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Abstract Background ID proteins are dominant negative inhibitors of basic helix-loop-helix transcription factors that have multiple functions during development and cellular differentiation. Ectopic (over-)expression of ID1 extends the lifespan of primary human epithelial cells. High expression levels of ID1 have been detected in multiple human malignancies, and in some have been correlated with unfavorable clinical prognosis. ID1 protein is localized at the centrosomes and forced (over-)expression of ID1 results in errors during centrosome duplication. Results Here we analyzed the steady state expression levels of the four ID-proteins in 18 tumor cell lines and assessed the number of centrosome abnormalities. While expression of ID1, ID2, and ID3 was detected, we failed to detect protein expression of ID4. Expression of ID1 correlated with increased supernumerary centrosomes in most cell lines analyzed. Conclusions This is the first report that shows that not only ectopic expression in tissue culture but endogenous levels of ID1 modulate centrosome numbers. Thus, our findings support the hypothesis that ID1 interferes with centrosome homeostasis, most likely contributing to genomic instability and associated tumor aggressiveness.

Objective: This study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PKs) of different doses of a long-acting release (LAR) formulation of pasireotide in healthy subjects. Design: Single-center, open-label, randomized Phase I study. Methods: Twelve healthy male subjects received a single s.c. dose of pasireotide 300 &mgr;g followed by a washout period of 7 days (or at least 5 days), before receiving an i.m. injection of pasireotide -LAR 40 mg (n=5) or 60 mg (n=7). Assessments included adverse events (AEs), PKs, and glucose, insulin, glucagon, and HbA1c levels Results: Pasireotide LAR showed an extended-release profile over 1 month with two concentration peaks observed 1 and around 20 days after injection. The area under curve exposure of pasireotide LAR was dose proportional when the dose levels were compared, and the bioavailability of the LAR relative to the s.c. formulation was complete. Administration of pasireotide LAR resulted in an increase in fasting and postprandial glucose levels; however, an attenuation of the hyperglycemic effect was observed after 15 days. The most frequently reported AEs were mild-to-moderate diarrhea, abdominal pain, and flatulence. Only gastrointestinal AEs and injection site reactions were suspected to be drug related. Conclusions: Pasireotide LAR was generally well tolerated with mostly mild AEs at doses up to 60 mg and showed a dose-proportional, extended-release profile in healthy subjects. Based on the favorable results of this study, further clinical development of pasireotide LAR is under way, which will give insight into the PKs, efficacy, and safety of pasireotide LAR in patient populations. [ABSTRACT FROM AUTHOR]

Inhibitors of differentiation or DNA binding (Id) proteins have been shown to be involved in tumor growth, invasiveness, metastasis, and angiogenesis. Overexpression of Id proteins, especially Id1, correlates with unfavorable clinical prognosis. Thus, they are attractive molecular targets for anticancer therapy. Overexpression of Id proteins mediates breast cancer metastasis to lung. Targeting Id1 and Id3 expression in breast cancer cells reduces breast cancer metastasis in animal models. Different breast tumors failed to grow and/or metastasize in Id1 Id3 mice. Id1 and Id3 preferentially dimerize with the key regulatory E-proteins which inhibit the expression of different tumor suppressor genes. Nevertheless, the inhibition of tumorigenic activities of Id1 and Id3 at protein level has never been studied. Here, we isolated a novel peptide aptamer, Id1/3-PA7, specifically interacting with Id1 and Id3 from randomized combinatorial expression library using yeast and mammalian two-hybrid systems. Intracellular delivered Id1/3-PA7 co-localized to Id1 and Id3 and interfered with their functions. It repressed E47 protein sequestration by Id1 and Id3, activated the E-box promoter and increased the expression level of cyclin-dependent kinase inhibitors (CDKN1A and CDKN1B) in a dose-dependent fashion, paralleled by the cleavage of poly ADP ribose polymerase (PARP). These effects were counteracted by ectopically overexpressed Id1 and Id3. Peptide aptamer Id1/3-PA7 induced cell cycle arrest and apoptosis in breast cancer cells MCF7 and MDA-MB-231. In conclusion, Id1/3-PA7 could represent a nontoxic exogenous agent that can significantly provoke antiproliferative and apoptotic effects in breast cancer cells, which are associated with deregulated expression of Id1 and Id3. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) has been suggested to be associated with different neoplasms. Of 589 consecutive patients with MM, 59 (10%%) had different neoplasms: solid tumors in 78%% and hematological neoplasms in 22%%. Different neoplasms were separated into those emerging prior or synchronously (p/s; n == 41) versus subsequently after the MM ( n == 18). The rate of different neoplasms at the time of MM diagnosis was estimated as 6.6%%, and estimated different neoplasm rates at 2, 5, and 10 years were 7.8%%, 10.3%%, and 11.6%%, respectively. Patients with MM with p/s different neoplasms showed a hazard ratio (HR) for impaired overall survival of 1.2 (95%% CI 0.8--2.0), whereas in those with subsequent neoplasms the HR was 2.5 (95%% CI 1.4--4.4). This demonstrates that (1) p/s are more frequent compared with subsequent different neoplasms, and (2) the prognosis is more impaired with subsequent different neoplasms. Age ≥≥60 years was a confounding covariable with a HR of 2.021 (95%% CI 1.6--2.6). [ABSTRACT FROM AUTHOR]

Presents a letter to the editor related to Keratinocyte stem cells.

An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) are causative agents of a number of malignancies in humans, including cervical cancer. Their tumorigenic potential is linked to expression of the viral E6/E7 genes which can interfere with normal cell cycle control by targeting p53, p21WAF1, p27KIP1, and pRb. We show here that nontumorigenic and tumorigenic HPV-positive keratinocytes (HPK) exhibit striking differences in the response of cell cycle regulatory genes towards transforming growth factor beta-β1. Treatment with this agent led to an efficient induction of p53 and the growth-inhibitory p15INK4 and p21WAF1 genes only in nontumorigenic HPKs and was linked to an efficient reduction in viral E6/E7 oncogene expression. This was associated with increased pRb levels, exhibiting sustained hypophosphorylation, and a permanent growth arrest in the G1 phase of the cell cycle. In contrast, tumorigenic HPKs exhibited only a modest rise in p53 protein levels and a substantially reduced induction of the p15INK4 and p21WAF1 genes, which was linked to a lesser degree of viral oncogene repression. In addition, tumorigenic HPKs rapidly resumed cell growth after a transient G1 arrest, concomitantly with the reappearance of hyperphosphorylated pRb. These results support the notion that the progression of HPV-positive cells to a malignant phenotype is associated with increased resistance to growth inhibition by transforming growth factor-β1. This is linked in the tumorigenic cells to a lack of persistent G1 arrest, inefficient induction of several cell cycle control genes involved in growth inhibition, and inefficient repression of the growth-promoting viral E6/E7 oncogenes. [ABSTRACT FROM AUTHOR]

Aim: To investigate the expression and clinical relevance of inhibitor of differentiation (ID) proteins in biliary tract cancer., Methods: ID protein expression was analyzed in 129 samples from patients with advanced biliary tract cancer (BTC) (45 extrahepatic, 50 intrahepatic, and 34 gallbladder cancers), compared to normal controls and correlated with clinical an pathological parameters., Results: ID1-3 proteins are frequently overexpressed in all BTC subtypes analyzed. No correlation between increased ID protein expression and tumor grading, tumor subtype or treatment response was detected. Survival was influenced primary tumor localization (extrahepatic vs intrahepatic and gall bladder cancer, OS 1.5 years vs 0.9 years vs 0.7 years, P = 0.002), by stage at diagnosis (OS 2.7 years in stage I vs 0.6 years in stage IV, P < 0.001), resection status and response to systemic chemotherapy. In a multivariate model, ID protein expression did not correlate with clinical prognosis. Nevertheless, there was a trend of shorter OS in patients with loss of cytoplasmic ID4 protein expression (P = 0.076)., Conclusion: ID protein expression is frequently deregulated in BTC but does not influence clinical prognosis. Their usefulness as prognostic biomarkers in BTC is very limited.

History and Clinical Findings: We report the case of a woman who presented to the medical emergency room with upper thoracic inlet syndrome six months after being treated for cancer of the left breast with surgery, radiation, and chemotherapy. A port-related occlusion of the superior vena cava was diagnosed on the basis of the history, physical findings, and diagnostic images., Methods: The local standards for the handling of port systems are presented., Discussion: Implanted port systems facilitate the treatment of the chronically ill by enabling easy and safe venous access. As the number of patients with such systems is growing, there is an increased need for optimized handling and care, awareness of the risks (such as catheter occlusion, thrombosis, and infection), and recognition of complications when they arise.