Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

Given that cancer is one of the main causes of death worldwide, many efforts have been directed toward discovering new treatments and approaches to cure or control this group of diseases. Chemotherapy is the main treatment for cancer; however, a conventional schedule based on maximum tolerated dose (MTD) shows several side effects and frequently allows the development of drug resistance. On the other side, low dose chemotherapy involves antiangiogenic and immunomodulatory processes that help host to fight against tumor cells, with lower grade of side effects. In this review, we present evidence that metronomic chemotherapy, based on the frequent administration of low or intermediate doses of chemotherapeutics, can be better than or as efficient as MTD. Finally, we present some data indicating that noncytotoxic concentrations of antineoplastic agents are able to both up-regulate the immune system and increase the susceptibility of tumor cells to cytotoxic T lymphocytes. Taken together, data from the literature provides us with sufficient evidence that low concentrations of selected chemotherapeutic agents, rather than conventional high doses, should be evaluated in combination with immunotherapy. Copyright © 2012 UICC.

Use of a Low Dose of Equine Purified FSH to Induce Multiple Ovulations in Mares

The effects of a low dose of equine purified FSH (eFSH) on incidence of multiple ovulations and embryo recovery rate in mares were studied. During the physiological breeding season in Brazil (19 degrees 45'45'S), 14 Mangalarga Marchador donor mares were used in a crossover study and another 25 mares of the same breed, between 3 years and 12 years of age were used as recipients for the embryo transfers. Donors were monitored during two consecutive oestrus cycles, an untreated control cycle followed by a treated cycle, when eFSH was administered. In both cycles, after an embryo collection attempt on day 8 post-ovulation all mares received 7.5 mg dinoprost and had their two largest follicles tracked daily by ultrasonography until the period of ovulation. Mares were inseminated every 48 h with extended fresh semen from a single stallion after the identification of a 35-mm follicle until the period of ovulation. Ovulations were induced by intravenous administration of 2.500 IU of human chorionic gonadotropin, upon detection of a 35- to 40-mm follicle. In the treated cycle, 5 mg eFSH was given intramuscularly once a day, from day 8 post previous ovulation until at least one follicle reached 35 mm in diameter. Embryo flushes were performed on day 8 of dioestrus (day 0 = ovulation). Treatment with eFSH resulted in higher (p < 0.05) ovulation rate and incidence of multiple ovulations compared to the control (1.6 vs 1.0 and 50% vs 0%, respectively - one mare had triple ovulation). However, embryo recovery rates in the control and treated cycles were similar (0.8 and 1.0, respectively; p > 0.05). Pregnancy rates in the recipient mares following embryo transfer were similar for the control and eFSH cycles (11/11 and 10/14, respectively). Additional studies are necessary in order to develop a low-dose protocol for the use of eFSH that brings a more consistent contribution to the efficiency of commercial equine embryo transfer programs.

Early Changes Induced by Short-Term Low-Dose Cadmium Exposure in Rat Ventral and Dorsolateral Prostates

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Induction of mitotic crossing-over in diploid strains of Aspergillus nidulans using low-dose X-rays

As a contribution towards detecting the genetic effects of low doses of genotoxic physical agents, this paper deals with the consequences of low-dose X-rays in the Aspergillus nidulans genome. The irradiation doses studied were those commonly used in dental clinics (1-5 cGy). Even very low doses promoted increased mitotic crossing-over frequencies in diploid strains heterozygous for several genetic markers including the ones involved in DNA repair and recombination mechanisms. Genetic markers of several heterozygous strains were individually analyzed disclosing that some markers were especially sensitive to the treatments. These markers should be chosen as bio-indicators in the homozygotization index assay to better detect the recombinogenic/ carcinogenic genomic effects of low-dose X-rays. ©FUNPEC-RP.

Low dose of dichloroacetate infusion reduces blood lactate after submaximal exercise in horses

The acute administration of an indirect activator of the enzyme pyruvate dehydroge-nase (PDH) in human athletes causes a reduction in blood lactate level during and after exercise. A single IV dose (2.5m.kg-1) of dichloroacetate (DCA) was administered before a submaximal incremental exercise test (IET) with five velocity steps, from 5.0 m.s-1 for 1 min to 6.0, 6.5, 7.0 and 7.5m.s-1 every 30s in four untrained mares. The blood collections were done in the period after exercise, at times 1, 3, 5, 10, 15 and 20 min. Blood lactate and glucose (mM) were determined electro-enzymatically utilizing a YSI 2300 automated analyzer. There was a 15.3% decrease in mean total blood lactate determined from the values obtained at all assessment times in both trials after the exercise. There was a decrease in blood lactate 1, 3, 5, 10, 15 and 20 min after exercise for the mares that received prior DCA treatment, with respective mean values of 6.31±0.90 vs 5.81±0.50, 6.45±1.19 vs 5.58±1.06, 6.07±1.56 vs 5.26±1.12, 4.88±1.61 vs 3.95±1.00, 3.66±1.41 vs 2.86±0.75 and 2.75±0.51 vs 2.04±0.30. There was no difference in glucose concentrations. By means of linear regression analysis, V140, V160, V180 and V200 were determined (velocity at which the rate heart is 140, 160, 180, and 200 beats/minute, respectively). The velocities related to heart rate did not differ, indicating that there was no ergogenic effect, but prior administration of a relatively low dose of DCA in mares reduced lactatemia after an IET.

Poly [1,1'-bis(ethynyl)-4,4'-biphenyl(bis-tributylphosphine)Pt(II)] solutions used as low dose ionizing radiation dosimeter

In this work, the effect of gamma radiation on the optical properties of polymetallayne poly[1,1'-bis(ethynyl)-4,4'-biphenyl(bis-tributylphosphine)Pt(II) ] (Pt-DEBP) in chloroform solution is studied. The samples were irradiated at room temperature with doses from 0.01 Gy to 1 Gy using a 60Co gamma ray source. A new band at 420 nm is observed in the emission spectra, in superposition to the emission maximum at 398 nm, linearly dependent on dose. We propose to use the ratio of the emission amplitude bands as the dosimetric parameter. This method proved to be robust, accurate, and can be used as a dosimeter in medical applications. © 2013 AIP Publishing LLC.

Low Dose of the Anesthetic Propofol Does Not Induce Genotoxic or Mutagenic Effects in Nile Tilapia

We demonstrate the efficacy of propofol (2,6-diisopropylphenol) as an anesthetic when administered to fish in an immersion bath and show the absence of genetic side effects following short-term exposure to the drug. All tested fish were anesthetized (as indicated by loss of posture and lack of response to physical stimulation), and both the comet assay (tail intensity) and the micronucleus assay revealed that propofol does not induce primary DNA damage or chromosome damage in the fish Nile Tilapia Oreochromis niloticus. Our results should be considered in light of our particular test conditions, including the water temperature (similar to 25 degrees C), the life stage and size of the fish, and the single exposure to the anesthetic. We suggest that propofol is a promising anesthetic in terms of its lack of genotoxic effects, at least in low dosages in adult Nile Tilapia.Received June 25, 2013; accepted October 15, 2013

Graves ophthalmopathy: low-dose glucocorticoid increases peroxisome proliferator-activated receptor-gamma gene expression

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Immunomodulatory effects of low dose chemotherapy and perspectives of combanation with immunotherapy

Nowadays cancer is one of the main causes of death and many efforts worldwide have been driven to find out new treatments and approaches in order to extinguish or reduce this group of disorder. Chemotherapy is the main treatment for cancer, however, conventional schedule based on maximum tolerated dose (MTD) show several side effects and frequently allow the development of drug resistance. In this review we present the evidence that metronomic chemotherapy, based on the frequent administration of low or intermediate doses of chemotherapeutics is as efficient as MTD and works better in some situations. Finally, we present some data indicating that noncytotoxic concentrations of antineoplastic agents are able to both up-regulate the immune system and increase the susceptibility of tumor cells to cytotoxic T lymphocytes. Taken together, data from the literature provide us the evidence that low concentrations of selected chemotherapeutics agents, rather than conventional high doses, should be chosen for combination with immunotherapy

Low-dose combined oral contraceptive use is associated with lower bone mineral content variation in adolescents over a 1-year period

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of low-dose combined oral contraceptives on bone mineral density in adolescents: a 1-year follow-up

Purpose: To assess the bone mineral density (BMD) and bone mineral content (BMC) of female adolescents in use of standard low-dose combined oral contraceptives (COC) (EE 20 mcg/ Desogestrel 150 mcg) for a one-year period and to compare results against healthy controls matched for age and gender not in use of COC. Methods: A prospective, longitudinal study was conducted.Fifty adolescents, 12 to 20 years of age, were divided into a COC user group (n 35) and a control group (n 15) and submitted to a Bone Densitometry scan using dual-energy X-ray absorptiometry (DXA) at study inclusion and again at 12-month follow-up. Results: Results showed no statistically significant differences between the COC user and control groups at the initial moment. However, at 12-month follow-up, COC users showed negative mean percentage variation between initial and follow-up values for lumbar spine BMD and BMC of -1.09% and -1.58%, respectively, whereas controls had positive variations of +12.44% and +15.87%, respectively. Thus, the adolescents in use of COC showed a loss, albeit slight, in bone mass whereas the control group showed an increase. Conclusions: The low dose COC assessed (EE 20 mcg/Desogestrel 150 mcg) appeared to negatively affect the process of bone mass acquisition which occurs during adolescence.

PS-042c is low-dose combined oral contraceptives use associated to lower bone mineral content variation in adolescents over a one-year period?

Background Low dose combined oral contraceptives (COC) can interfere in bone mass acquisition during adolescence. To evaluate bone mineral density (BMD) and bone mineral content (BMC) in female adolescents taking a standard low-dose (EE 20 µg/Desogestrel 150 µg) combination oral contraceptive (COC) over a one-year period and compare with healthy adolescents from the same age group not taking COCs.Methods A non-randomised parallel control study with one-year follow-up. Sixty-seven adolescents from 12 to 20 years of age, divided into COC users (n = 41) taking 20 µg EE/150 µg Desogestrel and non-user controls (n = 26), were evaluated through bone densitometry examinations at baseline and 12 months later. Comparisons between groups at study start was done through the Mann-Whitney test with significance level fixed at 5% or corresponding p value; comparisons between groups at study start and 12 months later used variations in median percentages for bone mass variables.Results COC users presented low bone mass acquisition in the lumbar spine and BMD and BMC median variations between baseline and at 12 months of 2.07% and +1.57% respectively whereas the control group presented variations of +12.16% and +16.84% for BMD and BMC, respectively, over the same period. The total body BMD and BMC presented similar evolution during the study in both groups. Statistical significance (pConclusion The use of a low COC dose (EE 20 µg/Desogestrel 150 µg) was associated to lower bone mass acquisition in adolescents during the study period.Trial registration: (Register Number):RBR-5 h9b3c

Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)