In-depth investigation of the molecular pathogenesis of bladder cancer in a unique 26-year old patient with extensive multifocal disease: A case report

Background. The molecular characteristics and the clinical disease course of bladder cancer (BC) in young patients remain largely unresolved. All patients are monitored according to an intensive surveillance protocol and we aim to gain more insight into the molecular pathways of bladder tumors in young patients that could ultimately contribute to patient stratification, improve patient quality of life and reduce associated costs. We also determined whether a biomarker-based surveillance could be feasible. Case Presentation. We report a unique case of a 26-year-old Caucasian male with recurrent non-muscle invasive bladder tumors occurring at a high frequency and analyzed multiple tumors (maximal pTaG2) and urine samples of this patient. Analysis included FGFR3 mutation detection, FGFR3 and TP53 immunohistochemistry, mircosatellite analysis of markers on chromosomes 8, 9, 10, 11 and 17 and a genome wide single nucleotide polymorphism-array (SNP). All analyzed tumors contained a mutation in FGFR3 and were associated with FGFR3 overexpression. None of the tumors showed overexpression of TP53. We found a deletion on chromosome 9 in the primary tumor and this was confirmed by the SNP-array that showed regions of loss on chromosome 9. Detection of all recurrences was possible by urinary FGFR3 mutation analysis. Conclusions. Our findings would suggest that the BC disease course is determined by not only a patient's age, but also by the molecular characteristics of a tumor. This young patient contained typical genetic changes found in tumors of older patients and implies a clinical disease course comparable to older patients. We demonstrate that FGFR3 mutation analysis on voided urine is a simple non-invasive method and could serve as a feasible follow-up approach for this young patient presenting with an FGFR3 mutant tumor

Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand–foot syndrome and a combination of grade 1–2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity

Survival of non-Western first generations immigrants with stomach cancer in North East Netherlands

Background: Isolated groups, such as first generation non-Western immigrants, are at risk for suboptimal utilisation of the health care system resulting in a worse outcome. Methods: From 1989 to 2007, all patients with stomach cancer were selected from the Comprehensive Cancer Centre North-East cancer registry. Associations between country of birth and patient, tumour and treatment characteristics were determined using χ2 analysis. Relative survival analysis was used to estimate relative excess risk of dying according to country of birth (non-Western vs Western). Results: After adjusting for confounding factors (patient, tumour and treatment related), the risk of dying was lower for first generation non-Western immigrants (relative excess risk 0.55, 95% confidence interval 0.43–0.70) compared with Western patients. Conclusion: Although the better survival of first generation non-Western immigrants with stomach cancer remains unexplained, it argues against accessibility problems within the Dutch health care syste

Gender-Related Differences in the Prevalence of Cardiovascular Disease Risk Factors and their Correlates in Urban Tanzania.

\ud Urban areas in Africa suffer a serious problem with dual burden of infectious diseases and emerging chronic diseases such as cardiovascular diseases (CVD) and diabetes which pose a serious threat to population health and health care resources. However in East Africa, there is limited literature in this research area. The objective of this study was to examine the prevalence of cardiovascular disease risk factors and their correlates among adults in Temeke, Dar es Salaam, Tanzania. Results of this study will help inform future research and potential preventive and therapeutic interventions against such chronic diseases. The study design was a cross sectional epidemiological study. A total of 209 participants aged between 44 and 66 years were included in the study. A structured questionnaire was used to evaluate socioeconomic and lifestyle characteristics. Blood samples were collected and analyzed to measure lipid profile and fasting glucose levels. Cardiovascular risk factors were defined using World Health Organization criteria. The age-adjusted prevalence of obesity (BMI > or = 30) was 13% and 35%, among men and women (p = 0.0003), respectively. The prevalence of abdominal obesity was 11% and 58% (p < 0.0001), and high WHR (men: >0.9, women: >0.85) was 51% and 73% (p = 0.002) for men and women respectively. Women had 4.3 times greater odds of obesity (95% CI: 1.9-10.1), 14.2-fold increased odds for abdominal adiposity (95% CI: 5.8-34.6), and 2.8 times greater odds of high waist-hip-ratio (95% CI: 1.4-5.7), compared to men. Women had more than three-fold greater odds of having metabolic syndrome (p = 0.001) compared to male counterparts, including abdominal obesity, low HDL-cholesterol, and high fasting blood glucose components. In contrast, female participants had 50% lower odds of having hypertension, compared to men (95%CI: 0.3-1.0). Among men, BMI and waist circumference were significantly correlated with blood pressure, triglycerides, total, LDL-, and HDL-cholesterol (BMI only), and fasting glucose; in contrast, only blood pressure was positively associated with BMI and waist circumference in women. The prevalence of CVD risk factors was high in this population, particularly among women. Health promotion, primary prevention, and health screening strategies are needed to reduce the burden of cardiovascular disease in Tanzania.\u

Increased Mast Cell Density and Airway Responses to Allergic and Non-Allergic Stimuli in a Sheep Model of Chronic Asthma

BACKGROUND: Increased mast cell (MC) density and changes in their distribution in airway tissues is thought to contribute significantly to the pathophysiology of asthma. However, the time sequence for these changes and how they impact small airway function in asthma is not fully understood. The aim of the current study was to characterise temporal changes in airway MC density and correlate these changes with functional airway responses in sheep chronically challenged with house dust mite (HDM) allergen. METHODOLOGY/PRINCIPAL FINDINGS: MC density was examined on lung tissue from four spatially separate lung segments of allergic sheep which received weekly challenges with HDM allergen for 0, 8, 16 or 24 weeks. Lung tissue was collected from each segment 7 days following the final challenge. The density of tryptase-positive and chymase-positive MCs (MC(T) and MC(TC) respectively) was assessed by morphometric analysis of airway sections immunohistochemically stained with antibodies against MC tryptase and chymase. MC(T) and MC(TC) density was increased in small bronchi following 24 weeks of HDM challenges compared with controls (P<0.05). The MC(TC)/MC(T) ratio was significantly increased in HDM challenged sheep compared to controls (P<0.05). MC(T) and MC(TC) density was inversely correlated with allergen-induced increases in peripheral airway resistance after 24 weeks of allergen exposure (P<0.05). MC(T) density was also negatively correlated with airway responsiveness after 24 challenges (P<0.01). CONCLUSIONS: MC(T) and MC(TC) density in the small airways correlates with better lung function in this sheep model of chronic asthma. Whether this finding indicates that under some conditions mast cells have protective activities in asthma, or that other explanations are to be considered requires further investigation

A genome-wide genetic map of NB-LRR disease resistance loci in potato

Like all plants, potato has evolved a surveillance system consisting of a large array of genes encoding for immune receptors that confer resistance to pathogens and pests. The majority of these so-called resistance or R proteins belong to the super-family that harbour a nucleotide binding and a leucine-rich-repeat domain (NB-LRR). Here, sequence information of the conserved NB domain was used to investigate the genome-wide genetic distribution of the NB-LRR resistance gene loci in potato. We analysed the sequences of 288 unique BAC clones selected using filter hybridisation screening of a BAC library of the diploid potato clone RH89-039-16 (S. tuberosum ssp. tuberosum) and a physical map of this BAC library. This resulted in the identification of 738 partial and full-length NB-LRR sequences. Based on homology of these sequences with known resistance genes, 280 and 448 sequences were classified as TIR-NB-LRR (TNL) and CC-NB-LRR (CNL) sequences, respectively. Genetic mapping revealed the presence of 15 TNL and 32 CNL loci. Thirty-six are novel, while three TNL loci and eight CNL loci are syntenic with previously identified functional resistance genes. The genetic map was complemented with 68 universal CAPS markers and 82 disease resistance trait loci described in literature, providing an excellent template for genetic studies and applied research in potato

Arm rotated medially with supination – the ARMS variant: description of its surgical correction

<p>Abstract</p> <p>Background</p> <p>Patients who have suffered obstetric brachial plexus injury (OBPI) have a high incidence of musculoskeletal complications stemming from the initial nerve injury. The presence of muscle imbalances and contractures leads to typical bony changes affecting the shoulder, including the SHEAR (Scapular Hypoplasia, Elevation and Rotation) deformity. The SHEAR deformity commonly occurs in conjunction with Medial Rotation Contracture (MRC) of the arm. OBPI also causes muscle imbalances at the level of the forearm, that lead to a fixed supination deformity (SD) in a small number of patients. Both MRC and SD will cause severe functional limitations without surgical intervention.</p> <p>Methods</p> <p>Fourteen OBPI patients were diagnosed with MRC of the shoulder and SD of the forearm along with SHEAR deformity during a 16 month study period, with eight patients available to long-term follow-up (age range 2.2 – 18 years). Surgical correction of the MRC was performed as a triangle tilt or humeral osteotomy depending on the age of the child, after which, the patients were treated with a radial osteotomy to correct the fixed supination deformity. Function was assessed using the modified Mallet scale, examination of apparent supination and appearance of the extremity at rest.</p> <p>Results</p> <p>Significant functional improvements were observed in patients with surgical reconstruction. Mallet score increased by an average of 5.2 (p < 0.05). Overall forearm position was not significantly changed from an average of 5° to an average of 34° maximum apparent supination after both shoulder rotation and forearm rotation corrective surgeries.</p> <p>Conclusion</p> <p>The simultaneous presence of two opposing deformities in the same limb will visually offset each other at the level of the wrist and hand, giving the false impression of neutral positioning of the limb. In reality, the neutral-appearing position of the hand indicates a fixed supination posture of the forearm in the face of a medial rotation contracture of the shoulder. Both of these deformities require surgical attention, and the presence of concurrent MRC and SD should be monitored for in OBPI patients.</p

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency &gt;3%, and were also present in the mutant library, had fitness levels that were &gt;40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

An AFM study of solid-phase bilayers of unsaturated PC lipids and the lateral distribution of the transmembrane model peptide WALP23 in these bilayers

An altered lipid packing can have a large influence on the properties of the membrane and the lateral distribution of proteins and/or peptides that are associated with the bilayer. Here, it is shown by contact-mode atomic force microscopy that the surface topography of solid-phase bilayers of PC lipids with an unsaturated cis bond in their acyl chains shows surfaces with a large number of line-type packing defects, in contrast to the much smoother surfaces observed for saturated PC lipids. Di-n:1-PC (n = 20, 22, 24) and (16:0,18:1)-PC (POPC) were used. Next, the influence of an altered lipid environment on the lateral distribution of the single α-helical model peptide WALP23 was studied by incorporating the peptide in the bilayers of di-n:1-PC (n = 20, 22, 24) and (16:0,18:1)-PC unsaturated lipids. The presence of WALP23 leads to an increase in the number of packing defects but does not lead to the formation of the striated domains that were previously observed in bilayers of saturated PC lipids and WALP. This is ascribed to the less efficient lateral lipid packing of the unsaturated lipids, while the increase in packing defects is probably an indirect effect of the peptide. Finally, the fact that an altered lipid packing affects the distribution of WALP23 is also confirmed in an additional experiment where the solvent TFE (2,2,2-trifluorethanol) is added to bilayers of di-16:0-PC/WALP23. At 3.5 vol% TFE, the previous striated ordering of the peptide is abolished and replaced by loose lines