Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A.

Effects of Percutaneous Endoscopic Gastrostomy in Patients With Huntington Disease.

Objective: To determine the impact of percutaneous endoscopic gastrostomy (PEG) tubes in patients with advanced Huntington disease (HD).

Methods: A retrospective chart review of patients with HD was conducted to assess the rate of pneumonia and pressure ulcer, length of life, changes in weight, and serologic nutritional measures. Surviving and deceased patients with and without PEG tubes were compared using descriptive statistical analysis.

Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer.

Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies.

Surgical antibiotic prophylaxis use and infection prevalence in non-cosmetic breast surgery procedures at a tertiary hospital in Western Australia-a retrospective study.

Background: Surgical site infections (SSIs) are a common complication following breast surgery procedures, despite being considered a clean surgery. The prevalence of SSIs can be minimised with the appropriate use of antibiotic prophylaxis as outlined in the Australian Therapeutic Guidelines (eTG). The aims of this study were to evaluate adherence to the eTG for antibiotic prophylaxis in breast surgery procedures at a Western Australian teaching hospital following an update of the guidelines in 2014 and examine the impact of prophylactic antibiotics on SSI incidence and length of hospital stay.

Appropriateness of surgical antibiotic prophylaxis for breast surgery procedures.

Background Guidelines for the appropriate use of antibiotic prophylaxis are provided in the Therapeutic Guidelines: Antibiotics (eTG) in Australia. Inappropriate use of antibiotics is problematic. Objective To examine adherence with therapeutic guidelines (eTG) in breast surgery and trends in non-adherence dependent on the type of breast surgery performed.

Phage display and structural studies reveal plasticity in substrate specificity of caspase-3a from zebrafish.

The regulation of caspase-3 enzyme activity is a vital process in cell fate decisions leading to cell differentiation and tissue development or to apoptosis. The zebrafish, Danio rerio, has become an increasingly popular animal model to study several human diseases because of their transparent embryos, short reproductive cycles, and ease of drug administration. While apoptosis is an evolutionarily conserved process in metazoans, little is known about caspases from zebrafish, particularly regarding substrate specificity and allosteric regulation compared to the human caspases.

Tunable allosteric library of caspase-3 identifies coupling between conserved water molecules and conformational selection.

The native ensemble of caspases is described globally by a complex energy landscape where the binding of substrate selects for the active conformation, whereas targeting an allosteric site in the dimer interface selects an inactive conformation that contains disordered active-site loops. Mutations and posttranslational modifications stabilize high-energy inactive conformations, with mostly formed, but distorted, active sites. To examine the interconversion of active and inactive states in the ensemble, we used detection of related solvent positions to analyze 4,995 waters in 15 high-resolution (<2.

OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.

Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM.

Extending dental nurses' duties: a national survey investigating skill-mix in Scotland's child oral health improvement programme (Childsmile).

Background: Childsmile is Scotland's national child oral health improvement programme. To support the delivery of prevention in general dental practice in keeping with clinical guidelines, Childsmile sought accreditation for extended duty training for dental nurses to deliver clinical preventive care. This approach has allowed extended duty dental nurses (EDDNs) to take on roles traditionally undertaken by general dental practitioners (GDPs).

Modifying caspase-3 activity by altering allosteric networks.

Caspases have several allosteric sites that bind small molecules or peptides. Allosteric regulators are known to affect caspase enzyme activity, in general, by facilitating large conformational changes that convert the active enzyme to a zymogen-like form in which the substrate-binding pocket is disordered. Mutations in presumed allosteric networks also decrease activity, although large structural changes are not observed.

Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients.

Purpose: We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol.

Experimental Design: Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles.

A comparison of urban-rural injury mortality rates across two South African provinces, 2007.

This study explored urban-rural variations in the magnitude and patterns of fatal injuries in South Africa. The National Injury Mortality Surveillance System was utilised to select South African mortality cases for the 2007 period and a cross-sectional methodology was employed in order to comparatively analyse injury mortality rates in the urban province of Gauteng and the rural province of Mpumalanga. The results reveal several differences in urban-rural injury trends across the two South African provinces.

Redesigning the procaspase-8 dimer interface for improved dimerization.

Caspase-8 is a cysteine directed aspartate-specific protease that is activated at the cytosolic face of the cell membrane upon receptor ligation. A key step in the activation of caspase-8 depends on adaptor-induced dimerization of procaspase-8 monomers. Dimerization is followed by limited autoproteolysis within the intersubunit linker (IL), which separates the large and small subunits of the catalytic domain.

Lengthening the intersubunit linker of procaspase 3 leads to constitutive activation.

The conformational ensemble of procaspase 3, the primary executioner in apoptosis, contains two major forms, inactive and active, with the inactive state favored in the native ensemble. A region of the protein known as the intersubunit linker (IL) is cleaved during maturation, resulting in movement of the IL out of the dimer interface and subsequent active site formation (activation-by-cleavage mechanism). We examined two models for the role of the IL in maintaining the inactive conformer, an IL-extension model versus a hydrophobic cluster model, and we show that increasing the length of the IL by introducing 3-5 alanines results in constitutively active procaspases.

Slow folding and assembly of a procaspase-3 interface variant.

Caspases execute apoptosis and exist in the cell as inactive zymogens (procaspases) prior to activation. Initiator procaspases are monomers that must dimerize for activation, while effector procaspases, such as procaspase-3, are stable dimers that must be processed for activation. The dimer interface regions of the two subfamilies are different, although the role of the interface in oligomerization is not known.

Death by caspase dimerization.

Controlled cell death, or apoptosis, occurs in response to many different environmental stimuli. The apoptotic cascade that occurs within the cell in response to these cues leads to morphological and biochemical changes that trigger the dismantling and packaging of the cell. Caspases are a family of cysteine-dependent aspartate-directed proteases that play an integral role in the cascade that leads to apoptosis.

A bifunctional allosteric site in the dimer interface of procaspase-3.

The dimer interface of caspase-3 contains a bifunctional allosteric site in which the enzyme can be activated or inactivated, depending on the context of the protein. In the mature caspase-3, the binding of allosteric inhibitors to the interface results in an order-to-disorder transition in the active site loops. In procaspase-3, by contrast, the binding of allosteric activators to the interface results in a disorder-to-order transition in the active site.

SDOCT imaging to identify macular pathology in patients diagnosed with diabetic maculopathy by a digital photographic retinal screening programme.

Introduction: Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME.

The potential for caspases in drug discovery.

Caspases are a family of proteases that are involved in the execution of apoptosis and the inflammatory response. A plethora of diseases occur as a result of the dysregulation of apoptosis and inflammation, and caspases have been targeted as a therapeutic strategy to halt the progression of such diseases. Hundreds of peptide and peptidomimetic inhibitors have been designed and tested, but only a few have advanced to clinical trials because of poor drug-like properties and pharmacological constraints.

Ultrastructure and retinal imaging of internal limiting membrane: a clinicopathologic correlation of trypan blue stain in macular hole surgery.

Purpose: The purpose of this study was to correlate the ultrastructural morphology of epiretinal and retinal tissue with optical coherence tomography assessment and to investigate the effects of trypan blue staining on internal limiting membrane (ILM) tissue.

Methods: This was a prospective case-comparative study. Consecutive patients were recruited and underwent ILM peel with 0.

Ultrastructure and retinal imaging of epiretinal membrane: a clinicopathologic correlation of trypan blue staining in epiretinal membrane surgery.

Purpose: The purpose of this study was to correlate the ultrastructural morphology of epiretinal tissue with optical coherence tomography and to investigate the effects of trypan blue staining on epiretinal membrane (ERM) ultrastructure and clinical outcome.

Methods: A prospective, case-comparative study. Consecutive patients were recruited and underwent vitrectomy and ERM peeling with 0.

Bevacizumab (avastin) for corneal neovascularization--corneal light shield soaked application.

Purpose: To describe a case where topical bevacizumab (Avastin) was used in an attempt to reduce corneal neovascularization before corneal graft.

Methods: Topical bevacizumab was applied through a corneal light shield for 20 minutes once a week for 11 weeks to the cornea.

Results: Corneal vascularization was not reduced.