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PubMed2025

Cross-omics risk scores of inflammation markers are associated with all-cause mortality: The Canadian Longitudinal Study on Aging.

Inflammation is a critical component of chronic diseases, aging progression, and lifespan. Omics signatures may characterize inflammation status beyond blood biomarkers. We leveraged genetics (polygenic risk score [PRS]), metabolomics (metabolomic risk score [MRS]), and epigenetics (epigenetic risk score [ERS]) to build multi-omics-multi-marker risk scores for inflammation status represented by the level of circulating C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α). We found that multi-omics risk scores generally outperformed single-omics risk scores in predicting all-cause mortality in the Canadian Longitudinal Study on Aging. Compared with circulating inflammation biomarkers, some multi-omics risk scores had a higher hazard ratio (HR) for all-cause mortality when including both score and circulating IL-6 in the same model (1-SD IL-6 MRS-ERS: HR = 2.20 [1.55-3.13] vs. 1-SD circulating IL-6 HR = 0.94 [0.67,1.32]. 1-SD IL-6 PRS-MRS: HR = 1.47 [1.35,1.59] vs. 1-SD circulating IL-6 HR = 1.33 [1.18, 1.51]. 1-SD PRS-MRS-ERS: HR = 1.95 [1.40, 2.70] vs. 1-SD circulating IL-6: HR = 0.99 [0.71, 1.39]). In the Nurses' Health Study (NHS), NHS II, and Health Professional Follow-up Study with available omics, 1 SD of IL-6 PRS and 1-SD IL-6 PRS-MRS had HR = 1.12 [1.00,1.26] and HR = 1.13 [1.01,1.26] among individuals >65 years old without mutual adjustment of the score and circulating IL-6. Our study demonstrates that some multi-omics scores for inflammation markers may characterize important inflammation burden for an individual beyond those represented by blood biomarkers and improve our prediction capability for the aging process and lifespan.

Humans↗
PubMed2006

Comparing intracytoplasmic sperm injection and in vitro fertilization in patients with single oocyte retrieval.

OBJECTIVE: To compare the efficacy of intracytoplasmic sperm injection (ICSI) and conventional IVF in patients with favorable and poor sperm parameters in which only a single oocyte was available for insemination. DESIGN: Retrospective analysis. SETTING: University-affiliated IVF center. PATIENT(S): A total of 311 patients (425 cycles) who underwent either stimulated or spontaneous IVF cycles that resulted in single oocyte retrieval. INTERVENTION(S): The ICSI was indicated when fertilization failure was anticipated because of sperm quality or other confounding female factors. MAIN OUTCOME MEASURE(S): Fertilization rates and pregnancy rates (PRs) were analyzed according to the woman's age (< or =39 or >39 years), sperm quality, and mode of insemination. RESULT(S): In patients <39 years old with favorable semen quality, ICSI and standard insemination produced similar fertilization rates (67.1% vs. 75.0%) and PRs (0.0 vs. 8.2%). Conversely, in cases with apparent lower semen quality, ICSI gave a significantly higher fertilization rate (85.4% vs. 44.2%) but no significant difference in PRs (14.6% vs. 4.7%). In patients >39 years old and with favorable semen quality, ICSI and standard insemination produced similar fertilization rates (82.4% vs. 68.4%) and PRs (0.0 vs. 1.1%). The ICSI for lower semen quality, however, produced both higher fertilization rates (84.0% vs. 52%) and higher PRs (8.0% vs. 0). CONCLUSION(S): Our results suggest that in poorly responding patients, semen quality should remain the most important determinant when considering whether to perform ICSI. We have found that the values of 20 x 10(6)/mL and 35% motility are good predictors of success in such patients.

Adult↗
PubMed2026

Polygenic Risk Based Detection and Treatment of Subclinical Coronary Atherosclerosis in the PROACT Clinical Trials.

BACKGROUND: Coronary artery disease (CAD) polygenic risk scores (PRS) may identify individuals at elevated genetic risk "flying under the radar" in contemporary practice. The aims of the PROACT (Polygenic Risk Based Detection and Treatment of Subclinical Coronary Atherosclerosis) trials are to prospectively identify these individuals, quantify subclinical coronary plaque, and slow its progression with pharmacologic interventions. OBJECTIVES: The aim of this study is to report interim feasibility and implementation findings from PROACT, a genotype-first, biobank-enabled trial, characterizing eligibility yield, callback engagement, and subclinical coronary atherosclerosis on coronary computed tomographic angiography among individuals with high CAD PRS. METHODS: Within a hospital-based biobank, adults 40 to 75 years of age with high CAD PRS, without cardiovascular disease, and not on lipid-lowering therapy were invited. The authors characterize 2,495 eligible individuals with high CAD PRS, report on the feasibility and early operational outcomes of a genotype-first callback strategy for a clinical trial in the first 1,314 invited, and describe plaque prevalence by age and sex in the first 204 participants using coronary computed tomographic angiography. RESULTS: Among 64,092 genotyped participants, 2,495 (3.9%) were eligible and had high CAD PRS despite low clinical risk (median 10-year pooled cohort equations risk for atherosclerotic cardiovascular disease 3%; Q1-Q3: 1%-8%). Recruitment showed high engagement: among 1,314 invited individuals, 283 (21.5%) opted in, and 204 (15.5%) completed baseline imaging. Compared with participants who did not opt in, those who opted in had higher specialty care engagement and lived closer to the study site. Analysis of the first 204 participants enrolled by January 31, 2025 (mean age 56.3 &#xb1; 8.5 years, 69% women), showed that despite the low clinical risk and favorable cardiovascular health (mean Life's Essential 8 score 73.3 &#xb1; 11.5 vs the U.S. average of &#x223c;65), one-half the participants (102 of 204) had subclinical plaque. Subclinical plaque prevalence was 76.2% in men and 38.3% in women and was high across age groups. CONCLUSIONS: These exploratory findings highlight the feasibility of implementing genotype-first recruitment for prevention trials and reveal a large proportion of "silent" high-genetic risk individuals with subclinical plaque for whom pharmacotherapy could be beneficial but who remain undetected by standard clinical assessments. (Polygenic Risk Based Detection of Subclinical Coronary Atherosclerosis and Change in Cardiovascular Health [PROACT 1], NCT05819814; Polygenic Risk Based Detection of Subclinical Coronary Atherosclerosis and Intervention With Statin and Colchicine [PROACT 2], NCT05850091).

Adult↗
PubMed2004

Production rates of cortisol in men with hypogonadism.

Healthy men have a larger endogenous cortisol production rate (PR) than healthy women. To investigate whether this sex-specific difference is maintained in men with low serum testosterone concentrations the endogenous PRs (2 pm to 6 pm) of testosterone, dihydrotestosterone (DHT), and cortisol were simultaneously determined in 10 hypogonadal men. As expected, hypogonadal men were characterized by subnormal PRs of testosterone (19.6 +/- 5.7 microg/h; normal, 180 to 346 microg/h) and of DHT (1.6 +/- 1.1 microg/h; normal, 11 to 20 microg/h). In hypogonadal patients with an intact pituitary-adrenal axis (n = 8), plasma concentrations (7.3 +/- 1.8 microg/dL), metabolic clearance rates (MCRs) (10.0 +/- 4.6 L/h), and endogenous PRs (0.6 +/- 0.2 mg/h) of cortisol were comparable to those seen in eugonadal men. Hence, the sex-specific difference in endogenous cortisol PRs does not depend on the prevailing serum concentrations and on the endogenous PRs of testosterone.

Adult↗
PubMed2006

Assessment of the reliability and validity of panoramic imaging for assessment of mandibular condyle morphology using both MRI and clinical examination as the gold standard.

OBJECTIVES: The purpose of this study was to evaluate both reliability and validity of the assessment of the shape of the mandibular condyle in panoramic images of the TMJ. STUDY DESIGN: Forty subjects were included and were examined according to the Research Diagnostic Criteria for Temporomandibular Disorders. Panoramic radiographs (PRs) and magnetic resonance images (MRIs) were completed for all subjects. Both MRIs and PRs were rated by raters blinded to the clinical diagnosis. Kappa statistics were used to compare the results of the raters of the PRs. Additionally, the specificity and the sensitivity of the PRs were calculated for 2 scenarios: one with MRI and the other with clinical findings as the gold standard. RESULTS: The sensitivity was 0.94 (specificity = 0.45) for the assumption that MRI is the gold standard and 0.86 (specificity = 0.49) for the assumption that the clinical examination is the gold standard. For reliability, the results for kappa ranged from 0.06 to 0.327. CONCLUSION: It can be concluded that PRs are not a reliable method of accurately judging the shape of the mandibular condyle.

Adolescent↗
PubMed2023

Low and differential polygenic score generalizability among African populations due largely to genetic diversity.

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African&#xa0;ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.

Humans↗
PubMed2005

Expression of progesterone receptor is a favorable prognostic marker in ovarian cancer.

OBJECTIVE: Receptors for estrogen (ER), progesterone (PR), or androgen (AR) are predictive and prognostic markers of malignancy of multiple endocrine organs, including endometrial and breast cancer. However, the role of ERs, PRs, or ARs in the carcinogenesis of ovarian cancer, another sex hormone-dependent malignancy, is still controversial despite numerous studies that have attempted to determine their role. The disagreement in the findings may result from the fact that the numbers of tumor samples in studies have been small and that different immunohistochemical methods have been used that can introduce variation in the scoring of the histology. We therefore examined the pattern of expression of ERs, PRs, and ARs in a large number of samples of primary ovarian carcinoma by using a tissue microarray technique. METHODS: We constructed a tissue microarray with 322 samples of primary ovarian carcinoma obtained at surgery performed at The University of Texas M. D. Anderson Cancer Center between 1990 and 2000. Immunohistochemistry studies were performed by using the immunoperoxidase technique against primary antibodies (ER, PR, and AR). RESULTS: ERs, PRs, and ARs were differently expressed in different histotypes of ovarian cancer: ERs were expressed in 77.3% of all cases but more highly expressed in serous and endometrioid types; PRs were expressed in 26.2% of all cases but most highly expressed in the endometrioid type < 64.2%; and ARs were expressed in 43.7% of all cases but were most highly expressed in serous (47.5%) carcinomas. Of particular importance, the expression of PRs, but not ERs or ARs, was associated with better survival (P < 0.0001) in univariate and multivariate analyses. CONCLUSIONS: The PR is an independent marker, with its overexpression associated with a favorable prognosis in women with ovarian cancer.

Adult↗
PubMed1995

Successful implantation of frozen sibling embryos is influenced by the outcome of the cycle from which they were derived.

OBJECTIVES: To determine if the success of frozen embryos obtained from assisted reproductive technology (ART) cycles is dependent upon the outcome of the ART cycle from which they were derived and to determine if the length of time in cryostorage affects pregnancy rates (PRs). DESIGN: Retrospective analysis of pregnancy outcome of consecutive frozen ETs compared with their corresponding "'fresh" cycles. SETTING: University-affiliated private ART program. PATIENTS: Between July 1986 and December 1992, 375 oocyte retrieval cycles had at least one subsequent frozen ET for comparison. Of the 375 patients, 94 achieved a clinical pregnancy during their fresh cycle (group A) and 281 patients did not (group B). INTERVENTIONS: Frozen ETs were performed using either natural (unstimulated) cycles (n = 79) or artificial cycles (n = 296). Transfers during natural cycles were timed with a combination of serum LH levels and ultrasound (US). These transfers were performed 2 days after ovulation. Ovarian suppression with leuprolide acetate followed by sequential estrogen and P replacement were used in the artificial cycles. These transfers were performed on the 3rd day of P administration. Clinical pregnancies were defined as the presence of a gestational sac on transvaginal US. MAIN OUTCOME MEASURES: Patients were compared based on the pregnancy outcome of their frozen ET cycle and fresh ART cycle. chi 2 analysis and Student's-tests were used to test for statistical significance. RESULTS: Twenty-three patients (24.1%) from group A achieved a pregnancy from their frozen transfers compared with only 24 patients (8.5%) in group B who achieved a pregnancy from their frozen cycle. PRs did not differ based on the method of follicle aspiration, laparoscopy versus transvaginal US retrieval. Significantly lower PRs were noted in frozen ETs done within the first 10 months after cryopreservation compared with fresh cycle PRs. CONCLUSIONS: Sibling embryos from a prior successful ART cycle are more likely to initiate a frozen pregnancy and prolonged cryostorage did not affect PRs. This higher PR probably reflects better quality in both fresh and frozen embryos. Therefore, the outcome of the initial cycle can be used to predict the success or failure of subsequent frozen transfers and oocyte-embryo quality appears to be key.

Adult↗
PubMed1997

Consequences of premature progesterone elevation on the outcome of in vitro fertilization: insights into a controversy.

OBJECTIVE: To investigate whether the consequences of premature P elevation on IVF-ET outcome are modulated by the quality of the ovarian response to controlled ovarian hyperstimulation (COH). DESIGN: Retrospective analysis. SETTING: Assisted Reproduction Unit, Clamart, France. PATIENT(S): One thousand twelve women undergoing 1,189 IVF-ET cycles. INTERVENTION(S): Patients underwent COH with a time-released GnRH agonist and hMG. The ovarian response to COH was classified as strong (< or = 50 hMG ampules, peak E2 levels > 2,500 pg/mL, and > or = 10 mature oocytes; n = 340), weak (> 50 hMG ampules, peak E2 levels < or = 1,500 pg/mL, and < or = 5 mature oocytes; n = 285), or intermediate (remaining cases; n = 564). The IVF-ET outcome in each group was analyzed according to whether or not plasma P levels exceeded 0.9 ng/mL. MAIN OUTCOME MEASURE(S): Pregnancy rates (PRs). RESULT(S): Clinical PRs were similar irrespective of low or high P levels in the strong (30% and 34%, respectively) and intermediate (31% and 30%, respectively) groups. However, in the weak group, P levels > 0.9 ng/mL were associated with lower PRs (3.2% and 23%, respectively). CONCLUSION(S): In the presence of an adequate response to COH, P levels > 0.9 ng/mL were not associated with lower PRs, indicating that good embryo quality may compensate for the adverse endometrial effects of P. Conversely, when the response to COH was weak, premature P elevation led to drastically reduced PRs.

Adult↗
PubMed1998

The adverse effect of hydrosalpinges on in vitro fertilization pregnancy rates and the benefit of surgical correction.

OBJECTIVE: To test the hypothesis that IVF-ET pregnancy rates (PRs) for patients with tubal factor infertility are decreased in patients with hydrosalpinges and that surgical correction reverses this effect. DESIGN: Retrospective chart review. SETTING: Private practice IVF-ET program. PATIENT(S): Patients (n = 160) undergoing 238 cycles of IVF-ET were stratified into groups based on the presence of hydrosalpinges and whether surgical correction had been performed. Patients >39 years old and patients with male factor infertility were excluded from the study. INTERVENTION(S): Patients with hydrosalpinges were offered surgical correction. MAIN OUTCOME MEASURE(S): Clinical pregnancy defined by an intrauterine gestational sac. RESULT(S): Patients with hydrosalpinges had significantly decreased implantation rates and PRs per transfer (2.8% and 8.5%, respectively) than patients with tubal factor infertility but without hydrosalpinges (15.7% and 38.6%). Surgical correction improved implantation rates and PRs in patients with prior failed cycles (16.1% and 37.5%) and in patients undergoing surgery before IVF-ET (21.8% and 51.7%). The type of surgery performed did not affect success rates in the small number of patients evaluated. CONCLUSION(S): The presence of a hydrosalpinx during an IVF-ET cycle results in significant decreases in implantation rates and PRs. Surgical treatment of hydrosalpinges before IVF-ET cycles improves implantation rates and PRs.

Adult↗
PubMed1998

Culturing human embryos with and without glucose.

OBJECTIVE: To review published data and to compare pregnancy rates (PRs) after culturing human embryos with and without glucose and phosphate. DESIGN: Comparison of results from various programs. SETTING: Assisted Reproductive Technology Program. PATIENT(S): Patients were enrolled in various studies. INTERVENTION(S): Human embryos were cultured with and without glucose and phosphate. MAIN OUTCOME MEASURE(S): Pregnancy rates after different techniques of embryo culture. RESULT(S): Some studies reported higher PRs in patients undergoing IVF after embryos were cultured in media without glucose and phosphate versus media with glucose and phosphate. One study showed that PRs were lower when embryos were cultured in media lacking glucose and phosphate compared with media containing glucose and phosphate. Some studies have also shown similar PRs with the two types of culture media. CONCLUSION(S): The PRs in IVF patients will not necessarily be enhanced if the embryos are cultured in media without glucose and phosphate.

Culture Media↗
PubMed2003

Homothorax switches function of Drosophila photoreceptors from color to polarized light sensors.

Different classes of photoreceptors (PRs) allow animals to perceive various types of visual information. In the Drosophila eye, the outer PRs of each ommatidium are involved in motion detection while the inner PRs mediate color vision. In addition, flies use a specialized class of inner PRs in the "dorsal rim area" of the eye (DRA) to detect the e-vector of polarized light, allowing them to exploit skylight polarization for orientation. We show that homothorax is both necessary and sufficient for inner PRs to adopt the polarization-sensitive DRA fate instead of the color-sensitive default state. Homothorax increases rhabdomere size and uncouples R7-R8 communication to allow both cells to express the same opsin rather than different ones as required for color vision. Homothorax expression is induced by the iroquois complex and the wingless (wg) pathway. However, crucial wg pathway components are not required, suggesting that additional signals are involved.

Animals↗
PubMed1998

Mapping of androgen, estrogen and progesterone receptors in the anal continence organ.

OBJECTIVE: To investigate the expression of androgen, estrogen and progesterone receptors (ARs, ERs, PRs) in the tissues of the anal continence organ using immunohistochemical techniques. STUDY DESIGN: Thirty-nine samples of anorectal tissue were obtained from 23 patients (seven men, seven premenopausal women and nine postmenopausal women). Immunostaining for ARs, ERs and PRs was performed by the ABC technique using 3,3'-diaminobenzidine tetrahydrochloride as the chromogen. RESULTS: Specific immunostaining for ARs, ERs and PRs was found exclusively over cell nuclei. ARs were found in the smooth muscle cells of the internal anal sphincter in all but one of the females (10/11) and all males (7/7), ERs were found in 12/12 females and 4/7 males, and PRs were found in 4/10 females and 1/7 males. The squamous epithelium exhibited a similar pattern of immunostaining. The nuclei of the striated muscle fibers expressed none of the sex steroid receptors investigated. CONCLUSION: The intense expression of ARs, ERs and, in some cases, PRs in the tissues of the anal continence organ at all ages and in both sexes indicates that this organ is a target for sex steroid hormones.

Adult↗
PubMed2003

Progesterone receptors in mammary gland development and tumorigenesis.

The steroid hormone, progesterone (P), is a central coordinator of all aspects of female reproductive activity and plays a key role in pregnancy-associated mammary gland morphogenesis and mammary tumorigenesis. The effects of P on the mammary gland are mediated by two structurally and functionally distinct nuclear receptors PR-A and PR-B that arise from a single gene. Null mutation of both receptors in PR knockout (PRKO) mice has demonstrated a critical role for PRs in mediating pregnancy-associated mammary ductal branching and lobuloalveolar differentiation and in initiation of mammary tumors in response to carcinogen. Analysis of the molecular genetic pathways disrupted in PRKO mice has recently yielded important insights into the molecular mechanisms of regulation of mammary gland morphogenesis by PRs. In addition to its essential role in regulating proliferative and differentiative responses of the adult mammary gland during pregnancy, P plays a critical role in the protection against mammary tumorigenesis afforded by early parity. Thus, the effects of P on postnatal developmental plasticity of the mammary gland differ between young and adult glands. This review will summarize recent advances in our understanding of 1) the molecular mechanisms by which PRs mediate pregnancy-associated mammary gland morphogenesis, 2) the role of PRs in mediating tumorigenic responses of the adult mammary gland to carcinogen, and 3) the role of P in long-term protection of the juvenile mammary gland against tumorigenesis. In addition, we will summarize recent insights into the isoform selective contributions to some of these activities of PRs obtained from comparative analysis of P-dependent mammary gland development in PR isoform specific knockout mice lacking either the PR-A (PRAKO) or PR-B (PRBKO).

Animals↗
PubMed2002

Platelets stimulate proliferation of bone cells: involvement of platelet-derived growth factor, microparticles and membranes.

Platelets have been implicated in accelerated bone regeneration in grafting applications. The beneficial effects of platelets may involve their ability to stimulate the proliferation of osteoblasts. We therefore determined the mitogenic response of human trabecular bone-derived cells to human platelets and supernatants of thrombin-activated platelets. We can show a approximately 50-fold increase in DNA-synthesis of bone cells (BC) cultured in the presence of platelets as determined by [3H]-thymidine incorporation. Preventing cell-to-cell contact by a membrane filter did not abrogate the stimulatory effect, indicating the release of soluble factor(s) that are mitogenic for BC. The lipid fraction of the platelets had no effect on [3H]-thymidine uptake into the DNA of BC. Platelet-released supernatant (PRS) increased the rate of [3H]-thymidine incorporation to approximately 20-fold and retained 56% of their activity after incubation at 56 degrees C, and 27% at 100 degrees C, respectively. Neutralizing antibodies raised against platelet-derived growth factor (PDGF) partially suppressed the mitogenic potential of PRS. Gel exclusion chromatography analysis showed that molecules ranging from 25 kDa to more than 70 kDa within the PRS can stimulate BC proliferation. The highest amount of PDGF was detected in fractions corresponding to a molecular weight of 28-37 kDa as determined by immunoassay. The mitogenic activity was not restricted to soluble growth factors because microparticles in the PRS and platelet membranes also increased BC proliferation. Our data indicate that native platelets, the respective PRS, microparticles, and platelet membranes can stimulate the mitogenic activity of BC, thereby contributing to the regeneration of mineralized tissue.

Aged↗
PubMed1997

Effects of an educational intervention on residents' knowledge and attitudes toward interactions with pharmaceutical representatives.

To assess primary care resident and faculty knowledge and attitudes concerning interactions between physicians and pharmaceutical representatives (PRs) and to measure changes in residents' knowledge and attitudes after an educational intervention, we conducted preintervention and postintervention surveys with a causal-comparative group in a university-based primary care residency program. All primary care internal medicine and internal medicine-pediatrics residents and faculty were given the voluntary survey. In general, residents and faculty demonstrated similar responses for the preintervention survey. Differences between faculty and resident opinions were seen in two areas. Faculty were more likely than residents to believe that PRs sometimes use unethical marketing practices (p < .05) and that the amount of contact with PRs in the outpatient clinic is excessive (p < .01). The postintervention survey of residents demonstrated significant differences between the control and intervention groups for three attitude scales. After the intervention, residents showed an increased belief that PRs may use unethical marketing practices (p < .01), that marketing gifts with no patient benefit may be inappropriate (p = .05), and that other physicians' prescribing patterns could be negatively influenced through the acceptance of gifts (p < .05). A brief educational intervention can change resident attitudes concerning physician interactions with PRs.

Data Collection↗
PubMed2005

Retrograde signaling from the brain to the retina modulates the termination of the light response in Drosophila.

A critical factor in visual function is the speed with which photoreceptors (PRs) return to the resting state when light intensity dims. Several elements subserve this process, many of which promote the termination of the phototransduction cascade. Although the known elements are intrinsic to PRs, we have found that prompt restoration to the resting state of the Drosophila electroretinogram can require effective communication between the retina and the underlying brain. The requirement is seen more dramatically with long than with short light pulses, distinguishing the phenomenon from gross disruption of the termination machinery. The speed of recovery is affected by mutations (in the Hdc and ort genes) that prevent PRs from transmitting visual information to the brain. It is also affected by manipulation (using either drugs like neostigmine or genetic tools to inactivate neurotransmitter release) of cholinergic signals that arise in the brain. Intracellular recordings support the hypothesis that PRs are the target of this communication. We infer that signaling from the retina to the optic lobe prompts a feedback signal to retinal PRs. Although the mechanism of this retrograde signaling remains to be discerned, the phenomenon establishes a previously unappreciated mode of control of the temporal responsiveness of a primary sensory neuron.

Animals↗
PubMed1997

Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells.

Alveolar rhabdomyosarcoma (ARMS) cells often harbor one of two unique chromosomal translocations, either t(2;13)(q35;q14) or t(1;13)(p36;q14). The chimeric proteins expressed from these rearrangements, PAX3-FKHR and PAX7-FKHR, respectively, are potent transcriptional activators. In an effort to exploit these unique cancer-specific molecules to achieve ARMS-specific expression of therapeutic genes, we have studied the expression of a minimal promoter linked to six copies of a PAX3 DNA binding site, prs-9. In transient transfections, expression of the prs-9-regulated reporter genes was approximately 250-fold higher than expression of genes lacking the prs-9 sequences in cell lines derived from ARMS, but remained at or below baseline levels in other cells. High expression of these prs-9-regulated genes was also observed in a cancer cell line that lacks t(2;13) but was stably transfected with a plasmid expressing PAX3-FKHR. Transfection of a plasmid containing the diphtheria toxin A chain gene regulated by prs-9 sequences (pA3-6PED) was selectively cytotoxic for PAX3-FKHR-expressing cells. This was shown by inhibition of gene expression from cotransfected plasmids and by direct cytotoxicity after transfected cells were isolated by cell sorting. Gene transfer of pA3-6PED may thus be useful as a cancer-specific treatment strategy for t(2;13)- or t(1;13)-positive ARMS. Furthermore, gene transfer of fusion protein-regulated toxin genes might also be applied to the treatment of other cancers that harbor cancer-specific chromosomal translocations involving transcription factors.

DNA-Binding Proteins↗