Minimum intervention oral care: staging and grading dental carious lesions in clinical practice.

Developmental staging of carious lesions is pivotal for appropriate ethical clinical decision-making in contemporary caries management. Accurate assessment of lesion extent/severity (staging) and activity (grading) allows practitioners to provide the most appropriate preventive advice and suitable interventions, enabling the implementation of evidence-based, person-focused, prevention-based, team-delivered and susceptibility-related phased minimum intervention oral care. Minimally invasive dentistry remains an important operative interventive option for cavitated lesions, but intervening at the right stage ensures patients are not started on an irreversible, destructive restorative cycle unnecessarily.

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity.

Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4.

Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α.

Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach.

ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails.

High-Throughput Screening and Hit Validation of Extracellular-Related Kinase 5 (ERK5) Inhibitors.

The extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP progressive binding system, and used to identify hits from a library of 57 617 compounds. Four distinct chemical series were evident within the screening hits.

Born too soon: care for the preterm baby.

As part of a supplement entitled “Born Too Soon”, this paper focuses on care of the preterm newborn. An estimated 15 million babies are born preterm, and the survival gap between those born in high and low income countries is widening, with one million deaths a year due to direct complications of preterm birth, and around one million more where preterm birth is a risk factor, especially amongst those who are also growth restricted. Most premature babies (>80%) are between 32 and 37 weeks of gestation, and many die needlessly for lack of simple care.

SIOP PODC: clinical guidelines for the management of children with Wilms tumour in a low income setting.

Wilms tumour is a relatively common and curable paediatric tumour. Known challenges to cure in low income countries are late presentation with advanced disease, malnutrition, failure to complete treatment and limited facilities. In this article, management recommendations are given for a low income setting where only the minimal requirements for treatment with curative intent are available (setting 1).

The efficacy and toxicity of SIOP preoperative chemotherapy in Malawian children with a Wilms tumour.

Background: In Malawi, preoperative chemotherapy for Wilms tumour is a logical strategy, but detailed information on toxicity and efficacy in such a resource limited setting has been unavailable.

Procedure: Patients diagnosed with a unilateral Wilms tumour received preoperative chemotherapy-a two-drug 4-week regimen for localized disease and 6 weeks of a three-drug regimen for metastatic disease. Estimated maximum tumour diameter, decrease in tumour size, resectability, stage distribution and haematological toxicity during therapy were documented.

Capacity for stochastic self-renewal and differentiation in mammalian spermatogonial stem cells.

Mammalian spermatogenesis is initiated and sustained by spermatogonial stem cells (SSCs) through self-renewal and differentiation. The basic question of whether SSCs have the potential to specify self-renewal and differentiation in a cell-autonomous manner has yet to be addressed. Here, we show that rat SSCs in ex vivo culture conditions consistently give rise to two distinct types of progeny: new SSCs and differentiating germ cells, even when they have been exposed to virtually identical microenvironments.

Spermatogonial culture medium: an effective and efficient nutrient mixture for culturing rat spermatogonial stem cells.

An economical and simplified procedure to derive and propagate fully functional lines of undifferentiated rat spermatogonia in vitro is presented. The procedure is based on the formulation of a new spermatogonial culture medium termed SG medium. The SG medium is composed of a 1:1 mixture of Dulbecco modified Eagle medium:Ham F12 nutrient, 20 ng/ml of GDNF, 25 ng/ml of FGF2, 100 microM 2-mercaptoethanol, 6 mM l-glutamine, and a 1x concentration of B27 Supplement Minus Vitamin A solution.

Spermatogonial stem cell self-renewal requires OCT4, a factor downregulated during retinoic acid-induced differentiation.

The long-term production of billions of spermatozoa relies on the regulated proliferation and differentiation of spermatogonial stem cells (SSCs). To date only a few factors are known to function in SSCs to provide this regulation. Octamer-4 (OCT4) plays a critical role in pluripotency and cell survival of embryonic stem cells and primordial germ cells; however, it is not known whether it plays a similar function in SSCs.

Undergraduate requirements in restorative dentistry in the UK and Ireland.

Objectives: To ascertain the requirements in restorative dentistry that undergraduate dental students have to fulfil in order to sit the finals examinations in dental schools in the UK and Ireland and to compare those requirements with the competencies stipulated by the GDC in The first five years.

Methods: Fifteen anonymised questionnaires, of open and closed question design, were sent by post to academics in the university departments of restorative dentistry in each of the undergraduate dental schools in the UK and Ireland. The first section concerned numerical information regarding total numbers of procedures that were required to be completed in undergraduate restorative dentistry.