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PubMed2005

Potential inflammatory biomarkers in Alzheimer's disease.

The role of the brain's innate immune system in Alzheimer pathogenesis is now well established. Proinflammatory cytokines elaborated by this system, in particular activated microglia-derived interleukin-1 (IL-1), drive a cascade of neurotoxic changes that are important for the development and progression of both the neuritic plaques and neurofibrillary tangles characteristic of Alzheimer's disease. Cytokine expression may also be modulated by variants of genes. For instance, inheritance of certain IL-1 gene variants is associated with Alzheimer's disease. The potential for using blood levels of proinflammatory cytokines as biomarkers of disease progression, however, remains unrealized. The interpretation of cytokine levels in the blood is complicated by the fact, for example, that the overexpression of IL-1 in Alzheimer brain may act to increase adrenal cortisol production through the hypothalamic-pituitary-adrenal axis, which acts to limit macrophage activation and peripheral cytokine production.

Alzheimer Disease↗

PubMed1999

(TA)8 allele in the UGT1A1 gene promoter of a Caucasian with Gilbert's syndrome.

BACKGROUND AND OBJECTIVE: Gilbert's syndrome, a chronic non-hemolytic unconjugated hyperbilirubinemia, is caused by a reduction in the activity of hepatic bilirubin UDP-glucuronosyltransferase (UGT1A1). This reduction has been shown to be due to a polymorphism in the promoter region of the UGT1A1 gene. The presence of seven thymine adenine (TA) repeats reduces the efficiency of transcription of the UGT1A1 gene. To elucidate the genetic background of a patient affected by Gilbert's syndrome, we collected blood samples from family members for the analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene. DESIGN AND METHODS: Analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene was performed by PCR. Estimation of UGT1A1 promoter containing the variable (TA) repeats was performed by using a luciferase reporter system. RESULTS: Three different genotypes were identified due to the presence of (TA)6, (TA)7 and (TA)8 repeats. The production of luciferase decreases in inverse relation to the number of repeats. INTERPRETATION AND CONCLUSIONS: The (TA)7 polymorphism, associated with Gilbert syndrome, is the only allele found up to now in white populations, while two other variants (TA)5 and (TA)8 have been identified in black populations. We describe here the first case of a subject affected by Gilbert's syndrome who is heterozygous for the (TA)8 allele in the promoter region of the UGT1A1 gene. This polymorphism, as well as the (TA)7 one, is associated with an increased level of bilirubin and a significant reduction of transcription activity of the UGT1A1 gene.

Alleles↗

PubMed1999

Simultaneous detection of FV Q506 and prothrombin 20210 A variation by allele-specific PCR.

BACKGROUND AND OBJECTIVE: Factor V Leiden is the most important risk factor for hereditary thromboembolism, whereas the mutation in the 3'-untranslated region of the prothrombin gene seems to be only a mild risk factor for thrombotic events. On the other hand the factor V mutation (Arg 506) is frequently coinherited with the prothrombin 3'-untranslated region G20210A variant and there is increasing evidence that the co-segregated prothrombin variant is an additional risk factor for venous thromboembolism, contributing to thrombotic manifestations. A rapid, simple and cost-effective screening method is, therefore, required for the detection of both factor V Leiden and the prothrombin variant A20210G. DESIGN AND METHODS: Eighty-eight patients were enrolled in this study. Forty-four had a previously identified factor V and/or prothrombin mutation, the remaining 44 patients served as negative controls. A multiplex allele specific oligonucleotide PCR was established for the simultaneous detection of the two genetic risk factors for thrombophilia. To test the specificity of the simultaneous ASO PCR approach, the mutated and physiological factor V and prothrombin amplification products were sequenced. RESULTS: The factor V Leiden mutation and the prothrombin variant were correctly identified in all of 44 patients with known mutations. Furthermore the test was able to detect the mutated factor V and the II variant alone, as well as in the cosegregated pattern. Five patients with a homozygous pattern of factor V Leiden or prothrombin variant were also correctly identified. The sensitivity of the test is therefore 100%. In none of the 44 control cases were false positive results seen. INTERPRETATION AND CONCLUSIONS: The ASO PCR test is a rapid, simple and cost-effective screening test for thrombophilia.

Activated Protein C Resistance↗

PubMed2001

Validation of short tandem repeats (STRs) for forensic usage: performance testing of fluorescent multiplex STR systems and analysis of authentic and simulated forensic samples.

The amplification and typing conditions for the 13 core CODIS loci and their forensic applicability were evaluated. These loci are CSF1PO, FGA, TH01, TPOX, vWA, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, and D21S11. Results were obtained using the multiplex STR systems AmpFlSTR Profiler Plus and AmpFlSTR COfiler (Applied Biosystems, Foster City, CA), GenePrint PowerPlex (Promega Corporation, Madison, WI), and subsets of these kits. For detection of fluorescently labeled amplified products, the ABI Prism 310 Genetic Analyzer, the ABI Prism 377 DNA Sequencer, the FMBIO II Fluorescent Imaging Device, and the Fluorlmager were utilized. The following studies were conducted: (a) evaluation of PCR parameter ranges required for adequate performance in multiplex amplification of STR loci, (b) determination of the sensitivity of detection of the systems, (c) characterization of non-allelic PCR products, (d) evaluation of heterozygous peak intensities, (e) determination of the relative level of stutter per locus, (f) determination of stochastic PCR thresholds, (g) analysis of previously typed case samples, environmentally insulted samples, and body fluid samples deposited on various substrates, and (h) detection of components of mixed DNA samples. The data demonstrate that the commercially available multiplex kits can be used to amplify and type STR loci successfully from DNA derived from human biological specimens. There was no evidence of false positive or false negative results and no substantial evidence of preferential amplification within a locus. Although at times general balance among loci labeled with the same fluorophore was not observed, the results obtained were still valid and robust. Suggested criteria are provided for determining whether a sample is derived from a single source or from more than one contributor. These criteria entail the following: (a) the number of peaks at a locus, (b) the relative height of stutter products, and (c) peak height ratios. Stochastic threshold levels and the efficiency of non-templated nucleotide addition should be considered when evaluating the presence of mixtures or low quantity DNA samples. Guidelines, not standards, for interpretation should be developed to interpret STR profiles in cases, because there will be instances in which the standards may not apply. These instances include (a) a primer binding site variant for one allele at a given locus, (b) unusually high stutter product, (c) gene duplication, and (d) translocation.

DNA Fingerprinting↗

PubMed1990

Immunohistochemistry of solid tumors. Brief review of selected problems.

The immunohistochemical approach to tumor typing has dramatically improved our possibilities in the objective diagnosis of neoplasms. Use of optimal material and careful techniques will help to maintain good sensitivity, specificity, and reproducibility of immunohistochemistry. However, the complexity of antigen patterns in tumors, and lack of comprehensive knowledge about them requires caution in the interpretation of results, and may prohibit the simple use of diagnostic algorithms. Especially it is not certain whether the results obtained from typical representatives of various tumor entities will pertain to borderline cases and to undifferentiated variants of the same entities. Use of panels of antibodies rather than the use of single "diagnostic" tests will help to avoid these diagnostic pitfalls. However, all tumor types do not have immunohistochemically distinctive features. This emphasizes the need to use other techniques in such cases, and also suggests that some entities, such as malignant fibrous histiocytoma, are from the point of view of immunohistochemistry diagnoses only made by exclusion rather than being specifically diagnosable entities. All diagnostic immunohistochemistry has to be interpreted in the context of standard histological examination.

Antigens, Neoplasm↗

PubMed2026

[State Changes and Stability Grading of Driver Genes in Non-small Cell Lung Cancer Based on Repeated NGS Testing].

BACKGROUND: Next-generation sequencing (NGS)-based driver gene testing has become a routine component of molecular subtyping and precision therapy for non-small cell lung cancer (NSCLC). Dynamic genomic monitoring facilitates early detection of resistance-related molecular alterations and informs timely therapeutic adjustments. However, standardized criteria for evaluating the stability of serial NGS testing are currently lacking, and the applicability of NGS using formalin-fixed paraffin-embedded (FFPE) specimens for dynamic monitoring remains poorly defined. This study aims to establish a stability grading system for driver gene status alterations based on repeated NGS testing, and to provide evidence-based support for clinical repeat biopsy strategies. METHODS: Data from 1232 patients with NSCLC who underwent two or more NGS tests on FFPE tissue specimens at Beijing Chest Hospital between June 2019 and April 2026 were collected retrospectively. Patients with an interval of ≥4 months between the initial and last tests were included to ensure the representativeness of temporal analysis, resulting in a main analysis cohort of 942 patients. The Kappa consistency test was used to evaluate the state stability of nine core driver genes [epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), mesenchymal‑epithelial transition factor (MET), rearranged during transfection (RET), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), erb‑b2 receptor tyrosine kinase 2 (ERBB2), and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA)] and to construct a five‑level grading system. Paired variant allele frequency (VAF) differences were compared using the Wilcoxon signed‑rank test. Independent influencing factors for mutation accumulation were identified by binary Logistic regression. RESULTS: The state stability of the nine genes was classified into five levels: EGFR showed high stability (Kappa=0.838), ROS1/ALK/KRAS good stability, BRAF/PIK3CA/RET moderate stability, and ERBB2 low stability, and MET showed high instability. MET exhibited the highest rate of state change (9.3%) with a raw observed agreement of 90.7%. Its Kappa value (0.172) was influenced by the low prevalence (3.7%) compression effect and should therefore be interpreted alongside the observed agreement (90.7%) and the prevalence-adjusted and bias-adjusted Kappa (PABAK). The VAF of PIK3CA increased significantly (P=0.005). T790M positivity increased from 5.8% to 10.8%, and 30 new C797S mutations were detected at the last test (13 with T790M, 17 without). The overall rate of new driver gene variants in the main cohort was 18.0%. Binary Logistic regression showed that a lower number of initial mutated genes was the only independent predictor of new variants [odds ratio (OR)=0.399, P<0.001], while sex and detection interval showed no independent association. CONCLUSIONS: A five level stability grading system for state changes of driver genes in NSCLC based on repeated NGS testing has been established. MET showed the most frequent state changes, which should be interpreted in conjunction with the prevalence effect. The VAF increase of PIK3CA is an observational finding, and its clinical significance requires further prospective validation. A lower initial mutation burden may reflect tumor clonal complexity and was associated with a higher likelihood of subsequent acquisition of new variants. FFPE based NGS is applicable for repeated testing at clinical treatment decision nodes.

Humans↗

PubMed2006

Autoimmunity in systemic lupus erythematosus: integrating genes and biology.

Susceptibility to the autoimmune phenotype of systemic lupus erythematosus (SLE) is heritable. Linkage analysis and recent advances in the field of single nucleotide polymorphisms (SNPs) have resulted in the identification of several genetic loci and functional allelic variants of signaling proteins which have become the mainstay of understanding disease susceptibility and exploring the basis of autoimmunity in SLE. However, genetic heterogeneity and possible epistatic interactions among genetic elements have precluded replication of these findings in multiple population groups and thus complicated their interpretation. In this regard, the discovery that a plethora of normal signaling proteins are expressed in abnormal amounts in immune cells from patients with SLE has gained significance. Thus, the key to precise elucidation of the pathologic basis of autoimmunity in SLE lies in tying genetics and disease biology. This review highlights recent discoveries of important functional genetic variants and altered expression of normal signaling proteins that network together to disrupt peripheral tolerance and initiate the autoimmune process in SLE.

Animals↗

PubMed2003

Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.

Alleles↗

PubMed2026

Hypoxia-Inducible Factor-1α Gene (HIF1A) rs11549465 (1772 C>T) Polymorphism, Body Mass Index, Smoking, and Cutaneous Melanoma: An Observational Case-Control Study.

BACKGROUND: Hypoxia and oxidative stress are central features of cutaneous melanoma biology. Body mass index (BMI) and smoking, both of which can influence systemic hypoxia, inflammation, and oxidative stress, have shown inconsistent associations with melanoma. We investigated the association of the hypoxia-inducible factor-1 alpha gene (HIF1A) rs11549465 (1772 C>T; Pro582Ser) polymorphism, alone and in combination with overweight/obesity or smoking habits, with cutaneous melanoma susceptibility and clinicopathological characteristics. METHODS: This observational case-control study included 132 Caucasian Italian patients with cutaneous melanoma and 312 healthy controls. The rs11549465 polymorphism was genotyped by genomic DNA restriction fragment analysis. Logistic regression provided age- and sex-adjusted and mutually adjusted estimates. RESULTS: Genotype and allele frequencies did not differ between patients and controls. Within the melanoma cohort, smoking for ≥20 years remained associated with metastatic disease after adjustment for BMI ≥ 25 kg/m2, age at diagnosis, and sex (aOR = 3.12, p = 0.006), whereas BMI did not (aOR = 1.23, p = 0.612). Compared with healthy controls, metastatic melanoma was independently associated with BMI ≥ 25 kg/m2 (aOR = 2.26, p = 0.010) and smoking for ≥20 years (aOR = 3.85, p < 0.001). Mean pack-years were higher in melanoma patients than controls (9.4 ± 16.7 vs. 5.1 ± 12.2; p = 0.002), and ≥10 and ≥20 pack-years remained associated after age- and sex-adjustment (aOR = 2.19, p = 0.001 and aOR = 3.31, p < 0.001, respectively). Mean pack-years were higher in MetM than NMetM (13.1 ± 21.0 vs. 5.9 ± 10.0; p = 0.013), and ≥20 pack-years was associated with MetM (OR = 3.05, p = 0.017). Adjusted associations with head/neck melanoma (n = 13) were observed for CC plus BMI ≥ 30 kg/m2 (aOR = 9.07, p < 0.001), ≥20 cigarette/day (aOR = 5.96, p = 0.004), ≥20 years smoking (aOR = 6.64, p = 0.003), and other smoking measures. CONCLUSIONS: To our knowledge, this is the first report on the interplay between the rs11549465 polymorphism and cutaneous melanoma. HIF1A rs11549465 was not independently associated with melanoma susceptibility. Associations involving smoking, BMI, joint genotype-lifestyle exposures, and anatomical localization had wide confidence intervals and were exploratory; small subgroups and multiple comparisons require cautious interpretation and independent validation.

cigarette smoke↗

PubMed2005

Improved resolution of serum bisalbumin on electrophoresis and investigation of bisalbumin in urine.

OBJECTIVES: : The aims of this study were to improve the resolution of albumin variants (bisalbumins, especially albumin Naskapi) from albumin in commercial serum protein electrophoresis systems; to compare the separation of bisalbumin from albumin on these improved methods against the recognized gold standard of capillary electrophoresis; and to investigate the presence of albumin variants in urine. DESIGN AND METHODS: : Electrophoresis was performed using the Sebia Hydrasys 15/30 beta1beta2 system, as well as modified methods on the Sebia Hydrasys HR and the Beckman Paragon systems. The interpretation of electrophoretic gels was performed by manual visualization and densitometric scanning. Serum samples were also analyzed using capillary electrophoresis at Sebia Electrophoresé located in Paris, France. Urine samples were concentrated using Vivaproducts concentration tubes and were electrophoresed using the Sebia Hydrasys HR system. RESULTS: : Representative gels and scans of serum samples demonstrate the improved resolution of modified electrophoresis methods compared to routine methods. The raw data from the gels and scans were compiled to calculate concordance and discordance for each method. DISCUSSION: : The various commercial serum protein electrophoresis systems showed improved resolution using the modified methods. In comparison with capillary electrophoresis, the modified Sebia Hydrasys HR and Beckman Paragon methods using visualization demonstrated 100% concordance and thus performed equally as well as the gold standard. Urine studies found that variant albumins are also excreted in the urine in the same 50-50 ratio as that found in the serum.

Albumins↗

PubMed2001

ALK positive lymphohistiocytic variant of anaplastic large cell lymphoma in an adult.

BACKGROUND AND OBJECTIVES: The lymphohistiocytic (LH) variant of anaplastic large cell lymphoma (ALCL) has, for a long time, been considered typical of children and adolescents. The aim of this study is a detailed characterization of a case of this peculiar ALCL subtype affecting an adult patient. DESIGN AND METHODS: A 36-year old male presented with diffuse adenopathy and systemic symptoms (high fever, anorexia, asthenia); a diagnosis of CD30+/ALK+ ALCL, LH variant, was morphologically suspected and corroborated by immunohistochemistry that was crucial for the definitive diagnosis and subtyping. RESULTS: The neoplastic population consisted of cells highly variable in size and shape but more often isolated and largely obscured by a predominant reactive cellular infiltrate of histiocytes and plasma cells. The lymphoma cells exhibited a null non-B non-T antigenic profile, but reacted strongly for the Ber-H2/CD30, EMA, ALKc anti-TIA-1 monoclonal antibodies. The patient underwent chemotherapy plus bone marrow transplantation and, one year after diagnosis, he is well and in complete remission. INTERPRETATION AND CONCLUSIONS: Our findings provide additional evidence that: a) ALK+ lymphoma represents a single disease with a broad spectrum of morphology; b) clinicians and pathologists should be aware of the possible occurrence of LH variant of ALK+ ALCL also in adults in whom a favorable response to therapy may be expected despite systemic disease and an aggressive clinical presentation.

Adult↗

PubMed1991

Computer simulations and experimental studies of gel mobility patterns for weak and strong non-cooperative protein binding to two targets on the same DNA: application to binding of tet repressor variants to multiple and single tet operator sites.

A series of computer simulations of gel patterns assuming non-cooperative binding of a protein to two targets on the same DNA fragment was performed and applied to interprete gel mobility shift experiments of Tet repressor-tet operator binding. While a high binding affinity leads to the expected distribution of free DNA, DNA bound by one repressor dimer and DNA bound by two repressor dimers, a lower affinity or an increased electrophoresis time results in the loss of the band corresponding to the singly occupied complex. The doubly occupied complex remains stable under these conditions. This phenomenon is typical for protein binding to DNA fragments with two identical sites. It results from statistical disproportionation of the singly occupied complex in the gel. The lack of the singly occupied complex is commonly taken to indicate cooperative binding, however, our analysis shows clearly, that cooperativity is not needed to interprete these results. Tet repressor proteins and small DNA fragments with two tet operator sites have been prepared from four classes of tetracycline resistance determinants. The results of gel mobility shift analyses of various complexes of these compounds confirm the predictions. Furthermore, calculated gel patterns assuming different gel mobilities of the two singly occupied complexes show discrete bands only if the electrophoresis time is shorter than the inverse of the microscopic dissociation rate constant. Simulations assuming increasing dissociation rates predict that the two bands first merge into one, which then disappears. This behavior was verified by gel mobility analyses of Tet repressor-tet operator titrations at increased salt concentrations as well as by direct footprinting of the complexes in the gel. It is concluded that comparison of the intensities of the single and the double occupation bands allow a rough estimation of the dissociation rate constant. On this basis the sixteen possible Tet repressor-tet operator combinations can be ordered with decreasing binding affinities by a simple gel shift experiment. The implications of these results for gel mobility analyses of other protein-DNA complexes are discussed.

Binding Sites↗

PubMed1976

R-factor-mediated resistance to sulfonamides by a plasmid-borne, drug-resistant dihydropteroate synthase.

Evidence was found for the existence of an episome-specified variant of the enzyme dihydropteroate synthase involved in folic acid formation. Since the plasmid-borne enzyme showed a decreased susceptibility for sulfonamide inhibition and was transferable together with resistance to this drug, it is proposed that diploidy for the target enzyme in some cases could be the mechanism of R-factor-mediated resistance to sulfonamides. Two types of evidence were obtained. One was the rescue from temperature sensitivity of bacterial mutants with a lesion in the chromosomal dihydropteroate synthase by the R factor R1dr19 mediating sulfonamide resistance. The other evidence was found by the determination of dihydropteroate forming activity in extracts from R(-) and R(+) bacteria. Cells harboring R1dr19 were found to contain an enzyme activity which was far less susceptible to sulfonamide inhibition than the corresponding activity from R(-) cells.

Dihydropteroate Synthase↗

PubMedDate not supplied

HIV-1 drug resistance in newly infected individuals.

CONTEXT: There is concern that the widespread use of antiretroviral drugs to treat human immunodeficiency virus 1 (HIV-1) infection may result in the increased transmission of drug-resistant virus. OBJECTIVE: To determine the prevalence of drug resistance-conferring mutations and phenotypic resistance to antiretroviral agents in a cohort of individuals newly infected with HIV-1. DESIGN: Case series with genetic analyses of the HIV-1 plasma-derived pol gene using reverse transcriptase polymerase chain reaction followed by direct sequencing of polymerase chain reaction products. Phenotypic analysis was performed with a recombinant virus assay. SETTING AND PATIENTS: Eighty individuals referred, on average, 1.7 months after infection with HIV-1 to the Aaron Diamond AIDS Research Center between July 1995 and April 1999. Subjects were from large urban areas (65 from New York, NY; 11 from Los Angeles, Calif); 60 (75%) were white, and 75 (93.8%) were homosexual men. MAIN OUTCOME MEASURES: Prevalence of known resistance-conferring genotypes and reduced susceptibility to individual antiviral agents by phenotype. RESULTS: Thirteen individuals (16.3%) had genotypes associated with drug resistance to any antiretroviral agent. Virus with known resistance-conferring mutations to any nucleoside reverse transcriptase inhibitors was found in 10 individuals, to any nonnucleoside reverse transcriptase inhibitors in 6 subjects, and to any protease inhibitors in 2 cases. Multidrug-resistant virus was identified in 3 individuals (3.8%). Extensive polymorphism in the protease gene was identified. Interpretation of genotypes and phenotypes was concordant in 57 (85%) of the 67 cases in which both studies were performed. CONCLUSION: The prevalence of HIV-1 variants with known resistance-conferring genotypes to any antiretroviral agent in this cohort of 80 newly infected individuals is 16.3%. These data support expanded use of resistance testing in the setting of primary HIV-1 infection. Clinical trials should be initiated to establish whether therapy guided by resistance testing, compared with the use of empirical triple combination antiretroviral therapy, provides additional virological and immunological benefit when treating primary HIV-1 infection. Further efforts to expand the study of transmission of drug-resistant HIV-1 variants, particularly in cohorts with different epidemiological profiles, are indicated.

Adult↗

PubMed1983

Bilateral asymmetry in cone epiphysis of the middle phalanx, fifth finger.

The form of epiphyseal-diaphyseal dysostosis in the phalanges of the hand having the appearance of a cone-and-crater (cone-shaped epiphysis) is a common variant in otherwise normal individuals. Dysplasia on the radial margins of the epiphysis and diaphysis, typically resulting in clinodactyly, is another variant and is also common in Down's syndrome. Both variants frequently involve brachymesophalangia. The strong female bias in cone epiphyses and the lack of such bias in dysplasia not involving cones has led to the interpretation of distinct etiologies for the two patterns. A single case displaying brachymesophalangia with cone epiphysis in the middle phalanx of the left fifth finger and brachymesophalangia with clinodactyly in the corresponding bone of the right hand is reported. This is evidence that in certain cases the two patterns of mid-5 dysostosis are manifestations of the same condition.

Abnormalities, Multiple↗

PubMed1977

Hemoglobin SC, SS/GPhiladelphia and SOArab diseases diagnostic importance of an integrative analysis of clinical, hematologic and electrophoretic findings.

Hemoglobin studies are presented on two children in whom electrophoretic analysis of hemolysates at alkaline pH initially suggested the diagnosis of hemoglobin SC disease. In both patients the course of the disease was unusually severe, blood smears contained irreversibly sickled cells, and crystal formation did not occur when red cells were incubated in 3 per cent sodium chloride solution. Each of these findings is inconsistent with the interpretation of the electrophoretic patterns. Family studies demonstrated that one of the patients had sickle cell anemia and was also a carrier of an alpha chain variant; citrate agar electrophoresis at pH 6.2 of the second child's hemolysate revealed that the "C-like" hemoglobin was not hemoglobin C. Tryptic peptide analyses of the nonhemoglobin S fractions showed that the first child has SS/GPhiladelphia disease and that the second child has SOArab disease. These observations emphasize the importance of integrating the clinical and hematologic data with the results of electrophoretic procedures in order to define precisely the hemoglobin abnormality in patients with sickling disorders.

Anemia, Sickle Cell↗

PubMed2026

A cross-sectional study of oxidative stress pathway genotypes and their interactions with environmental pollutant levels identifies associations with gene expression and lung function.

BACKGROUND: Asthma is a heterogeneous disease influenced by genetic and environmental factors. Fine particulate matter (PM2.5) exacerbates asthma, likely through oxidative stress pathways, but whether genetic variation modifies this effect remains unclear. METHODS: We analysed data on 948 adults with asthma from the Severe Asthma Research Program (SARP), linking ZIP-code-level PM2.5 exposure with whole-genome sequencing data. We tested 4337 single nucleotide polymorphisms (SNPs) in 120 oxidative stress pathway genes for gene-environment (GxE) interactions with PM2.5 on lung function (forced expiratory volume in 1 s [FEV1] % predicted) using weighted linear regression. Gene expression data from bronchial epithelial cells (n = 170) were used to assess cis-expression quantitative trait loci (eQTLs). FINDINGS: Higher PM2.5 exposure was associated with lower FEV1% predicted (β per μg/m3 = -0.7, p = 0.01). We identified 20 SNPs across seven genes (OXSR1, PXDN, TPO, LRRK2, APP, MSRA, MSRB2) with significant GxE interactions after multiple-testing correction. Five SNPs were also eQTLs, linking PM2.5-modified gene expression to lung function. Minor alleles in OXSR1 and PXDN were associated with reduced gene expression and worsened FEV1% under high PM2.5 exposure. Conversely, TPO variants were associated with higher baseline expression and lower lung function, but under increasing PM2.5 exposure, minor allele carriers showed suppressed TPO expression and improved FEV1%. INTERPRETATION: This study identified 20 SNPs in oxidative stress pathway genes that modify the effect of PM2.5 on lung function in asthma. These findings highlight the importance of integrating environmental context in genetic studies and suggest potential therapeutic targets for pollution-sensitive asthma phenotypes. FUNDING: Supported by NIH grants.

Cross-Sectional Studies↗

PubMed2005

Transposable elements--is there a link between evolution and cancer?

Currently, the most predominant theory concerning the formation of cancer is that it is a genetic accident. Accordingly, various agents are thought to cause DNA damage which then subsequently activates oncogenes and inactivates tumor suppressor genes. This article, however, describes a theory that interprets cancer as a misguided adaptation. Stressors, which cannot be compensated for with the usual cell possibilities might arouse evolutionary mechanisms intended to create new protein variants. One of these is the activation of transposable elements which leads to a reformatting of the genome. The result of this process is either a cell that survives very well under stress (and will, therefore, never be detected), a dead cell (in case the process is ineffective), or a more or less abnormal and harmful cell that builds up a new but cancerous organ. This theory explains the complex genetic alterations which are present in almost all cancer cells. It also explains the action of non-mutagenic carcinogens. As part of the reformatting process of the cancer cell genome, activation of oncogenes and inactivation of tumor suppressor genes are not stochastic events but the result of an unlucky genomic composition.

Carcinogens↗