group presented attenuated Stroop bias following exposure to HCF relative to NF images, as well as a lower late positive potential component (LPPb; 450–495 ms) in both frontal and occipital regions. In the total cohort, a correlation was found between the Stroop bias and the LPPb amplitude. These results point to biobehavioral hypervigilance in response to addictive food triggers in overweight/obese adults with FA. This resembles other addictive disorders but is absent in overweight/obesity without FA.     

In whom does horizontal canal BPPV recur?

Purpose

The objective of this study is to examine the rate of horizontal canal BPPV recurrence of the same type and search for predisposing factors.     

Prospective evaluation of serum IL-16 and risk of prostate cancer in the Prostate,Lung, Colorectal,and Ovarian Cancer Screening Trial

Background

Sexually transmitted infections and chronic inflammation have been associated with an increased risk of prostate cancer. Inflammatory mediators, such as cytokines and free radicals, have been hypothesized to play a role.

Methods

To explore the role of inflammation in prostate cancer risk further, we examined the association between pre-diagnostic serum levels of interleukin-16 (IL-16), an important pleiotropic cytokine, and prostate cancer risk among 932 Caucasian cases and 942 controls and 154 African-American cases and 302 controls in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Serum IL-16 was quantified using enzyme-linked immunoassay. Logistic regression was used to estimate associations between IL-16 and prostate cancer risk, separately by race.

Results

Although no association between IL-16 and prostate cancer overall was observed among Caucasians (p?=?0.27), a significantly increased risk of high-grade prostate cancer, defined as Gleason ≥?7 (p_het?=?0.02), was observed with increasing levels of IL-16 (OR_{3rd vs. 1st tertile}?=?1.37, 95% CI 1.04–1.81, p_trend?=?0.02). We also discovered a significant interaction between IL-16 and history of gonorrhea (p?=?0.04). Among Caucasian men with a history of gonorrhea, elevated IL-16 levels were associated with an increased risk of prostate cancer (OR_{3rd vs. 1st tertile}?=?3.64, 95% CI 1.14–11.6) but no association was seen among those without a history of gonorrhea (OR_{3rd vs. 1st tertile}?=?1.06, 95% CI 0.83–1.34). No associations were observed among African-Americans.

Conclusions

This study found evidence that higher pre-diagnostic IL-16 levels may be associated with increased risk of high-grade disease, supporting inflammation as potential mechanism by which sexually transmitted diseases may increase risk.