<Emphasis Type="Italic">FGFR1</Emphasis> amplification in breast carcinomas: a chromogenic <Emphasis Type="Italic">in situ</Emphasis>hybridisation analysis

Background  

The amplicon on 8p11.2 is reported to be found in up to 10% of breast carcinomas. It has been demonstrated recently that this amplicon has four separate cores. The second core encompasses important oncogene candidates, including the fibroblast growth factor receptor 1 (FGFR1) gene. Recent studies have demonstrated that specific FGFR1 amplification correlates with gene expression and that FGFR1 activity is required for the survival of a FGFR1 amplified breast cancer cell line.     

Intracervical versus vaginal misoprostol for cervical dilatation prior to operative hysteroscopy—a comparative study

Background

Hysteroscopic surgery requires pre-operative cervical ripening to facilitate adequate dilatation of the cervix for insertion of operative hysteroscope. This study was conducted to compare the efficacy of intracervical misoprostol with vaginal misoprostol in achieving cervical ripening before operative hysteroscopy.

Methods

In this randomised comparative study conducted at a tertiary care teaching hospital, 56 patients needing operative hysteroscopy were divided into two groups of 28 patients, one for intracervical misoprostol and the other for vaginal misoprostol. Four hundred microgram of misoprostol was inserted on the night before and in the morning of operative hysteroscopy intracervically in group I and vaginally in group II.

Results

Primary outcome measure was number of patients achieving 7 mm preoperative dilatation of cervix. Largest Hegar dilator that could be passed into the uterine cavity past the internal optic sheath without resistance was noted in each case. Mean cervical dilatation prior to operative hysteroscopy was calculated. In addition, incidence of slipping of vulsellum and cervical laceration was also noted. Time to achieve full cervical dilatation was recorded. In 23/28 cases of group I and 5/28 in group II, size 7 Hegar dilator could be passed without effort. Mean cervical dilatation was 7.5 mm in group I and 5.7 mm in group II. Slipping of the vulsellum and cervical lacerations were seen in significantly less patients in group I. Mean time to achieve cervical dilatation to 10 mm was 43.39 seconds in group I and 103.96 seconds in group II (P<0.0001).

Conclusion

Intracervical administration of misoprostol is an effective method of achieving cervical ripening for easy cervical dilatation up to 10 mm prior to operative hysteroscopy.     

Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery

1,25-Dihydroxyvitamin D(3) and vitamin D(3) analogues, such as EB 1089, potentiate the response to ionizing radiation in breast tumor cells. The current studies address the basis for this interaction by evaluating DNA damage and repair, the effect of interference with reactive oxygen generation, the involvement of p53 and caspase-3, signaling through c-myc, as well as the induction of senescence and multiple modes of cell death. EB 1089 failed to increase the extent of radiation-induced DNA damage or to attenuate the rate of DNA repair. The reactive oxygen scavengers N-acetyl-l-cysteine and reduced glutathione failed to protect the cells from the promotion of cell death by EB 1089 and radiation. Whereas MCF-7 cells expressing caspase-3 showed significant apoptosis with radiation alone as well as with EB 1089 followed by radiation, EB 1089 maintained its ability to confer susceptibility to radiation-induced cell killing, in large part by interference with proliferative recovery. In contrast, in breast tumor cells lacking p53, where radiation promoted extensive apoptosis and the cells failed to recover after radiation treatment, EB 1089 failed to influence the effect of radiation. EB 1089 treatment interfered with radiation-induced suppression of c-myc; however, induction of c-myc did not prevent senescence by radiation alone or radiation-induced cell death promoted by EB 1089. EB 1089 did not increase the extent of micronucleation, indicative of mitotic catastrophe, induced by radiation alone. However, EB 1089 did promote extensive autophagic cell death in the irradiated cells. Taken together, these studies suggest that the effect of EB 1089 treatment on the radiation response is related in part to enhanced promotion of autophagic cell death and in part to interference with the proliferative recovery that occurs with radiation alone in p53 wild-type breast tumor cells.     

EICOSAPENTAENOIC ACID IN TREATMENT-RESISTANT DEPRESSION ASSOCIATED WITH SYMPTOM REMISSION,STRUCTURAL BRAIN CHANGES AND REDUCED NEURONAL PHOSPHOLIPID TURNOVER

The n-3 essential fatty acid eicosapentaenoic acid (EPA) was added to the conventional antidepressant treatment of a treatment-resistant severely depressed and suicidal male patient with a seven-year history of unremitting depressive symptoms. The niacin skin flush test and cerebral magnetic resonance scanning were carried out at baseline and nine months later. The addition of ethyl-EPA led to a dramatic and sustained clinical improvement in all the symptoms of depression, including a cessation of previously unremitting severe suicidal ideation, within one month. Symptoms of social phobia also improved dramatically. During the nine-month period the volumetric niacin response increased by 30%, the relative concentration of cerebral phosphomonesters increased by 53%, and the ratio of cerebral phosphomonesters to phosphodiesters increased by 79%, indicating reduced neuronal phospholipid turnover. Registered difference images showed that the EPA treatment was accompanied by structural brain changes including, in particular, a reduction in the lateral ventricular volume.     

Systemic monoclonal antibody therapy for eliminating minimal residual leukemia in a rat bone marrow transplant model

In an animal bone marrow transplant (BMT) model that mimics the human clinical condition, we evaluated the effectiveness of monoclonal antibody (MoAb) therapy in eliminating minimal residual disease (MRD) in a leukemic host. Leukemic rats were prepared with marrow ablative but noncurative doses of busulfan (BU) and cyclophosphamide (CY). Two days after syngeneic BMT, rats were treated with MoAb. Although all control rats died of leukemia relapse, 58% of those treated with MoAb were cured without any demonstrable effect on the rate of peripheral blood leukocyte recovery. Furthermore, the level of complement, an important effector in suppressing leukemia proliferation in the normal rat, was not adversely affected by BU/CY, BMT and MoAb. Thus, we demonstrated in an animal model that MoAb therapy may be a useful, nontoxic adjunct to high-dose chemotherapy and BMT in eliminating MRD.     

Intracellular acidification alters myogenic responsiveness and vasomotion of mouse middle cerebral arteries

Intracellular pH (pH_i) in the vascular wall modulates agonist-induced vasocontractile and vasorelaxant responses in mesenteric arteries, whereas effects on myogenic tone have been unsettled. We studied the role of Na⁺,HCO₃⁻ cotransporter NBCn1 in mouse isolated middle cerebral arteries and the influence of pH_i disturbances on myogenic tone. Na⁺,HCO₃⁻ cotransport was abolished in arteries from NBCn1 knockout mice and steady-state pH_i ∼0.3 units reduced compared with wild-type mice. Myogenic tone development was low under control conditions but increased on treatment with the NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME). This effect of L-NAME was smaller in arteries from NBCn1 knockout than wild-type mice. Myogenic tone with L-NAME present was significantly lower in arteries from NBCn1 knockout than wild-type mice and was abolished by rho-kinase inhibitor Y-27632. The arteries displayed vasomotion, and this rhythmic contractile pattern was also attenuated in arteries from NBCn1 knockout mice. No differences in membrane potential or intracellular [Ca²⁺] were seen between arteries from NBCn1 knockout and wild-type mice. We propose that NO production and rho-kinase-dependent Ca²⁺ sensitivity are reduced at low pH_i in pressurized mouse middle cerebral arteries. This likely impedes the ability to adjust to changes in perfusion pressure and regulate cerebral blood flow.     

Effect of LVAD outflow conduit insertion angle on flow through the native aorta

Background and aim: The goal of this study was to evaluate the effect of surgical anastomosis configuration of the aortic outflow conduit (AOC) from a continuous flow left ventricular assist device (LVAD) on the flow fields in the aorta using CFD simulations. The geometry of the surgical integration of the LVAD is an important factor in the flow pattern that develops both in series (aortic valve closed, all flow through LVAD) and in parallel (heart pumping in addition to LVAD).

Methods: CFD models of the AOC junctions simulate geometry as cylindrical tubes that intersect at angles ranging from 30° to 90°. Velocity fields are computed over a range of cardiac output for both series and parallel flow.

Results: Our results demonstrate that the flow patterns are significantly affected by the angle of insertion of the AOC into the native aorta, both during series and parallel flow conditions. Zones of flow recirculation and high shear stress on the aortic wall can be observed at the highest angle, gradually decreasing in size until disappearing at the lowest angle of 30°. The highest velocity and shear stress values were associated with series flow.

Conclusions: The results suggest that connecting the LVAD outflow conduit to the proximal aorta at a shallower angle produces fewer secondary flow patterns in the native cardiovascular system.