A phase I/IIa study with succinylated human serum albumin (Suc-HSA), a candidate HIV-1 fusion inhibitor

BACKGROUND: Succinylated human serum albumin (Suc-HAS) is a negatively charged neo-glycoprotein that binds to the positively charged V3-loop of HIV-1 gp120, acting as HIV-1-fusion inhibitor in vitro (IC50: 0.5-5.0 microg/ml). Suc-HSA was safe in rats and monkeys, and showed antiretroviral effect in a human-to-mouse model. We evaluated safety and pharmacokinetics of single and multiple doses of Suc-HSA in HIV-1-infected individuals. METHODS: First, six untreated, chronically HIV-1-infected patients were randomized to a single dose of 1 or 10 mg/kg Suc-HSA intravenously. Second, five consecutive daily doses (10 mg/kg, based on the results of the single dose study) were given to four patients. Safety laboratory assessments, Suc-HSA plasma levels, plasma HIV-1 RNA (pVL), and CD4+ T-cell counts were determined. RESULTS: Increase of liver transaminases (grade 1/2) occurred in one of six patients in the single-dose phase and in three of four patients in the multiple-dosing phase. Suc-HSA plasma levels were undetectable 4 h after a single dose of 1 mg/kg. After a dose of 10 mg/kg, plasma levels were more sustained, but declined under the target plasma concentration (10 microg/ml) 12-24 h post-dosing. After multiple dosing, plasma levels reached peak values 2h post-dosing as predicted by our kinetic model. However, trough levels were below the target concentrations. There was no change in pVL or CD4+ T-cell count in either the single- or multiple-dosing phase. CONCLUSIONS: At the chosen dosing regimens, adequate antiviral plasma levels were not maintained, probably because the hepatic clearance was more rapid than expected. This may partially explain the lack of effect on pVL and CD4+ T-cell count. The observed liver transaminase increases prohibit further dose escalation.     

A Limited role for p21Cip1/Waf1 in maintaining normal hematopoietic stem cell functioning

Several studies have suggested that the cyclin-dependent kinase (CDK) inhibitor p21 plays a crucial role in regulating hematopoietic stem and progenitor pool size. To allow assessment of long-term stem cell functioning in vivo, we have backcrossed a p21 null allele to C57BL/6 (B6) mice, the most commonly used mouse strain in hematopoietic stem cell research. In various in vitro assays, the homozygous deletion of the p21 allele did not affect the number of hematopoietic cells in B6 mice. Furthermore, the competitive repopulation ability was not different between p21-deficient and wild-type stem cells from both young and aged (20-month-old) mice. These results show that p21 is not essential for regulation of stem cell number in steady state. When proliferative stress was applied on p21-deficient stem cells by serial transplantation of 1,500 Lin(-)Sca-1(+)c-kit(+) (LSK) cells, again no detrimental effect was observed on cobblestone area-forming cell (CAFC) frequency and competitive repopulating ability. However, when bone marrow cells from mice that received 2 Gy of irradiation were transplanted, p21 deficiency resulted in a more than fourfold reduction in competitive repopulation index. Finally, we did not find major differences in cell cycle status and global gene expression patterns between LSK cells from p21-deficient and wild-type mice. Our findings indicate that the background of mice used for studying the function of a gene by genetic modification may determine the outcome. Cumulatively, our data fail to support the notion that p21 is essential for stem cell function during steady-state hematopoiesis, but may be relatively more important under conditions of cellular stress.     

The association of hypertensive disorders of pregnancy with weight gain over the subsequent 21 years: findings from a prospective cohort study

Obesity is an important risk factor for hypertensive disorders of pregnancy, but most cases of hypertensive disorders of pregnancy occur in women of normal weight. There may be predisposing factors to both hypertensive disorders of pregnancy and obesity. To test this hypothesis, the authors compared changes in body mass index (weight (kg)/height (m)2) over time in women with and without hypertensive disorders of pregnancy. They used data from 3,572 women who received antenatal care at a major public hospital in Brisbane, Australia, between 1981 and 1984 and who were followed up for 21 years. A total of 318 women (8.9%) had experienced hypertensive disorders in the index pregnancy, and 233 of them (73.3%) had a baseline body mass index of or=5 kg/m2 were 59% greater for women who experienced hypertensive disorders of pregnancy compared with those who did not (odds ratio=1.59, 95% confidence interval: 1.24, 2.04). The authors concluded that hypertensive disorders of pregnancy are associated with increased weight gain over 21 years.     

Neural correlates of the emergence of consciousness of thirst

Thirst was induced by rapid i.v. infusion of hypertonic saline (0.51 M at 13.4 ml/min). Ten humans were neuroimaged by positron-emission tomography (PET) and four by functional MRI (fMRI). PET images were made 25 min after beginning infusion, when the sensation of thirst began to enter the stream of consciousness. The fMRI images were made when the maximum rate of increase of thirst occurred. The PET results showed regional cerebral blood flow changes similar to those delineated when thirst was maximal. These loci involved the phylogenetically ancient areas of the brain. fMRI showed activation in the anterior wall of the third ventricle, an area that is key in the genesis of thirst but is not an area revealed by PET imaging. Thus, this region plays as major a role in thirst for humans as for animals. Strong activations in the brain with fMRI included the anterior cingulate, parahippocampal gyrus, inferior and middle frontal gyri, insula, and cerebellum. When the subjects drank water to satiation, thirst declined immediately to baseline. A precipitate decline in intensity of activation signal occurred in the anterior cingulate area (Brodmann area 32) putatively related to consciousness of thirst. The intensity of activation in the anterior wall of the third ventricle was essentially unchanged, which is consistent with the fact that a significant time (15-20 min) would be needed before plasma Na concentration changed as a result of water absorption from the gut.     

Probiotics and Pregnancy

Polycystic ovary syndrome is a frequent disorder in women of reproductive age that consists of a heterogeneous combination of hyperandrogenism, chronic anovulation, and polycystic ovaries. Hyperandrogenism and anovulation are clearly linked to insulin resistance and compensatory hyperinsulinism, with an ovarian androgenic hyperresponsiveness to circulating insulin. Evidence is increasing that suggests that lipotoxicity, which is a key mechanism in the development of insulin resistance and type 2 diabetes, could also explain the androgen overproduction. During adolescence, diagnosis of polycystic ovarian syndrome (PCOS) may be difficult but is of importance because PCOS increases future risk of type 2 diabetes and metabolic complications. Metabolic perturbations begin early in adolescence and also exist in adolescent relatives of women with PCOS, even before clinical signs of PCOS. Screening for impaired glucose tolerance or type 2 diabetes is also important in this population, and treatment should focus on PCOS clinical manifestations as well as long-term metabolic risk.     

Profile of atrial fibrillation inpatients: Cardiovascular risk factors and cardiac rehabilitation programme delivery and referral patterns

Atrial fibrillation (AF) is increasingly common; however, the cardiovascular risk factor profile and the patterns of delivery and referral to cardiac rehabilitation (CR) in this population are poorly described. We conducted an audit of medical records (n = 145) of patients admitted with AF in one local health district in Sydney, Australia. Patients were aged a mean 72 years, and 51% were male. Lack of risk factor documentation was common. Despite this, 65% had two or more modifiable cardiovascular risk factors, including hypertension (63%) and hypercholesterolaemia (52%). Referral to Phase II CR occurred for 25% and was decreased with permanent AF diagnosis and increased with more risk factors. AF patients admitted to hospital have multiple cardiovascular risk factors but limited risk factor screening and/or referral to outpatient CR programmes.     

Reduced rate of copy number aberrations in mucinous colorectal carcinoma

Background

Mucinous carcinoma (MC) is found in 10%–15% of colorectal cancer (CRC) patients. It differs from the common adenocarcinoma (AC) in histopathological appearance and clinical behavior.

Methods

Genome-wide DNA copy number and survival data from MC and AC primary CRC samples from patients from two phase III trials (CAIRO and CAIRO2) was compared. Chromosomal copy number data from The Cancer Genome Atlas (TCGA) was used for validation. Altogether, 470 ACs were compared to 57 MCs.

Results

MC showed a reduced amount of copy number aberrations (CNAs) compared with AC for the CAIRO/CAIRO2 cohort, with a median amount of CNAs that was 1.5-fold lower (P = 0.002). Data from TCGA also showed a reduced amount of CNAs for MC. MC samples in both cohorts displayed less gain at chromosome 20q and less loss of chromosome 18p. A high rate of chromosomal instability was a strong negative prognostic marker for survival in MC patients from the CAIRO cohorts (hazard ratio 15.60, 95% CI 3.24–75.05).

Conclusions

Results from this study indicate that the distinct MC phenotype is accompanied by a different genetic basis when compared with AC and show a strong association between the rate of chromosomal instability and survival in MC patients.     

Melanoma-associated antigen A11 reduces erlotinib and afatinib efficacy in head and neck cancer

Melanoma-associated antigen A (MAGE-A) proteins are members of the cancer/testis antigens (CTA), and the expression of these proteins is almost exclusively limited to malignant cells, making them an attractive treatment target. MAGE-A expression is correlated with poor overall survival in several cancers, including head and neck squamous cell carcinoma (HNSCC). Among others, MAGE-A11 was found to be associated with resistance to different antineoplastic and targeted compounds, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We searched The Cancer Genome Atlas (TCGA) database with a focus on MAGE-A and found that MAGE-A overexpression is a common event in HNSCC (27.5%). Furthermore, MAGE-A overexpression was correlated with significantly reduced overall survival (35.45 months vs. 64.78 months, P = 0.0173). In particular, MAGE-A11 overexpression was found in 9% of specimens. We then examined MAGE-A11 expression, the efficacy of EGFR and the EGFR mutational status and the effects of the pan-HER (human EGFR) TKIs erlotinib and afatinib in HNSCC cell lines. Next, we used a model of stable MAGE-A11 overexpression to demonstrate that MAGE-A11 impaired the efficacy of erlotinib and afatinib. In summary, our study provides evidence that MAGE-A11 contributes to erlotinib and afatinib resistance in head and neck cancer cell lines.