Directing the use of DDR kinase inhibitors in cancer treatment

Introduction: Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1.

Areas covered: We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use.

Expert opinion: Novel DDR inhibitors present promising candidates in cancer treatment and have the potential to elicit synthetic lethal effects. In order to fully exploit their potential and maximize their utility, identifying highly penetrant predictive biomarkers of single agent and combinatorial DDR inhibitor sensitivity are critical. Identifying the optimal drug combination regimens that could used with DDR inhibitors is also a key objective.     

Antioxidant capacity and phenolic content of selected commercially available cruciferous vegetables

Antioxidant activity, free radical scavenging activity and phenolic content of red cabbage (Brassica oleracea var. capitata rubra), Chinese cabbage (Brassica rapa pekinensis var cylindrica), green cabbage (Brassica oleracea var capitata), mustard cabbage (Brassica juncea var rugosa) and Chinese white cabbage (Brassica rapa var chinensis), grown in Malaysia, were evaluated. Red cabbage had the highest antioxidant activity and phenolic content compared to the other cruciferous vegetables studied (p < 0.05). The contributions of all cruciferous vegetables to the antioxidant activity was >79%. The radical scavenging activity was in the order of Chinese white cabbage > red cabbage > mustard cabbage > Chinese cabbage > green cabbage. There was a significant difference (p < 0.05) in the means of scavenging activity observed between cabbage, Chinese cabbage and Chinese mustard. Phenolic content was significantly different (p < 0.05) among all the cruciferous vegetables studied, and was in the order of red cabbage > Chinese white cabbage > green cabbage > Chinese cabbage >mustard cabbage. The study indicated that red cabbage possessed the highest antioxidant capacity and phenolic compounds concentration among all the cruciferous vegetables studied.     

Hormone modulation: a novel therapeutic approach for women with severe mental illness

OBJECTIVES: Accumulating evidence describes the effects of oestrogen and other gonadal hormones on the central nervous system and, in particular, on the mental state of women. Evidence supporting the psychotherapeutic effects of exogenous oestrogen has started to emerge only over the past two decades. The purpose of the present paper was to provide an overview of different applications of adjunctive hormones, as treatments for symptoms of severe mental illness in women. METHODS: Three case reports are presented: in each case the woman selected had participated in large, double-blind, randomized controlled trials exploring hormone modulation. Case study 1 presents a premenopausal woman with schizophrenia, who received an 8 week trial of daily adjunctive 200 microg transdermal oestradiol. Case study 2 presents a postmenopausal woman with schizophrenia on a 12 week trial of adjunctive raloxifene hydrochloride 120 mg per day. Case study 3 presents a woman with schizoaffective disorder, in the manic phase, who received tamoxifen 40 mg per day for 28 days. RESULTS: Adjunctive oestradiol was associated with an improvement in symptoms of psychosis in a premenopausal woman with schizophrenia; adjunctive raloxifene was associated with an improvement in cognitive functioning in a postmenopausal woman with schizophrenia; and adjunctive tamoxifen was associated with an improvement in symptoms of mania in a woman with schizoaffective disorder. CONCLUSIONS: These findings are consistent with preliminary research trials suggesting that adjunctive hormone modulation is a promising area of gender-specific treatment for serious mental illness.     

Presenting features of newly diagnosed rheumatic heart disease patients in Mulago Hospital: a pilot study

Introduction

Rheumatic heart disease (RHD) continues to cause gross distortions of the heart and the associated complications of heart failure and thromboembolic phenomena in this age of numerous high-efficacy drugs and therapeutic interventions. Due to the lack of contemporary local data, there is no national strategy for the control and eradication of the disease in Uganda. This study aimed to describe the presenting clinical features of newly diagnosed patients with RHD, with particular reference to the frequency of serious complications (atrial fibrillation, systemic embolism, heart failure and pulmonary hypertension) in the study group.

Methods

One hundred and thirty consecutive patients who satisfied the inclusion criteria were recruited over a period of eight months from June 2011 to January 2012 at the Mulago Hospital, Uganda. Data on demographic characteristics, disease severity and presence of complications were collected by means of a standardised questionnaire.

Results

Seventy-one per cent of the patients were female with a median age of 33 years. The peak age of the study group was 20 to 39 years, with the commonest presenting symptoms being palpitations, fatigue, chest pain and dyspnoea. The majority of the patients presented with moderate-to-severe valvular disease. Pure mitral regurgitation was the commonest valvular disease (40.2%), followed by mitral regurgitation plus aortic regurgitation (29%). Mitral regurgitation plus aortic regurgitation plus mitral stenosis was found in 11% of patients. There was only one case involving the tricuspid valve. The pulmonary valves were not affected in all patients; 45.9% of patients presented in severe heart failure in NYHA class III/IV, 53.3% had pulmonary hypertension, 13.9% had atrial fibrillation and 8.2% had infective endocarditis. All patients presented with dilated atria (> 49 mm).

Conclusion

A significant proportion of RHD patients present to hospital with severe disease associated with severe complications of advanced heart failure, pulmonary hypertension, infective endocarditis and atrial fibrillation. There is a need to improve awareness of the disease among the population, and clinical suspicion in primary health workers, so that early referral to specialist management can be done before severe damage to the heart ensues.     

Intensive care information system reduces documentation time of the nurses after cardiothoracic surgery

OBJECTIVE: Nowadays, registration of patient data on paper is gradually being replaced by registration using an intensive care information system (ICIS). The aim of this study was to evaluate the effect of the use of an ICIS on nursing activity. DESIGN: Randomized controlled trial with a crossover design. SETTING: An 18-bed medical-surgical ICU in a teaching hospital. PATIENTS, NURSES AND INTERVENTIONS: During a 6week period 145 consecutive adult patients admitted to the ICU after uncomplicated cardiothoracic surgery were randomized into two groups: for one group the documentation was carried out using a paper-based registration (Paper), in the second group an ICIS was used for documentation. MEASUREMENTS AND RESULTS: The nursing activities for these patients were studied during two separate periods: the admission period and the registration phase (the period directly following the admission procedure). The duration of the admission procedure was measured by time-motion analysis and the nursing activities in the registration phase were studied by work sampling methodology. All nursing activities during the registration phase were grouped in four main categories: patient care, documentation, unit-related and personal time. The duration of the admission procedure was longer in the ICIS group (18.1+/-4.1 versus 16.8+/-3.1 min, p<0.05). In the registration phase, a 30% reduction in documentation time (Paper 20.5% of total nursing time versus ICIS 14.4%, p<0.001), corresponding to 29 min (per 8h nursing shift) was achieved. This time was completely re-allocated to patient care. CONCLUSIONS: The use of the present ICIS in patients after cardiothoracic surgery alters nursing activity; it reduces the time for documentation and increases the time devoted to patient care. Electronic supplementary material: is available if you access this article at http://dx.org/10.1007/s00134-002-1542-9. On that page (frame on the left side), a link takes you directly to the supplementary material.     

The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a cyclin D homolog, K cyclin, that is thought to promote viral oncogenesis. However, expression of K cyclin in cultured cells not only triggers cell cycle progression but also engages the p53 tumor suppressor pathway, which probably restricts the oncogenic potential of K cyclin. Therefore, to assess the tumorigenic properties of K cyclin in vivo, we transgenically targeted expression of K cyclin to the B and T lymphocyte compartments via the E micro promoter/enhancer. Around 17% of E micro -K cyclin animals develop lymphoma by 9 months of age, and all such lymphomas exhibit loss of p53. A critical role of p53 in suppressing K cyclin-induced lymphomagenesis was confirmed by the greatly accelerated onset of B and T lymphomagenesis in all E micro -K cyclin/p53(-/-) mice. However, absence of p53 did not appear to accelerate K cyclin-induced lymphomagenesis by averting apoptosis: E micro -K cyclin/p53(-/-) end-stage lymphomas contained abundant apoptotic cells, and transgenic E micro -K cyclin/p53(-/-) lymphocytes in vitro were not measurably protected from DNA damage-induced apoptosis compared with E micro -K cyclin/p53(wt) cells. Notably, whereas aneuploidy was frequently evident in pre-lymphomatous tissues, end-stage E micro -K cyclin/p53(-/-) tumors showed a near-diploid DNA content with no aberrant centrosome numbers. Nonetheless, such tumor cells did harbor more restricted genomic alterations, such as single-copy chromosome losses or gains or high-level amplifications. Together, our data support a model in which K cyclin-induced genome instability arises early in the pre-tumorigenic lymphocyte population and that loss of p53 licenses subsequent expansion of tumorigenic clones.     

Cognitive dysfunction is associated with poor diabetes control in older adults

OBJECTIVE: To evaluate the association between cognitive dysfunction and other barriers and glycemic control in older adults with diabetes. RESEARCH DESIGN AND METHODS: Patients over the age of 70 years presenting to a geriatric diabetes clinic were evaluated for barriers to successful diabetes management. Patients were screened for cognitive dysfunction with the Mini Mental State Examination (MMSE) and a clock-drawing test (CDT) scored by 1) a method validated by Mendez et al. and 2) a modified CDT (clock in a box [CIB]). Depression was evaluated with the Geriatric Depression Scale. Interview questionnaires surveyed activities of daily living (ADLs) and instrumental ADLs (IADLs), as well as other functional disabilities. RESULTS: Sixty patients (age 79 +/- 5 years, diabetes duration 14 +/- 13 years) were evaluated. Thirty-four percent of patients had low CIB (< or =5), and 38% of patients had low CDT (< or =13). Both CIB as well as CDT were inversely correlated with HbA(1c), suggesting that cognitive dysfunction is associated with poor glycemic control (r = -0.37, P < 0.004 and r = -0.38, P < 0.004, respectively). Thirty-three percent of patients had depressive symptoms with greater difficulty completing the tasks of the IADL survey (5.7 +/- 1.7 vs. 4.6 +/- 2.0; P < 0.03). These older adults with diabetes had a high incidence of functional disabilities, including hearing impairment (48%), vision impairment (53%), history of recent falls (33%), fear of falls (44%), and difficulty performing IADLs (39%). CONCLUSIONS: Older adults with diabetes have a high risk of undiagnosed cognitive dysfunction, depression, and functional disabilities. Cognitive dysfunction in this population is associated with poor diabetes control.