The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation

Deciphering regulatory events that drive malignant transformation represents a major challenge for systems biology. Here we analyzed genome-wide transcription profiling of an in-vitro transformation process. We focused on a cluster of genes whose expression levels increased as a function of p53 and p16INK4A tumor suppressors inactivation. This cluster predominantly consists of cell cycle genes and constitutes a signature of a diversity of cancers. By linking expression profiles of the genes in the cluster with the dynamic behavior of p53 and p16INK4A, we identified a promoter architecture that integrates signals from the two tumor suppressive channels and that maps their activity onto distinct levels of expression of the cell cycle genes, which in turn, correspond to different cellular proliferation rates. Taking components of the mitotic spindle as an example, we experimentally verified our predictions that p53-mediated transcriptional repression of several of these novel targets is dependent on the activities of p21, NFY and E2F. Our study demonstrates how a well-controlled transformation process allows linking between gene expression, promoter architecture and activity of upstream signaling molecules.Comment: To appear in Molecular Systems Biolog

EB Ford revisited: assessing the long-term stability of wing-spot patterns and population genetic structure of the meadow brown butterfly on the Isles of Scilly

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Data files of wing spot sizes and AFLP genotypes available from the Dryad Digital Repository: http://dx.doi.org/10.5061/dryad.j7v42.Understanding selection in the wild remains a major aim of evolutionary ecology and work by Ford and colleagues on the meadow brown butterfly Maniola jurtina did much to ignite this agenda. A great deal of their work was conducted during the 1950s on the Isles of Scilly. They documented island-specific wing-spot patterns that remained consistent over about a decade, but patterns on some islands changed after environmental perturbation. It was suggested that these wing-spot patterns reflected island-specific selection and that there was little migration between islands. However, genetic studies to test the underlying assumption of restricted migration are lacking and it is also unknown whether the originally described wing-spot patterns have persisted over time. We therefore collected female butterflies from five of Ford's original study locations, including three large islands (St Mary's, St Martin's and Tresco) and two small islands (Tean and St Helen's). Wing-spot patterns had not changed appreciably over time on three of the islands (two large and one small), but were significantly different on the other two. Furthermore, analysis of 176 amplified fragment length polymorphisms revealed significant genome-wide differentiation among the five islands. Our findings are consistent with Ford's conclusions that despite the close proximity of these islands, there is restricted gene flow among them.Heredity advance online publication, 2 November 2016; doi:10.1038/hdy.2016.94.We thank the Genetics Society for a fieldwork grant (to DJH) that funded the collection trip and DJH thanks Mike Johnson for sparking interest in this area. SWB is supported by the Australian Research Council and a Ramsay Fellowship, NW by a Royal Society Wolfson Fellowship and NERC and DJH by the Leverhulme Trust

Tuberculous extensor tenosynovitis of the wrist with extensor pollicis longus rupture: a case report

<p>Abstract</p> <p>Introduction</p> <p>The tendon sheaths constitute an uncommon target of extra-articular tuberculosis.</p> <p>Case presentation</p> <p>We present a rare case of tuberculous tenosynovitis of the wrist involving the extensor tendon with rupture of the extensor pollicis longus tendon in a 55-year-old Indian man.</p> <p>Conclusion</p> <p>Prompt surgical debridement and tissue diagnosis are essential for the diagnosis and treatment of this type of infection. With an accurate and timely diagnosis, appropriate surgery and antituberculous treatment may eradicate these infections and prevent complications.</p

Analysis of the functional repertoire of a mutant form of survivin, K129E, which has been linked to lung cancer

Background Survivin is a protein that is normally present only in G2 and M-phases in somatic cells, however, in cancer cells, it is expressed throughout the cell cycle. A prosurvival factor, survivin is both an inhibitor of apoptosis and an essential mitotic protein, thus it has attracted much attention as a target for new oncotherapies. Despite its prevalence in cancer, reports of survivin mutations have mostly been restricted to loci within its promoter, which increase the abundance of the protein. To date the only published mutation within the coding sequence is an adenine > guanine substitution in exon 4. This polymorphism, which was found in a cohort of Korean lung cancer patients, causes a lysine > glutamic acid mutation (K129E) in the protein. However, whether it plays a causative role in cancer has not been addressed. Methods Using site directed mutagenesis we recapitulate K129E expression in cultured human cells and assess its anti-apoptotic and mitotic activities. Results K129E retains its anti-apoptotic activity, but causes errors in mitosis and cytokinesis, which may be linked to its reduced affinity for borealin. Conclusion K129E expression can induce genomic instability by introducing mitotic aberrations, thus it may play a causative role in cancer

Spitting Performance Parameters and Their Biomechanical Implications in the Spitting Spider, Scytodes thoracica

Spitting spiders Scytodes spp. subdue prey by entangling them at a distance with a mixture of silk, glue, and venom. Using high-speed videography and differential interference contrast microscopy, the performance parameters involved in spit ejection by Scytodes thoracica (Araneae, Scytodidae) were measured. These will ultimately need to be explained in biomechanical and fluid dynamic terms. It was found that the ejection of “spit” from the opening of the venom duct (near the proximal end of the fang) was orderly. It resulted in a pattern that scanned along a lateral-medial axis (due to fang oscillations) while traversing from ventral to dorsal (due to cheliceral elevation). Each lateral-to-medial sweep of a fang produced silk-borne beads of glue that were not present during each subsequent medial-to-lateral sweep. The ejection of “spit” was very rapid. A full scan (5–57 fang cycles, one upsweep of a chelicera) typically occupied less than 30 ms and involved fang oscillations at 278–1781 Hz. Ejection velocities were measured as high as 28.8 m/s. The “spit” was contractile. During the 0.2 s following ejection, silk shortened by 40–60% and the product of a full scan by both of the chelicerae could exert an aggregate contractile force of 0.1 – 0.3 mN. Based on these parameters, hypotheses are described concerning the biomechanical and fluid dynamic processes that could enable this kind of material ejection

Coronary artery to left ventricle fistula

BACKGROUND: Coronary cameral fistulas are an uncommon entity, the etiology of which may be congenital or traumatic. They involve abnormal termination of a coronary artery, usually the right coronary, into a cardiac chamber, usually the right ventricle. CASE PRESENTATION: We describe a case of female patient with severe aortic stenosis and interventricular septal hypertrophy that underwent bioprosthetic aortic valve replacement with concomitant septal myectomy. On subsequent follow-up an abnormal flow traversing the septum into the left ventricle was identified and Doppler interrogation demonstrated a continuous flow, with a predominantly diastolic component, consistent with coronary arterial flow. CONCLUSION: The literature on coronary cameral fistulas is reviewed and the etiology of the diagnostic findings discussed. In our patient, a coronary artery to left ventricle fistula was the most likely explanation secondary to trauma to the septal perforator artery during myectomy. Since the patient was asymptomatic at the time of diagnosis no intervention was recommended and has done well on follow-up

Resident physician and hospital pharmacist familiarity with patient discharge medication costs

Objective Cost-related medication non-adherence is associated with increased health-care resource utilization and poor patient outcomes. Physicians-in-training generally receive little education regarding costs of prescribed therapy and may rely on hospital pharmacists for this information. However, little is documented regarding either of these health care providers’ familiarity with out-of pocket medication expenses borne by patients in the community. The purpose of this study was to evaluate and compare resident physician and hospital pharmacist familiarity with what patients pay for medications prescribed once discharged. Setting A major tertiary patient care and medical teaching centre in Canada. Method Internal medicine residents and hospital pharmacists within a specific health care organization were invited to participate in an online survey. Eight patient case scenarios and associated discharge therapeutic regimens were outlined and respondents asked to identify the costs patients would incur when having the prescription filled once discharged. Main Outcome Measure Total number and proportion of estimates above and below actual cost were calculated and compared between the groups using χ2 tests. Responses ±10% of the true cost were considered correct. Mean absolute values and standard deviation estimated costs, as well as cost increments above and below 10%, were calculated to assess the magnitude of the discrepancy between the respondent estimates and the actual total cost. Results Forty-four percent of physician residents and 26% of hospital pharmacists accessed the survey. Overall 39% and 47% of medication costs were under-estimated, 32% and 33% were overestimated, and 29% and 21% were correctly estimated by residents and pharmacists, respectively (P = NS). Incorrect estimates were evident across all therapeutic classes and medical indications presented in the survey. The greatest absolute cost discrepancy for both groups was under-estimation of linezolid ($800 and$400) and over-estimation of clopidogrel ($80) and bisoprolol therapy ($22) by residents and pharmacists, respectively. Conclusion Resident physicians and hospital pharmacists are unfamiliar with what patients must pay for drug therapy once discharged