An autosomal dominant bull's-eye macular dystrophy (MCDR2) that maps to the short arm of chromosome 4

PURPOSE: To describe the phenotype of an autosomal dominant macular dystrophy and identify the chromosomal locus. METHODS: Eleven members of a five-generation, nonconsanguineous British family were examined clinically and also underwent automated perimetry, electrodiagnostic testing, fundus fluorescein angiography, and fundus autofluorescence imaging. Blood samples were taken for DNA extraction and linkage analysis was performed. RESULTS: The phenotype is characterized by bull's-eye macular dystrophy first evident in the first or second decade of life. There is mild visual impairment, central scotomata, and electrophysiological testing indicates that most affected individuals have disease confined to the central retina but older subjects have more widespread rod and cone abnormalities, demonstrated by flash ERG. Genetic linkage analysis established linkage to chromosome 4 at p15.2-16.3 with a maximum lod score of 3.03 at a recombination fraction of 0.00 for marker D4S391. The locus for this autosomal dominant macular dystrophy lies between flanking markers D4S3023 and D4S3022, and overlaps the Stargardt 4 locus. CONCLUSIONS: A new locus was identified for a bull's-eye macular dystrophy on the short arm of chromosome 4.     

Volume and dose-response effects for severe symptomatic pneumonitis after fractionated irradiation of canine lung

PURPOSE: To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. MATERIALS AND METHODS: A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5 Gy fractions over 6 weeks. RESULTS: No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose-response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2-66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5-52.0 Gy, 95% CI). The ED50 and ED5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2-53.5Gy, 95% CI) and 39.1 Gy (8.8-41.8 Gy, 95% CI) respectively. CONCLUSION: Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.     

A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas

Interleukin-12 (IL-12), a proinflammatory cytokine, shows anticancer properties. Systemically administered IL-12 causes dose-dependent toxicity. To achieve localized intratumoral gene expression, an adenoviral gene therapy vector with IL-12 controlled by a heat-inducible promoter (heat shock promoter 70B) was developed and tested in a phase I clinical trial in cats with spontaneously arising soft tissue sarcoma. A feasibility study was done in 16 cats with soft tissue sarcoma using murine IL-12 and/or enhanced green fluorescent protein adenoviral vectors under cytomegalovirus or heat shock promoter 70 control. Subsequently, we conducted a phase I clinical trial using an adenoviral feline IL-12 construct in 13 cats with soft tissue sarcoma. The soft tissue sarcomas were irradiated (48 Gy/16 fractions) followed by intratumoral injection of adenovirus. Twenty-four hours postinjection, tumors were heated (41 degrees C, 60 min). Tumor expression of feline IL-12 and IFN-gamma was determined. Cats were monitored for systemic toxicity. For the murine IL-12 construct, an association was noted between viral dose and murine IL-12 levels within tumor, whereas serum levels were minimal. Mild toxicity was noted at 10(11) plaque-forming units (pfu). With the feline IL-12 construct, high levels of feline IL-12 mRNA were detected in tumor biopsies with low or absent IFN-gamma mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-gamma mRNA in tumor. It is possible to localize gene expression and limit systemic toxicity of IL-12 using the hyperthermia-induced gene therapy approach. The maximum tolerated dose of the feline IL-12 adenoviral vector was 10(10) pfu/tumor as dose-limiting toxicities were noted at the 4 x 10(10) pfu dose.     

The role of racial segregation in treatment and outcomes among patients with hepatocellular carcinoma

BackgroundThere is a long history of segregation in the U.S.A with enduring impacts on cancer outcomes today. We evaluated the impact of segregation on racial disparities in Hepatocellular Carcinoma (HCC) treatment and outcomes.MethodsWe obtained data on black and white patients with HCC from the SEER program (2005–2015) within the 100 most populous participating counties. Our exposure was the index of dissimilarity (IoD), a validated measure of segregation. Outcomes were overall survival, advanced stage at diagnosis (Stage III/IV) and surgery for localized disease (Stage I/II). Cancer-specific survival was assessed using Kaplan–Meier estimates.ResultsBlack patients had a 1.18 times increased risk (95%CI 1.14,1.22) of presenting at advanced stage as compared to white patients and these disparities disappeared at low levels of segregation. In the highest quartile of IoD, black patients had a significantly lower survival than white (17 months vs 27 months, p < 0.001), and this difference disappeared at the lowest quartile of IoD.ConclusionsOur data illustrate that structural racism in the form racial segregation has a significant impact on racial disparities in the treatment of HCC. Urban and health policy changes can potentially reduce disparities in HCC outcomes.     

The relationship between intracellular and extracellular pH in spontaneous canine tumors.

Recently, it has been suggested that the cellular uptake of chemotherapeutic drugs may be dependent on the pH gradient between the intracellular (pHi) and extracellular (pHe) compartments. It has been demonstrated in murine tumor models that the extracellular environment is acidic, relative to the intracellular environment, thus favoring preferential accumulation of drugs that are weak acids into cells. However, concomitant measurements of pHi and pHe in spontaneous tumors have not been reported, so it is not certain how well the murine results translate to the clinical scenario. In this study, both types of measurements were performed in dogs with spontaneous malignant soft tissue tumors. On average, pHe was more acidic than pHi, with maintenance of a more physiologically balanced intracellular tumor environment. However, the magnitude of the gradient varied widely, and individual tumors had both positive and negative pH gradients (pHi - pHe). These data suggest that the magnitude and direction of the pH gradient may need to be measured for individual patient tumors and/or that manipulation of pHe may be required if exploitation of the pH gradient is to be achieved for tumor-selective augmentation of intracellular drug delivery.     

Task interspersal and performance of matching tasks by preschoolers with autism

The current study examined the effects of task interspersal on the performance of matching-to-sample tasks by three children with autism. A pre-baseline assessed each child's mastery level of a large body of matching stimuli. These matching tasks included matching identical and non-identical animals, numbers, letters, and shapes. Through this assessment mastered and non-mastered matching-to-sample stimuli were determined empirically. Following a baseline condition that presented only non-mastered stimuli in succession, treatment was introduced in a multiple-baseline design across children. During the treatment condition, trials with mastered stimuli were interspersed with trials with non-mastered stimuli. For all three children, the percentage of correct matching responses to the non-mastered stimuli increased systematically with the introduction of the interspersal procedure. Following treatment, a third condition was conducted that reduced the total number of reinforcers available per session to baseline levels. The data demonstrated that all three participants maintained treatment levels of correct responding during this third condition. Thus the increased reinforcement density during treatment was not needed for maintenance of correct responding. The discussion addresses additional control procedures that would be needed to evaluate the role of reinforcement density during treatment.