Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still to be investigated. Here, we studied the functional significance and the druggability of the oncogenic lncRNA MALAT1 in MM. Targeting MALAT1 by novel LNA-gapmeR antisense oligonucleotide antagonized MM cell proliferation and triggered apoptosis both in vitro and in vivo in a murine xenograft model of human MM. Of note, antagonism of MALAT1 downmodulated the two major transcriptional activators of proteasome subunit genes, namely NRF1 and NRF2, and resulted in reduced trypsin, chymotrypsin and caspase-like proteasome activities and in accumulation of polyubiquitinated proteins. NRF1 and NRF2 decrease upon MALAT1 targeting was due to transcriptional activation of their negative regulator KEAP1, and resulted in reduced expression of anti-oxidant genes and increased ROS levels. In turn, NRF1 promoted MALAT1 expression thus establishing a positive feedback loop. Our findings demonstrate a crucial role of MALAT1 in the regulation of the proteasome machinery, and provide proof-of-concept that its targeting is a novel powerful option for the treatment of MM

Effect of a home based, low intensity, physical exercise program in older adults dialysis patients: A secondary analysis of the EXCITE trial

Background: Older adults dialysis patients represent the frailest subgroup of the End Stage Renal Disease (ESRD) population and physical exercise program may mitigate the age-related decline in muscle mass and function. Methods: Dialysis patients of the EXCITE trial aged > 65 years (n = 115, active arm, n = 53; control arm, n = 62) were submitted in random order to a home based, low intensity physical exercise program. At baseline and 6 months after exercise training 6-min walking distance (6MWD) and 5-time sit-to-stand test (5STS) were performed, and quality of life (QoL) was tested. Results: The training program improved both the 6MWD (6-months: 327 \ub1 86 m versus baseline: 294 \ub1 74 m; P < 0.001) and the 5STS time (6-months: 19.8 \ub1 5.6 s versus baseline: 22.5 \ub1 5.1 s; P < 0.001) in the exercise group whereas they did not change in the control group (P = 0.98 and 0.25, respectively). The between-arms differences (6 months-baseline) in the 6MWD (+ 34.0 m, 95% CI: 14.4 to 53.5 m) and in the 5STS time changes (- 1.9 s, 95% CI: -3.6 to - 0.3 s) were both statistically significant (P = 0.001 and P = 0.024, respectively). The cognitive function dimension of QoL significantly reduced in the control arm (P = 0.04) while it remained unchanged in the active arm (P = 0.78) (between groups difference P = 0.05). No patient died during the trial and the training program was well tolerated. Conclusions: This secondary analysis of the EXCITE trial shows that a home-based, exercise program improves physical performance and is well tolerated in elderly ESRD patients. Trial registration: The trial was registered in ClinicalTrials.Gov (Clinicaltrials.gov identifier: NCT01255969) on December 8, 2010

Politerapia e polifarmacia nell&apos;anziano con scompenso cardiaco cronico

Population aging is associated with an increasing prevalence of chronic diseases(including chronic heart failure) and comorbidities(the presence of one or more diseases in addition to an index disease, potentially contributing to disability) which, in turn, expands the need for healthcare services. Therefore, the already elevated costs in the National Health Services are expected to rise further over the next decades, along with increasing aging of the population. This epidemiologic trend is responsible for the increasing occurrence of polytherapy(multiple medications prescribed to an individual patient) and polypharmacy(multiple medications not directly prescribed by a physician). Owing to often unpredictable interactions, polytherapy and polypharmacy are associated with higher risk of adverse drug reactions with increased mortality and hospitalizations that contribute to increase direct and indirect National Health Services costs. Physicians, patients and caregivers should be instructed in strategies aimed at reducing adverse drug reactions while maintaining optimal management of conditions that, such as chronic heart failure, are at high risk of death, functional impairment and deteriorated quality of life. Strategies consist of a variety of interventions, such as reducing inappropriate medication prescriptions and number of medications and doses taken, avoiding drugs with greater potential of interactions, and increasing patient adherence

Forty Keratin-Associated beta-Proteins (beta-Keratins) Form the Hard Layers of Scales, Claws, and Adhesive Pads in the Green Anole Lizard, Anolis carolinensis

Using bioinformatic methods we have detected the genes of 40 keratin-associated beta-proteins (KAbetaPs) (beta-keratins) from the first available draft genome sequence of a reptile, the lizard Anolis carolinensis (Broad Institute, Boston). All genes are clustered in a single but not yet identified chromosomal locus, and contain a single intron of variable length. 5'-RACE and RT-PCR analyses using RNA from different epidermal regions show tissue-specific expression of different transcripts. These results were confirmed from the analysis of the A. carolinensis EST libraries (Broad Institute). Most deduced proteins are 12-16 kDa with a pI of 7.5-8.5. Two genes encoding putative proteins of 40 and 45 kDa are also present. Despite variability in amino acid sequences, four main subfamilies can be described. The largest subfamily includes proteins high in glycine, a small subfamily contains proteins high in cysteine, a third large subfamily contains proteins high in cysteine and glycine, and the fourth, smallest subfamily comprises proteins low in cysteine and glycine. An inner region of high amino acid identity is the most constant characteristic of these proteins and maps to a region with two to three close beta-folds in the proteins. This beta-fold region is responsible for the formation of filaments of the corneous material in all types of scales in this species. Phylogenetic analysis shows that A. carolinensis KAbetaPs are more similar to those of other lepidosaurians (snake, lizard, and gecko lizard) than to those of archosaurians (chick and crocodile) and turtles

Dose-related impact of alcohol consumption on cognitive function in advanced age : results of a multicenter survey

Background: Moderate alcohol consumption has been associated in several studies with decreased risk of cardiovascular and cerebrovascular events; however, available data on the effects of alcohol intake on cognitive functioning are conflicting. We assessed the association between alcohol consumption and cognitive impairment in a series of older subjects enrolled in a multicenter pharmacoepidemiology survey. Methods: The association between average alcoholic intake and cognitive performance was assessed in 15,807 patients admitted to participating centers during the survey periods. Demographic variables, comorbid conditions, medications, and objective tests that were associated with cognitive impairment (as indicated by a Hodkinson Abbreviated Mental Test score <7) in separate logistical regression models were examined as potential confounders in a summary model. Results: Cognitive impairment was detected in 1693 (19%) of 8755 drinkers and 2008 (29%) of 7052 nondrinkers (Fisher's exact test, p < 0.0001). After adjusting for potential confounders, alcohol consumption was associated with decreased probability of cognitive impairment (odds ratio, 0.75; 95% confidence interval, 0.66-0.85). The relationship between drinking level and cognitive dysfunction was nonlinear, because the probability of cognitive impairment was decreased for moderate alcohol use as compared with abstinence, but it was increased for daily consumption exceeding one wine-equivalent liter among men and 0.5 liter among women. This nonlinear association persisted when cerebrovascular and Alzheimer's disease were considered separately. Conclusions: Alcohol abuse is associated with increased prevalence of cognitive dysfunction among older subjects; however, a daily alcohol consumption of less than 40 g for women and 80 g or less for men might be associated with a decreased probability of cognitive impairment. This possible protective effect of alcohol consumption should be further assessed by prospective studies

Forty keratin-associated b-proteins (b-keratins) form the hard layers of scales, claws, and adhesive pads in the green anole lizard, Anolis carolinensis

Using bioinformatic methods we have detected the genes of 40 keratin-associated b-proteins (KAbPs) (b-keratins) from the first available draft genome sequence of a reptile, the lizard Anolis carolinensis (Broad Institute, Boston). All genes are clustered in a single but not yet identified chromosomal locus, and contain a single intron of variable length. 50-RACE and RT-PCR analyses using RNA from different epidermal regions show tissue-specific expression of different transcripts. These results were confirmed from the analysis of the A. carolinensis EST libraries (Broad Institute). Most deduced proteins are 12–16 kDa with a pI of 7.5–8.5. Two genes encoding putative proteins of 40 and 45 kDa are also present. Despite variability in amino acid sequences, four main subfamilies can be described. The largest subfamily includes proteins high in glycine, a small subfamily contains proteins high in cysteine, a third large subfamily contains proteins high in cysteine and glycine, and the fourth, smallest subfamily comprises proteins low in cysteine and glycine. An inner region of high amino acid identity is the most constant characteristic of these proteins and maps to a region with two to three close b-folds in the proteins. This b-fold region is responsible for the formation of filaments of the corneous material in all types of scales in this species. Phylogenetic analysis shows that A. carolinensis KAbPs are more similar to those of other lepidosaurians (snake, lizard, and gecko lizard) than to those of archosaurians (chick and crocodile) and turtles

Interaction of HDL cholesterol concentrations on the relationship between physical function and inflammation in community-dwelling older persons

Background: the existence of a relationship among inflammation, high-density lipoprotein cholesterol (HDL-C) and physical function has been suggested. Objective: the aim of the study is to investigate the possible interaction of HDL-C on inflammation and physical function. Design: cross-sectional study. Setting: town of Tuscania (Italy). Subjects: all the 329 community-dwelling older persons aged 6575years (mean age 79.8\ub15.2years, women 56.2%). Methods: HDL-C, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and interleukin-6 (IL-6) were measured. Activities of daily living (ADL), instrumental ADL (IADL) and 4-m walking speed were assessed. Linear regression models were performed. Results: given the multiple significant interactions, models were stratified according to HDL-C concentrations. In participants with normal HDL-C concentrations, only IL-6 showed a significant association with IADL (\u3b2=-0.439, SE=0.176, P=0.01). In participants with low HDL-C concentrations, all three inflammatory biomarkers were significantly associated with 4-m walking speed and IADL. IL-6 was also significantly associated with ADL (\u3b2=-0.755, SE=0.259, P=0.006), whereas borderline significances were reported for CRP and ESR. Conclusions: the association between inflammation and physical function is particularly enhanced in elders with low HDL-C concentrations. Though HDL-C may merely act as a wellbeing index, HDL-C concentrations should be considered in studies evaluating inflammation and physical function

Use of calcium antagonists and worsening renal function in patients receiving angiotensin-converting-enzyme inhibitors

Objective: The objective of this study was to assess whether calcium antagonists, which have been proven to dilate the afferent glomerular arteriole, might prevent increases in serum creatinine levels among older subjects who started treatment with angiotensin-converting enzyme (ACE) inhibitors. Methods: We explored the association between use of calcium antagonists and incident increases in serum creatinine in 780 elderly patients with baseline creatinine levels < 1.2 mg/dL (106.19 \uce\ubcmol/L), who were enrolled in a multicenter pharmacoepidemiology study, and who started using ACE inhibitors during their hospital stay. Among these participants, 279 also started using calcium antagonists. Demographic variables, comorbid conditions, medications, and objective tests, which were associated with increasing serum creatinine levels in separate regression models, were examined as potential confounders in a summary model. Results: Among patients receiving ACE inhibitors, serum creatinine levels increased in 22% of participants who were dispensed calcium antagonists, and in 31% of other patients (P=0.005). In the summary regression model, use of calcium antagonists was associated with a decreased risk of worsening renal function (RR 0.56, 95% CI 0.37-0.84). The adjusted risk of increasing serum creatinine was lower (RR 0.25, 95% CI 0.05-0.95) in participants receiving higher calcium antagonists dosages than in those taking lower dosages. This protective effect of calcium antagonists was not detected in patients not dispensed ACE inhibitors. Conclusion: ACE inhibitors are underused in older subjects, mainly because of the higher incidence of renal damage among geriatric populations. Our results indicate that among elderly patients receiving ACE inhibitors, the use of calcium antagonists is associated with a reduced risk of worsening renal function. Thus, these results warrant trials aiming at establishing whether combined treatment with calcium antagonists might allow the use of ACE inhibitors in clinical practice to be expanded to the elderly population

Use of angiotensin-converting enzyme inhibitors and variations in cognitive performance among patients with heart failure

Aims: Cognitive dysfunction is a prevalent condition among patients with heart failure, and is independently associated with disability and mortality. Angiotensin-converting enzyme (ACE)-inhibitors might increase cerebral blood flow in subjects with heart failure. Our aim was to assess whether starting treatment with ACE-inhibitors might improve cognition in patients with heart failure. Methods and results: Analyses involved 12 081 subjects, 1220 of whom had a verified diagnosis of heart failure, enrolled in a multi-centre pharmaco-epidemiology survey. None of these participants received ACE-inhibitors before hospitalisation. Among participants with heart failure, cognitive performance improved in 30% of 446 participants who started ACE-inhibitors, but only in 22% of remaining patients (P = 0.001). Among participants without heart failure, cognition improved in 19% of those receiving ACE-inhibitors, and in 18% of untreated patients (P = 0.765). Use of ACE-inhibitors among patients with heart failure was associated with improving cognition (odds ratio = 1.57; 95% Cl 1.18-2.08) also in the multivariable regression modelling, independently of baseline or discharge blood pressure levels. The probability of improving cognitive performance was higher for dosages above the median values, as compared with lower doses (odds ratios = 1.90 and 1.42; P for trend = 0.001), and increased with duration of treatment (odds ratios for the lower, middle, and upper tertiles = 1.25, 1.34, and 1.59; P for trend = 0.007). Conclusion: Treatment with ACE-inhibitors might selectively improve cognitive performance in patients with heart failure. However, up-titration of these agents might be required to yield the greatest benefit