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PubMed1980

Pressor effect of the baroreceptor reflex, depressor effect of septal stimulation and their interactions.

Experiments on limbic modulation of the baroreceptor system show that changes in blood pressure caused by electrical stimulation of the septal area (PRS), carotid occlusion (PRC) and the interaction of these factors (PRI) can be described by power functions, if the pressure curves are divided into two branches, taking into account the minimum pressure attained during PRS and the time of occlusion release during PRC and PRI. A system analysis approach may be an important tool to disclose characteristics of changes undergone by blood pressure, which remain otherwise undetected.

Animals↗

PubMed1990

Platelet-derived mitogenic activity and bone marrow fibrosis in myeloproliferative disorders.

Mitogenic activity, measured as 3H-thymidine incorporation by NIH 3T3 cells, following stimulation with platelet-rich-plasma-derived serum (PRS), platelet-poor-plasma-derived serum and platelet extract was studied in 14 patients with myeloproliferative disorders (MPD) and 7 normal subjects. Reduced mitogenic activity was found in PRS and platelet extract of patients with MPD, as compared to controls. The average levels of platelet-derived growth factor (PDGF) equivalents were as follows: 16.3 +/- 7.2 pg/10(6) platelets in controls, 6.2 +/- 2.2 pg/10(6) (p less than 0.05) platelets in patients with polycythaemia vera, 1.8 +/- 0.4 pg/10(6) (p less than 0.01) platelets in patients with idiopathic myelofibrosis and 4.0 +/- 0.8 pg/10(6) (p less than 0.05) platelets in patients with essential thrombocythaemia (Dunnett test). A reduction of intraplatelet levels of beta-thromboglobulin, although not statistically significant, was found in the same patients. No apparent relation was found between the amount of PDGF equivalents and the degree of bone marrow fibrosis.

Adult↗

PubMed1992

Platinum/oral etoposide therapy in non-small cell lung cancer.

Encouraging response rates have been observed with long-term daily administration of oral etoposide to treat lung cancer. Reasons why EP (etoposide/cisplatin) has been used to treat non-small cell lung cancer (NSCLC), despite the fact that etoposide has demonstrated only a modest degree of activity against this disease, are preclinical suggestions of cisplatin/etoposide synergism and successful results for the combination in treating small cell lung cancer (SCLC). We evaluated a long-term daily oral etoposide regimen in combination with cisplatin for NSCLC. One course consisted of cisplatin on day 1 and etoposide from day 1 through day 21. The course was repeated, beginning at day 29. We concluded that the maximum tolerated dose in this schedule was 50 mg/m2/day oral etoposide for 21 days plus 80 mg/m2 intravenous (i.v.) cisplatin on day 1. The major dose-limiting toxic effect was myelosuppression, and mucositis was also significant in some patients. During this phase I study of 22 patients (18 evaluable), we observed partial responses (PRs) in 4 patients, 1 each with uterine cancer and SCLC, and 2 with squamous cell lung cancers. We then designed a phase II pilot study in patients with advanced NSCLC. The recommended treatment schedule is 80 mg/m2 i.v. cisplatin on day 1 plus 40 mg/m2/day oral etoposide for 21 consecutive days. Of the 13 evaluable patients, PRs were observed in 4 (30.8%), in 2 patients with adenocarcinoma and 2 with squamous cell carcinoma. None of the side effects were severe or life-threatening. Nearly all of the projected doses were given, with delays of 7-10 days. In this pilot phase II study, the response rate of advanced NSCLC was above 30%. Future studies should combine long-term administration of oral etoposide with radiation therapy or surgery to treat stage III NSCLC.

Administration, Oral↗

PubMed1993

A Pain Rating Scale and a Pain Behavior Checklist for clinical use: development, norms, and the consistency score.

A Pain Rating Scale [PRS] and a Pain Behavior Checklist [PBC] were developed for use during a clinical pain interview. Norms were based on 395 chronic pain patients referred for pain management. The PRS obtained ratings of present pain, and worst and least pain during the previous 30 days. The PBC recorded 16 pain behaviors during the 45- to 60-min interview. Normative data were given for seven measures: (1) worst pain rating, past month; (2) least pain rating, past month; (3) present pain rating; (4) difference between worst and least pain ratings; (5) pain behavior score; (6) total pain score (based on Nos. 1, 2, 3, and 5), and (7) consistency score. The consistency score reflects the agreement (or discrepancy) between the pain behavior and present pain ratings. A moderate overall relationship was found between pain behavior and present pain ratings (r = 0.46, p < 0.001). The frequency of good agreement between pain behavior and present pain ratings was unaffected by sex, race, age, pain site, type of injury, duration of pain, legal representation, and evaluating psychologist; but it varied markedly with conscious symptom magnification. Patients seen as consciously exaggerating pain (n = 127) gave higher pain ratings (all p values < 0.001); and had frequent (64.6%) discrepancies between their pain report and pain behavior compared to others (14.2%). The report of present pain was unrelated to pain behavior for conscious exaggerators (r = 0.04, NS); in contrast there was a moderately high relationship for other patients (r = 0.68, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Activities of Daily Living↗

PubMedDate not supplied

Expression of pS2 protein and estrogen and progesterone receptor status in breast cancer.

OBJECTIVE: To investigate pS2 protein expression and estrogen (ER) and progesterone receptor (PR) status of imprints from surgical biopsies of breast cancer cases in relation to the histologic grade of malignancy. STUDY DESIGN: The study group consisted of 50 cases of primary breast carcinomas. For the demonstration of pS2 protein expression an immunocyto-chemical avidin-biotin complex technique was applied. Monoclonal antibody pS2 was used as the primary antibody, diaminobenzidine as the chromogene and hematoxylin as the counterstain. For the evaluation of ERs and PRs, a biochemical method was applied. RESULTS: Sixty-two percent of breast cancer cases showed positive expression of pS2. Of the 31 pS2+ cases, 74% had positive ERs and PRs. A statistically significant difference was observed between pS2 protein expression, ER+, PR+ and histologic grade of malignancy (P < .001). CONCLUSION: Two groups of breast cancer cases can be distinguished: one group that is ER+, PR+ and pS2+, with low malignancy potential, and another group that is ER-, PR- and pS2-, with high malignancy potential.

Adult↗

PubMed1976

Renin, renin substrate and angiotensin II concentration in renal venous blood.

In 22 hypertensive patients with unilateral renal artery stenosis (RAS) and in 8 patients with unilateral or bilateral renal or renal arterial disease, plasma renin activity (PRA), renin substrate (PRS), and angiotensin II (AT II) concentrations were measured in both renal veins and in a peripheral vein 1-2 h after stimulation of renin secretion by injection of frusemide. In patients with elevated PRA in venous blood from a kidney with RAS, AT II was either also elevated, lower than or equal to PRA in peripheral blood, while the contralateral kidney almost invariably extracted AT II. In the 8 patients with variable renal diseases, the concordance between PRA and AT II measurements was better. Results suggest that AT II measurements in renal venous blood are less useful in assessing the functional significance of a RAS than those of PRA. Since PRS is not different in venous plasma of the diseased and the normal kidney, PRA measurements can be regarded as proportional to plasma renin concentration in this condition.

Adult↗

PubMed2006

Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans.

OBJECTIVE: Whereas postprandial hyperlipidemia is a well-described feature of insulin-resistant states and type 2 diabetes, no previous studies have examined intestinal lipoprotein production rates (PRs) in relation to hyperinsulinemia or insulin resistance in humans. METHODS AND RESULTS: Apolipoprotein B-48 (apoB-48)-containing lipoprotein metabolism was examined in the steady-state fed condition with a 15-hour primed constant infusion of [D3]-l-leucine in 14 nondiabetic men with a broad range of body mass index (BMI) and insulin sensitivity. To examine the relationship between indices of insulin resistance and intestinal lipoprotein PR data were analyzed in 2 ways: by correlation and by comparing apoB-48 PRs in those whose fasting plasma insulin concentrations were above or below the median for the 14 subjects studied (60 pmol/L). ApoB-48 PR was significantly higher in hyperinsulinemic, insulin-resistant subjects (1.73+/-0.39 versus 0.88+/-0.13 mg/kg per day; P<0.05) and correlated with fasting plasma insulin concentrations (r=0.558; P=0.038), despite great heterogeneity in apoB-48 kinetic parameters, particularly among the obese subjects. There was no significant difference in clearance of apoB-48 between the 2 groups, nor was there a significant correlation between apoB-48 fractional clearance rate and fasting insulin or homeostasis model assessment-insulin resistance. CONCLUSIONS: These are the first human data to conclusively demonstrate that intestinal apoB-48-containing triglyceride-rich lipoprotein PR is increased in hyperinsulinemic, insulin-resistant humans. Intestinal lipoprotein particle overproduction is a newly described feature of insulin resistance in humans.

Adult↗

PubMed1993

Increased production rates of LDL are common in individuals with low plasma levels of HDL cholesterol, independent of plasma triglyceride concentrations.

Reduced plasma levels of high density lipoprotein (HDL) cholesterol are associated with increased risk for coronary heart disease. Although plasma HDL levels are, in general, inversely related to plasma triglyceride (TG) concentrations, a small proportion of individuals with low HDL cholesterol concentrations have normal plasma TG levels. We wished to determine whether subjects with low plasma levels of HDL cholesterol could be characterized by common abnormalities of lipoprotein metabolism independent of plasma TGs. Therefore, we studied the metabolism of low density lipoprotein (LDL) apolipoprotein B (apo B) and HDL apolipoprotein A-I (apo A-I) in subjects with low plasma HDL cholesterol concentrations with or without hypertriglyceridemia. Nine subjects with low plasma HDL cholesterol levels and normal levels of plasma TGs and LDL cholesterol were studied. Autologous 131I-LDL and 125I-HDL were injected intravenously, and blood samples were collected for 2 weeks. LDL apo B and HDL apo A-I levels were measured by specific radioimmunoassays. Fractional catabolic rates (FCRs, pools per day) and production rates (PRs, milligrams/kilogram.day) for each apolipoprotein were determined. The results were compared with those obtained previously in nine subjects with low plasma HDL cholesterol levels and hypertriglyceridemia and in seven normal subjects. The normal subjects had an HDL apo A-I FCR (mean +/- SD) of 0.21 +/- 0.04. Despite large differences in plasma TG levels, the HDL apo A-I FCRs were similar in the low-HDL, normal-TG group (0.30 +/- 0.09) and the low-HDL, high-TG group (0.33 +/- 0.10), although only the latter value was significantly increased versus control subjects (p < 0.03). Increased apo A-I FCRs were associated with reduced HDL apo A-I levels in both groups of patients. Apo A-I PRs were similar in all groups. In contrast, LDL apo B PR was increased approximately 50% in the low-HDL, normal-TG group (19.3 +/- 6.6; p < 0.01) compared with normal subjects (12.5 +/- 2.6). There was a strong trend toward a greater LDL apo B PR in the low-HDL, high-TG group (17.6 +/- 4.5; p = 0.06 versus normal subjects) as well. LDL apo B FCRs were similar in all three groups. LDL apo B concentrations were also increased in the group with low HDL cholesterol and normal TG levels. Both groups with low HDL cholesterol levels had cholesterol-depleted LDL and HDL particles.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1999

Variant estrogen and progesterone receptor messages in human vascular smooth muscle.

BACKGROUND: Estrogens stimulate growth of breast or uterine cells but have the opposite effect on vascular smooth muscle cells, in which they protect against coronary artery disease with or without concomitant administration of progesterone. A possible cause of differences in hormone action is variable tissue-specific expression of hormone receptor. Therefore, we analyzed the structure of estrogen receptors (ERs) and progesterone receptors (PRs) in human vascular smooth muscle. METHODS AND RESULTS: RNA was isolated from human vascular smooth muscle, and the functional domains of ER-alpha and PR were characterized by reverse transcriptase and polymerase chain reaction. Interestingly, in addition to wild-type ER-alpha and PR, 5 variant ER-alpha and 2 variant PR transcripts were found. These variants contained precise deletions of exons encoding regions of the hormone-binding domain. The PR transcripts lacked exon 4 (PRDelta4) and exon 6 (PRDelta6). The ER-alpha transcripts were missing exon 4 (ERDelta4), exon 5 (ERDelta5), exon 6 (ERDelta6), exon 7 (ERDelta7), and exons 6 and 7, (ERDelta6,7). ER-beta variants were also detected. The PR variants were functionally characterized, and PRDelta6 was found to be a dominant-negative transcription inhibitor of wild-type receptors. Variant PR was present in premenopausal women but absent in postmenopausal women. CONCLUSIONS: Variant PR and ER transcripts are extensively expressed in human vascular smooth muscle. The complex tissue-specific effects of sex hormones may be mediated by the expression of heterogeneous forms of their cognate receptors. The presence of variant ERs and PRs may be of importance in altering the physiological effects of estrogens or progestins in vascular smooth muscle.

Adult↗

PubMedDate not supplied

Plasma renin activity, reactivity, concentration and substrate following hypertension during pregnancy. Effect of oral contraceptive agents.

Plasma renin activity is suppressed in approximately 25% of patients with essential hypertension, and the rate of in vitro angiotensin I production after addition of exogenous renin (renin reactivity) is increased in plasma of hypertensive patients. We have recently observed that blood pressure (116 +/- 1.5/68 +/- 1.7 mm Hg) of young women who had hypertension during a first pregnancy 3--6 years earlier (n = 63) was higher (p less than 0.005) than blood pressure (109 +/- 1.4/61 +/- 1.7 mm Hg) of women who remained normotensive during pregnancy (n = 52). To determine if alterations of the renin-angiotensin axis observed in patients with established hypertension also occur in young adults with relatively high blood pressure, plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate (PRS) and plasma renin reactivity (PRR) were compared in these two groups of subjects. Overall, PRA and PRC were inversely related to systolic blood pressure (p less than 0.02). Excluding women on oral contraceptive agents, the PRA response to standardized treadmill exercise was suppressed (less than 1.0 ng/ml/hr) in 19% of women with a history of hypertension during pregnancy and in no women who remained normotensive throughout a previous pregnancy; PRR did not differ (p greater than 0.8) in the two groups of young mothers (27.1 ng/ml/30 min +/- 1.2 SE VS 26.2 ng/ml/30 min +/- 0.9 SE). Thus, renin suppression, but not increased PRR, precedes the onset of hypertension. Oral contraceptive usage was associated with higher systolic blood pressures, increased PRS, and low PRC. Highest blood pressures and lowest PRA occurred in women with a history of hypertension during pregnancy who were taking oral contraceptive agents at the time of study.

Adolescent↗

PubMedDate not supplied

Low plasma renin activity in normotensive patients with diabetes mellitus: relationship to neuropathy.

To determine the effect of diabetes mellitus on the renin-aldosterone system, independent of age, nephropathy, or hypertension, 16 normotensive diabetics with long-term disease (mean duration, 15 years) and no (14) or minimal (2) proteinuria, were compared to nine age-matched, normotensive controls. Plasma renin activity (PRA) measured supine and after 4 hours of quiet ambulation, both on an ad libitum diet and on Day 4 of a 10 mEq low sodium diet, was always lower in the diabetics (31%-56% of control values). After the combined stimulus of sodium depletion and ambulation, PRA was 2.2 +/- 0.4 in the diabetics compared to 3.4 +/- 0.2 ng/ml/hr in controls (p less than 0.025). On the low sodium diet, PRA and the postural response of PRA correlated directly with the degree of autonomic dysfunction as quantitated by the velocity of esophageal peristalsis (r = 0.60, p less than 0.05; r = 0.75, p less than 0.005 respectively), suggesting that autonomic neuropathy was an important factor contributing to low PRA in these patients. No other parameters correlated with PRA. Plasma renin substrate (PRS) tended to be lower in diabetics (1053 +/- 95 vs 1358 +/- 132 ng AI/ml; p less than 0.07) but not sufficiently so to account for the substantial difference in PRA. Furthermore, PRS did not correlate with PRA. Fasting blood sugar, while higher in diabetics (209 vs 96 mg/dl), and creatinine clearance, which was lower (112 +/- 13 vs 78 +/- 4 ml/min; p less than 0.01), also did not correlate with PRA. Other factors, including serum creatinine, serum potassium, urinary aldosterone, blood pressure, and body weight, and the responses of these parameters to sodium depletion, were similar in diabetics and controls. These data implicate visceral neuropathy as a major factor in the hyporeninemia of these diabetics.

Autonomic Nervous System Diseases↗

PubMed2003

An RCS-like retinal dystrophy phenotype in mer knockout mice.

PURPOSE: To determine whether mice that are homozygous for a targeted disruption of the Mer receptor tyrosine kinase gene (mer(kd)) manifest a retinal dystrophy phenotype similar to RCS rats, which carry a mutation in the orthologous gene MERTK: METHODS: Eyes of mer(kd) and C57BL/6 wild-type (WT) mice were examined by light and electron microscopy, whole-eye rhodopsin measurement, and Ganzfeld electroretinography (ERG). RESULTS: The mer(kd) mice showed rapid, progressive degeneration of the photoreceptors (PRs). Features of the phenotype common to mer(kd) mice and RCS rats included the absence or near absence of phagosomes in the retinal pigment epithelium (RPE) at the peak of outer segment (OS) disc shedding, accumulation of debris and whorls of membranes at the RPE-OS interface, transient supernormal rhodopsin content and OS lengths, the presence of OS vacuoles beginning at early ages, and a relatively slow removal of pyknotic PR nuclei. Most PRs were missing, and OS debris was removed by approximately postnatal day (P)45. Scotopic ERG responses were lower than age-matched WT responses and declined with PR loss. Photopic responses were preserved better than scotopic responses, corresponding with preferential cone preservation as judged histologically. ERG amplitudes were usually unmeasurable beyond P40, although a small-amplitude scotopic threshold response (STR) could still be elicited at P253 in some mice when only scattered PR nuclei remained. CONCLUSIONS: Ablation of Mer function in mer(kd) mice results in a retinal phenotype almost identical with that of RCS rats. The similarity in phenotypes between the two rodent models suggests that an RPE phagocytic defect is a feature of all types of retinal degeneration caused by loss of function of Mer tyrosine kinase, perhaps including mutations in human MERTK.

Animals↗

PubMed1969

Production rates and metabolic clearance rates of human follicle-stimulating hormone in premenopausal and postmenopausal women.

The production rates (PR) and the metabolic clearance rates (MCR) of human follicle-stimulating hormone (HFSH) were determined in six pre- and five postmenopausal women. Human FSH (PER-780) labeled with (131)I to specific activities of 50-150 muc/mug was used as a tracer. Both double antibody and trichloroacetic acid (TCA) precipitation techniques were used to determine HFSH-(131)I levels in infusate and plasma. In four of the subjects MCRs measured by both constant infusion and single injection techniques were the same. By constant infusion, plasma HFSH-(131)I levels reached equilibrium between 4-5 hr.MCRs in six premenopausal women were 14.2+/-1.1 (mean +/-SE) ml/min. MCRs in five postmenopausal women were 12.6 +/-1.1 ml/min. Simultaneous HFSH and human luteinizing hormone (HLH) MCRs were determined in a single patient using HFSH-(125)I and HLH-(131)I as tracers by both constant infusion and single injection methods. These studies showed that the MCR of HFSH was 10.8-11.1 ml/min, and the MCR of HLH was 18.5-19.4 ml/min. From these data and previous MCR and PR studies of HLH from this laboratory, it appears that the MCR of HFSH is about one-half that of HLH. Endogenous HFSH and HLH levels were measured by radioimmunoassay. The PRs of HFSH, calculated by the product of endogenous level and MCR, were 146 +/-27mU/min in the premenopausal women and 2141 +/-264 mM/min in the postmenopausal women. 24-hr PRs, based on these results, compared with reports of 24-hr urinary excretions of biologically active HFSH indicate that 3-5% of production is found in urine in biologically active form. After our single injections of HFSH-(131)I, 8-29% was recovered in urine over 24 hr.

Adult↗

PubMed1995

The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.

The genetic and functional basis of phosphoribosylpyrophosphate synthetase (PRS) superactivity associated with purine nucleotide inhibitor-resistance was studied in six families with this X chromosome-linked purine metabolic and neurodevelopmental disorder. Cloning and sequencing of PRS1 and PRS2 cDNAs, derived from fibroblast total RNA of affected male patients by reverse transcription and PCR amplification, demonstrated that each PRS1 cDNA contained a distinctive single base substitution predicting a corresponding amino acid substitution in the PRS1 isoform. Overall, the array of substitutions encompassed a substantial portion of the translated sequence of PRS1 cDNA. Plasmid-mediated expression of variant PRS1 cDNAs in Escherichia coli BL21 (DE3/pLysS) yielded recombinant mutant PRS1s, which, in each case, displayed a pattern and magnitude of purine nucleoside diphosphate inhibitor-resistance comparable to that found in cells of the respective patient. Kinetic analysis of recombinant mutant PRS1s showed that widely dispersed point mutations in the X chromosome-linked PRPS1 gene encoding the PRS1 isoform result in alteration of the allosteric mechanisms regulating both enzyme inhibition by purine nucleotides and activation by inorganic phosphate. The functional consequences of these mutations provide a tenable basis for the enhanced production of phosphoribosylpyrophosphate, purine nucleotides, and uric acid that are the biochemical hallmarks of PRS superactivity.

Base Sequence↗

PubMed2005

Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus.

Elevated plasma levels of VLDL triglycerides (TGs) are characteristic of patients with type 2 diabetes mellitus (T2DM) and are associated with increased production rates (PRs) of VLDL TGs and apoB. Lipoprotein lipase-mediated (LPL-mediated) lipolysis of VLDL TGs may also be reduced in T2DM if the level of LPL is decreased and/or the level of plasma apoC-III, an inhibitor of LPL-mediated lipolysis, is increased. We studied the effects of pioglitazone (Pio), a PPARgamma agonist that improves insulin sensitivity, on lipoprotein metabolism in patients with T2DM. Pio treatment reduced TG levels by increasing the fractional clearance rate (FCR) of VLDL TGs from the circulation, without changing direct removal of VLDL particles. This indicated increased lipolysis of VLDL TGs during Pio treatment, a mechanism supported by our finding of increased plasma LPL mass and decreased levels of plasma apoC-III. Lower apoC-III levels were due to reduced apoC-III PRs. We saw no effects of Pio on the PR of either VLDL TG or VLDL apoB. Thus, Pio, a PPARgamma agonist, reduced VLDL TG levels by increasing LPL mass and inhibiting apoC-III PR. These 2 changes were associated with an increased FCR of VLDL TGs, almost certainly due to increased LPL-mediated lipolysis.

Adiponectin↗

PubMed1986

Cisplatin plus vindesine versus cisplatin plus VP16 versus doxorubicin plus cytoxan in non-small-cell carcinoma of the lung. A randomized study.

From March 1981 to January 1984, 116 patients with advanced non-small-cell carcinoma of the lung (NSCCL) were randomly assigned to 3 combinations as follows: CDDP + DVA, CDDP + VP16 and DXR + CTX. 94 patients were evaluable for response, 106 for toxicity and survival. Of 31 patients, 15 (48%; 3 CRs and 12 PRs) responded to CDDP + DVA; of 33 patients, 12 (36%, 2 CRs and 10 PRs) responded to CDDP + VP16; of 30 patients, 3 (10%) obtained a PR with DXR + CTX (CDDP + DVA vs DXR + CTX, P less than 0.005; CDDP + VP16 vs DXR + CTX, P less than 0.05; CDDP + DVA vs CDDP + VP16, P = NS). The median duration of response was 22 weeks in the CDDP-DVA group, 17 weeks in the CDDP-VP16 group, and 16 weeks in the DXR + CTX group. No significant difference in survival was observed among the 3 groups (median: 43, 47, 41 weeks, respectively). Hematologic and neurologic toxicities were significantly higher in the DVA-containing regimen. Despite the lack of improvement of overall survival with the CDDP-containing combinations over the DXR + CTX control group, the good response rate makes them suitable to be used in combined therapeutic strategies.

Adult↗

PubMed2025

Genomewide association study of a homogeneous multiple sclerosis cohort: Tumefactive demyelination.

BACKGROUND: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. OBJECTIVE: A GWAS was performed to identify variants associated with TD. METHODS: The case-control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p-value threshold of 5 × 10-8 was GWAS significant and 5 × 10-6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. RESULTS: Variants on chromosome 14 (rs117797734, p = 2.06 × 10-11, odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10-7, OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. CONCLUSION: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.

Humans↗

PubMed2004

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

Adult↗