Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling.

Unlabelled: H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and nonredundant roles within the cell.

Predictors of hip arthroscopy outcomes for labral tears at minimum 2-year follow-up: the influence of age and arthritis.

Purpose: The purpose of this study was to perform a retrospective case-control outcome analysis at a minimum 2-year follow-up using a validated hip arthroscopy outcome measure to determine whether arthritis or age is predictive of outcomes after hip arthroscopy for labral pathology.

Methods: We identified 176 consecutive patients undergoing hip arthroscopy for labral tears performed between 2001 and 2009 to complete the Modified Harris Hip Score (MHHS) and Hip Outcome Score questionnaires. Patients who underwent additional surgeries or reported an MHHS of less than 80 were compared with the control group of patients who achieved good to excellent surgical results on the MHHS (>80) to calculate odds ratios with 95% confidence intervals by use of the independent variables of patient age of 40 years or older and age below 40 years and the presence of grade 4 Outerbridge changes found at arthroscopy.

Surgeon fatigue: a prospective analysis of the incidence, risk, and intervals of predicted fatigue-related impairment in residents.

Hypothesis: A novel approach to identify at-risk periods among orthopedic surgical residents may direct fatigue risk mitigation and facilitate targeted interventions.

Design: A prospective cohort study with a minimum 2-week continuous assessment period. Data on sleep and awake periods were processed using the sleep, activity, fatigue, and task effectiveness model.

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1.

The Ras/mitogen-activated protein kinase (MAPK) pathway plays a critical role in transducing mitogenic signals from receptor tyrosine kinases. Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway; however, the underlying molecular mechanism is poorly understood.

Factor H autoantibodies in membranoproliferative glomerulonephritis.

Factor H autoantibodies are found in ~10% of aHUS patients. Most are associated with complete deficiency of factor H related proteins 1/3 and bind to the C terminal recognition domain. MPGN, like aHUS, is characterised by complement activation.

Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas.

The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235--a dual PI3K/mTOR inhibitor--and RAD001--an mTOR inhibitor--in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification).

Mapping breastfeeding services: a method to inform effective implementation and evaluation of evidence-based policy in practice.

This paper aims to introduce a method for mapping local service provision to local demographic and health outcome data, to inform evidence-based policy and practice in public health. A mapping exercise was conducted in London, England with the aims of: (1) describing services provided for breastfeeding women in primary and tertiary health care sectors and government, voluntary and private sectors; and (2) linking this information with routine data on deprivation, breastfeeding rates and health outcomes. Quantitative data on local breastfeeding services were collected via an online questionnaire by a designated 'mapping lead' in each locality.

Support for healthy breastfeeding mothers with healthy term babies.

Background: There is extensive evidence of important health risks for infants and mothers related to not breastfeeding. In 2003, the World Health Organization recommended infants be exclusively breastfed until six months of age, with breastfeeding continuing as an important part of the infant's diet till at least two years of age. However, breastfeeding rates in many countries currently do not reflect this recommendation.

Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge.

Background: Preterm infants are often growth-restricted at hospital discharge. Feeding infants after hospital discharge with nutrient-enriched formula rather than standard term formula might facilitate "catch-up" growth and improve development.

Objectives: To determine the effect of feeding nutrient-enriched formula compared with standard term formula on growth and development for preterm infants following hospital discharge.

Stress fractures in runners.

Stress fractures are a relatively common entity in athletes, in particular, runners. Physicians and health care providers should maintain a high index of suspicion for stress fractures in runners presenting with insidious onset of focal bone tenderness associated with recent changes in training intensity or regimen. It is particularly important to recognize “high-risk” fractures, as these are associated with an increased risk of complication.

Therapeutic strategies for targeting ras proteins.

Ras genes are frequently activated in cancer. Attempts to develop drugs that target mutant Ras proteins have, so far, been unsuccessful. Tumors bearing these mutations, therefore, remain among the most difficult to treat.

Vascular safe zones in hip arthroscopy.

Background: Hip arthroscopy is an evolving surgical technique being performed in greater numbers because of advances in skill, improved technology, and increased demand. Identifying vascular safe zones using anatomic and intracapsular landmarks provides a valuable intraoperative guide to reduce the risk of damage to the femoral head blood supply during femoral neck osteoplasty and psoas tendon release.

Purpose: This series is presented to identify vascular safe zones for use in hip arthroscopy.

Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies.

The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies.

Cancer therapy based on oncogene addiction.

Tumor cells contain multiple mutations, yet they often depend on continued expressed of a single oncoprotein for survival. Targeting these proteins has led to dramatic responses. Unfortunately, patients usually progress, through drug resistance or adaptive resistance through reprogramming of signaling networks.

Promoting growth for preterm infants following hospital discharge.

Preterm infants, especially very preterm infants, are usually growth-restricted at the time of hospital discharge. Proposed interventions to promote catch-up growth following hospital discharge include multinutrient fortification of expressed breast milk for breastfed infants and nutrient-enriched formula milk for formula-fed infants. The current evidence to support these strategies is limited.

Mutant onco-proteins as drug targets: successes, failures, and future prospects.

Mutant onco-proteins play a direct, causal role in cancer and are therefore considered attractive drug targets. Clinical experience has supported this view, with some exceptions. However, clinical benefit has often been restricted by rapid emergence of drug-resistant clones through several distinct mechanisms.

Mad2 inhibits the mitotic kinesin MKlp2.

We identified the mitotic kinesin-like protein 2 (MKlp2), a kinesin required for chromosome passenger complex (CPC)-mediated cytokinesis, as a target of the mitotic checkpoint protein Mad2. MKlp2 possesses a consensus Mad2-binding motif required for Mad2 binding. Mad2 prevents MKlp2 from loading onto the mitotic spindle, a prerequisite step for its function as a mitotic kinesin.

Association between timing of introducing solid foods and obesity in infancy and childhood: a systematic review.

Determining early-life risk factors for obesity in later life is essential in order to effectively target preventative interventions to reduce obesity. The aim of this systematic review was to investigate current evidence to determine whether the timing of introducing solid foods is associated with obesity in infancy and childhood. Relevant randomized and observational studies from developed countries were identified by searching the following six bio-medical databases (Medline, Embase, British Nursing Index, CINAHL, Maternity and Infant Care, and PsycINFO) and hand-searching reference lists.

Comparison of oncolytic adenoviruses for selective eradication of oral cancer and pre-cancerous lesions.

Oncolytic adenoviruses are being investigated as potential anti-cancer agents. Selective lytic replication in cancer cells is essential for an effective and safe treatment. In this study, we compared 11 oncolytic adenoviruses in relevant cell cultures to assess their use for treating oral cancer and pre-cancerous lesions.

Integrin alphavbeta5 is a primary receptor for adenovirus in CAR-negative cells.

Background: Viruses bind to specific cellular receptors in order to infect their hosts. The specific receptors a virus uses are important factors in determining host range, cellular tropism, and pathogenesis. For adenovirus, the existing model of entry requires two receptor interactions.

Multinutrient fortification of human breast milk for preterm infants following hospital discharge.

Background: Preterm infants are usually growth restricted at hospital discharge. Feeding preterm infants after hospital discharge with multinutrient fortified breast milk rather than unfortified breast milk may facilitate more rapid catch-up growth and improve neurodevelopmental outcomes.

Objectives: To determine the effect of feeding with multinutrient fortified human breast milk versus unfortified breast milk on growth and development in preterm or low birth weight infants following hospital discharge.

Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator.

Uptake of the anticancer drug cisplatin is mediated by the copper transporter CTR1 in cultured cells. Here we show in human ovarian tumors that low levels of Ctr1 mRNA are associated with poor clinical response to platinum-based therapy. Using a mouse model of human cervical cancer, we demonstrate that combined treatment with a copper chelator and cisplatin increases cisplatin-DNA adduct levels in cancerous but not in normal tissues, impairs angiogenesis, and improves therapeutic efficacy.