Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells.

Pharmacological resistance is a serious threat to the clinical success of hormone therapy for breast cancer. The antiproliferative response to antagonistic drugs such as tamoxifen (Tam) critically depends on the recruitment of NCoR/SMRT corepressors to estrogen receptor alpha (ERα) bound to estrogen target genes. Under certain circumstances, as demonstrated in the case of interleukin-1ß (IL-1ß) treatment, the protein Tab2 interacts with ERα/NCoR and causes dismissal of NCoR from these genes, leading to loss of the antiproliferative response. In Tam-resistant (TamR) ER-positive breast cancer cells, we observed that Tab2 presents a shift in mobility on sodium dodecyl sulfate--PAGE (SDS-PAGE) similar to that seen in MCF7 wt upon stimulation with IL-1ß, suggesting constitutive activation. Accordingly, TamR treatment with Tab2-specific short interfering RNA, restored the antiproliferative response to Tam in these cells. As Tab2 is known to directly interact with the N-terminal domain of ERα, we synthesized a peptide composed of a 14-aa motif of this domain, which effectively competes with ERα/Tab2 interaction in pull-down and co-immunoprecipitation experiments, fused to the carrier TAT peptide to allow internalization. Treatment of TamR cells with this peptide resulted in partial recovery of the antiproliferative response to Tam, suggesting a strategy to revert pharmacological resistance in breast cancer. Silencing of Tab2 in TamR cells by siRNA caused modulation of a gene set related to the control of cell cycle and extensively connected to BRCA1 in a functional network. These genes were able to discern two groups of patients, from a published data set of Tam-treated breast cancer profiles, with significantly different disease-free survival. Altogether, our data implicate Tab2 as a mediator of resistance to endocrine therapy and as a potential new target to reverse pharmacological resistance and potentiate antiestrogen action.

Congestive heart failure. A new milestone for a better life.

Congestive heart failure (CHF) represents the 1st cause of death in the civil world. Despite considerable advances in the diagnosis and medical treatment of CHF, this condition remains a real "malignant" disease. The cardiac transplantation (CT) remains "gold standard" option for the treatment of patients with severe CHF in all age group; but only a small number of patients can receive it due to scarcity of donor organs. The increased successful clinical experience with the ventricular assist device (VAD) confirmed the indisputable importance of long-term mechanical circulatory support for patients who suffer acute hemodynamic deterioration. Over the past years, several miniaturized continuous flow VAD have been developed for clinical use. The authors report the data of worldwide and particularly Italian experience about middle and long-term pump performance in patients supported with axial-flow pump MicroMed DeBakey VAD in the bridge to cardiac transplantation setting.

First successful Italian clinical experience with DeBakey VAD.

The growing number of patients waiting for heart transplantation more than tripled between 1989 and 1998. Various non-pulsatile mechanical circulatory support devices have been developed as bridge to heart transplantation in recent years. We report the first successful Italian clinical experience with an axial-flow pump, DeBakey VAD, in a patient supported as bridge to transplantation for 55 days.

[Left monoventricular assistance with DeBakey VAD continuous flow pump: initial clinical Italian experience]. / Assistenza monoventricolare sinistra con pompa a flusso continuo DeBakey VAD: prima esperienza clinica italiana.

BACKGROUND: The shortage of heart donors causes a rise in mortality among candidates for cardiac transplantation and increases the waiting list. Consequently mechanical circulatory support for bridge to transplant is now a standard clinical procedure utilized in the most representative cardiac surgery centers. Recently, continuous-axial-flow pumps have been introduced in the clinical practice and have led to new perspectives. METHODS: Four patients suffering from end-stage heart failure were implanted with a DeBakey ventricular assist device (VAD) continuous-flow pump as a bridge to heart transplant. The DeBakey VAD is smaller than the pulsatile devices commonly employed, the pump is totally implantable and is connected to a small controller and two batteries by a transcutaneous drive line. RESULTS: One patient died of multiorgan failure during assistance; 3 patients were fully rehabilitated and were successfully transplanted after 55, 42 and 141 days respectively. In the early postoperative period the mean pump flow was 4.27 +/- 0.55 l/min, after 1 week of assistance the flow rose to 5.32 +/- 0.57 l/min and then progressively increased to 5.83 +/- 0.57 l/min. CONCLUSIONS: This experience demonstrated the possibility of continuous-flow left ventricular support with the DeBakey VAD for mid-term mechanical ventricular assistance. This pump presents new interesting aspects and opens new perspectives for the future of left ventricular mechanical assistance. Increasing experience will define the role of this device in the scenario of heart failure.

Papillary muscle rupture and pericardial injuries after blunt chest trauma.

Non-penetrating cardiac trauma resulting in mitral valve rupture is uncommon, requiring a high degree of suspicion for diagnosis. Sudden and severe mitral regurgitation, unless surgically corrected rapidly lead to congestive heart failure and death. We report a patient with traumatic rupture of the antero-lateral papillary muscle of the mitral valve and pericardial injury, after a lateral blunt chest trauma, who successfully underwent emergency mitral valve replacement.

Tricuspid regurgitation secondary to mitral valve disease: tricuspid annulus function as guide to tricuspid valve repair.

METHODS: A prospective analysis was performed on 50 patients (pts) with rheumatic mitral disease and associate secondary tricuspid insufficiency who underwent mitral valve replacement from January 1995 to December 1998. Surgical indication to tricuspid annuloplasty was considered in patients with echocardiographic tricuspid annulus diameter > 21 mm/m2, regardless semiquantitative evaluation of tricuspid insufficiency. De Vega annuloplasty was performed in 33 out of 50 patients. RESULTS: Hospital mortality was 2.0% (CL 0.3-3.6). The follow up of the discharged patients ranged from 3 to 48 months (mean 25 +/- 15.9). Three late deaths occurred (6.1% CL 2.8-9.2). Forty-two patients out of the 46 followed up (91.3% CL 84.9-93.8) were in I or II NYHA class. In eight patients (16.3% of discharged patients) the obtained result has been considered as 'negative late results': persisting moderate (three cases) or moderate-severe (five cases) TrI, together with congestive heart failure requiring a furosemide intake of > 25 mg/day. No patients had severe TrI at follow up. The statistics analysis demonstrated the 'preoperative fraction shortening of the tricuspid annulus' (P = 0.038) as factor predictive of late negative result. The incidence of late negative result was 57.1% among patients with fractional shortening lower than 25% and 0% among those patients with fractional shortening greater than 25% (P = 0.0001). CONCLUSIONS: The choice to treat the tricuspid insufficiency according to indexed tricuspid annulus dimension (> 21 mm/m2) has been effective in terms of clinical efficacy and of late functional result. Fractional shortening of the tricuspid annulus, expression of right ventricular cardiomyopathy in patients with poorest prognosis, affects the postoperative evolution of tricuspid insufficiency.