New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological ...stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino4,3,2-klacridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.
Soft sensors are inferential estimators, drawing conclusions from process observations when hardware sensors are unavailable or unsuitable, they have an important auxiliary role in sensor validation ...when performance declines through senescence or fault accumulation. The non-linear behaviour exhibited by many industrial processes can be usefully modelled with the techniques of computational intelligence: neural networks, fuzzy systems and nonlinear partial least squares. Soft Sensors for Monitoring and Control of Industrial Processes underlines the real usefulness of each approach and the sensitivity of the individual steps in soft-sensor design to the choice of one or the other. Design paths are suggested and readers shown how to evaluate the effects of their choices. All the case studies reported, resulting from collaborations between the authors and a number of industrial partners, raised challenging soft-sensor-design problems. The applications of soft sensors presented in this volume are designed to cope with the whole range from measuring system backup and what-if analysis through real-time prediction for plant control to sensor diagnosis and validation. Some of the soft sensors developed here are implemented on-line at industrial plants. Features: soft-sensor design, advice on data selection and choice of model structure, model validation, strategies for the improvement of soft-sensor performance, uses of soft sensors in fault detection and sensor validation, soft sensors in use in industrial applications such as a debutanizer column and a sulfur recovery unit. This monograph guides interested readers - researchers, graduate students and industrial process technologists - through the design of their own soft sensors. It is self-contained with full references and appraisal of existing literature and data sets for some of the case studies can be downloaded from springer.com.
Re-usable air/water and suction valves used in endoscopes often demonstrate risk of infection. To the authors' knowledge, the safety and efficacy of re-usable and single-use valves have not been ...compared to date. As such, a laboratory investigation was undertaken to compare the safety and efficacy of re-usable and single-use valves at 11 Italian endoscopy sites. Safety was evaluated by analysing the rinse liquid of reprocessed re-usable valves ready for use, and efficacy was assessed based on the completion of endoscopic procedures without valve malfunction. This study found significantly lower contamination of single-use valves compared with re-usable valves (0 vs 29.1%, respectively; P=0.007) and similar efficacy (97.6 vs 98.8%, respectively; P=ns). Microbiological analysis of the rinse liquid of reprocessed re-usable valves identified various surviving micro-organisms and highlighted their potential pathogenicity. Such data suggest that sterile single-use valves may be safer than re-usable valves, and have comparable performance.
The paper deals with the design of neural based soft sensors to improve product quality monitoring and control in a refinery by estimating the stabilized gasoline concentration (C5) in the top flow ...and the butane (C4) concentration in the bottom flow of a debutanizer column, on the basis of a set of available measurements. Three-step predictive dynamic neural models were implemented in order to evaluate in real time the top and bottom product concentrations in the column. The soft sensors designed overcome the great time delay introduced by the corresponding gas chromatograph, giving on-line estimations that are suitable for monitoring and control purposes.
Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD ...patients who failed previous treatment with other biologics.
194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients.
At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment.
UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.
We compared Campylobacter jejuni/coli multilocus sequence types (STs) from pets (dogs/cats) and their owners and investigated risk factors for pet-associated human campylobacteriosis using a combined ...source-attribution and case-control analysis. In total, 132/687 pet stools were Campylobacter-positive, resulting in 499 strains isolated (320 C. upsaliensis/helveticus, 100 C. jejuni, 33 C. hyointestinalis/fetus, 10 C. lari, 4 C. coli, 32 unidentified). There were 737 human and 104 pet C. jejuni/coli strains assigned to 154 and 49 STs, respectively. Dog, particularly puppy, owners were at increased risk of infection with pet-associated STs. In 2/68 cases vs. 0·134/68 expected by chance, a pet and its owner were infected with an identical ST (ST45, ST658). Although common sources of infection and directionality of transmission between pets and humans were unknown, dog ownership significantly increased the risk for pet-associated human C. jejuni/coli infection and isolation of identical strains in humans and their pets occurred significantly more often than expected.
We describe the epidemiological trends and spatial distribution of human brucellosis in Italy over 13 years (1998–2010). In the study period 8483 cases were notified in Italy, with a relevant ...decrease (−89%) from 1998 to 2010. Most cases were notified in southern Italy (Campania, Apulia, Calabria, Sicily). In these regions we observed relevant differences in the risk of brucellosis at province level. Cases were distributed with a seasonal pattern, male patients represented 60% of the cases and no significant differences were observed between age groups. We modelled the underreporting rate that ranged between 2 and 21 (average 12·5). According to our estimates the true number of cases would have ranged from 41 821 to 155 324 providing a far more severe picture of human brucellosis in Italy than the one provided by the surveillance system.
Purpose The aim of this study was to evaluate the results of the surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in a large cohort. Materials and Methods A retrospective ...cohort multicenter study was designed. Patients were enrolled if they were diagnosed with BRONJ and received operative treatment. Data on demographic, health status, perioperative, and surgical factors were collected retrospectively. The primary outcome variable was a change in BRONJ staging (improvement, worsening, or no change). Interventions were grouped by local debridement and resective surgery. Data were collected for other variables as cofactors. Univariate analysis and logistic regressions were then performed. Results Of the 347 BRONJ-affected subjects, 59% showed improvement, 30% showed no change, and 11% showed worsening. Improvement was observed in 49% of cases treated with local debridement and 68% of cases treated with resective surgery. Multivariate analysis indicated that maxillary location, resective surgery, and no additional corticosteroid treatment were associated with a positive outcome. Conclusions Surgical treatment of BRONJ appeared to be more effective when resective procedures were performed. Nonetheless, other factors, such as the absence of symptoms and the types of drug administration, should be taken into account before clinical decisions are made.
Calcium and phosphate are essential for cell functions, and their serum concentrations result from the balance between intestinal absorption, bony storage, and urinary excretion. Fibroblast growth ...factor 23 (FGF23), expressed by osteocytes and osteoblasts, acts in the kidney, leading to hypophosphatemia and low 1,25‐dihydroxycholecalciferol synthesis, but suppresses parathyroid function. The aim of this study was to explore the effects of a high‐energy demanding cycling race on this bone–kidney–parathyroid axis. We studied nine cyclists during the 2011 Giro d'Italia stage race. Pre‐analytical and analytical phases followed academic and anti‐doping recommendations. Serum parathyroid hormone (PTH), 25(OH)D, total calcium, inorganic phosphorus, and plasma FGF23 were measured on days −1, 12, and 22 and corrected for changes in plasma volume. Dietary calcium and phosphorus, anthropometric parameters (height, weight, and body mass index) and indexes of metabolic effort (net energy expenditure, power output) were recorded. Dietary calcium and phosphorus intakes were kept at the same levels throughout the race. Twenty‐five (OH)D, PTH, and calcium concentrations remained stable. FGF23 increased 50% with a positive correlation with the indexes of metabolic effort and, consequently, phosphorous decreased, although only in the first half. The strong metabolic effort acts on the bone–kidney–parathyroid system, and the rise in FGF23 plasma concentration might be aimed at maintaining calcium and phosphorus homeostasis.
There is conflicting evidence on the benefits of foods rich in vitamin E (α-tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of ...these substances as supplements in patients who had myocardial infarction.
From October, 1993, to September, 1995, 11 324 patients surviving recent (≤3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (1 g daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3·5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way).
Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relativerisk decrease 10% 95% CI 1–18 by two-way analysis, 15% 2–26 by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% 3–24 two-way, 20% 6–33 four-way) and cardiovascular death (17% 3–29 two-way, 30% 13–44 four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% 1–26) and for fatal events (20% 5–33).
Dietary supplementation with n-3 PUFA led to a clinically important and satistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.
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