Society for immunotherapy of cancer (SITC) statement on the proposed changes to the common rule

The Common Rule is a set of ethical principles that provide guidance on the management of human subjects taking part in biomedical and behavioral research in the United States. The elements of the Common Rule were initially developed in 1981 following a revision of the Declaration of Helsinki in 1975. Most academic facilities follow the Common Rule in the regulation of clinical trials research. Recently, the government has suggested a revision of the Common Rule to include more contemporary and streamlined oversight of clinical research. In this commentary, the leadership of the Society for Immunotherapy of Cancer (SITC) provides their opinion on this plan. While the Society recognizes the considerable contribution of clinical research in supporting progress in tumor immunotherapy and supports the need for revisions to the Common Rule, there is also some concern over certain elements which may restrict access to biospecimens and clinical data at a time when high throughput technologies, computational biology and assay standardization is allowing major advances in understanding cancer biology and providing potential predictive biomarkers of immunotherapy response. The Society values its professional commitment to patients for improving clinical outcomes with tumor immunotherapy and supports continued discussion with all stakeholders before implementing changes to the Common Rule in order to ensure maximal patient protections while promoting continued clinical research at this historic time in cancer research

Protein trafficking through the endosomal system prepares intracellular parasites for a home invasion

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles

Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2

<p>Abstract</p> <p>Background</p> <p>The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses.</p> <p>Methods</p> <p>Subjects with stage II (≥ 6 +LN), III, or stage IV breast cancerwith > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact.</p> <p>Results</p> <p>All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6–6.7 years of follow-up.</p> <p>Conclusion</p> <p>Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00005956</p

Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: A literature review. "Assessment remains troublesome"

Background: Prolonged administration of benzodiazepines and/or opioids to children in a pediatric intensive care unit (PICU) may induce physiological dependence and withdrawal symptoms. Objective: We reviewed the literature for relevant contributions on the nature of these withdrawal symptoms and on availability of valid scoring systems to assess the extent of symptoms. Methods: The databases PubMed, CINAHL, and Psychinfo (1980-June 2006) were searched using relevant key terms. Results: Symptoms of benzodiazepine and opioid withdrawal can be classified in two groups: central nervous system effects and autonomic dysfunction. However, symptoms of the two types show a large overlap for benzodiazepine and opioid withdrawal. Symptoms of gastrointestinal dysfunction in the PICU population have been described for opioid withdrawal only. Six assessment tools for withdrawal symptoms are used in children. Four of these have been validated for neonates only. Two instruments are available to specifically determine withdrawal symptoms in the PICU: the Sedation Withdrawal Score (SWS) and the Opioid Benzodiazepine Withdrawal Scale (OBWS). The OBWS is the only available assessment tool with prospective validation; however, the sensitivity is low. Conclusions: Withdrawal symptoms for benzodiazepines and opioids largely overlap. A sufficiently sensitive instrument for assessing withdrawal symptoms in PICU patients needs to be developed

Forty years on: clathrin-coated pits continue to fascinate

Clathrin mediated endocytosis (CME) is a fundamental process in cell biology and has been extensively investigated throughout the last several decades. Every cell biologist learns about it at some point during their education and the beauty of this process has led many of us to go deeper and make it the topic of our own research. Great progress has been made towards elucidating the mechanisms of CME and the field is becoming increasingly complex with several hundred new publications every year. This makes it easy to get lost in the vast amount of literature and to forget about the fundamentals of the field, based on the careful interpretation of simple observations made over 40 years ago. A study performed by Anderson, Brown and Goldstein in 1977 (Anderson et al., 1977) is a prime example of this. We therefore want to take a step back and examine how this seminal study was pivotal to our understanding of CME and its progression into ever increasing complexity over the last four decades