Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study

The occurrence of chronic myeloid leukemia in pregnancy is rare and its management poses a clinical challenge for physicians treating these patients. We report a 30-year-old woman with chronic myeloid leukemia who became pregnant twice successfully. Philadelphia-positive CML in its chronic phase was diagnosed at 16 weeks of her first gestation. At that time, she received no treatment throughout her pregnancy. At 38 weeks of gestation, a normal infant was delivered by cesarean section. At six weeks postpartum, the patient underwent imatinib mesylate therapy but she could not tolerate the treatment. The treatment was then changed to nilotinib at 400 mg orally b.i.d. Two years later, she became pregnant again while she was on nilotinib 200 mg b.i.d. The unplanned pregnancy was identified during her 7.4 weeks of gestation. Because the patient elected to continue her pregnancy, nilotinib was stopped immediately, and no further treatment was given until delivery. Neither obstetrical complications nor structural malformations in neonates in both pregnancies were observed. Both babies' growth and development have been normal. Although this experience is limited to a single patient, the success of this patient demonstrates that the management of chronic myeloid leukemia in pregnant women may be individualized based on the relative risks and benefits of the patient and fetus

Building pathway clusters from Random Forests classification using class votes

<p>Abstract</p> <p>Background</p> <p>Recent years have seen the development of various pathway-based methods for the analysis of microarray gene expression data. These approaches have the potential to bring biological insights into microarray studies. A variety of methods have been proposed to construct networks using gene expression data. Because individual pathways do not act in isolation, it is important to understand how different pathways coordinate to perform cellular functions. However, there are no published methods describing how to build pathway clusters that are closely related to traits of interest.</p> <p>Results</p> <p>We propose to build pathway clusters from pathway-based classification methods. The proposed methods allow researchers to identify clusters of pathways sharing similar functions. These pathways may or may not share genes. As an illustration, our approach is applied to three human breast cancer microarray data sets. We found that our methods yielded consistent and interpretable results for these three data sets. We further investigated one of the pathway clusters found using PubMatrix. We found that informative genes in the pathway clusters do have more publications with keywords, like estrogen receptor, compared with informative genes in other top pathways. In addition, using the shortest path analysis in GeneGo's MetaCore and Human Protein Reference Database, we were able to identify the links which connect the pathways without shared genes within the pathway cluster.</p> <p>Conclusion</p> <p>Our proposed pathway clustering methods allow bioinformaticians and biologists to investigate how informative genes within pathways are related to each other and understand possible crosstalk between pathways in a cluster. Therefore, building pathway clusters may lead to a better understanding of molecular mechanisms affecting a trait of interest, and help generate further biological hypotheses from gene expression data.</p

Prions in Milk from Ewes Incubating Natural Scrapie

Since prion infectivity had never been reported in milk, dairy products originating from transmissible spongiform encephalopathy (TSE)-affected ruminant flocks currently enter unrestricted into the animal and human food chain. However, a recently published study brought the first evidence of the presence of prions in mammary secretions from scrapie-affected ewes. Here we report the detection of consistent levels of infectivity in colostrum and milk from sheep incubating natural scrapie, several months prior to clinical onset. Additionally, abnormal PrP was detected, by immunohistochemistry and PET blot, in lacteal ducts and mammary acini. This PrPSc accumulation was detected only in ewes harbouring mammary ectopic lymphoid follicles that developed consequent to Maedi lentivirus infection. However, bioassay revealed that prion infectivity was present in milk and colostrum, not only from ewes with such lympho-proliferative chronic mastitis, but also from those displaying lesion-free mammary glands. In milk and colostrum, infectivity could be recovered in the cellular, cream, and casein-whey fractions. In our samples, using a Tg 338 mouse model, the highest per ml infectious titre measured was found to be equivalent to that contained in 6 µg of a posterior brain stem from a terminally scrapie-affected ewe. These findings indicate that both colostrum and milk from small ruminants incubating TSE could contribute to the animal TSE transmission process, either directly or through the presence of milk-derived material in animal feedstuffs. It also raises some concern with regard to the risk to humans of TSE exposure associated with milk products from ovine and other TSE-susceptible dairy species

Differential gonadotropin responses to N-methyl-D,L-aspartate in metestrous, proestrous, and ovariectomized rats.

Peripheral administration of N-methyl-D,L-aspartate (NMA), an analogue of the excitatory amino acid aspartate, elicits LH and prolactin (PRL) release in rats, most likely by increasing endogenous releasing-hormone secretion. These experiments were carried out to assess the degree to which NMA stimulates FSH and to analyze the relationship between endocrine status and responsiveness to NMA in female rats, in contrast to male rats, as described in the companion paper [Biol Reprod 48:000-000]. In experiment 1, estrous rats (n = 10) and diestrous rats (n = 10) and in experiment 2, estrous rats (n = 11) and rats ovariectomized (OVX) 8 days previously (n = 10) were fitted with atrial catheters and injected s.c. with 100 micrograms of an LHRH antagonist or vehicle at 2100 h. Starting at 0900 h the next day (metestrus, proestrus, or Day 9 post-OVX), blood was withdrawn every 10 min for 3 h. Each animal received i.v. 5 mg NMA after the first hour and i.v. 500 ng LHRH after the second hour. NMA significantly increased LH in metestrous and proestrous females, and LHRH antagonist blunted the increases. In OVX females, LH decreased after NMA. FSH was not affected by NMA in any group. PRL increased after NMA in proestrous and metestrous animals. LHRH caused surge-like LH and small FSH increases in vehicle groups; these increases did not differ in amplitude between intact and OVX animals and were blunted by pretreatment with LHRH antagonist. In experiment 3, 10 diestrous rats were fitted with atrial catheters and were serially bled at 2-h intervals from 1200 h on the following day (proestrus) until 0600 h on estrus morning. After the first sample the animals were injected s.c. with 0.2 mg/kg MK801, a noncompetitive NMA receptor antagonist, or with saline. Four of the 5 saline-treated animals exhibited surges of LH and FSH as well as elevated progesterone levels, with LH and progesterone peaking at 2000 h. Five of 5 MK801-treated animals failed to have elevated LH, FSH, or progesterone levels at any time point. These data demonstrate that LHRH mediates the LH response to NMA in rats and that endogenous NMA receptor binding may be necessary for the preovulatory gonadotropin surges. The lack of FSH responses to NMA during periods of low-level gonadotropin secretion suggests that physiological increments in endogenous LHRH secretion sufficient to induce a pulse of LH are insufficient to stimulate pulse-like FSH release.(ABSTRACT TRUNCATED AT 400 WORDS

Differential gonadotropin responses to N-methyl-D,L-aspartate in metestrous, proestrous, and ovariectomized rats.

Peripheral administration of N-methyl-D,L-aspartate (NMA), an analogue of the excitatory amino acid aspartate, elicits LH and prolactin (PRL) release in rats, most likely by increasing endogenous releasing-hormone secretion. These experiments were carried out to assess the degree to which NMA stimulates FSH and to analyze the relationship between endocrine status and responsiveness to NMA in female rats, in contrast to male rats, as described in the companion paper [Biol Reprod 48:000-000]. In experiment 1, estrous rats (n = 10) and diestrous rats (n = 10) and in experiment 2, estrous rats (n = 11) and rats ovariectomized (OVX) 8 days previously (n = 10) were fitted with atrial catheters and injected s.c. with 100 micrograms of an LHRH antagonist or vehicle at 2100 h. Starting at 0900 h the next day (metestrus, proestrus, or Day 9 post-OVX), blood was withdrawn every 10 min for 3 h. Each animal received i.v. 5 mg NMA after the first hour and i.v. 500 ng LHRH after the second hour. NMA significantly increased LH in metestrous and proestrous females, and LHRH antagonist blunted the increases. In OVX females, LH decreased after NMA. FSH was not affected by NMA in any group. PRL increased after NMA in proestrous and metestrous animals. LHRH caused surge-like LH and small FSH increases in vehicle groups; these increases did not differ in amplitude between intact and OVX animals and were blunted by pretreatment with LHRH antagonist. In experiment 3, 10 diestrous rats were fitted with atrial catheters and were serially bled at 2-h intervals from 1200 h on the following day (proestrus) until 0600 h on estrus morning. After the first sample the animals were injected s.c. with 0.2 mg/kg MK801, a noncompetitive NMA receptor antagonist, or with saline. Four of the 5 saline-treated animals exhibited surges of LH and FSH as well as elevated progesterone levels, with LH and progesterone peaking at 2000 h. Five of 5 MK801-treated animals failed to have elevated LH, FSH, or progesterone levels at any time point. These data demonstrate that LHRH mediates the LH response to NMA in rats and that endogenous NMA receptor binding may be necessary for the preovulatory gonadotropin surges. The lack of FSH responses to NMA during periods of low-level gonadotropin secretion suggests that physiological increments in endogenous LHRH secretion sufficient to induce a pulse of LH are insufficient to stimulate pulse-like FSH release.(ABSTRACT TRUNCATED AT 400 WORDS

Differential gonadotropin responses to N-methyl-D,L-aspartate in intact and castrated male rats.

Peripheral administration of N-methyl-D,L-aspartate (NMA), a neuroexcitatory amino acid agonist, probably stimulates LH release through an increase in endogenous LHRH secretion. In the present study, NMA and a potent LHRH antagonist were used to determine the degree to which release of FSH is similarly dependent upon the acute secretion of LHRH. A second aim was to compare responsiveness of LHRH neurons to NMA in castrated and intact male rats. Adult male rats were castrated (n = 10) or sham castrated (n = 11) on the morning of Day 0. After 8 days, rats were fitted with atrial catheters between 0900 and 1200 h; at 2100 h they received s.c. either oil vehicle or 100 micrograms of an LHRH antagonist. Starting at 0900 h on Day 9, 0.5-ml blood samples were collected every 10 min for 3 h. After 1 h of sampling each animal received i.v. 5 mg of NMA in 0.5 ml 0.9% saline. An hour later each rat received i.v. 500 ng of LHRH in 0.5 ml saline. Plasma LH, FSH, and prolactin (PRL) levels were determined by RIA. In the oil-treated sham castrates, mean plasma LH levels were increased by 110% (p &lt; 0.01) within 10 min and remained elevated for 30 min after the injection of NMA. The profile of this LH secretory response was similar to or slightly more robust than endogenous LH pulses observed previously. The NMA-induced LH release was completely blocked by pretreatment with LHRH antagonist. In both oil- and antagonist-treated sham-castrated rats, NMA administration failed to elicit a concomitant increase in plasma FSH levels.(ABSTRACT TRUNCATED AT 250 WORDS