Tumor suppressor genes

Although tumor suppressor genes continue to be discovered, the most recent advances have been made in attributing new and exciting functions to existing ones - such as the apparent role of VHL as a regulator of proteolysis. Great insights have also come from piecing genes together into pathways and networks. For instance the discovery that cyclin D1 is regulated by beta-catenin/Tcf-4 allows us to tie the APC pathway to the RB pathway and cell cycle control. Similarly, tumor suppressor genes have been fitted together with oncogenes into the various pathways that regulate apoptosis such that tumor suppressor function is now attributed to some of the basic components of the apoptotic machinery, such as caspases and Apaf-1. The great pace at which mouse models of tumorigenesis continue to advance our knowledge of tumor suppressor gene function has led us to look anew at the role of genes such as TCF-1 and SMAD-3 in human cancer. Finally, the realisation that different growth regulatory pathways give rise to generic signals suggests that future work may lie in integrating the signals from different pathways and in understanding the importance of protein levels to cellular function.     

A Pilot Study of Applications to the Four Ontario Medical Schools for Admission to the First Professional Year

In the fall of 1964, newspaper accounts of the medical school applicant situation in Canada reported that hundreds of fully qualified applicants were being turned away because of shortage of places. Such reports precipitated a pilot study of the applications received by the four Ontario medical schools for the first professional year of medicine and it was found, first of all, that the total of 1352 applications represented only 880 individuals. Nearly 32% of these applicants were American and 18% were citizens of Commonwealth or other countries. While a majority of the applicants met the minimal requirements of the schools, very few of the rejected applicants had academic records that justified admission when the informal standards of the schools were applied. It was concluded that it is erroneous to speak of a surplus of well-qualified applicants at the present time and that the need for recruiting programs still remains.     

MAR1-a Regulator of the HMa and HMalpha Loci in SACCHAROMYCES CEREVISIAE

A mutation in the MAR1 (mating-type regulator) locus causing sterility in Saccharomyces cerevisiae is reported. The mutation maps on the left arm of linkage group IV between trp1 and cdc2 at a distance of about 27 cM from trp1 and about 31 cM from cdc2. Haploid strains with genotype MATalpha HMalpha HMa mar1-1 and MATa HMalpha HMamar1-1 are sterile. However, MATalpha hmalpha HMa mar1-1 and MATa HMalpha hma mar1-1 strains exhibit alpha and a mating type, respectively. The sterile strains can be "rare mated" with standard strains as a consequence of mutational changes at HMa and HMalpha. It is proposed that the MAR1 locus blocks the expression of MATalpha and MATa information thought to exist at HMa and HMalpha loci, respectively (Hicks, Strathern and Herskowitz, 1977). In a mar1-1 mutant, the expression of both HMalpha and HMa information leads to a nonmating phenotype similar to that of MATa/MATalpha diploids. The genetic evidence reported here is consistent with a central feature of the "cassette model", namely that HMalpha and hma carry MATa information and HMa and hmalpha carry MATalpha information.     

Broad-scale effects of marine salmonid aquaculture on macrobenthos and the sediment environment in southeastern Tasmania

A comparison of sediments and associated macrobenthos at sites sampled within 20 fish farm leases distributed across southeastern Tasmania indicated major natural changes along a regional cline. Introduced taxa were strongly represented in the fauna, comprising 45% of total macrofaunal biomass. Large differences were evident between sites affected by different levels of organic farm waste. Sites located adjacent (< 10 m) to farm cages possessed significantly depressed sediment redox levels, a dominance of capitellid and dorvilleid polychaetes, and low macrofaunal species richness. Subtle impacts extended across farm lease areas in the form of depressed redox potential at 40 mm depth and changes to the macrobenthic community, including a prevalence of the dogwhelk Nassarius nigellus and a paucity of the heart urchin Brissus sp. and the maldanid polychaetes Asychis sp. and Rhodine sp. Minor farm effects were also evident at sites sampled 35 m outside farm lease boundaries, most notably as elevated population numbers of the polychaete Terrebellides sp., bivalve Mysella donaciformis and heart urchin Echinocardium cordatum. Amongst the univariate metrics examined, redox potential at 40 mm depth and the ratio of bivalves to total molluscs provided the most sensitive indicators of farm impacts, with the latter metric relatively insensitive to spatial variation between locations within the region studied.     

MAGI: Methylation analysis using genome information

By incorporating annotation information into the analysis of next-generation sequencing DNA methylation data, we provide an improvement in performance over current testing procedures. Methylation analysis using genome information (MAGI) is applicable for both unreplicated and replicated data, and provides an effective analysis for studies with low sequencing depth. When compared with current tests, the annotation-informed tests provide an increase in statistical power and offer a significance-based interpretation of differential methylation.     

Failure to reduce an isolated Blowfly population by the sterile males method

In 1956 and 1957 pupae of L. sericata were irradiated at 6,000–7,000 rep, and allowed to emerge at three points on Holy Island. The sterilized population was maintained in preponderant numbers by regular replenishments. A test in 1958 showed no reduction in the density of the species. Possible causes of failure of the method are examined, and it is concluded that either the sterilization was inadequate or that the sterilized males were unable to compete with the native males.

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Zusammenfassung Die Methode sterile Männchen zur Ausrottung einer Art zu benutzen, ist in ihrer Wirkung mathematisch zuverlässig, vorausgesetzt, daß die anerkannten biologischen Erfordernisse vorhanden sind; sie hat sich in der Praxis gegen Callitroga bominivorax (Myiasisfliege) als wirksam erwiesen. In einem in kleinen Maßstabe durchgeführten Versuch gegen die Goldfliege Lucilia sericata wurden Fliegen, die durch eine 6,000–7,000 rep Gamma-Strahlung sterilisiert worden waren, in überwiegenden Zahlen auf einer 5 km² großen Insel in zwei aufeinanderfolgenden Jahren freigelassen. Eine Reduktion der einheimischen L. sericata-Population ließ sich nicht nachweisen. Es wurde experimentell geprüft, daß eine Zuwanderung von Fliegen vom Festland zu vernachlässigen war; wiederholte Versuche bestätigten, daß die Bestrahlungsdosis ausreichte, um sexuelle Sterilität zu erzeugen. Der Ablauf und die technischen Einzelheiten der Versuche wurden analysiert in dem Bestreben, die Ursache des Versagens ausfindig zu machen.Das Verhältnis steriler zu eingeborenen Männchen könnte im ersten Jahr infolge hoher Mortalität der sterilisierten Puppen under die erwartete Relation 5 : 1 gesunken sein. Diese Mortalität stand offenbar mit der Zuchtmethode in Beziehung. Es wurde jedoch gefolgert, daß dies an sich nicht für das Versagen verantwortlich gemacht werden könnte.Er wird vorläufig angenommen, daß hier, als Ergebnis von Sauerstoffmangel, ein geringer aber signifikanter Grad von Resistenz gegen Bestrahlung vorliege, möglicherweise begleitet von einer ähnlich geringgradigen Erholungsfähigkeit von Strahlungswirkungen; andererseits versagte das sterilisierte Sperma in Konkurrenz mit fertilem Sperma bei Doppelbegattungen.

     

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective

To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.

Design

Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.

Results

We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation.

Conclusions

We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.     

Community Case Management of Fever Due to Malaria and Pneumonia in Children Under Five in Zambia: A Cluster Randomized Controlled Trial

Background

Pneumonia and malaria, two of the leading causes of morbidity and mortality among children under five in Zambia, often have overlapping clinical manifestations. Zambia is piloting the use of artemether-lumefantrine (AL) by community health workers (CHWs) to treat uncomplicated malaria. Valid concerns about potential overuse of AL could be addressed by the use of malaria rapid diagnostics employed at the community level. Currently, CHWs in Zambia evaluate and treat children with suspected malaria in rural areas, but they refer children with suspected pneumonia to the nearest health facility. This study was designed to assess the effectiveness and feasibility of using CHWs to manage nonsevere pneumonia and uncomplicated malaria with the aid of rapid diagnostic tests (RDTs).

Methods and Findings

Community health posts staffed by CHWs were matched and randomly allocated to intervention and control arms. Children between the ages of 6 months and 5 years were managed according to the study protocol, as follows. Intervention CHWs performed RDTs, treated test-positive children with AL, and treated those with nonsevere pneumonia (increased respiratory rate) with amoxicillin. Control CHWs did not perform RDTs, treated all febrile children with AL, and referred those with signs of pneumonia to the health facility, as per Ministry of Health policy. The primary outcomes were the use of AL in children with fever and early and appropriate treatment with antibiotics for nonsevere pneumonia. A total of 3,125 children with fever and/or difficult/fast breathing were managed over a 12-month period. In the intervention arm, 27.5% (265/963) of children with fever received AL compared to 99.1% (2066/2084) of control children (risk ratio 0.23, 95% confidence interval 0.14–0.38). For children classified with nonsevere pneumonia, 68.2% (247/362) in the intervention arm and 13.3% (22/203) in the control arm received early and appropriate treatment (risk ratio 5.32, 95% confidence interval 2.19–8.94). There were two deaths in the intervention and one in the control arm.

Conclusions

The potential for CHWs to use RDTs, AL, and amoxicillin to manage both malaria and pneumonia at the community level is promising and might reduce overuse of AL, as well as provide early and appropriate treatment to children with nonsevere pneumonia.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00513500","term_id":"NCT00513500"}}NCT00513500 Please see later in the article for the Editors'' Summary