Background Patients with self-reported penicillin allergy are frequently denied β-lactam antibiotics. Objective To identify and correlate clinical and genetic risk factors of self-reported penicillin ...allergy. Methods We conducted a case-control study of adults recruited from allergists' offices. Cases had a history of urticaria, angioedema, wheeze, hypotension, vomiting, or anaphylaxis after a dose of penicillin. DNA from buccal swabs was genotyped for variants associated with candidate genes linked to immediate hypersensitivity ( IL4 , IL4R , and IL10 ) and penicillin metabolism ( LACTB ). Logistic regression was used to calculate the association between penicillin allergy and clinical and genetic factors. Results Seventeen allergists identified 76 adults. Complete data were available for 23 cases and 39 controls. Penicillin allergy was associated with a history of penicillin allergy in first-degree relatives ( P = .002), a history of other adverse drug reactions ( P = .008), and atopy ( P = .039). However, in the multivariable analysis, only family history of penicillin allergy remained significant. IL4 single nucleotide polymorphisms (SNPs) rs11740584 ( P = .012), rs10062446 ( P = .021), and rs2070874 ( P = .035) were associated and LACTB SNP rs2729835 ( P = .058) was marginally associated with penicillin allergy. Adding rs11740584 or rs10062446 individually improved the clinical multivariable model ( R2 increased from 0.23 to 0.33). Haplotype analysis did not provide additional information to the SNP analysis. Conclusion Self-reported penicillin allergy may be influenced by clinical and genetic factors such as IL4.
Opioids have been linked to limbic system activation and, in animals, to neurotoxicity. Limbic system nonpharmacologic activation patterns have been linked to the Apolipoprotein E (ApoE) allelic ...distribution. We tested the hypothesis that, in the absence of surgery, small doses of remifentanil produce limbic system activation in humans which varies with dose and ApoE genotype.
Twenty-seven ASA I-II volunteers received a remifentanil (Ultiva) infusion at four sequentially increasing doses: 0, 0.05, 0.1, and 0.2 microg x kg(-1) x min(-1) while receiving 100% oxygen. Cerebral blood flow (CBF) was measured at each dose globally and in the amygdala, cingulate, hippocampus, insula, and thalamus regions by pulsed arterial spin labeling magnetic resonance imaging. ApoE single nucleotide polymorphisms were determined in each subject.
Significant dose-related CBF increases, without correction for Paco(2), were detected in all areas. After normalizing for global CBF to correct for Paco(2) effects, the remifentanil-mediated increased CBF in the cingulate persisted, with decreased flow occurring in the hippocampus and amygdala. All these Paco(2)-corrected effects were reversed in the presence of the ApoE4 polymorphism.
Remifentanil at sedative doses produces both activating and depressing effects in various limbic system structures. The cingulate cortex seems to have the most susceptibility to remifentanil activation, and ApoE4 seems to produce relative activation of the hippocampus and amygdala.
Reported associations of ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer have been inconsistent and understudied in African Americans. We evaluated the role of 16 sequence variants in these ...genes with prostate cancer using 888 European American and 131 African American cases, and 473 European American and 163 African American, controls. We observed significant differences in ELAC2, RNASEL, and MSR1 allele frequencies by race. However, we did not observe significant associations between prostate cancer and any variants examined for both races combined. Associations were observed when stratified by race, family history, or disease severity. European American men homozygous for MSR1 IVS7delTTA had an elevated risk for localized stage odds ratio, (OR), 3.5; 95% confidence interval (95% CI), 1.4-6.9, low-grade (OR, 3.2; 95% CI, 1.4-7.3) disease overall, and with low-grade (OR, 2.9; 95% CI, 1.2-7.2) or late-stage disease (OR, 5.2; 95% CI, 1.1-25.7) in family history-negative African Americans. MSR1 Arg293X was associated with family history-negative high-grade disease (OR, 4.0; 95% CI, 1.1-14.1) in European Americans. RNASEL Arg462Gln was associated with low-grade (OR, 1.5; 95% CI, 1.04-2.2) and early-stage (OR, 1.5; 95% CI, 1.02-2.1) disease in family history-negative European Americans. In family history-positive individuals, Arg462Gln was inversely associated with low-grade (OR, 0.43; 95% CI, 0.21-0.88) and low-stage (OR, 0.46; 95% CI, 0.22-0.95) disease. In African Americans, Arg462Gln was associated with positive family history high-stage disease (OR, 14.8; 95% CI, 1.6-135.7). Meta-analyses revealed significant associations of prostate cancer with MSR1 IVS7delTTA, -14,742 A>G, and Arg293X in European Americans; Asp174Tyr in African Americans; RNASEL Arg462Gln in European American's overall and in family history-negative disease; and Glu265X in family history-positive European Americans. Therefore, MSR1 and RNASEL may play a role in prostate cancer progression and severity.
Tissue-based immune monitoring I Hagemann, Andrea R.; Cadungog, Mark; Hagemann, Ian S. ...
Cancer biology & therapy,
8/15/2011, 2011/08/15, 2011-Aug-15, 2011-08-15, 20110815, Letnik:
12, Številka:
4
Journal Article
Recenzirano
Odprti dostop
We sought to assess the feasibility and reproducibility of performing tissue-based immune characterization of the tumor microenvironment using CT-compatible needle biopsy material. Three independent ...biopsies were obtained intraoperatively from one metastatic epithelial ovarian cancer lesion of 7 consecutive patients undergoing surgical cytoreduction using a 16-gauge core biopsy needle. Core specimens were snap-frozen and subjected to immunohistochemistry (IHC) against human CD3, CD4, CD8, and FoxP3. A portion of the cores was used to isolate RNA for 1) real-time quantitative (q)PCR for CD3, CD4, CD8, FoxP3, IL-10 and TGF-beta, 2) multiplexed PCR-based T cell receptor (TCR) CDR3 Vβ region spectratyping, and 3) gene expression profiling. Pearson's correlations were examined for immunohistochemistry and PCR gene expression, as well as for gene expression array data obtained from different tumor biopsies. Needle biopsy yielded sufficient tissue for all assays in all patients. IHC was highly reproducible and informative. Significant correlations were seen between the frequency of CD3+, CD8+ and FoxP3+ T cells by IHC with CD3ε, CD8A, and FoxP3 gene expression, respectively, by qPCR (r=0.61, 0.86, and 0.89; all p<0.05). CDR3 spectratyping was feasible and highly reproducible in each tumor, and indicated a restricted repertoire for specific TCR Vβ chains in tumor-infiltrating T cells. Microarray gene expression revealed strong correlation between different biopsies collected from the same tumor. Our results demonstrate a feasible and reproducible method of immune monitoring using CT-compatible needle biopsies from tumor tissue, thereby paving the way for sophisticated translational studies during tumor biological therapy.
Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors. How early translocations appear during primary cancer treatment has not ...been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia. The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation. The karyotypic del(11)(q23) was a cryptic t(11;17). GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed. The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia. MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.
The ex vivo priming and expansion of human cytotoxic T lymphocytes (CTLs) has potential for use in immunotherapy applications for cancer and infectious diseases. To overcome the difficulty in ...obtaining sufficient numbers of CTLs, we have developed artificial antigen-presenting cells (aAPCs) expressing ligands for the T-cell receptor (TCR) and the CD28 and 4-1BB co-stimulatory surface molecules. These aAPCs reproducibly activate and rapidly expand polyclonal or antigen-specific CD8(+) T cells. The starting repertoire of CD8+ T cells was preserved during culture. Furthermore, apoptosis of cultured CD8(+) T cells was diminished by this approach. This approach may have important therapeutic implications for adoptive immunotherapy.
Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine ...p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used.
Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing.
Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion.
p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.
Background: Patients with self-reported penicillin allergy are frequently denied ?-lactam antibiotics. Objective: To identify and correlate clinical and genetic risk factors of self-reported ...penicillin allergy. Methods: We conducted a case-control study of adults recruited from allergists' offices. Cases had a history of urticaria, angioedema, wheeze, hypotension, vomiting, or anaphylaxis after a dose of penicillin. DNA from buccal swabs was genotyped for variants associated with candidate genes linked to immediate hypersensitivity (IL4, IL4R, and IL10) and penicillin metabolism (LACTB). Logistic regression was used to calculate the association between penicillin allergy and clinical and genetic factors. Results: Seventeen allergists identified 76 adults. Complete data were available for 23 cases and 39 controls. Penicillin allergy was associated with a history of penicillin allergy in first-degree relatives (P = .002), a history of other adverse drug reactions (P = .008), and atopy (P = .039). However, in the multivariable analysis, only family history of penicillin allergy remained significant. IL4 single nucleotide polymorphisms (SNPs) rs11740584 (P = .012), rs10062446 (P = .021), and rs2070874 (P = .035) were associated and LACTB SNP rs2729835 (P = .058) was marginally associated with penicillin allergy. Adding rs11740584 or rs10062446 individually improved the clinical multivariable model (R2 increased from 0.23 to 0.33). Haplotype analysis did not provide additional information to the SNP analysis. Conclusion: Self-reported penicillin allergy may be influenced by clinical and genetic factors such as IL4.
Diagnosis of hydatidiform mole by histology and ploidy analysis is limited by overlap of criteria for nonmolar hydropic abortion, complete mole, and partial mole. With early presentation, diagnosis ...is difficult due to limited tissue and lack of clinical features. Accurate diagnosis of these entities is important for both prognosis and patient management. We assessed a polymerase chain reaction (PCR) assay for polymorphic short tandem repeats (STR) for discrimination between nonmolar hydropic abortion, complete mole, and partial mole based on the genetic composition of molar pregnancies.
Seventeen cases of products of conception (POC) diagnosed by histology and flow cytometry ploidy analysis were studied retrospectively. PCR was performed using maternal and chorionic villus DNA extracted from microdissected, formalin-fixed, paraffin-embedded tissue sections. Allelic patterns for up to eight well-characterized polymorphic STR loci were determined using the GenePrint Fluorescent STR System (Promega Corporation, Madison, WI). The presence of three villus alleles at a single locus was interpreted as partial mole. Detection of only one allele in the villi, different from all maternal allele(s) at the same locus, was interpreted as a complete mole.
This technique identified eight complete moles previously diagnosed as complete mole (3), hydatidiform mole, otherwise unspecified (1), hydropic villi (2), hydropic villi versus partial mole (1), and partial mole (1). The diagnoses of five partial moles by the molecular assay were consistent with the diagnoses by histology and flow cytometry. One nonmolar gestation was identified, which had been diagnosed previously as hydropic villi. In three cases, maternal DNA amplification was insufficient for definitive diagnosis.
Molecular genetic testing of POC from paraffin-embedded tissue accurately distinguishes complete mole, partial mole, and nonmolar hydropic abortion. Identification of triploidy by flow cytometry can confirm a histological impression of partial mole. Histological and ploidy analysis of POC results in underdiagnosis of complete moles.
Non-Hodgkin's lymphoma is the most common primary testicular neoplasm of older men but is rare in young men. The vast majority of primary testicular lymphomas are intermediate- to high-grade ...lymphomas. Peripheral T-cell lymphomas of the testes are rare; most are large cell lymphomas. We describe an unusual case of a primary small lymphocytic, CD4+, peripheral T-cell lymphoma that presented as a Staphylococcus aureus scrotal abscess in a 30-year-old male. Clonal rearrangement of the T-cell receptor beta gene was demonstrated by Southern analysis. To our knowledge, low-grade, peripheral T-cell lymphoma of the testes has not been previously reported.
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