The 48-hour tetrahydrobiopterin loading test in patients with phenylketonuria: evaluation of protocol and influence of baseline phenylalanine concentration.

Background: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 μmol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and the necessity of the 400 μmol/l minimum baseline phenylalanine concentration.

Methods: Data on 186 phenylketonuria patients were collected.

Diurnal variations in blood phenylalanine of PKU infants under different feeding regimes.

Unlabelled: In phenylketonuria (PKU) patients, diurnal fluctuations of blood phenylalanine (Phe) are different from healthy individuals. Until now this pattern has been studied in PKU patients over one year of age.

Objective: The aim of this observational study was to investigate diurnal patterns in PKU infants under one year of age receiving both the natural protein and Phe-free formula at the same time or in an alternating feeding scheme.

Optimising growth in phenylketonuria: current state of the clinical evidence base.

Patients with phenylketonuria (PKU) must follow a strict low-phenylalanine (Phe) diet in order to minimise the potentially disabling neuropsychological sequelae of the disorder. Research in this area has unsurprisingly focussed largely on managing blood Phe concentrations to protect the brain. Protein requirements in dietary management of PKU are met mostly from Phe-free protein substitutes with the intake of natural protein restricted to patient tolerance.

Nutrition in phenylketonuria.

The same basic principles are used to deliver dietary treatment in PKU that was developed sixty years ago. Dietary treatment is undoubtedly very successful, but it has gradually evolved and been guided commonly by individual experience and expert opinion only. There is little international consensus about dietary practice with improvements in specialist dietary products concentrating on taste and presentation rather than nutritional composition.

SMURF1 amplification promotes invasiveness in pancreatic cancer.

Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling.

CSF1 expression in nongynecological leiomyosarcoma is associated with increased tumor angiogenesis.

Leiomyosarcoma (LMS) is a malignant tumor of smooth muscle cells for which few effective therapies exist. A subset of LMS cases express macrophage colony-stimulating factor (CSF1) and the resultant tumor-associated macrophage (TAM) infiltration predicts poor clinical outcome. Further, TAMs have been shown to increase tumor angiogenesis.

Increased midkine expression correlates with desmoid tumour recurrence: a potential biomarker and therapeutic target.

Desmoid tumours (DTs) are soft tissue monoclonal neoplasms exhibiting a unique phenotype, consisting of aggressive local invasiveness without metastatic capacity. While DTs can infrequently occur as part of familial adenomatosis polyposis, most cases arise sporadically. Sporadic DTs harbour a high prevalence of CTNNB1 mutations and hence increased β-catenin signalling.

PKU: high plasma phenylalanine concentrations are associated with increased prevalence of mood swings.

Unlabelled: In phenylketonuria, knowledge about the relation between behavior and plasma phenylalanine is scarce. The aim of this study was to determine whether high phenylalanine is associated with disturbed behavior noticed by the patient and or close environment (parents or partners). 48 early treated PKU patients (median age 8.

A tri-marker proliferation index predicts biochemical recurrence after surgery for prostate cancer.

Prostate cancer exhibits tremendous variability in clinical behavior, ranging from indolent to lethal disease. Better prognostic markers are needed to stratify patients for appropriately aggressive therapy. By expression profiling, we can identify a proliferation signature variably expressed in prostate cancers.

Adult patients with well-controlled phenylketonuria tolerate incidental additional intake of phenylalanine.

Background/aims: In patients with phenylketonuria (PKU), target ranges of blood phenylalanine (Phe) concentrations have been tightened in order to improve long-term outcomes. We investigated day-to-day and week-to-week variations in blood Phe concentration and the effect of an additional Phe load.

Methods: We performed a longitudinal study in 6 adult PKU patients.

Adjusting diet with sapropterin in phenylketonuria: what factors should be considered?

The usual treatment for phenylketonuria (PKU) is a phenylalanine-restricted diet. Following this diet is challenging, and long-term adherence (and hence metabolic control) is commonly poor. Patients with PKU (usually, but not exclusively, with a relatively mild form of the disorder) who are responsive to treatment with pharmacological doses of tetrahydrobiopterin (BH4) have either lower concentrations of blood phenylalanine or improved dietary phenylalanine tolerance.

Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry.

Leiomyosarcomas (LMSs) constitute approximately one quarter of all sarcomas and are usually defined by morphologic criteria and/or immunoreactivity for actin or desmin. Among high-grade lesions, the distinction from undifferentiated pleomorphic sarcoma (UPS) can be problematic, and previous studies have shown that a significant number of LMS cases may be hiding under the diagnosis of UPS. We recently described 3 novel molecular LMS subtypes that are distributed similarly over LMSs of gyneocologic and non-gyneocologic origins.

Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker.

Purpose: We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC).

Patients And Methods: We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) to identify genes differentially expressed between these two groups. To characterize the clinical relevance of two highly-ranked differentially-expressed genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC.

Spreading of complex regional pain syndrome: not a random process.

Complex regional pain syndrome (CRPS) generally remains restricted to one limb but occasionally may spread to other limbs. Knowledge of the spreading pattern of CRPS may lead to hypotheses about underlying mechanisms but to date little is known about this process. The objective is to study patterns of spread of CRPS from a first to a second limb and the factors associated with this process.

Uterine leiomyosarcomas: tumor size, mitotic index, and biomarkers Ki67, and Bcl-2 identify two groups with different prognosis.

Background: Prognostic factors for uterine leiomyosarcomas are not well established. Although most tumors are associated with poor prognosis even when apparently confined to the uterus (stage I), some cases that exhibited morphologic features of malignancy had prolonged survival.

Methods: Using tissue microarrays of 84 uterine leiomyosarcomas, we investigated conventional clinico-pathologic parameters, including International Federation of Gynecology and Obstetrics (FIGO) stage, together with expression of Ki67, p53, p16, and Bcl-2, attempting to distinguish leiomyosarcomas with different prognosis.

The prognostic value of tumor-associated macrophages in leiomyosarcoma: a single institution study.

Introduction: High numbers of tumor-associated macrophages (TAMs) have been associated with poor outcome in several solid tumors. In 2 previous studies, we showed that colony stimulating factor-1 (CSF1) is secreted by leiomyosarcoma (LMS) and that the increase in macrophages and CSF1 associated proteins are markers for poor prognosis in both gynecologic and nongynecologic LMS in a multicentered study. The purpose of this study is to evaluate the outcome of patients with LMS from a single institution according to the number of TAMs evaluated through 3 CSF1 associated proteins.

Physical activity and low back pain: a systematic review of recent literature.

The objective of the study is to systematically evaluate the available evidence on the association between physical activity (i.e. occupational load and non-occupational physical activities) and low back pain (LBP).

Thermal hypesthesia in patients with complex regional pain syndrome related dystonia.

The quantitative thermal test showed cold and warmth hypesthesia without increased heat pain sensitivity in the affected limbs of complex regional pain syndrome (CRPS) patients with tonic dystonia (n = 44) in comparison with healthy controls with a similar age and sex distribution (n = 35). The degrees of cold and warmth hypesthesia were strongly correlated. We conclude that dysfunction in small nerve fiber (i.

Blood phenylalanine control in phenylketonuria: a survey of 10 European centres.

Background: Only limited data are available on the blood phenylalanine (Phe) concentrations achieved in European patients with phenylketonuria (PKU) on a low-Phe diet.

Objective: A survey was conducted to compare blood Phe control achieved in diet-treated patients with PKU of different age groups in 10 European centres.

Methods: Centres experienced in the management of PKU from Belgium, Denmark, Germany, Italy, The Netherlands, Norway, Poland, Spain, Turkey and the United Kingdom provided retrospective audit data of all patients with PKU treated by diet over a 1-year period.

Endogenous versus tumor-specific host response to breast carcinoma: a study of stromal response in synchronous breast primaries and biopsy site changes.

Purpose: We recently described two types of stromal response in breast cancer derived from gene expression studies of tenosynovial giant cell tumors and fibromatosis. The purpose of this study is to elucidate the basis of this stromal response--whether they are elicited by individual tumors or whether they represent an endogenous host reaction produced by the patient.

Experimental Design: Stromal signatures from patients with synchronous dual primaries were analyzed by immunohistochemistry on a tissue microarray (n = 26 pairs) to evaluate the similarity of stromal responses in different tumors within the same patient.

Serum vitamin B12 concentrations within reference values do not exclude functional vitamin B12 deficiency in PKU patients of various ages.

Unlabelled: Homocysteine (Hcy) and in particular methylmalonic acid (MMA) are considered reliable parameters for vitamin B(12) status in healthy individuals. Phenylketonuria (PKU) patients are at risk for functional vitamin B(12) deficiency based on their diet.

Objective: The aim of this study was to investigate the prevalence of functional vitamin B(12) deficiency in continuously treated PKU patients and the association of parameters of vitamin B(12) and metabolic control.

Large neutral amino acids in the treatment of PKU: from theory to practice.

Notwithstanding the success of the traditional dietary phenylalanine restriction treatment in phenylketonuria (PKU), the use of large neutral amino acid (LNAA) supplementation rather than phenylalanine restriction has been suggested. This treatment modality deserves attention as it might improve cognitive outcome and quality of life in patients with PKU. Following various theories about the pathogenesis of cognitive dysfunction in PKU, LNAA supplementation may have multiple treatment targets: a specific reduction in brain phenylalanine concentrations, a reduction in blood (and consequently brain) phenylalanine concentrations, an increase in brain neurotransmitter concentrations, and an increase in brain essential amino acid concentrations.

Gross genomic alterations and gene expression profiles of high- grade serous carcinoma of the ovary with and without BRCA1 inactivation.

Background: BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary.

Methods: DNA ploidy and gene expression profile were used in order to compare gross genomic alteration and gene expression pattern between cases with BRCA1 loss through mutation, BRCA1 epigenetic loss, and no BRCA1 loss in cases of high-grade serous carcinoma with known BRCA1 and BRCA 2 status.

Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271.

The question of whether tumorigenic cancer stem cells exist in human melanomas has arisen in the last few years. Here we show that in melanomas, tumour stem cells (MTSCs, for melanoma tumour stem cells) can be isolated prospectively as a highly enriched CD271(+) MTSC population using a process that maximizes viable cell transplantation. The tumours sampled in this study were taken from a broad spectrum of sites and stages.