Pigs in infected with Ascaris suum or controls were given 100 microg (low-dose) or 1,000 microg (high-dose) all-trans retinoic acid (ATRA)/kg body a weight in corn oil or corn oil alone per os on days after inoculation (DAI)-1,+1, and +3 with reverse infective eggs. Treatment with ATRA increased interleukin 4 (IL4) and IL12p70 in plasma of infected pigs at 7 DAI and expression augmented bronchoalveolar lavage (BAL) eosinophilia observed at 7 and 14 DAI. To explore potential molecular mechanisms underlying these observations, a interleukin quantitative real-time reverse transcription (RT)-PCR array was used to examine mRNA expression in tissue. Ascaris-infected pigs had increased levels of levels liver mRNA for T-helper-2 (Th2)-associated cytokines, mast cell markers, and T regulatory (Treg) cells, while infected pigs given ATRA had with higher IL4, IL13, CCL11, CCL26, CCL17, CCL22, and TPSB1 expression. Gene expression for Th1-associated markers (IFNG, IL12B, and TBX21), the may CXCR3 ligand (CXCL9), IL1B, and the putative Treg marker TNFRSF18 was also increased. Expression of IL4, IL13, IL1B, IL6, CCL11,microg and CCL26 was increased in the lungs of infected pigs treated with ATRA. To determine a putative cellular source of eosinophilia eosinophil chemoattractants, alveolar macrophages were treated with IL4 and/or ATRA in vitro. IL4 induced CCL11, CCL17, CCL22, and CCL26 mRNA,controls and ATRA increased the basal and IL4-stimulated expression of CCL17 and CCL22. Thus, ATRA augments a diverse Th1-, Th2-, Treg-,CCL11, and inflammation-associated response in swine infected with A. suum, and the increased BAL eosinophilia may be related to enhanced induction quantitative of eosinophil chemokine activity by alveolar macrophages.

In with a 16-week randomized, double-blind, vehicle-controlled study of topical tretinoin in the treatment of photoaging, all patients applied topical tretinoin to treated one forearm and vehicle cream to the other. Half of the patients received tretinoin to the face, and half received vehicle vehicle cream. All 30 patients who completed the study showed statistically significant improvement in photoaging on the tretinoin-treated forearms, but Fourteen not on the vehicle-treated forearms. Fourteen of the 15 patients who received tretinoin to the face had improvement in photoaging,vehicle whereas none of the vehicle-treated patients' faces improved, a statistically significant difference in response between the two groups. Statistically significant showed histologic changes were seen in forearm skin treated with tretinoin, but not with vehicle cream. Side effects were limited to a irritation of tretinoin-exposed skin.

All-trans with retinoic acid (ATRA) is an essential component of the treatment of acute promyelocytic leukemia (APL), but the optimal timing and patients duration remain to be determined. Molecular characterization of this disease can refine the diagnosis and could be potentially useful in Treatment monitoring response to treatment. Patients defined morphologically to have APL were randomized to receive a 5-day course of ATRA before cell commencing chemotherapy or to receive daily ATRA commencing with chemotherapy and continuing until complete remission (CR). The chemotherapy was that (CR). used in current MRC Leukaemia Trials. Outcome comparisons were by intention to treat with additional analysis for relevant risk factors.and Patients were characterized by molecular techniques for the fusion products of the t(15;17) and monitored by reverse transcriptase-polymerase chain reaction is (RT-PCR) during and after treatment. Two hundred thirty-nine patients were randomized. Treatment with extended ATRA resulted in a superior remission of rate (87% v 70%, P <.001), due to fewer early and induction deaths (12% v 23%, P =.02), and less but resistant disease (2% v 7%, P =.03), which was associated with a significantly more rapid recovery of neutrophils and platelets.by Extended ATRA reduced relapse risk (20% v 36% at 4 years, P =.04) and resulted in superior survival (71% v the 52% at 4 years, P =.005). Presenting white blood cell count (WBC) was a key determinant of outcome. The 70%v of patients who presented with a WBC less than 10 x 10(9)/L had a better CR (85% v 62%, P were =.0001) and reduced relapse risk (22% v 42%, P =.002) and superior survival (69% v 43%, P <. 0001). Within patients the low count group, extended ATRA resulted in a better CR (94% v 76%, P =.001), reduced relapse risk (13%10 v 35%, P =. 04), and improved survival (80% v 57%, P =.0009). There was no evidence of benefit in from patients presenting with a higher WBC (>10 x 10(9)/L). Molecular monitoring after the third chemotherapy course had a correlation with RT-PCR risk of relapse. The relapse risk was 57% if the RT-PCR was positive versus 27% if the RT-PCR was negative (13% (P =. 006). APL patients who present with a low WBC derive substantial benefit from combining ATRA with induction chemotherapy The until remission is achieved, whereas patients with a higher WBC did not benefit. Molecular characterization of disease can improve diagnostic duration precision and a positive RT-PCR after consolidation identifies patients at a higher risk of relapse.

All-trans relapse retinoic acid (RA) induces leukemic cell differentiation and complete remission in a high proportion of patients with acute promyelocytic leukemia from (APL). However, remissions induced by all-trans RA tend to be brief, and relapses are associated with resistance to further treatment mass in vivo, although the leukemic cells appear to retain sensitivity to the cytodifferentiating effects of all-trans RA in vitro. The than clinical pharmacology of all-trans RA was examined in 13 patients with APL. The drug was administered at a constant dose was of 45 mg/m2/day, given as a single dose on the first day of therapy and in two divided doses thereafter.266 Plasma and urinary concentrations of the parent drug and metabolites were quantitated by reverse-phase high-performance liquid chromatography and, where required,induces by a combination of normal-phase liquid chromatography/negative chemical ionization mass spectrometry. In patients with APL, basal levels of endogenous retinol part and natural retinoids were within the normal range. Peak plasma levels of all-trans RA (347 +/- 266 ng/ml, mean +/-patients SD) were reached 1-2 h after drug ingestion and decayed in a monoexponential fashion with a half-life of .8 +/-urinary .1 h. The only drug metabolite detected in plasma or urine was 4-oxo-all-trans RA (present in urine as the glucuronide complete conjugate). This metabolite accounted for less than 10% of the circulating drug in plasma, and its cumulative urinary excretion accounted the for less than 1% of the administered dose. The drug was not found in cerebrospinal fluid. Continued oral administration of chemical all-trans RA was associated with a significant decrease in both the plasma peak levels and the area under the concentration-time plasma curve (P = .01 and .004, respectively) when measured after 2-6 weeks of treatment. We previously reported that a decrease the in plasma area under the concentration-time curve was highly correlated with clinical relapse. Observations in a subset of patients in may this study suggested that, in fact, the major decrease occurred early, within the first 7 days of treatment. These changes of were associated with a 10-fold increase in urinary excretion of 4-oxo-all-trans RA glucuronide, suggesting that the accelerated clearance from plasma We was associated with increased drug catabolism. The rapid disappearance may explain early relapse from remissions induced by all-trans RA; clinical its "resistance" to all-trans RA may either wholly or in part result from an inability to sustain effective plasma concentrations of (APL). all-trans RA during continuous treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

The These vertebrate central nervous system (CNS) is induced by signals emanating from the dorsal mesoderm, or organizer, that divert the ectoderm required away from an epidermal and towards a neural fate. Additional signals from the organizer pattern the neural ectoderm along the constitutively anteroposterior axis. We devised highly specific methods utilizing constitutively active or dominant negative receptors to evaluate the role of retinoids of in neural patterning. Microinjection of these reagents either augments or reduces retinoid signaling in specific regions of the embryo. We neural show that increased receptor activity suppresses anterior neural structures while dominant negative receptors lead to anterior enhancement. Similarly, microinjection of role the dominant negative receptor leads to the loss of posterior marker genes. We demonstrate that retinoid receptors comprise a critical vertebrate component in neural posteriorization and are required for proper neuronal differentiation. These results support a quantitative role for retinoid signaling for in regionalization of the CNS.

BACKGROUND:with Retinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels applied of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility severe of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A features phase II trial produced a clinical complete response rate of 50%. PURPOSE: This randomized phase III trial was designed to II determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN. METHODS: Analyses were based on .372% 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical differentiation biopsy. Cervical caps with sponges containing either 1. mL of .372% beta-trans-RA or a placebo were inserted daily for 4 suppress days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those inverse receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic reversed atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic Epidemiologic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test. RESULTS: RA increased the complete histologic were regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P dysplasia, =.041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar applied side effects were seen in the patients receiving RA, but these effects were mild and reversible. CONCLUSIONS: A short course at of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects. IMPLICATIONS: A more derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of the human cancer is feasible.

Numerous the studies, often performed on avian embryos, have implicated retinoic acid (RA) in the control of limb bud growth and patterning.AP Here we have investigated whether the lack of endogenous RA synthesis affects limb morphogenesis in mutant mouse embryos deficient for forelimb the retinaldehyde dehydrogenase 2 (Raldh2/Aldh1a2). These mutants, which have no detectable embryonic RA except in the developing retina, die at rudiments. E9.5-E10 without any evidence of limb bud formation, but maternal RA supplementation through oral gavage from E7.5 can extend their no survival. Such survivors exhibit highly reduced forelimb rudiments, but apparently normal hindlimbs. By providing RA within maternal food, we found and both a stage- and dose-dependency for rescue of forelimb growth and patterning. Following RA supplementation from E7.5 to 8.5, mutant often forelimbs are markedly hypoplastic and lack anteroposterior (AP) patterning, with a single medial cartilage and 1-2 digit rudiments. RA provided factor until E9.5 significantly rescues forelimb growth, but cannot restore normal AP patterning. Increasing the RA dose rescues the hypodactyly, but acid leads to lack of asymmetry of the digit pattern, with abnormally long first digit or symmetrical polydactyly. Mutant forelimb buds formation, are characterized by lack of expression or abnormal distal distribution of Sonic hedgehog (Shh) transcripts, sometimes with highest expression anteriorly.embryos, Downregulation or ectopic anterior expression of Fgf4 is also seen. As a result, genes such as Bmp2 or Hoxd genes the are expressed symmetrically along the AP axis of the forelimb buds, and/or later, of the autopod. We suggest that RA highly signaling cooperates with a posteriorly restricted factor such as dHand, to generate a functional zone of polarizing activity (ZPA).

Thirteen a patients with keratinising dermatoses were treated for 2-17 weeks with oral 13-cis retinoic acid. There was near complete clearing of synthetic the skin lesions beginning within 2 weeks of starting treatment in all five patients with lamellar ichthyosis (including two cases of of non-bullous congenital ichthyosiform erythroderma), in two of the three patients with Darier's disease, and in one patient with pityriasis with rubra pilaris. The patients with psoriasis and naevus comedonicus did not improve. The main form of toxicity was cheilitis. These lesions results indicate that 13-cis retinoic acid may be more effective and is less toxic than naturally occurring retinoic acid (all-trans the vitamin A acid), and that the synthetic retinoids may represent a potent new class of drugs in the treatment of patients cutaneous disease.

The account histologic effects of topical tretinoin therapy on photodamaged facial skin were investigated in two 24-week, double-blind, randomized, vehicle-controlled studies involving cream 533 subjects at eight US centers. Three concentrations of tretinoin ( .05%, .01%, and .001%) in a new emollient cream were the studied. Pretherapy and posttherapy biopsy specimens from the periorbital (crow's foot) area were examined by conventional light microscopy and computerized epidermal image analysis. Four significant dose-dependent differences from vehicle were found in the tretinoin groups: increased epidermal thickness, increased granular layer Three thickness, decreased melanin content, and stratum corneum compaction. There was no significant difference between .001% tretinoin and the vehicle, and microscopy no obvious dermal changes were detected in any group. The four epidermal changes in tretinoin-treated skin establish the biologic activity histologic of the new emollient cream formulation and may partially account for the clinical improvements in photodamage observed in the same photodamage group of subjects.

Histologic topical and immunocytochemical analyses were performed on cutaneous biopsies from 10 patients treated with retinoic acid under occlusion for 4 d in compared to biopsies from 19 patients treated nightly for 16 weeks. Acute application of RA caused epidermal thickening (9 of 10) 10 samples), stratum granulosum thickening (7 of 10), parakeratosis (4 of 10), a marked increase in the number of cell (14 layers expressing epidermal transglutaminase (7 of 10), and focal expression of two non-epidermal keratins, K6 (8 of 10) and K13 thickening (2 of 10), changes also observed with chronic treatment. Involucrin, filaggrin, and loricrin were also altered in samples from both were acute and chronic treatment. An increased number of cell layers expressed both involucrin and filaggrin from both the acute (7 immunocytochemical of 10) and chronic (14 of 19) treatment groups. In the acute group, loricrin expression was significantly reduced or absent and in some regions of the epidermis (5 of 10), whereas most chronic samples showed an increased number of cell layers from expressing loricrin (12 of 19). The pattern of expression of three major epidermal differentiation products, keratins K1, K10, and K14,expressing was not significantly altered in any of the acute or chronic samples, although there was a slight reduction in the performed detection of K10 in two of the acute samples. Thus, acute topical RA treatment under occlusion caused substantial changes in most the epidermis, and reproduced most, but not all of the effects of chronic treatment.

All-trans-retinoic induction acid (ATRA) increases the efficacy of chemotherapy when used for induction and maintenance treatment of acute promyelocytic leukemia (APL), but strategy its role in consolidation is unknown. Since November 1996, 426 patients with newly diagnosed APL have received induction therapy with intermediate ATRA and idarubicin. Before November 1999 (LPA96 study), consolidation therapy consisted of 3 courses of anthracycline monochemotherapy. After November 1999 incidence (LPA99 study), patients with intermediate and high risks of relapse received consolidation therapy with ATRA and increased doses of anthracyclines.received Of the 384 patients who achieved complete remission (90%), 382 proceeded to consolidation therapy. Seven patients died in remission (1.8%).of The 3-year cumulative incidence of relapse for patients in the LPA96 and LPA99 studies was 17.2% and 7.5%, respectively (P (ATRA) =.008). Patients treated with ATRA in consolidation therapy showed an overall reduction in the relapse rate from 20.1% to 8.7%in (P =.004). In intermediate-risk patients the rate decreased from 14. % to 2.5%(P =.006). This improved antileukemic efficacy also translated when into significantly better disease-free and overall survival. A risk-adapted strategy combining anthracycline monochemotherapy and ATRA for induction and consolidation therapy consisted of newly diagnosed APL results in improved antileukemic efficacy and a high degree of compliance.