ATM activation in hypoxia - causes and consequences.

The DNA damage response is a complex signaling cascade that is triggered by cellular stress. This response is essential for the maintenance of genomic integrity and is considered to act as a barrier to the early stages of tumorigenesis. The integral role of ataxia telangiectasia mutated (ATM) kinase in the response to DNA damaging agents is well characterized; however, ATM can also be activated by non-DNA damaging agents.

Development and evaluation of a clinical staging system for amyotrophic lateral sclerosis.

Background: Staging of disease severity is useful for prognosis, decision-making and resource planning. However, no commonly used, validated staging system exists for amyotrophic lateral sclerosis (ALS). Our purpose was to develop an ALS staging system (ALS Milano-Torino Staging) that captures the observed progressive loss of independence and function.

Oxygen content and oxidation in frying oil.

The relation between oxygen content and oxidation was investigated in frying oils. When canola oil, a canola-soybean oil blend or a trioctanoylglycerol (glycerol tricaprate) sample were heated with stirring, their dissolved oxygen content decreased abruptly at about 120°C and the carbonyl values (CV) increased gradually with heating and reached values of 6-7 at 180°C in the blended and canola oils, while the CV of trioctanoylglycerol was zero up to 150°C. Probably this abrupt decrease in oxygen content above 120°C can be attributed to the solubility of oxygen in oil rather than because of oxidative reactions.

Replication stress and chromatin context link ATM activation to a role in DNA replication.

ATM-mediated signaling in response to DNA damage is a barrier to tumorigenesis. Here we asked whether replication stress could also contribute to ATM signaling. We demonstrate that, in the absence of DNA damage, ATM responds to replication stress in a hypoxia-induced heterochromatin-like context.

The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation.

During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail.

Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues.

The tetrasaccharide heparan sulfate (HS) mimetic PG545, a clinical anti-cancer candidate, is an inhibitor of the HS-degrading enzyme heparanase. The kinetics of heparanase inhibition by PG545 and three structural analogues were investigated to understand their modes of inhibition. The cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode.

The burden of acute traumatic spinal cord injury among adults in the united states: an update.

The current incidence estimate of 40 traumatic spinal cord injuries (TSCI) per million population/year in the United States (U.S.) is based on data from the 1990s.

Lower extremity functional electrical stimulation cycling promotes physical and functional recovery in chronic spinal cord injury.

Objective: To examine the effect of long-term lower extremity functional electrical stimulation (FES) cycling on the physical integrity and functional recovery in people with chronic spinal cord injury (SCI).

Design: Retrospective cohort, mean follow-up 29.1 months, and cross-sectional evaluation.

Older individuals with HIV infection have greater memory deficits than younger individuals.

The prevalence of HIV-associated neurocognitive disorder (HAND) remains persistently high in the era of combination antiretroviral therapy. We aimed to characterize the pattern of neurocognitive dysfunction in older subjects with HAND in particular amnestic versus non-amnestic impairment. One hundred six subjects from the Johns Hopkins University NIMH Clinical Outcomes cohort underwent standardized neuropsychological (NP) testing between November 2006 and June 2010.

Use of the xCELLigence system for real-time analysis of changes in cellular motility and adhesion in physiological conditions.

Investigation of the mechanisms behind the regulation of cellular motility and adhesion is key to understanding metastasis and the biology of tumor spreading. There are many technologies available for these studies, but the majority of them are either dependent on the use of labels or limited to endpoint analysis. The xCELLigence RTCA (real-time cell analysis) provides a platform for label free and operator independent investigation of the migration, invasion and adhesion proprieties of cells in physiologically relevant conditions.

Role of international registries in enhancing the care of familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is a relatively common genetic disorder associated with high risk of coronary heart disease that is preventable by early diagnosis and treatment. In a previous article, we reviewed the evidence for clinical management, models of care and health economic evaluations. The present commentary emphasises that collective action is needed to strengthen our approaches to evidence-based care, including better diagnosis and access to effective therapies.

Antibacterial effect of Manuka honey on Clostridium difficile.

Background: Manuka honey originates from the manuka tree (Leptospermum scoparium) and its antimicrobial effect has been attributed to a property referred to as Unique Manuka Factor that is absent in other types of honey. Antibacterial activity of Manuka honey has been documented for several bacterial pathogens, however there is no information on Clostridium difficile, an important nosocomial pathogen. In this study we investigated susceptibility of C.

CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A.

The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis.

Targeting ATR in DNA damage response and cancer therapeutics.

The ataxia telangiectasia and Rad3-related (ATR) plays an important role in maintaining genome integrity during DNA replication through the phosphorylation and activation of Chk1 and regulation of the DNA damage response. Preclinical studies have shown that disruption of ATR pathway can exacerbate the levels of replication stress in oncogene-driven murine tumors to promote cell killing. Additionally, inhibition of ATR can sensitise tumor cells to radiation or chemotherapy.

Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1).

Ictal adiponectin levels in episodic migraineurs: a randomized pilot trial.

Objective: To assess ictal adiponectin (ADP) levels before and after acute abortive treatment in women episodic migraineurs.

Methods: Peripheral blood specimens were collected from women episodic migraineurs before and after acute abortive treatment with sumatriptan/naproxen sodium vs placebo. Univariate and multivariate models were utilized to examine the relationship between serum total ADP (T-ADP), ADP oligomers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]-ADP), and ADP ratio levels and pain severity.

Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG) 94-08.

Purpose: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08.

Methods And Materials: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis.

PG545, a heparan sulfate mimetic, reduces heparanase expression in vivo, blocks spontaneous metastases and enhances overall survival in the 4T1 breast carcinoma model.

PG545 is a clinically relevant heparan sulfate (HS) mimetic which, in addition to possessing anti-angiogenic properties, also acts as a heparanase inhibitor which may differentiate its mechanism(s) of action from approved angiogenesis inhibitors. The degradation of HS by heparanase has been strongly implicated in cell dissemination and the metastatic process. Thus, the anti-metastatic activity of PG545 has been linked to the enzymatic function of heparanase - the only endoglycosidase known to cleave HS, an important component of the extracellular matrix (ECM) which represents a potential avenue for therapeutic intervention for certain metastatic cancer indications.

Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.

Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization.

Oxidation of frying oils during intermittent usage.

We reported previously that in oils used for frying by commercial establishments, a high correlation was observed among their Gardner colors, polar compound contents (PC), carbonyl values (CV) and acid values (AV). However, this was not true for frying oils used in hospitals. In the present study, oils that had been used for deep-frying in hospital kitchens were collected and assayed for PC, CV, AV, and Gardner color value to determine the reason for the differences from oil used in commercial establishments.

Is advanced age a barrier to effective cancer treatment? The experience of nonagenarians receiving radiation therapy.

Aim: Decision-making about elderly patients is difficult due to the absence of clinical experience or evidence-based results to develop optimal treatment plans. This study aims to determine the tolerability and impact of radiation therapy (RT) when delivered to patients aged >89 years.

Methods: A retrospective review was conducted on all nonagenarian patients (defined as aged 90 years or over) managed with RT between 2005 and 2007.

Key outcomes from stakeholder workshops at a symposium to inform the development of an Australian national plan for rare diseases.

Background: Calls have been made for governments to adopt a cohesive approach to rare diseases through the development of national plans. At present, Australia does not have a national plan for rare diseases. To progress such a plan an inaugural Australian Rare Diseases Symposium was held in Western Australia in April 2011.

Targeting radiation-resistant hypoxic tumour cells through ATR inhibition.

Background: Most solid tumours contain regions of sub-optimal oxygen concentration (hypoxia). Hypoxic cancer cells are more resistant to radiotherapy and represent the most aggressive fraction of a tumour. It is therefore essential that strategies continue to be developed to target hypoxic cancer cells.

Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy.

Background And Purpose: For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies.

Evaluation of MDM2, p16, and p53 staining levels as biomarkers of biochemical recurrence following salvage radiation therapy for recurrent prostate cancer.

Background And Purpose: The selection of appropriate candidates for salvage radiation therapy (SRT) to address a rising PSA following radical prostatectomy remains challenging. Herein, we provide the first evaluation of the ability of staining levels of the tumor based biomarkers MDM2, p16, and p53 to aid in prediction of biochemical recurrence (BCR) among men undergoing SRT for recurrent prostate cancer.

Material And Methods: We identified 152 patients who were treated with SRT between July 1987 and July 2003.