HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama

Background

We wanted to quantify HLA-A and -B phenotype and haplotype frequencies in Alabama index patients with common variable immunodeficiency (CVID) and selective IgG subclass deficiency (IgGSD), and in control subjects.

Methods

Phenotypes were detected using DNA-based typing (index cases) and microlymphocytotoxicity typing (controls).

Results

A and B phenotypes were determined in 240 index cases (114 CVID, 126 IgGSD) and 1,321 controls and haplotypes in 195 index cases and 751 controls. Phenotyping revealed that the "uncorrected" frequencies of A*24, B*14, B*15, B*35, B*40, B*49, and B*50 were significantly greater in index cases, and frequencies of B*35, B*58, B*62 were significantly lower in index cases. After Bonferroni corrections, the frequencies of phenotypes A*24, B*14, and B*40 were significantly greater in index cases, and the frequency of B*62 was significantly lower in index cases. The most common haplotypes in index cases were A*02-B*44 (frequency 0.1385), A*01-B*08 (frequency 0.1308), and A*03-B*07 (frequency 0.1000), and the frequency of each was significantly greater in index cases than in control subjects ("uncorrected" values of p < 0.0001, 0.0252, and 0.0011, respectively). After performing Bonferroni corrections, however, the frequency of A*02-B*44 alone was significantly increased in probands (p < 0.0085). Three other haplotypes were also significantly more frequent in index cases (A*03-B*14, A*31-B*40, and A*32-B*14). The combined frequencies of three latter haplotypes in index patients and control subjects were 0.0411 and 0.0126, respectively ("uncorrected" value of p < 0.0002; "corrected" value of p = 0.0166). Most phenotype and haplotype frequencies in CVID and IgGSD were similar. 26.7% of index patients were HLA-haploidentical with one or more other index patients. We diagnosed CVID or IgGSD in first-degree or other relatives of 26 of 195 index patients for whom HLA-A and -B haplotypes had been ascertained; A*01-B*08, A*02-B*44, and A*29-B*44 were most frequently associated with CVID or IgGSD in these families. We conservatively estimated the combined population frequency of CVID and IgGSD to be 0.0092 in adults, based on the occurrence of CVID and IgGSD in spouses of the index cases.

Conclusions

CVID and IgGSD in adults are significantly associated with several HLA haplotypes, many of which are also common in the Alabama Caucasian population. Immunoglobulin phenotype variability demonstrated in index cases and family studies herein suggests that there are multiple gene(s) on Ch6p or other chromosomes that modify immunoglobulin phenotypes of CVID and IgGSD. The estimated prevalence of CVID and IgGSD in central Alabama could be reasonably attributed to the fact that many HLA haplotypes significantly associated with these disorders are also common in the general population.     

A phase II trial of intraperitoneal EGEN-001, an IL-12 plasmid formulated with PEG–PEI–cholesterol lipopolymer in the treatment of persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal cancer: A Gynecologic Oncology Group study

Objective

The purpose of this phase II trial was to evaluate the toxicity and antitumor activity of EGEN-001 in platinum resistant recurrent ovarian cancer.

Methods

Eligible patients had weekly IP infusion of EGEN-001 at a dose of 24 mg/m². Toxicity and antitumor activity were evaluated using CTCAE and RESIST criteria, respectively. Co-primary endpoints were tumor response and survival without progression (PFS) for at least 6 months. Survival without progression before going onto a subsequent therapy (EFS) for at least six months was also considered.

Results

A total of 58 EGEN-001 cycles were administered to 20/22 enrolled patients (median 2 cycles, range 1–9). The most frequently associated adverse events related specifically to EGEN-001 treatment were grade 1/2 fatigue, fever, chills, abdominal pain, nausea, vomiting, anemia, thrombocytopenia, and leukopenia. Three of 20 EGEN-001 treated patients evaluable for toxicity elected to withdraw from the study motivated in part by grade 1 treatment related toxicities. There were no patients with partial or complete response (0%; 90% CI 0–10.9%). Seven (35%) of 16 patients evaluable for response had stable disease, and 9 (45%) had progressive disease. Six (30%) patients had a PFS of greater than six months, although three had gone off study and onto other therapies before six months. The estimated six-month EFS was 15%. The median PFS and OS were 2.89 and 9.17 months, respectively.

Conclusion

EGEN-001 at the dose and schedule evaluated was associated with some but limited activity and was seemingly less tolerated in platinum resistant recurrent ovarian cancer patients.     

AAV-mediated persistent bevacizumab therapy suppresses tumor growth of ovarian cancer

Rationale

Anti-angiogenesis therapies such as bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), have been used against ovarian cancer, but transient and low peritoneal drug levels are likely a factor in treatment failure. We hypothesized that a single administration of adeno-associated virus (AAV)-mediated intraperitoneal expression of bevacizumab would direct persistent expression and suppress growth and metastasis of ovarian cancer.

Methods

AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab, was evaluated for the capacity of a single intraperitoneal administration to persistently suppress peritoneal tumor growth in an intraperitoneal model of ovarian carcinomatosis with human ovarian cancer cells in nude immunodeficient mice.

Results

The data demonstrates that AAVrh10.BevMab mediates persistent and high levels of bevacizumab in the peritoneal cavity following a single intraperitoneal administration in mice. In AAVrh10.BevMab treated A2780 human ovarian cancer-bearing mice, tumor growth was significantly suppressed (p < 0.05) and the area of blood vessels in the tumor was decreased (p < 0.04). Survival of mice with A2780 xenografts or SK-OV3 xenografts was greatly prolonged in the presence of AAVrh10.BevMab (p < 0.001). Administration of AAVrh10.BevMab 4 days after A2780-luciferase cell implantation reduced tumor growth (p < 0.01) and increased mouse survival (p < 0.0001). Combination of AAVrh10.BevMab with cytotoxic reagents paclitaxel or topotecan proved to be more effective in increasing survival than treatment with cytotoxic reagent alone.

Conclusion

A single administration of AAVrh10.BevMab provides sustained and high local expression of bevacizumab in the peritoneal cavity, and significantly suppresses peritoneal carcinomatosis and increases survival in an ovarian cancer murine model.     

Correlating pharmaceutical data with a national health survey as a proxy for estimating rural population health

Background  

Chronic disease accounts for nearly three-quarters of US deaths, yet prevalence rates are not consistently reported at the state level and are not available at the sub-state level. This makes it difficult to assess trends in prevalence and impossible to measure sub-state differences. Such county-level differences could inform and direct the delivery of health services to those with the greatest need.     

Deforestation and Malaria in Mancio Lima County, Brazil

Malaria is the most prevalent vector-borne disease in the Amazon. We used malaria reports for health districts collected in 2006 by the Programa Nacional de Controle da Malária to determine whether deforestation is associated with malaria incidence in the county (município) of Mâncio Lima, Acre State, Brazil. Cumulative percent deforestation was calculated for the spatial catchment area of each health district by using 60 × 60–meter, resolution-classified imagery. Statistical associations were identified with univariate and multivariate general additive negative binomial models adjusted for spatial effects. Our cross-sectional study shows malaria incidence across health districts in 2006 is positively associated with greater changes in percentage of cumulative deforestation within respective health districts. After adjusting for access to care, health district size, and spatial trends, we show that a 4.3%, or 1 SD, change in deforestation from August 1997 through August 2000 is associated with a 48% increase of malaria incidence.     

Prefrontal activation in preschool children is associated with maternal adversity and child temperament: A preliminary fNIRS study of inhibitory control

Exposure to adversity is a well-documented risk factor for cognitive, behavioral, and mental health problems. In fact, the consequences of adversity may be intergenerational. A growing body of research suggests that maternal exposures to adversity, including those prior to childbirth, are associated with offspring biobehavioral development. In a sample of 36 mothers and their preschool-age children (mean child age = 4.21 ± 0.92 years), we used functional near-infrared spectroscopy to replicate and extend this work to include brain activation during inhibitory control in young children. We found that measures of maternal exposure to adversity, including cumulative, childhood, and preconception exposures, were significantly and positively associated with activation in the right frontopolar prefrontal cortex (PFC) and in the left temporal and parietal clusters during inhibitory control. In addition, and consistent with previous findings, children's increased negative affect and decreased effortful control were associated with increased right PFC activation during inhibitory control. These findings provide preliminary evidence that maternal and dispositional risk factors are linked to alterations in PFC functioning during the preschool years. Children of mothers with a history of exposure to adversity, as well as children who are less temperamentally regulated, may require increased neural resources to meet the cognitive demands of inhibitory control.     

FTDP‐17 with Pick body‐like inclusions associated with a novel tau mutation,p.E372G

Mutations in microtubule‐associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17). Here, we describe a patient with FTDP‐17 and a novel missense mutation in exon 13 of MAPT, p.E372G. We compare clinicopathologic features of this patient to two previously unreported patients with another exon 13 mutation, p.G389R. The patient with the p.E372G mutation was a 40‐year‐old man with behavioral variant frontotemporal dementia (bvFTD), who subsequently developed agrammatic speech and parkinsonism. One of the FTDP‐17 patients with p.G389R mutation presented at age 24 with agrammatic variant of primary progressive aphasia, and subsequently behavioral dysfunction. The other presented at age 53 with bvFTD, followed by agrammatic speech and corticobasal syndrome. Neuropathologic features of FTDP‐17 due to p.E372G were similar to those of p.G389R, including tau‐immunoreactive Pick body‐like neuronal inclusions and swollen, tapering thread‐like processes in white matter immunoreactive for 3‐repeat and 4‐repeat tau. Biochemical analysis of insoluble tau showed similar isoform compositions in p.E372G and p.G389R. Functional studies of the p.E372G mutation showed marked increase in tau filament formation and its reduced ability to promote microtubule assembly. Together these findings indicate that p.E372G is a pathogenic MAPT mutation that causes FTDP‐17 similar to p.G389R.     

Existing Antilisterial Immunity Does Not Inhibit the Development of a Listeria monocytogenes-Specific Primary Cytotoxic T-Lymphocyte Response

Infection of BALB/c mice with Listeria monocytogenes stimulates an antilisterial immune response evident by the appearance of H2-K^d-restricted CD8⁺ cytotoxic T lymphocytes (CTLs) specific for the nanomer peptides amino acids (aa) 91 to 99 of listeriolysin O (LLO 91–99) and aa 217 to 225 of the p60 molecule (p60 217–225). We have introduced point mutations at anchor residues within LLO 91–99 (92F) or p60 217–225 (218F), and BALB/c mice infected with L. monocytogenes strains containing these point mutations do not develop CTLs specific for LLO 91–99 or p60 217–225, respectively. We have used these strains to test whether primary CTL responses against L. monocytogenes-derived determinants can be stimulated within an environment of existing antilisterial immunity. We found that the development of a primary L. monocytogenes-specific CTL response is not altered by existing immunity to L. monocytogenes. For example, primary immunization with the p60 218F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of p60 217–225-specific CTLs at primary response levels and LLO 91–99-specific effectors at levels consistent with a memory CTL response. Similarly, primary immunization with the 92F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of LLO 91–99-specific CTLs at primary response levels and p60 217–225-specific effectors at levels consistent with a memory CTL response. These results provide additional support for the use of L. monocytogenes as a recombinant vaccine vector and show that antivector immunity does not inhibit the development of a primary CTL response when the epitope is delivered by L. monocytogenes as the vaccine strain.     

Comparative genomic hybridization of ductal carcinoma in situ of the breast—evidence of multiple genetic pathways

There is strong evidence that ductal carcinoma in situ (DCIS) represents a precursor lesion of invasive breast cancer. In order to analyse specific chromosomal alterations of DCIS, 38 paraffin-embedded specimens of DCIS and six associated invasive carcinomas were examined by means of comparative genomic hybridization (CGH). Losses of 16q material were seen almost exclusively in well- and intermediately-differentiated DCIS. These two subgroups differed in the average number of genetic imbalances, 2·5 and 5·5 respectively. Additionally, a higher frequency of gains of 1q and losses of 11q material was seen in intermediately-differentiated in contrast to well-differentiated DCIS. Poorly-differentiated DCIS displayed a higher frequency of amplifications (17q12, 11q13) and a higher average rate of genetic imbalances (7·1). Analysis of adjacent invasive breast carcinoma revealed a genetic pattern almost identical to the one seen in the DCIS counterpart. These data characterize DCIS as a genetically far-advanced, heterogeneous lesion and as a direct precursor of invasive breast cancer. Copyright © 1999 John Wiley & Sons, Ltd.