Identification of stemness-related glycosylation changes in head and neck squamous cell carcinoma.

BACKGROUND: Altered glycosylation is a hallmark of cancer associated with therapy resistance and tumor behavior. In this study, we investigated the glycosylation profile of stemness-related proteins OCT4, CIP2A, MET, and LIMA1 in HNSCC tumors. METHODS: Tumor, adjacent normal tissue, and blood samples of 25 patients were collected together with clinical details. After tissue processing, lectin-based glycovariant screens were performed. RESULTS: Strong correlation between glycosylation profiles of all four stemness-related proteins was observed in tumor tissue, whereas glycosylation in tumor tissue, adjacent normal tissue, and serum was differential. CONCLUSIONS: A mannose- and galactose-rich glycosylation niche associated with stemness-related proteins was identified.

Autotracing of Escherichia coli acetate CoA-transferase alpha-subunit structure using 3.4 A MAD and 1.9 A native data.

The automation of protein structure determination is an essential component for high-throughput structural analysis in protein X-ray crystallography and is a key element in structural genomics. This highly challenging undertaking relies at present on the availability of high-quality native and derivatized protein crystals diffracting to high or moderate resolution, respectively. Obtaining such crystals often requires significant effort. The present study demonstrates that phases obtained at low resolution (>3.0 A) from crystals of SeMet-labeled protein can be successfully used for automated structure determination. The crystal structure of acetate CoA-transferase alpha-subunit was solved using 3.4 A multi-wavelength anomalous dispersion data collected from a crystal containing SeMet-substituted protein and 1.9 A data collected from a native protein crystal.

Reproductive hormones, cancers, and conditions in relation to a common genetic variant of luteinizing hormone.

A variant of the beta-subunit of luteinizing hormone (v-LH) is more common among populations also at higher risk for breast and ovarian cancer. To explore the possible relationship between these cancers and v-LH, we examined its frequency in premenopausal women, including 100 with a family history of ovarian cancer, 94 with carcinoma- in-situ of the breast, and 153 age and residence-matched controls. Reproductive histories were assessed and v-LH status measured by immunological assays from plasma drawn during the early follicular phase of cycles. For the entire study population, 283 (81.5%) were wild type; 61 (17.6%) were heterozygous; and three (0.9%) were homozygous for v-LH. Carrier frequency was not elevated among women with a family history of ovarian cancer or personal history of carcinoma-in-situ of the breast compared with controls. Women with the v-LH variant were less likely to report menstrual weight gain or ovarian cysts, more likely to report infertility, and have higher early follicular phase LH concentrations compared with women who were wild type. While there is no evidence from this study that v-LH increases risk for ovarian or breast cancer, we conclude that possession of v-LH may impact on some aspects of reproductive history and LH concentrations.

The free-to-total prostate specific antigen ratio improves the specificity of prostate specific antigen in screening for prostate cancer in the general population.

PURPOSE: The ratio between free and total prostate specific antigen (PSA) in serum improves the specificity of total serum PSA for the detection of prostate carcinoma in select populations. The value of the free-to-total PSA ratio for a PSA of 4.0 to 10.0 ng./ml. was analyzed in a screening population. MATERIALS AND METHODS: From 4,800 participants 55 to 76 years old 977 biopsies were obtained because of an abnormal digital rectal examination, suspicious transrectal ultrasonography and total serum PSA 4.0 ng./ml. or more. Of 191 patients with prostate carcinoma detected 101 had a serum PSA of 4.0 to 10.0 ng./ml. and 54 of them underwent radical prostatectomy. A free-to-total PSA ratio of 0.20, age specific PSA reference ranges and a PSA density of 0.12 ng./ml./cc were evaluated for the ability to increase the specificity of total serum PSA in predicting positive prostate biopsy results. RESULTS: Receiver operating characteristics curves for the free-to-total PSA ratio showed a significant increase in specificity compared to PSA. Retrospective application of age specific PSA reference ranges, the free-to-total PSA ratio and the PSA density decreased the number of biopsies significantly by up to 40% in our study, with a decrease in cancer detection rate of 12%. When used in combination with digital rectal examination, the pathological stage of undetected carcinomas appeared favorable. CONCLUSIONS: The free-to-total PSA ratio may be used to decrease biopsies in patients with an intermediate PSA of 4.0 to 10.0 ng./ml.

Serum screening for Down's syndrome between 8 and 14 weeks of pregnancy. International Prenatal Screening Research Group.

OBJECTIVE: To determine the value of serum screening for Down's syndrome at 8-14 weeks of pregnancy using seven potential serum markers (alpha-fetoprotein, unconjugated oestriol, total human chorionic gonadotrophin (hCG), free alpha-hCG, free beta-hCG, pregnancy associated plasma protein A (PAPP-A), and dimeric inhibin A). DESIGN: Stored blood samples collected from women at about 10 weeks of pregnancy, prior to having chorionic villus sampling procedure on account of advanced maternal age, were retrieved from pregnancies associated with Down's syndrome and from matched unaffected pregnancies. SETTING: Twenty-one obstetric centres in nine countries. SUBJECTS: Seventy-seven pregnancies associated with Down's syndrome each matched with five controls (except in two cases that were matched with four controls) for maternal age (same five year age groups), duration of storage of the serum sample (same calendar year), and gestational age (usually same week of pregnancy). RESULTS: The levels of two potential markers differed between affected and unaffected pregnancies sufficiently to be of value in screening--free beta-hCG and PAPP-A. The median free beta-hCG level in affected pregnancies was 1.79 times the median level for unaffected pregnancies, and the median PAPP-A level was 0.43 times the normal median. These two markers were combined with maternal age to estimate a woman's risk of having a fetus with Down's syndrome. A screening programme that used a risk cutoff level of 1:300 would detect 63% of affected pregnancies and also classify 5.5% of unaffected pregnancies as screen positive. None of the other five markers added more than 2% detection for the same false-positive rate. CONCLUSION: The performance of screening using maternal age and serum-free beta-hCG and PAPP-A at 10 weeks of pregnancy was better than the double test (alpha-fetoprotein and hCG with maternal age) and similar to the triple test (alpha-fetoprotein, unconjugated oestriol and hCG with maternal age) at 15-22 weeks.

Analgesic efficacy of immediate and sustained release paracetamol and plasma concentration of paracetamol. Double blind, placebo-controlled evaluation using painful laser stimulation.

The analgesic efficacy of single doses of immediate release paracetamol 500 mg and 1000 mg, sustained release paracetamol 2000 mg, and placebo was evaluated over a 12 h period in 10 healthy volunteers. The efficacy was related to the concurrent plasma concentrations of paracetamol. Experimental pain was induced by brief cutaneous application of argon laser pulses, and the analgesic effect was assessed as change in pricking pain threshold. Both 0.5 g and 1.0 g immediate release paracetamol had an analgesic effect superior to that of placebo from 1 to 5 h after administration. Peak analgesia was reached after 2 h. No difference was found in the analgesic effect of the two dosages. Sustained release paracetamol was not significantly superior to placebo at any time. The plasma concentration of paracetamol had peaked in the 1 h sample after of the immediate release tablet. The peak plasma concentration was reached 3-4 h after 2.0 g sustained release paracetamol. It is not known why the sustained release formulation did not produce any detectable analgesia. It is proposed, that the rate of increase in the plasma concentration of paracetamol might be important in the alleviation of acute (laser-induced) pain.

A double-blind, placebo controlled, cross-over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser-induced pain.

1. The analgesic efficacy of single oral doses (400 mg, 800 mg) of ibuprofen on argon laser-induced pain was studied in a double-blind, placebo controlled, three way cross-over comparison. Ten healthy volunteers participated. 2. Pain thresholds and plasma concentrations of the S- and R-enantiomers of ibuprofen were measured every hour up to 8 h after medication. 3. Ibuprofen (400 mg) produced an analgesic effect significantly superior (P less than 0.05) to placebo 1-4 h after medication. Ibuprofen (800 mg) was significantly superior to placebo 2-4 h after administration. No differences were found between 400 mg and 800 mg, when hourly threshold differences were compared. 4. Comparing total analgesic effect (area under effect curve), both active medications were superior to placebo (P less than 0.01-0.05), and 400 mg was superior to 800 mg (P less than 0.05). 5. Peak plasma concentrations of S- and R-ibuprofen occurred between 1.2 and 1.5 h. Concentrations after the 800 mg dose were higher than those after the 400 mg dose at all times.