Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients

Abstract:  The risks of developing malignant melanoma (MM) include ultraviolet irradiation and genetic factors. To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A ( CDKN2A ), cyclin-dependent kinase 4, melanocortin 1 receptor ( MC1R ) and tyrosinase ( TYR )] were resequenced in 109–135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R 'R' variants known or predicted to alter its function ( P  = 0.002), particularly the R160W variant ( P  = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer.     

In Vitro and in Vivo Evaluation of Whole and Half Tablets of Sustained-Release Adinazolam Mesylate

The mechanism of release from sustained-release adinazolam mesylate tablets was assessed by the Higuchi equation and by analysis of drug release profiles through 60% released using the Peppas equation. Computed values of the diffusional exponent, n, ranged from 0.59 to 0.66. Values of n in this range are consistent with a mixed mechanism of release, with diffusion of drug through the hydrated polymer matrix and relaxation of this matrix being the principal processes controlling release. The rate of in vitro drug release was increased for half tablets relative to whole tablets and is attributed to an increase in the surface to volume ratio of half tablets of about 16%. This increase in surface-to-volume ratio of half tablets was reflected by an increase in the constant, k, from the Peppas equation of 20–23% and by an increase in the slope of Higuchi plots of 12–18% for four lots of tablets. In vivo/in vitro relationships from two bioavailability studies were thoroughly evaluated. Using either a linear or a quadratic relationship, an in vivo/in vitro correlation exists for sustained-release adinazolam mesylate tablets.     

Cytoskeletal rearrangement by oxidative stress

The cytoskeleton is susceptible to oxidative stress and this occurs prior to membrane blebbing and cell lysis. Vimentin intermediary filaments in rheumatoid synoviocytes are more susceptible than in normal synoviocytes and this may have pathological significance. They are however no more susceptible to heat shock than other cell types.     

The impact of cystic fibrosis on recovery from orthopedic trauma: A case study

Cystic Fibrosis has effects on many body systems, including the skeletal system. In this case, we describe the impact of respiratory and endocrine disease on bone healing following orthopedic trauma in a 22-year-old woman. Limitations to mobility resulting from trauma complicated her respiratory condition. Disease-related effects on bone health and healing delayed her recovery from the trauma. It is important to recognize the multisystemic nature of CF, even when managing acute orthopedic injuries.     

Age trends in femur stresses from a simulated fall on the hip among men and women: evidence of homeostatic adaptation underlying the decline in hip BMD.

Age trends in proximal femur stresses were evaluated by simulating a fall on the greater trochanter using femur geometry from hip DXA scans of 5334 white men and women in the NHANES III survey. Expansion of femur outer diameter seems to counter net bone loss so that stresses remain similar across age groups, but stresses are higher in older women than in older men. INTRODUCTION: The age decline in hip BMD is caused by both bone loss and expansion of outer diameter that increases the region size over which mass is measured in a DXA scan. Because expansion has an opposing effect on structural strength, it may be a homeostatic adaptation to net bone loss to ensure that load stresses are kept within a narrow range. MATERIALS AND METHODS: Age trends in femur stresses were evaluated with an engineering beam simulation of a fall on the greater trochanter. Hip geometry was extracted from hip DXA scans using the Hip Structure Analysis (HSA) software on 2613 non-Hispanic white men and 2721 women from the third National Health and Nutrition Examination Survey (NHANES III). Using body weight as load, stresses were computed on the inferior-medial and superior-lateral femur neck at its narrowest point and the medial and lateral shaft 2 cm distal to the midpoint of the lesser trochanter. Stresses and the underlying geometries in men and women >50 years oaf age were compared with those 20-49 years of age. RESULTS: Compared with men <50 years of age, stresses in older men were 6% lower on both surfaces of the shaft, 4% lower on the inferior-medial neck, and not different on the superior-lateral neck. In women >50 years of age, stresses on the proximal shaft and inferior-medial neck remained within 3% of young values but were 13% greater on the superior-lateral neck. Neck stresses in young women were lower on the superior-lateral than the inferior-medial neck, but lateral stress increased to the level on the medial surface in older women. Stresses were higher in women than in men, with a greater gender difference in those >50 years of age. CONCLUSIONS: We conclude that femur expansion has a homeostatic effect in men and women that opposes bone loss so that stresses change little with age. Because expansion preserves stresses with progressively less bone mass, the process may reduce structural stability in the femoral neck under fall conditions, especially in the elderly female.     

Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.     

Understanding the minimum clinically important difference: a review of concepts and methods.

BACKGROUND CONTEXT: The effectiveness of spinal surgery as a treatment option is currently evaluated through the assessment of patient-reported outcomes (PROs). The minimum clinically important difference (MCID) represents the smallest improvement considered worthwhile by a patient. The concept of an MCID is offered as the new standard for determining effectiveness of a given treatment and describing patient satisfaction in reference to that treatment. PURPOSE: Our goal is to review the various definitions of MCID and the methods available to determine MCID. STUDY DESIGN: The primary means of determining the MCID for a specific treatment are divided into anchor-based and distribution-based methods. Each method is further subdivided and examined in detail. METHODS: The overall limitations of the MCID concept are first identified. The basic assumptions, statistical biases, and shortcomings of each method are examined in detail. RESULTS: Each method of determining the MCID has specific shortcomings. Three general limitations in the accurate determination of an MCID have been identified: the multiplicity of MCID determinations, the loss of the patient's perspective, and the relationship between pretreatment baseline and posttreatment change scores. CONCLUSIONS: An ideal means of determining the MCID for a given intervention is yet to be determined. It is possible to develop a useful method provided that the assumptions and methodology are initially declared. Our efforts toward the establishment of a MCID will rely on the establishment of specific external criteria based on the symptoms of the patient and treatment intervention being evaluated.     

Dépistage organisé du cancer colorectal

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