Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

Translating the Dutch walking stairs, walking ability and rising and sitting questionnaires into German and assessing their concurrent validity with VAS measures of pain and activities in daily living

<p>Abstract</p> <p>Background</p> <p>The Dutch Walking Stairs, Walking Ability and Rising and Sitting Questionnaires are three validated instruments to measure physical activity and limitations in daily living in patients with lower extremity disorders living at home of which no German equivalents are available. Our scope was to translate the Walking Stairs, Walking Ability and Rising and Sitting Questionnaires into German and to verify its concurrent validity in the two domains pain and activities in daily living by comparing them with the corresponding measures on the Visual Analogue Scale.</p> <p>Methods</p> <p>We translated the Walking Stairs, Walking Ability and Rising and Sitting Questionnaires according to published guidelines. Demographic data and validity were assessed in 52 consecutive patients with Complex Regional Pain Syndrome 1 of the lower extremity. Information on age, duration of symptoms, type of Complex Regional Pain Syndrome 1 and type of initiating event were obtained. We assessed the concurrent validity in the two domains pain and activities in daily living by comparing them with the corresponding measures on the Visual Analogue Scale.</p> <p>Results</p> <p>We found that variability in the German Walking Stairs, Walking Ability and Rising and Sitting Questionnaires was largely explained by measures of pain and activities in daily living on the Visual Analogue Scale.</p> <p>Conclusion</p> <p>Our study shows that the domains pain and activities in daily living are properly represented in the German versions of the Walking Stairs, Walking Ability and Raising and Sitting Questionnaires. We would like to propagate their use in clinical practice and research alike.</p

Maternal hyperleptinemia is associated with male offspring’s altered vascular function and structure in mice

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Lepr db/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under astandard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post-natal environments to contribute to altered vascular function in offspring of diabetic pregnancie

Hypertension in the very old; prevalence, awareness, treatment and control: a cross-sectional population-based study in a Spanish municipality

<p>Abstract</p> <p>Background</p> <p>Information on hypertension in the very elderly is sparse. Until recently evidence of benefits from pharmacological treatment was inconclusive. We estimated the prevalence of hypertension in subjects aged 80 or more, the proportion of awareness, treatment and control. Explanatory variables associated with good control were also studied.</p> <p>Methods</p> <p>Cross sectional, population-based study, conducted in Martorell, an urban Spanish municipality, in 2005. By simple random sampling from the census, 323 subjects aged 80 or more were included. Patients were visited at home or in the geriatric institution and after giving informed consent, the study variables were collected. These included: supine and standing blood pressure and information about diagnosis and treatment of hypertension. The estimation and 95% confidence interval were obtained and a logistic regression model was used to study explanatory variables associated with blood pressure below 140/90 mm Hg.</p> <p>Results</p> <p>The prevalence of hypertension was 72.8% (95%CI: 69.5 – 76.6%) and 93% of the patients were aware of this condition, of whom 96.3% (95%CI: 93.65 – 97.9%) had been prescribed pharmacological treatment and 30.7% (95%CI: 25.8 – 36.1%) had blood pressure below 140/90 mm Hg. Some of the patients (43%) had one antihypertensive drug and 39.5% had two in combination. Explanatory variables associated with blood pressure below 140/90 mm Hg included prescription of a diuretic, OR: 0.31 (95%CI: 0.14 – 0.66), and history of ischemic heart disease, OR: 0.21 (95%CI: 0.1 – 0.47).</p> <p>Conclusion</p> <p>The prevalence of hypertension in population aged 80 or more was over 70%. Most patients were aware of this condition and they had antihypertensive medication prescribed. Approximately one third of treated patients had blood pressure below 140/90 mm Hg. Patients with heart disease and with diuretics had more frequently blood pressure below this value.</p

Herbal therapy associated with antibiotic therapy: potentiation of the antibiotic activity against methicillin – resistant Staphylococcus aureus by Turnera ulmifolia L

<p>Abstract</p> <p>Background</p> <p><it>Staphylococcus </it>genus is widely spread in nature being part of the indigenous microbiota of skin and mucosa of animal and birds. Some <it>Staphylococcus </it>species are frequently recognized as etiological agents of many animal and human opportunistic infections This is the first report testing the antibiotic resistance-modifying activity of <it>Turnera ulmifolia </it>against methicillin-resistant <it>Staphylococcus aureus </it>– MRSA strain.</p> <p>Methods</p> <p>In this study an ethanol extract of <it>Turnera ulmifolia </it>L. and chlorpromazine were tested for their antimicrobial activity alone or in combination with aminoglycosides against an MRSA strain.</p> <p>Results</p> <p>The synergism of the ethanol extract and aminoglycosides were verified using microdillution method. A synergistic effect of this extract on gentamicin and kanamycin was demonstrated. Similarly, a potentiating effect of chlorpromazine on kanamycin, gentamicin and neomycin, indicating the involvement of an efflux system in the resistance to these aminoglycosides.</p> <p>Conclusion</p> <p>It is therefore suggested that extracts from <it>Turnera ulmifolia </it>could be used as a source of plant-derived natural products with resistance-modifying activity, constituting a new weapon against the problem of bacterial resistance to antibiotics demonstrated in MRSA strains.</p

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Relationships between quality of life and family function in caregiver

<p>Abstract</p> <p>Background</p> <p>There are caregivers who see their quality of life (QoL) impaired due to the demands of their caregiving tasks, while others manage to adapt and overcome the crises successfully. The influence of the family function in the main caregiver's situation has not been the subject of much evaluation. The aim of this study is to analyse the relationship between the functionality of the family and the QoL of caregivers of dependent relatives.</p> <p>Methods</p> <p>We conducted a cross-sectional study including 153 caregivers. Setting: Two health centers in the city of Salamanca(Spain). Caregiver variables analysed: demographic characteristics, care recipient features; family functionality (Family APGAR-Q) and QoL (Ruiz-Baca-Q) perceived by the caregiver. Five multiple regressions are performed considering global QoL and each of the four QoL dimensions as dependent variables. The Canonical Correspondence Analysis (CCA) was used to study the influence of the family function questionnaire on QoL.</p> <p>Results</p> <p>Family function is the only one of the variables evaluated that presented an association both with global QoL and with each of the four individual dimensions (p < 0.05). Using the CCA, we found that the physical and mental well-being dimensions are the ones which present a closer relationship with family functionality, while social support is the quality dimension that is least influenced by the Family APGAR-Q.</p> <p>Conclusion</p> <p>We find an association between family functionality and the caregiver's QoL. This relation holds for both the global measure of QoL and each of its four individual dimensions.</p

Effectiveness and costs of phototest in dementia and cognitive impairment screening

<p>Abstract</p> <p>Background</p> <p>To assess and compare the effectiveness and costs of Phototest, Mini Mental State Examination (MMSE), and Memory Impairment Screen (MIS) to screen for dementia (DEM) and cognitive impairment (CI).</p> <p>Methods</p> <p>A phase III study was conducted over one year in consecutive patients with suspicion of CI or DEM at four Primary Care (PC) centers. After undergoing all screening tests at the PC center, participants were extensively evaluated by researchers blinded to screening test results in a Cognitive-Behavioral Neurology Unit (CBNU). The gold standard diagnosis was established by consensus of expert neurologists. Effectiveness was assessed by the proportion of correct diagnoses (diagnostic accuracy [DA]) and by the kappa index of concordance between test results and gold standard diagnoses. Costs were based on public prices and hospital accounts.</p> <p>Results</p> <p>The study included 140 subjects (48 with DEM, 37 with CI without DEM, and 55 without CI). The MIS could not be applied to 23 illiterate subjects (16.4%). For DEM, the maximum effectiveness of the MMSE was obtained with different cutoff points as a function of educational level [k = 0.31 (95% Confidence interval [95%CI], 0.19-0.43), DA = 0.60 (95%CI, 0.52-0.68)], and that of the MIS with a cutoff of 3/4 [k = 0.63 (95%CI, 0.48-0.78), DA = 0.83 (95%CI, 0.80-0.92)]. Effectiveness of the Phototest [k = 0.71 (95%CI, 0.59-0.83), DA = 0.87 (95%CI, 0.80-0.92)] was similar to that of the MIS and higher than that of the MMSE. Costs were higher with MMSE (275.9 ± 193.3€ [mean ± sd euros]) than with Phototest (208.2 ± 196.8€) or MIS (201.3 ± 193.4€), whose costs did not significantly differ. For CI, the effectiveness did not significantly differ between MIS [k = 0.59 (95%CI, 0.45-0.74), DA = 0.79 (95%CI, 0.64-0.97)] and Phototest [k = 0.58 (95%CI, 0.45-0.74), DA = 0.78 (95%CI, 0.64-0.95)] and was lowest for the MMSE [k = 0.27 (95%CI, 0.09-0.45), DA = 0.69 (95%CI, 0.56-0.84)]. Costs were higher for MMSE (393.4 ± 121.8€) than for Phototest (287.0 ± 197.4€) or MIS (300.1 ± 165.6€), whose costs did not significantly differ.</p> <p>Conclusion</p> <p>MMSE is not an effective instrument in our setting. For both DEM and CI, the Phototest and MIS are more effective and less costly, with no difference between them. However, MIS could not be applied to the appreciable percentage of our population who were illiterate.</p

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies

Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern