Real-world impact of anti-HER2 therapy-related cardiotoxicity in patients with advanced HER2-positive breast cancer.

BACKGROUND: Anti-HER2 therapy-related cardiotoxicity is well described in the context of clinical trials, particularly in the setting of early stage disease, but there is more limited data in advanced breast cancer and in the real world setting. MATERIAL AND METHODS: A prospectively-maintained registry database with 312 consecutive patients diagnosed with HER2 positive advanced breast cancer in Australia was analysed. RESULTS: 287 patients (92%) received anti-HER2 therapy, 17 (6%) experienced anti-HER2 therapy-related cardiotoxicity. Patients who experienced cardiotoxicity were more likely to have ≥2 risk factors for cardiotoxicity (OR 3.9 95% CI 1.4-11.3 p = 0.01). A prior diagnosis of cardiovascular disease was significantly associated with cardiotoxicity (OR 7.1 95% CI 1.3-39.5). Cardiotoxicity resolved on imaging in 65% of patients; there was no association between severity and resolution. 11 patients (65%) received cardiologist input. Of the patients who developed cardiotoxicity, 12 patients (71%) received further anti-HER2 therapy in the first- or second-line setting without recurrent cardiotoxicity. DISCUSSION AND CONCLUSION: Therapy-related cardiotoxicity is an uncommon complication of anti-HER2 therapy in the real world setting. Cardiac toxicity resolved in the majority of affected patients, and further anti-HER2 therapy was administered without recurrence of cardiac issues. Our data suggests anti-HER2 therapy can be safely given in routine care, even in patients with risk factors for toxicity.

Polymer Capsules for Plaque-Targeted In Vivo Delivery.

Targeted polymer capsules can selectively bind to unstable plaques in mice after intravenous injection. Different formulations of the capsules are explored with a synthetic/biopolymer hybrid capsule showing the best stability and small-molecule drug retention. The synthetic polymer is composed of pH-sensitive blocks (PDPA), low-binding blocks (PEG), and click-groups for postfunctionalization with targeting peptides specific to plaques.

Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer.

The last three decades have seen significant progress in our understanding of the role of the pro-survival protein BCL-2 and its family members in apoptosis and cancer. BCL-2 and other pro-survival family members including Mcl-1 and BCL-XL have been shown to have a key role in keeping pro-apoptotic 'effector' proteins BAK and BAX in check. They also neutralize a group of 'sensor' proteins (such as BIM), which are triggered by cytotoxic stimuli such as chemotherapy. BCL-2 proteins therefore have a central role as guardians against apoptosis, helping cancer cells to evade cell death. More recently, an increasing number of BH3 mimetics, which bind and neutralize BCL-2 and/or its pro-survival relatives, have been developed. The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients. As BCL-2 is overexpressed in ~75% of breast cancer, there has been growing interest in determining whether this new class of drug could show similar promise in breast cancer. This review summarizes our current understanding of the role of BCL-2 and its family members in mammary gland development and breast cancer, recent progress in the development of new BH3 mimetics as well as their potential for targeting estrogen receptor-positive breast cancer.

Multifunctional Thrombin-Activatable Polymer Capsules for Specific Targeting to Activated Platelets.

Smart poly(2-oxazoline) (POx)-based multifunctional polymer capsules that specifically target glycoprotein (GP) IIb/IIIa on the surface of activated platelets are degraded by the serine protease thrombin and release the urokinase plasminogen activator loaded into the polymer capsules, only in the area of acute thrombosis.

Plasma levels of alpha-1-antichymotrypsin are elevated in patients with chronic heart failure, but are of limited prognostic value.

BACKGROUND: There is increasing interest in utilising novel markers of cardiovascular disease risk in patients with chronic heart failure (HF). Recently, it was shown that alpha-1-antichymotrypsin (ACT), an acute-phase protein and major inhibitor of cathpesin G, plays a role in the pathophysiology of HF and may serve as a marker for myocardial distress. OBJECTIVE: To assess whether ACT is independently associated with long-term mortality in chronic HF patients. METHODS: ACT plasma levels were categorised into quartiles. Survival times were analysed using Kaplan-Meier curves and Cox proportional hazards regression, without and with correction for clinically relevant risk factors, including sex, age, duration of HF, kidney function (MDRD), ischaemic HF aetiology and NT-proBNP. RESULTS: Twenty healthy individuals and 224 patients (mean age 71 years, 72 % male, median HF duration 1.6 years) with chronic HF were included. In total, 159 (71 %) patients died. The median survival time was 5.3 (95 % CI 4.5-6.1) years. ACT was significantly elevated in patients (median 433 µg/ml, IQR 279-680) in comparison with controls (median 214 µg/ml, IQR 166-271; p < 0.001). Cox regression analysis demonstrated that ACT was not independently related to long-term mortality in chronic HF patients (crude HR = 1.03, 95 % CI 0.75-1.41, p = 0.871; adjusted HR = 1.12, 95 % CI 0.78-1.60, p = 0.552), which was confirmed by Kaplan-Meier curves. CONCLUSION: ACT levels are elevated in chronic HF patients, but no independent association with long-term mortality can be established.

Ganciclovir antiviral therapy in advanced idiopathic pulmonary fibrosis: an open pilot study.

Hypothesis. Repeated epithelial cell injury secondary to viruses such as Epstein Barr and subsequent dysfunctional repair may be central to the pathogenesis of IPF. In this observational study, we evaluated whether a combination of standard and anti-viral therapy might have an impact on disease progression. Methods. Advanced IPF patients who failed standard therapy and had serological evidence of previous EBV, received ganciclovir (iv) at 5 mg/kg twice daily. Forced vital capacity (FVC), shuttle walk test, DTPA scan and prednisolone dose were measured before and 8 weeks post-treatment. Results. Fourteen patients were included. After ganciclovir, eight patients showed improvement in FVC and six deteriorated. The median reduction of prednisolone dose was 7.5 mg (44%). Nine patients were classified "responders" of whom four showed an improvement in all four criteria, while three of the five "non-responders" showed no response in any of the criteria. Responders showed reduction in prednisolone dosage (P = .02) and improved DTPA clearance (P = .001). Conclusion. This audit outcome suggests that 2-week course of ganciclovir (iv) may attenuate disease progression in a subgroup of advanced IPF patients. These observations do not suggest that anti-viral treatment is a substitute for the standard care, however, suggests the need to explore the efficacy of ganciclovir as adjunctive therapy in IPF.

Peripartum cardiomyopathy: the need for a national database.

Peripartum cardiomyopathy (PPCM) is a rare and life-threatening disease that affects young women in the last month of pregnancy or within 5 months of delivery. It is a form of dilated cardiomyopathy with left-sided systolic dysfunction. The incidence rate in the Western world is estimated to be 1:3000. Symptoms of PPCM vary greatly and may be obscured by common physiological aspects of pregnancy. Therefore, the incidence rate might be higher. Echocardiography or MRI can confirm or rule out PPCM. Unfortunately, there is no specific risk factor profile available. The clinical course varies from complete recovery to deterioration of cardiac function. Patients with PPCM, especially those whose ventricular function has not returned to normal, are advised against further pregnancy. Recently, more disease-specific therapeutic strategies have been developed with promising results for prolactin blockade by bromocriptine. Increasing awareness for PPCM among general practitioners, gynaecologists and cardiologists may help to diagnose patients efficiently in order to start adequate treatment. A national registry is warranted to identify risk factor profiles and to optimise treatment strategies.

The formation of an aligned 1D nanostructure on annealed Fe/ZnSe bilayers.

A highly aligned one-dimensional (1D) nanostructure was realized at the surface of Fe/ZnSe bilayers grown on GaAs(001) substrates through thermal annealing. These 1D nano-grooves were found to align along the [110] direction resulting in bent reflection high energy electron diffraction (RHEED) patterns when the sample was rotated relative to the e-beam. A model based on Ewald construction is presented to explain the unusual RHEED observation. The formation mechanism of this 1D nanostructure is possibly related to the minimization of surface energy, together with an Fe-Se exchange interaction and Fe-induced decomposition of several top ZnSe atomic layers during thermal annealing.

Parental perception of small ventricular septal defects in childhood.

OBJECTIVE: The main aim of this study was to determine the understanding and perception of parents following the diagnosis of a minor cardiac abnormality, namely a small ventricular septal defect, in the child. Other aims included discovering the reasons behind these perceptions and whether they affected the parents' management of their child and his/her cardiac problem. METHODS: Fifty-six infants and children from two tertiary centres and the private practices of the participating cardiologists were enrolled over a 5-month period. Questionnaires were prepared and distributed to all their parents. RESULTS: Complete data was obtained from 40 parents. Close to 80% of the parents perceived the small ventricular septal defect as a minor problem and most understood the nature of the defect. However, when asked about precautions for their child, only two-thirds recalled the need for antibiotic prophylaxis. Most parents experienced distress and anxiety when told initially of the diagnosis but none reportedly restricted their child's physical activity. CONCLUSIONS: Most parents have a clear understanding and perception of their child's small ventricular septal defect. There is a need for further improvement to facilitate parental understanding, especially with regard to the need for antibiotic prophylaxis.

Murine gammaherpes virus as a cofactor in the development of pulmonary fibrosis in bleomycin resistant mice.

Studies of human tissue have suggested an association between productive Epstein Barr virus and idiopathic pulmonary fibrosis (IPF). However, a pathogenic role for the virus has not been established. This study was undertaken to develop an animal model, which would explore the association between viral infection and pulmonary fibrosis. BALB/c mice (n=30), resistant to bleomycin, were primed with murine gammaherpesvirus 68 and then given intraperitoneal bleomycin. The mice were sacrificed at 28 days after bleomycin and their lungs assessed histologically and biochemically. Lung pathology was scored 0-3 for fibrotic and inflammatory change. BALB/c mice given virus and bleomycin showed more lung fibrosis (median score 2.2) compared to those given bleomycin alone (median 0), virus alone (median 0.2) or phosphate-buffered saline (PBS) control (median 0). Similarly mice given both virus and bleomycin showed more lung inflammation (median score 1.9) compared to those given bleomycin (median 0.5), virus (median 0.8), or PBS control (median 0.2). There was a significant difference in collagen content between the bleomycin and virus group (mean 1.86 mg) compared to the belomycin alone group (mean 1.52 mg). These results suggest that virus alone does not result in pulmonary fibrosis but that replicating virus in the presence of an exogenous injury may promote the development of pulmonary fibrosis.

Epstein-Barr virus and wild p53 in idiopathic pulmonary fibrosis.

Both Epstein-Barr virus (EBV) and p53 have independently been associated with idiopathic pulmonary fibrosis (IPF). This study explores further whether a relationship potentially exists between EBV and p53 in IPF, thereby providing a possible mechanism for the role of EBV in the disease progression of IPF. Lung tissue from open lung biopsies of 14 IPF patients was compared with a control group of 19 patients. EBV status was determined using both immunohistochemistry and PCR, while p53 expression was assessed with immunohistochemistry Seven of 14 IPF patients expressed p53 compared to one of 19 control subjects (P = 0.011). Eight IPF patients and no controls were positive for EBV (P < 0.01). Four IPF patients demonstrated both EBVand p53 expression compared with no controls, (P = 0.05). This study suggests that a relationship between EBV and p53 may exist in patients with IPF.

Amino acid and phenotypic changes in dengue 2 virus associated with escape from neutralisation by IgM antibody.

Two dengue 2-specific IgM monoclonal antibodies (MAb) recognised spatially unrelated epitopes on the envelope (E) protein of dengue 2 virus, which were also recognised by serum from 20 and 50%, respectively, of patients with a primary dengue 2 infection. Dengue 2 virus populations escaping neutralisation by MAb 6B2 (representing the majority population of dengue 2-specific IgM MAbs ) had a deduced amino acid change (G-S) in the pre-Membrane (prM) protein at position 15 and a second in the E protein at E311 (E-G). The change in the E protein was adjacent to the only other epitopes on dengue 2 virus (E307, E383-385) involved in neutralisation that have been identified but that were recognised by IgG antibodies. Dengue 2 virus escaping neutralisation by IgM MAb 10F2, representing the minority population of dengue 2-specific IgM MAbs, had the same deduced amino acid change (G-S) at prM15 as the 6B2 neutralisation escape mutant dengue 2 virus population and four deduced amino acid changes in the E protein (E69, T-I, in the glycosylation motif; E71, E-D; E112, S-G; E124, I-N), which may be close enough to each other to form a single epitope and a fifth at E402 (F-L) in a region of the E protein of TBE virus essential for the low pH-induced E protein dimer-trimer transition. The 10F2 neutralisation escape mutant, but not the 6B2 one, had lost its ability to cause fusion from within Aedes albopictus mosquito cells and was inactivated more rapidly than the 6B2 neutralisation escape mutant and wild type viruses at 42 degrees C. Dengue 2 viruses passaged in BHK cells in the absence of a selecting antibody, shared a common amino acid (S) at E53, which differed from both wild type and neutralisation escape mutant virus populations at this position (P) and may have been responsible for a significant reduction in the ability of these "passage control" virus populations to be neutralised by both 6B2 and 10F2 antibodies.

Cloning of leptin cDNA and assignment to the long arm of chromosome 5 in the marsupial Sminthopsis crassicaudata.

We have isolated and sequenced full-length cDNA clones for leptin in the dasyurid marsupial Sminthopsis crassicaudata (fat-tailed dunnart). Southern and in situ hybridisation data indicated a single leptin gene in the S. crassicauda- ta genome, localised to arbitrary chromosome bands 5q24--> q31 on the long arm of chromosome 5, the short-arm terminus of which bears the only nucleolar organising region. The nucleotide sequence of the cDNAs revealed that the primary translation product of S. crassicaudata leptin is composed of 167 amino acid residues, with a potential signal peptide of 21 residues. The mature protein of 146 amino acids is 82% similar to both the mouse and human proteins and is predicted to have a molecular weight of 16.26 kDa. Northern blot analysis revealed that the corresponding mRNA is approximately 3.9 kb in size and is expressed only in white adipose tissue of this marsupial species. Evolutionary analyses indicate that S. crassicaudata leptin cDNA has evolved at a significantly faster rate than cDNAs from eutherian mammals.

Human secretin (SCT): gene structure, chromosome location, and distribution of mRNA.

Secretin is an endocrine hormone that stimulates the secretion of bicarbonate-rich pancreatic fluids. Recently, it has been discussed that secretin deficiency may be implicated in autistic syndrome, suggesting that the hormone could have a neuroendocrine function in addition to its role in digestion. In the present study, the human secretin gene (SCT) was isolated from a bacterial artificial chromosome genomic library. SCT contains four exons, with the protein coding regions spanning 713 bp of genomic DNA. Human SCT is similar structurally to the secretin genes of other species. Amino acid conservation, however, is most pronounced within the exon encoding the biologically active mature peptide. Northern blot analysis shows that human SCT transcripts are located in the spleen, intestinal tract, and brain. Radiation hybrid mapping places the SCT locus on chromosome 11p15.5.

Viruses and idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is an increasingly recognized problem with a poor prognosis. The aetiology remains unclear. However, many patients date the onset of their disease to a recent viral infection, implying that viruses may have a potential role in disease progression. A number of studies have suggested an association between idiopathic pulmonary fibrosis and viruses including adenovirus, Epstein-Barr virus and hepatitis C. However, the molecular techniques used in identifying the viruses are extremely sensitive and may lead to erroneous associations being made. This review attempts to place into context the identification and potential role of viruses in patients with idiopathic pulmonary fibrosis.

Tissue factor overexpression in rat arterial neointima models thrombosis and progression of advanced atherosclerosis.

BACKGROUND: Tissue factor located in the atherosclerotic plaque might cause the clinically significant thrombotic events associated with end-stage disease. It might also affect intimal area by increasing matrix accumulation and stimulating smooth muscle cell (SMC) migration and proliferation. To test this hypothesis, we overexpressed tissue factor in a rat model of the human fibrous plaque. METHODS AND RESULTS: A neointima was generated by seeding tissue factor-overexpressing rat SMCs onto the luminal surface of a balloon-injured syngeneic rat carotid artery. The cells attached and expressed tissue factor over the long term. Mural thrombus accumulation was present at 4 and 7 days and increased neointimal SMC numbers and area by 2-fold at 2 and 4 weeks. Tissue factor overexpression accelerated reendothelialization compared with controls at 2 weeks and 1 month. Tissue factor-overexpressing SMCs exhibited increased migration both in vitro and in vivo. The increased migration by tissue factor-overexpressing SMCs in vitro was not dependent on activation of the coagulation cascade and could be blocked by an inhibitor of tissue factor. CONCLUSIONS: These results suggest that tissue factor plays a direct role in neointimal development by coagulation-dependent and -independent pathways.

Identification of INSL6, a new member of the insulin family that is expressed in the testis of the human and rat.

A new member of the insulin gene family (INSL6) was identified from an Expressed Sequence Tag database through a search for proteins containing the insulin family B-chain cysteine motif. Human and rat INSL6 encoded polypeptides of 213 and 188 amino acids, respectively. These orthologous sequences contained the B-chain, C-peptide, and A-chain motif found in other members of the insulin family. Human INSL6 was 43% identical to human relaxin H2 in the B- and A-chain regions. As with other family members, human and rat INSL6 had predicted dibasic sequences at the junction of the C-peptide and A-chain. Human INSL6 sequence had an additional dibasic site near the C-terminus of the A-chain. The presence of a single basic residue at the predicted junction of the B-chain and C-peptide suggests that multiple prohormone convertases are required to produce the fully mature hormone. INSL6 was found to be expressed at high levels in the testis as determined by Northern blot analysis and specifically within the seminiferous tubules in spermatocytes and round spermatids as detected by in situ hybridization analysis. Radiation hybrid mapping placed the human INSL6 locus at chromosome 9p24 near the placenta insulin-like homologue INSL4 and the autosomal testis-determining factor (TDFA) locus.