BRCA1: linking HOX to breast cancer suppression

Homeobox (HOX) genes play key roles in embryogenesis and tissue differentiation. Recently, a number of groups have reported altered HOX gene expression in breast cancer. However, the mechanism of HOX gene regulation and the search for direct targets of its transcriptional regulatory function have been minimally fruitful. Recently, Gilbert and colleagues reported that HOXA9 restrains breast cancer progression by upregulation of BRCA1, a tumor suppressor. This finding raises our hope that more, rather elusive targets of HOX genes important in tumor progression or suppression will be found in the future

The quality control theory of aging

The quality control (QC) theory of aging is based on the concept that aging is the result of a reduction in QC of cellular systems designed to maintain lifelong homeostasis. Four QC systems associated with aging are 1) inadequate protein processing in a distressed endoplasmic reticulum (ER); 2) histone deacetylase (HDAC) processing of genomic histones and gene silencing; 3) suppressed AMPK nutrient sensing with inefficient energy utilization and excessive fat accumulation; and 4) beta-adrenergic receptor (BAR) signaling and environmental and emotional stress. Reprogramming these systems to maintain efficiency and prevent aging would be a rational strategy for increased lifespan and improved health. The QC theory can be tested with a pharmacological approach using three well-known and safe, FDA-approved drugs: 1) phenyl butyric acid, a chemical chaperone that enhances ER function and is also an HDAC inhibitor, 2) metformin, which activates AMPK and is used to treat type 2 diabetes, and 3) propranolol, a beta blocker which inhibits BAR signaling and is used to treat hypertension and anxiety. A critical aspect of the QC theory, then, is that aging is associated with multiple cellular systems that can be targeted with drug combinations more effectively than with single drugs. But more importantly, these drug combinations will effectively prevent, delay, or reverse chronic diseases of aging that impose such a tremendous health burden on our society

Design and Evaluation of Meningococcal Vaccines through Structure-Based Modification of Host and Pathogen Molecules

Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps

Evaluating the use of the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS-Q) to estimate IQ in children with low intellectual ability

In situations where completing a full intellectual assessment is not possible or desirable the clinician or researcher may require an alternative means of accurately estimating intellectual functioning. There has been limited research in the use of proxy IQ measures in children with an intellectual disability or low IQ. The present study aimed to provide a means of converting total scores from a screening tool (the Child and Adolescent Intellectual Disability Screening Questionnaire: CAIDS-Q) to an estimated IQ. A series of linear regression analyses were conducted on data from 428 children and young people referred to clinical services, where FSIQ was predicted from CAIDS-Q total scores. Analyses were conducted for three age groups between ages 6 and 18 years. The study presents a conversion table for converting CAIDS-Q total scores to estimates of FSIQ, with corresponding 95% prediction intervals to allow the clinician or researcher to estimate FSIQ scores from CAIDS-Q total scores. It is emphasised that, while this conversion may offer a quick means of estimating intellectual functioning in children with a below average IQ, it should be used with caution, especially in children aged between 6 and 8 years old

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Health profiles of 996 melanoma survivors: the M. D. Anderson experience

BACKGROUND: The incidence and survival of melanoma are increasing, but little is known about its long-term health effects in adult survivors. METHODS: A health survey was available from 996 melanoma survivors (577 treated with surgery alone, and 391 with combined treatments). Their medical/physiologic and psychosocial responses were analyzed and compared with those of the survivors from other cancers. RESULTS: The melanoma survivors were 44.8 ± 12.8 years of age at diagnosis (significantly younger than the survivors of other cancers) and 63.7 ± 12.8 years at survey. Melanoma survivors were less likely to report that cancer had affected their health than survivors of other cancers (15.8% vs. 34.9%). The 577 individuals treated with surgery alone reported arthritis/osteoporosis, cataracts, and heart problems most frequently (less often than survivors of other cancers). The 391 individuals who had undergone combined treatments reported circulation problems and kidney problems generally as often as survivors of other cancers. Health problems were not associated with number of decades since diagnosis but with age at diagnosis, treatment modality, and family relationships. CONCLUSION: We present information from a large cohort of long-term survivors of melanoma. As a group, they were less likely to report that cancer had affected their overall health than survivors of other cancers; a number of disease related and psychosocial factors appear to influence their health profiles

Investigation of potential cognition factors correlated to fire evacuation

The design of a navigation system to support indoor fire evacuation depends not only on speed but also a relatively thorough consideration of the cognition factors. This study has investigated potential cognition factors which can affect the human behaviours and decision making during fire evacuation by taking a survey among indoor occupants in age of 20s under designed virtual scenarios. It mainly focuses on two aspects of Fire Responses Performances (FRP), i.e. indoor familiarity (spatial cognition) and psychological stress (situ-ated cognition). The collected results have shown that these cognition factors can be affected by gender and user height and they are correlated with each other in certain ways. It has also investigated users‟ attitudes to the navigation services under risky and non-risky conditions. The collected answers are also found to be correlated with the selected FRP factors. These findings may help to further design of personalized indoor navigation support for fire evacuation

Cost-effectiveness of collaborative care including PST and an antidepressant treatment algorithm for the treatment of major depressive disorder in primary care; a randomised clinical trial

BACKGROUND: Depressive disorder is currently one of the most burdensome disorders worldwide. Evidence-based treatments for depressive disorder are already available, but these are used insufficiently, and with less positive results than possible. Earlier research in the USA has shown good results in the treatment of depressive disorder based on a collaborative care approach with Problem Solving Treatment and an antidepressant treatment algorithm, and research in the UK has also shown good results with Problem Solving Treatment. These treatment strategies may also work very well in the Netherlands too, even though health care systems differ between countries. METHODS/DESIGN: This study is a two-armed randomised clinical trial, with randomization on patient-level. The aim of the trial is to evaluate the treatment of depressive disorder in primary care in the Netherlands by means of an adapted collaborative care framework, including contracting and adherence-improving strategies, combined with Problem Solving Treatment and antidepressant medication according to a treatment algorithm. Forty general practices will be randomised to either the intervention group or the control group. Included will be patients who are diagnosed with moderate to severe depression, based on DSM-IV criteria, and stratified according to comorbid chronic physical illness. Patients in the intervention group will receive treatment based on the collaborative care approach, and patients in the control group will receive care as usual. Baseline measurements and follow up measures (3, 6, 9 and 12 months) are assessed using questionnaires and an interview. The primary outcome measure is severity of depressive symptoms, according to the PHQ9. Secondary outcome measures are remission as measured with the PHQ9 and the IDS-SR, and cost-effectiveness measured with the TiC-P, the EQ-5D and the SF-36. DISCUSSION: In this study, an American model to enhance care for patients with a depressive disorder, the collaborative care model, will be evaluated for effectiveness in the primary care setting. If effective across the Atlantic and across different health care systems, it is also likely to be an effective strategy to implement in the treatment of major depressive disorder in the Netherlands