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PubMed2006

Activation of PI3K/Akt signaling and hormone resistance in breast cancer.

Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.

Adult↗

PubMed2005

Effects of genistein on the expression of hepatic genes in two rat strains (Sprague-Dawley and Wistar).

Information about the effects of phytoestrogens in the liver, the main organ of metabolism, is limited. In this study we have examined the dose dependent effects of the phytoestrogen genistein (GEN) on gene expression in rat liver in comparison to the potent estrogen ethinylestradiol (EE). Special attention was paid to strain specific differences between Wistar- (WIS) and Sprague-Dawley rats (SD). EE as well as GEN stimulated the gene expression of insulin like growth factor binding protein 1 (IGFBP-1), similarly in both strains. The mRNA expression of Vitamin D dependent calcium-binding protein (CaBP9k) was stimulated by EE in both strains but more pronounced in WIS rats. Interestingly GEN stimulates CaBP9k gene expression only in SD rats. Gene expression of apolipoprotein AI (ApoAI) was not affected in both strains neither by EE nor by GEN. These results are indicative of strain specific differences in the response of liver genes to GEN or EE.

Animals↗

PubMed2006

Overuse of antihypertensives in patients with acute ischemic stroke.

BACKGROUND: The Stroke Council of the American Heart Association/American Stroke Association (AHA/ASA) recommends conservative management of hypertension (HTN) during acute ischemic stroke (AIS), although clinicians often manage blood pressure more aggressively. Our hypothesis was that aggressive management of HTN in patients with AIS is associated with hypotensive events and worsened neurologic outcomes. METHODS: The study was a retrospective, observational cohort of patients who were admitted to the hospital with AIS. Classification of neurologic outcomes was based on nurses' neurologic assessments and were categorized as "worsened," "stayed the same," or "improved." The accuracy of these assessments was verified by review of physician's progress notes. Management of arterial HTN was recorded in all patients. RESULTS: Fifty medical records of patients with AIS who met inclusion criteria were reviewed. While only 22% of patients met the AHA/ASA criteria for hypertension treatment, 98% of the cohort were given antihypertensive therapy. Relative hypotension occurred in 64% of treated patients. Absolute hypotension associated with antihypertensive medications was uncommon but did occur in 2 of 15 patients who experienced neurologic worsening (13%), in 1 of 28 (3%) of patients who stayed the same, and in none of those who improved. Blood pressure was reduced excessively in all 11 of the patients who met AHA/ASA guidelines for treatment. CONCLUSIONS: Adherence to AHA/ASA guidelines for HTN management during AIS was poor. Initiation or intensification of antihypertensive drugs was not associated with worsened neurologic outcomes. Furthermore, relative hypotension, absolute hypotension and excessive reductions in blood pressure were not associated with worsened neurologic outcomes.

Aged↗

PubMed2000

Repeated oestrus synchronisation of beef cows with progesterone implants and the effects of a gonadotrophin-releasing hormone agonist at implant insertion.

A group of 97 spring-calving beef cows were initially oestrus synchronised with controlled internal drug release (CIDR) intravaginal progesterone implants inserted for nine days and a prostaglandin injection on day 7. Approximately half the cows were given 10 microg buserelin when the implants were inserted, and they all received a single fixed-time artificial insemination (AI) 56 hours after the withdrawal of the implants. The overall pregnancy rate to the first synchronised AI was 55 per cent, the buserelin-treated cows having a pregnancy rate of 63 per cent compared with 47 per cent in the untreated cows (P>0.05). Sixteen days after the first synchronised AI all the cows were re-implanted with used CIDR implants which were removed five days later, and the cows received a second synchronised AI on days 23 to 24. Cows which received the second AI were implanted with new CIDR devices 16 days later and these were removed after five days and the non-pregnant cows received a third synchronised AI. The pregnancy rates to the second and third synchronised services were 74 per cent and 75 per cent, respectively.

Administration, Intravaginal↗

PubMed1999

[Fungal infection in patients with serious disease. Risk analysis of fungal infection].

BACKGROUND: Candidemia is still a major source of high morbidity and mortality in severely disease patients. However, the etiology and risk factor is still unknown. PURPOSE: To evaluate the risk factor of fungal infection in intensive care patients. SUBJECTS AND METHOD: 505 patients who stayed in the intensive care unit of the Critical Care Center, Kyorin University more than 10 days between May 1, 1997 to June 31, 1998 were studied. They were divided into 7 groups: 1) trauma (injury severity score<10), 2) burn (burn index<10), 3) cerebro-vascular disease (unconsciousness 15), were in a coma, and had severe injury of lung parenchyme with chest AIS 3 or higher. In these serious patients, it is necessary to make a rapid diagnosis and treatment based on the surveillance culture and serological examination of sputum and urine for occult fungal infection.

Antifungal Agents↗

PubMed2002

[Antiestrogen therapy in the treatment of breast neoplasms].

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Adult↗

PubMed2004

Diterpenoids from Isodon melissoides.

Nine new diterpenoids, melissoidesins M-U (1-9), along with five known analogues, melissoidesin F (10), xindongnin B (11), melissoidesin G (12), melissoidesin E (13), and dawoensin A (14), were isolated from the aerial parts of Isodon melissoides. The structures of new compounds were elucidated by analysis of spectral evidence including extensive 2D NMR data. Compounds 2, 3, 7, 11, 12, and 14 showed cytotoxicity against the human tumor BGC-823 cell line with IC(50) values less than 10 microg/mL, respectively.

Antineoplastic Agents, Phytogenic↗

PubMed2026

Qingfei Dayuan granules alleviate the inflammatory response in lipopolysaccharide-induced acute lung injury mice by inhibiting the Nf-κB signaling pathway and regulating the complement pathway.

OBJECTIVES: The study aimed to explore the effects and mechanisms by which Qingfei Dayuan granules (QFDY) mitigate pulmonary inflammation in lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: We established an ALI mouse model by intraperitoneal injection of LPS. HE, Transmission electron microscopy, ELISA assay of inflammatory cytokines, and immunohistochemistry (IHC) were used to assess the degree of lung injury and inflammation. Utilizing network analysis and proteomics analysis, the potential targets and pathways of QFDY were identified. Western blot, IHC, and qRT-PCR analysis were used to evaluate the potential mechanism of QFDY. Additionally, the chemical composition of QFDY were performed using UPLC-MS/MS. KEY FINDINGS: QFDY reduced the pathologic changes and inflammatory cell infiltration in lung tissue inflammation. Network and proteomic analysis showed that the mechanism of QFDY protection against ALI is closely related to the Nuclear factor-kappa B (NF-κB) signaling pathway and complement pathway. Animal experiments showed that Qingfei Dayuan granules (QFDY) significantly reduced the levels of IL-1β, IL-6, TNF-α, and lung tissue F4/80-positive alveolar macrophages. Additionally, western blot and qRT-PCR analyses showed the inhibition of the NF-κB pathway. Notably, the levels of mannose-binding lectin (MBL2) were significantly increased, while complement C3a and complement C5a proteins were reduced in the QFDY group compared to the LPS group. CONCLUSIONS: QFDY suppressed the inflammation in LPS-induced ALI by inhibiting the NF-κB and complement pathway.

Animals↗

PubMed2003

On-demand therapy for Los Angeles grade A and B reflux esophagitis: esomeprazole versus omeprazole.

BACKGROUND AND PURPOSE: Reflux esophagitis of Los Angeles grade A or B is more common than grades C and D disease among Taiwanese. This study compared the efficacy of esomeprazole 40 mg and omeprazole 20 mg for starting on-demand therapy for grade A and B reflux esophagitis. METHODS: 100 patients with grade A and B reflux esophagitis were randomized to receive either esomeprazole 40 mg once daily (n = 50) or omeprazole 20 mg once daily (n = 50) for the first 4 weeks. Sustained symptomatic response (SSR) was defined as freedom from symptoms for the last 7 days of the 4-week treatment duration. On-demand therapy was used for the next 4 weeks in patients with SSR; patients without SSR continued with the same proton pump inhibitor regimen. Patients were asked to record their daily severity of acid regurgitation (AR) and heartburn (HB). Medication usage during on-demand therapy was recorded. RESULTS: Forty six patients in the esomeprazole group and 45 patients in the omeprazole group completed the study protocol. The rate of SSR was higher in the esomeprazole group than in the omeprazole group (per-protocol: 73.9% vs 51.1%, p < 0.05; intent-to-treat: 68% vs 46%, p < 0.05). The symptomatic scores for AR and HB were similar between patients taking medication continuously and those taking medication on-demand with both esomeprazole and omeprazole. For patients starting on-demand therapy, the total number of tablets used during 4 weeks was lower in the esomeprazole group than in the omeprazole group (13.5 vs 18.5, p < 0.05). CONCLUSIONS: In patients with grade A and B reflux esophagitis, esomeprazole 40 mg was more effective than omeprazole 20 mg for the initiation of on-demand therapy.

Anti-Ulcer Agents↗

PubMed2005

Effect of perductal paclitaxel exposure on the development of MNU-induced mammary carcinoma in female S-D rats.

BACKGROUND: Breast carcinoma and precancer are thought to start in the lining of the milk duct or lobule. METHODS: At 5weeks of age, rats received a intraperitoneal (ip) injection of MNU for carcinogenesis. After mammary tumors were identified macroscopically using fiberscope, the rats were treated with perductal (pd) or ip injection of paclitaxel tri-weekly. At 36 weeks after MNU injection, tumor burden (No. of >1cm palpable mammary tumors/rat), total number of mammary carcinoma, apoptosis (AI), and microvessel density (MVD) were measured. RESULTS: The administration of paclitaxel through the duct did not produce any toxic side effect. The tumor burden and total number of mammary carcinoma in the pd paclitaxel-treated group were significantly reduced compared to those seen in the ip paclitaxel-treated group. In addition, in the pd paclitaxel-treated group, AI was also increased and MVD was decreased, compared to those in the ip paclitaxel-treated group. CONCLUSION: Local administration of paclitaxel may be useful for treatment of breast cancer.

Alkylating Agents↗

PubMed1990

Loss of androgen dependence is associated with an increase in tumorigenic stem cells and resistance to cell-death genes.

Complete remissions of the androgen-dependent Shionogi mouse mammary carcinoma are observed after androgen withdrawal but invariably the disease recurs and is refractory to further hormonal manipulations. To determine the proportions of androgen-dependent (AD) and -independent (AI) tumorigenic stem cells in parent and recurrent tumors an in vivo limiting dilution assay was developed. There was a marked enrichment of stem cells in the recurrent tumors (1/200 tumor cells) relative to the parent tumors (1/4000 tumor cells) when assayed in male hosts. By assaying tumor takes in female mice, the proportion of AI stem cells was found to be 1/370,000 tumor cells in the parent vs 1/800 tumor cells in the recurrent carcinoma; a 500-fold increase in AI stem cells resulting from androgen-withdrawal. Unexpectedly, no enrichment of AI stem cells was evident in regressing parent tumors; rather, the proportion of such cells was very small (1/2,200,000 tumor cells). This finding implies that the AI cells which survive androgen withdrawal may result from the ability of small number of initially AD stem cells to adapt to an altered hormonal environment. This adaptive process was further defined in terms of the disappearance of androgen receptors from the nucleus and the expression of androgen-repressed genes including the proto-oncogenes, c-fos and c-myc, and the cell death gene, TRPM-2; all of which are constitutively active in recurrent AI tumor cells. Overall, our results indicate: (1) the tumor mass consists mainly of differentiated cells; (2) stem cells initially are AD but at most the killing effect of androgen-withdrawal will be limited to 2-3 logarithms before compensatory adaptive mechanisms supervene; and (3) progression of stem cells to an AI state, in which they are resistant to the killing effects of cell death genes, might be prevented by the inhibition of androgen-repressed adaptive mechanisms which come into play when androgens are withdrawn.

Androgens↗

PubMed2004

Hormonal treatments for the synchronisation of oestrus in dairy goats raised in the tropics.

In tropical areas, local goats are often reported as being able to reproduce throughout the year, whereas an influence of season is found to be a factor when importing different dairy breeds. In these areas, oestrus synchronisation in goats is of interest for both technical (synchronisation of kidding, adjustment to forage availability or to continuous milk supply) and genetic reasons (dissemination of improved genotypes by AI). The use of a progestagen vaginal sponge combined with equine chorionic gonadotrophin (eCG)-cloprostenol injections remains an efficient tool to achieve synchronisation in temperate and tropical zones. However, the oestrus synchronisation treatments currently used for goats in tropical regions were originally developed for goats bred in temperate regions. For this reason, several alternative possibilities for improving the efficiency of the hormonal treatment are evaluated. Oestrus synchronisation with luteolytic agents is efficient (resulting in more than 70% of goats in oestrus) and it takes into account female cyclicity. In developing regions of the tropics, the use of buck teasing appears to be a promising approach to control oestrus and ovulation. The use of this technique provides 60% of females in oestrus within 5 days of introducing the bucks. Considering the availability of nutrients as the ultimate regulator of reproduction in the tropics, the control of nutritional condition is essential before the use of hormonal treatments for oestrus synchronisation in goats bred in these regions takes place.

Animals↗

PubMedDate not supplied

Ovulation induction in rabbit does submitted to artificial insemination by adding buserelin to the seminal dose.

This study was aimed at determining if a GnRH analogue, buserelin, could be used for ovulation induction in rabbit does submitted to artificial insemination (AI) by intravaginal administration, by adding the hormone to the seminal dose. In a first experiment, 39 secondiparous experimental does (Hyplus strain PS19, Grimaud Frères, France, of about 30 weeks of age) were divided into 3 groups of 13 does each, which at the moment of AI received the following treatments, respectively: (1) control: an intramuscular injection of buserelin (0.8 microg/doe), (2) 8 microg/doe of buserelin added to the insemination dose, and (3) 16 microg/doe of buserelin added to the insemination dose. The experiment was done using 3 consecutive cycles at 42 day-intervals (n = 39). Four does from each of the 3 groups had blood taken at the fourth cycle for LH determination at 0, 60, 90, 120 and 150 min relative to AI. Kindling rates were 82% (28/34), 56% (29/36) and 85% (33/39), respectively for treatments 1, 2 and 3. In the does of groups 2 and 3, LH peaks were detected 60 min after AI, whereas in the does from group 1, the LH peak was detected 90 min after AI. Prolificacy was not different for the 3 treatments (average litter sizes ranged from 10.4 to 10.8). In a second experiment, 3 buserelin concentrations (8, 12 and 16 microg/doe) were used intravaginally and compared with the control treatment (0.8 microg/doe, via intramuscular). This experiment was done using 100 nulliparous rabbit does (Hyplus strain PS19, Grimaud Frères, France, of about 19 weeks of age) (4 groups of 25 does each) located on a commercial farm, to test if the previous results would be confirmed under field conditions. Kindling rates were no different (P < 0.05) for the 4 treatment groups [91.7% (22/24), 79.2% (19/24), 87.0% (20/23) and 87.5% (21/24) respectively for the control, 8, 12 and 16 microg of intravaginal buserelin], however, prolificacy was higher when using the maximal dose of intravaginal buserelin (11.7 vs. 9.4 for the control group). It was concluded that buserelin can be used for ovulation induction in rabbit does when included in the seminal dose, with similar AI results as those obtained when the hormone is administered intramuscularly.

Administration, Intravaginal↗

PubMed2006

Influence of seasons, extenders, slow and rapid freezing on seminal characters in Korean native bucks.

The success of AI technology is based on both semen quality and freezing process. In order to establish the semen freezing techniques in Korean native bucks, factors affecting the success were evaluated in the present study. Semen collected by electro-ejaculation from bucks during four distinct seasons was evaluated for semen volume and pH, sperm motility and survivability. The semen volume, concentration and total cell were higher in spring, summer and less in winter. Yet, there were no seasonal differences in the proportional data of live sperm, motility score and pH of semen among seasons. The percentage of live sperm after thawing was found to increase with increased concentration of lactose in Tris-Egg yolk-glycerol (TY-G), being highest in TY-G supplemented with 180 mm lactose (TYL180-G), but did not differ between TY-G and TYL120-G. Sperm motility was enhanced by employing 2.0 h equilibration time with rapid freezing method. In conclusion, semen could be frozen with high success rates for further use of AI in breeding techniques and to preserve the Korean native bucks.

Animals↗

PubMed2006

Inadvertent use of aromatase inhibitors in patients with breast cancer with residual ovarian function: cases and lessons.

Aromatase inhibitors (AIs) are important adjunctive therapy for postmenopausal women with hormone receptor-positive, early-stage breast cancer. At the present time, AIs have no role for the management of breast cancer in premenopausal women. We report on several cases of the inadvertent use of AI therapy among women with residual ovarian function. A common experience in these cases was the onset of chemotherapy-related amenorrhea before initiation of AI therapy, which confounded assessment of true menopausal status. We believe clinicians should be aware of the potential ovarian reserve among women with treatment-related amenorrhea so as to avoid use of AI therapy in patients in whom there is uncertainty about menopausal status.

Adult↗

PubMed2006

Novel therapies for acute ischemic stroke.

Acute ischemic stroke is one of the leading causes of mortality and chronic disability in the western world. Yet, despite the enormous socioeconomic burden that it imposes, therapies to combat AIS are not widely available. Moreover, revascularization of the ischemic tissue with tissue plasminogen activator, the only FDA-approved therapy for AIS, is hampered by a very narrow therapeutic time window and is only used in a minority of patients. Cerebral ischemia leads to brain damage caused by several pathologic mechanisms that can potentially be blocked by neuroprotective drugs that aim to salvage the ischemic penumbra. However, despite numerous clinical trials, no single drug candidate has proved efficacious in AIS. The current situation calls for novel therapeutic strategies to be used in acute ischemic stroke. This review surveys some of these novel and promising cutting edge therapies.

Benzenesulfonates↗

PubMed2003

Biomimetic surface modification of poly(L-lactic acid) with chitosan and its effects on articular chondrocytes in vitro.

The objective of this study was to investigate the efficiency of two treatments for poly(L-lactic acid) (PLLA) surface modification with chitosan, via entrapment and coupling by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide. The properties of original PLLA films, chitosan-entrapped and coupled PLLA films were investigated by water contact angle measurement and electron spectroscopy for chemical analysis (ESCA). The contact angle indicated the change in hydrophilicity and the ESCA data suggested that the modified PLLA films became enriched with nitrogen atoms. The cytocompatibility of modified PLLA films might be improved. Therefore, the attachment and proliferation of bovine articular chondrocyte seeded on modified PLLA films and control one were examined. A whole cell enzyme-linked immunosorbent assay (Cell ELISA) that detects the BrdU incorporation during DNA synthesis and collagen type II secretion was applied to evaluate the chondrocytes on different PLLA films and tissue culture plates. Cell viability was estimated by the MTT assay and cell function were assessed by measuring sulfated glycosaminoglycan secreted by chondrocytes. These results implied that chitosan used to modify PLLA surface through entrapment and coupling could enhance the chondrocyte adhesion, proliferation and function.

Animals↗

PubMed2000

Comparative study of different methods for dog semen cryopreservation and testing under clinical conditions.

The extenders and freezing rates from three different freezing protocols were combined and compared to each other in order to study the post-thawing acrosome integrity and fertility of frozen dog sperm. A commercial bovine TRIS-base extender (TRILADYL) and two self-made canine semen extenders (Norwegian and Dutch) were combined with a conventional bovine and two canine freezing regimes, and acrosome integrity of frozen/thawed spermatozoa was assessed by fluorescein isothiocyanate conjugated peanut agglutinin staining (FITC-PNA). Differences between freezing/thawing protocols were reflected in the proportion of cells with acrosomal damage and not based on motility results. It was concluded that during dog semen cryopreservation extenders had less influence on the post-thawing sperm quality than did the freezing rates. The optimal extender/freezing rate combination (TRILADYL/Norwegian) was used in the clinical practice to evaluate the fertility of frozen sperm administered by intrauterine insemination using a surgical approach. The pregnancy rate was 57% (4/7), but the average litter size was low (2.8). This may have been due to the insufficient sperm numbers contained in an insemination dose and/or to the incorrect timing of artificial insemination (AI). The final conclusion is that the commercial bovine extender is useful for freezing dog semen, and the TRILADYL/Norwegian freezing protocol is recommended as the most advantageous combination for the freezing of canine semen in the clinical practice.

Acrosome↗