A Novel p53 Mutant Found in Iatrogenic Urothelial Cancers Is Dysfunctional and Can Be Rescued by a Second-site Global Suppressor Mutation

Exposure to herbal remedies containing the carcinogen aristolochic acid (AA) has been widespread in some regions of the world. Rare A→T TP53 mutations were recently discovered in AA-associated urothelial cancers. The near absence of these mutations among all other sequenced human tumors suggests that they could be biologically silent. There are no cell banks with established lines derived from human tumors with which to explore the influence of the novel mutants on p53 function and cellular behavior. To investigate their impact, we generated isogenic mutant clones by integrase-mediated cassette exchange at the p53 locus of platform (null) murine embryonic fibroblasts and kidney epithelial cells. Common tumor mutants (R248W, R273C) were compared with the AA-associated mutants N131Y, R249W, and Q104L. Assays of cell proliferation, migration, growth in soft agar, apoptosis, senescence, and gene expression revealed contrasting outcomes on cellular behavior following introduction of N131Y or Q104L. The N131Y mutant demonstrated a phenotype akin to common tumor mutants, whereas Q104L clone behavior resembled that of cells with wild-type p53. Wild-type p53 responses were restored in double-mutant cells harboring N131Y and N239Y, a second-site rescue mutation, suggesting that pharmaceutical reactivation of p53 function in tumors expressing N131Y could have therapeutic benefit. N131Y is likely to contribute directly to tumor phenotype and is a promising candidate biomarker of AA exposure and disease. Rare mutations thus do not necessarily point to sites where amino acid exchanges are phenotypically neutral. Encounter with mutagenic insults targeting cryptic sites can reveal specific signature hotspots.     

Eye lens and thyroid gland radiation exposure for patients undergoing brain computed tomography examination

This study aims to estimate the effective radiation dose and organ dose from head CT procedures. It was conducted in three main private hospitals in Khartoum State-Sudan, using Toshiba machines with 64 slices. The total number of patients included in this study was 142 patients (82 males and 60 females). The effective dose and organ dose were calculated by CT Expo software. The effective dose slightly varied among patients according to gender and age. The effective dose for female patients (5.99 mSv) was higher than that for male patients (5.84 mSv), and the pediatric dose (5.46 mSv) was lower than the adults’ dose (5.94 mSv).The dose for eye lens was found lower for male patients (89.117 mSv) than the dose for female patients (94.62) mSv). According to patients’ age: the dose received by the lens of the eye was much lower in pediatric (79.93 mSv) than the adults (92.41 mSv). The dose for thyroid in female patients (33.52 mSv) was higher than the male patients (28 mSv). The pediatric dose (28.34 mSv) was lower than the adults’ dose (30.64 mSv).Departmental imaging protocol and lack of training among hospital staff are expected to be responsible for these variations. Therefore, this study recommends that the CT technologists be trained on suitable strategies to achieve dose optimization. Moreover, patients’ doses must be monitored regularly.     

Recognition of brain tumors in MRI images using texture analysis

ObjectivesBrain neoplasms or intracranial tumors, which are more common in older adults, can affect individuals of any age including pediatric and children. Exposure to carcinogenic agents including ionizing radiation and family history is one of the main causes of the disease. Early diagnosis is crucial to avoid prolonged. patients' suffering. The aim of the study was to efficiently recognize the brain tumors from the other brain tissues which include grey and white matter as well as cerebrospinal fluid (CSF).Materials and methodsThis study was performed using axial, sagittal and coronal views for fifty brain tumor patients randomly selected from a set of 200 patients, with a “control” set consisting of images showing no sign of disease; and the “test” brain MRI images for patients diagnosed with brain tumor. The study includes both genders with age ranging from 18 years to 83 years old, (56.5 ± 17.2). The brain images were acquired using a standard head coil Philips Intera 1.5 Tesla machine (USA). The thickness of each section in the entire sequence was 8 mm. Acquisition of T2-weighted and T1-weighted were performed. Interactive Data Language software was used to analyze the data.ResultsThe results of this study showed that: the overall accuracy of classification process was 94.8%, and for the tumor; the sensitivity was 97.3%. White matter and grey matter showed a classification accuracy of 95.7% and 89.7% and for CSF the accuracy was 94.3%.ConclusionThe results showed that brain tumor can be classified successfully and delineated using texture analysis with minimum efforts and with high accuracy for brain tumors.     

Bioenergetic theory predicts infection dynamics of human schistosomes in intermediate host snails across ecological gradients

Epidemiological dynamics depend on the traits of hosts and parasites, but hosts and parasites are heterogeneous entities that exist in dynamic environments. Resource availability is a particularly dynamic and potent environmental driver of within‐host infection dynamics (temporal patterns of growth, reproduction, parasite production and survival). We developed, parameterised and validated a model for resource‐explicit infection dynamics by incorporating a parasitism module into dynamic energy budget theory. The model mechanistically explained the dynamic multivariate responses of the human parasite Schistosoma mansoni and its intermediate host snail to variation in resources and host density. At the population level, feedbacks mediated by resource competition could create a unimodal relationship between snail density and human risk of exposure to schistosomes. Consequently, weak snail control could backfire if reductions in snail density release remaining hosts from resource competition. If resource competition is strong and relevant to schistosome production in nature, it could inform control strategies.     

Y chromosome lineage- and village-specific genes on chromosomes 1p22 and 6q27 control visceral leishmaniasis in Sudan

Familial clustering and ethnic differences suggest that visceral leishmaniasis caused by Leishmania donovani is under genetic control. A recent genome scan provided evidence for a major susceptibility gene on Chromosome 22q12 in the Aringa ethnic group in Sudan. We now report a genome-wide scan using 69 families with 173 affected relatives from two villages occupied by the related Masalit ethnic group. A primary ten-centimorgan scan followed by refined mapping provided evidence for major loci at 1p22 (LOD score 5.65; nominal p = 1.72 × 10⁻⁷; empirical p < 1 × 10⁻⁵; λ_S = 5.1) and 6q27 (LOD score 3.74; nominal p = 1.68 × 10⁻⁵; empirical p < 1 × 10⁻⁴; λ_S = 2.3) that were Y chromosome–lineage and village-specific. Neither village supported a visceral leishmaniasis susceptibility gene on 22q12. The results suggest strong lineage-specific genes due to founder effect and consanguinity in these recently immigrant populations. These chance events in ethnically uniform African populations provide a powerful resource in the search for genes and mechanisms that regulate this complex disease.     

Molecular signals in the trafficking of Toxoplasma gondii protein MIC3 to the micronemes

The protozoan parasite Toxoplasma gondii is equipped with a sophisticated secretory apparatus, including three distinct exocytic organelles, named micronemes, rhoptries, and dense granules. We have dissected the requirements for targeting the microneme protein MIC3, a key component of T. gondii infection. We have shown that MIC3 is processed in a post-Golgi compartment and that the MIC3 propeptide and epidermal growth factor (EGF) modules contain microneme-targeting information. The minimal requirement for microneme delivery is defined by the propeptide plus any one of the three EGF domains. We have demonstrated that the cleavage of the propeptide, the dimerization of MIC3, and the chitin binding-like sequence, which are crucial for host cell binding and virulence, are dispensable for proper targeting. Finally, we have shown that part of MIC3 is withheld in the secretory pathway in a cell cycle-dependent manner.     

Acetylcholinesterase associates differently with its anchoring proteins ColQ and PRiMA

Acetylcholinesterase tetramers are inserted in the basal lamina of neuromuscular junctions or anchored in cell membranes through the interaction of four C-terminal t peptides with proline-rich attachment domains (PRADs) of cholinesterase-associated collagen Q (ColQ) or of the transmembrane protein PRiMA (proline-rich membrane anchor). ColQ and PRiMA differ in the length of their proline-rich motifs (10 and 15 residues, respectively). ColQ has two cysteines upstream of the PRAD, which are disulfide-linked to two AChE(T) subunits ("heavy" dimer), and the other two subunits are disulfide-linked together ("light" dimer). In contrast, PRiMA has four cysteines upstream of the PRAD. We examined whether these cysteines could be linked to AChE(T) subunits in complexes formed with PRiMA in transfected COS cells and in the mammalian brain. For comparison, we studied complexes formed with N-terminal fragments of ColQ, N-terminal fragments of PRiMA, and chimeras in which the upstream regions containing the cysteines were exchanged. We also compared the effect of mutations in the t peptides on their association with the two PRADs. We report that the two PRADs differ in their interaction with AChE(T) subunits; in complexes formed with the PRAD of PRiMA, we observed light dimers, but very few heavy dimers, even though such dimers were formed with the PQ chimera in which the N-terminal region of PRiMA was associated with the PRAD of ColQ. Complexes with PQ or with PRiMA contained heavy components, which migrated abnormally in SDS-PAGE but probably resulted from disulfide bonding of four AChE(T) subunits with the four upstream cysteines of the associated protein.