Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.Subject terms: Acute myeloid leukaemia, Targeted therapies     

The FINDRISC questionnaire capacity to predict diabetes mellitus II,arterial hypertension and comorbidity in women from low-and-middle-income countries

Abstract

The Finnish Diabetes Risk Score (FINDRISC) has been implemented to assess diabetes risk. The authors aimed in this study to determine the prediction capacity of FINDRISC for the early detection of cardiovascular diseases in women. A prevalence study was carried out on 441 women of Pueblo Libre (Peru). Anthropometric variables, blood pressure, blood glucose and comorbidity were measured and entered in FINDRISC. 4.8% of the studied women suffered from DM2, 14.3% from AHT, 33% obesity and 8.6% comorbidity. We found that FINDRISC was the best method to discriminate DM, AHT and comorbidity. FINDRISC is an effective non-invasive tool for women from low-and-middle-income countries.     

The Association Between Physical Activity and Cataracts Among 17,777 People Aged 15–69 Years Residing in Spain

ABSTRACT

Purpose

The aim of the present study was to assess the association between levels of physical activity (PA) and the presence of cataracts in people aged 15–69 years residing in Spain.     

A qualitative scale of the 6-minute race test to evaluate maximum aerobic speed in physically active people from 18 to 25 years

[Purpose] To create a qualitative scale for the 6-minute race test in physically active participants from 18 to 25 years old. [Participants and Methods] The sample was 299 healthy participants (254 males and 45 females). All the participants were instructed to perform the greatest possible distance in the 6-minute race test. To evaluate the reliability of the 6-minute race test, 30 participants performed the 6-minute race test for a second time. The variable was distance in meters. The qualitative scale was constructed with the percentiles <25, 50, 75, 90 and >90 for the criteria poor, fair, good, very good and excellent, respectively; the reliability was calculated with the coefficient of variation, intra-class correlation coefficient and the standard error of the mean. [Results] In the 6-minute race test, the mean was 1,607 and 1,364 meters for males and females, respectively. The coefficient of variation=4.08%, intra-class correlation coefficient=0.93 and standard error of the mean=11.46. [Conclusion] The creation of the qualitative scale of the 6-minute race test allows us to evaluate and classify the level and increase of maximum aerobic speed in physically active participants from 18 to 25 years old.Key words: Maximum aerobic speed, 6-minute race test, Young adults     

Shaping of curved root canals instrumented with stainless steel and nickel titanium files

The cleaning efficiency and the quality of the surgical preparation is mainly conditioned by root canal anatomy, the instruments and the technique employed. The purpose of the present study was to evaluate the extent of straightening of curved root canals and the changes in endodontic anatomy caused by the use of Flex-R, Onyx-R and Nitiflex files with the balanced forces technique. Sixty mandibular molars were selected for evaluation of angulation and transportation. Pre and post instrumentation radiographs were taken of the mesiodistal and buccolingual aspects of each tooth. The radiographs were projected on a transparent sheet, the contours of each tooth and file were outlined and the canal curvature was measured. Pre and post instrumentation tracings were overlaid and the extent of transportation was measured with a micrometric caliper. Statistical analysis of the data was performed employing Student's "t" test, Analysis of Variance and Bonferroni's test. The results showed that all the instruments reduced canal curvature significantly. Transportation in the mesiodistal direction did not reach statistical significance whereas transportation in the buccolingual direction was statistically significant.     

A review of the clinical management of mobile teeth

The clinical management of mobile teeth can be a perplexing problem, especially if the underlying causes for that mobility have not been properly diagnosed. In some cases, mobile teeth are retained because patients decline multidisciplinary treatment that might otherwise include strategic extractions. This article discusses the relationship between occlusion and tooth mobility with an emphasis on identifying differences between increased mobility and increasing mobility. The indications, contraindications, and basic principles of tooth splinting are also reviewed. Provisional and definitive splints are defined and described with their respective occlusal considerations. Some mobile teeth can be treated through occlusal equilibration alone (primary occlusal trauma). Whereas mobile teeth with a compromised periodontium can be stabilized with the aid of provisional and/or definitive splinting (secondary occlusal trauma). It is important to consider splint therapy, because it may not only improve the prognosis of teeth, but may actually enhance the stability of the final prosthodontic treatment. The ultimate goal of successful management of mobile teeth is to restore function and comfort by establishing a stable occlusion that promotes tooth retention and the maintenance of periodontal health.     

A longitudinal study of the survival of All-on-4 implants in the mandible with up to 10 years of follow-up

BackgroundImmediate-function implants have become an accepted alternative for fixed restoration protocols in edentulous mandibles on the basis of documented high success rates. The All-on-4 concept (Nobel Biocare, Göteborg, Sweden), a surgical and prosthetic protocol for immediate function involving the use of four implants to support a fixed prosthesis in patients with completely edentulous mandibles, represents one of these protocols. The authors conducted a study to document long-term follow-up of the All-on-4 concept.MethodsThis longitudinal study included 245 patients with a total of 980 immediate-function implants (four per patient), all placed in the anterior region, to support fixed full-arch mandibular prostheses. The inclusion criterion was having an edentulous mandible, or a mandible with hopeless teeth, in need of fixed implant restorations.ResultsA total of 21 implants failed in 13 patients, giving cumulative patient-related and implant-related success rates of 94.8 percent and 98.1 percent, respectively, at five years, and 93.8 percent and 94.8 percent, respectively, with up to 10 years of follow-up. The prostheses’ survival rate was 99.2 percent with up to 10 years of follow up.ConclusionsThe results support the conclusion that use of the All-on-4 immediate-function implant concept in completely edentulous mandibles is viable in the long term.Clinical ImplicationsHigh prosthesis survival rates can be achieved by the use of four implants to support a full-arch fixed prosthesis in the mandible.     

The effectiveness of auxiliary features on a tooth preparation with inadequate resistance form

STATEMENT OF PROBLEM: No study has evaluated the efficacy of auxiliary tooth preparation elements for crowns with originally reduced resistance form. PURPOSE: This study evaluated the effects of different auxiliary preparation features on the resistance form of crowns with reduced axial wall and total occlusal convergence. MATERIAL AND METHODS: An Ivorine tooth was prepared on a milling machine with 20-degree total occlusal convergence (TOC), 2.5 mm of occlusocervical dimension, and a shoulder finish line. This design lacked geometric resistance form. The crown preparation was subsequently modified to include mesiodistal grooves, mesiodistal boxes, buccolingual grooves, occlusal inclined planes, an occlusal isthmus, and reduced TOC in the axial wall from 20 to 8 degrees TOC in the cervical 1.5 mm of the axial wall. The grooves and boxes were placed into the tooth with the same 20-degree TOC as the initial axial walls. Ten standardized metal dies were used for each preparation design. Standardized complete metal crowns were fabricated for all specimens. The metal crowns were cemented on metal dies with resin-modified glass ionomer cement. A strain gauge was placed at the mid-lingual cervical area of each crown preparation margin. The resistance of each specimen was evaluated when force was applied at a 45-degree angulation to the long axis of the die in a lingual to buccal direction. The peak loads during crown dislodgment, as well as the tensile stress at the mid-lingual cervical area, were measured using a universal testing machine (Kgs) for each specimen. The control group consisted of 10 dies, with the original crown preparation having no geometric resistance form and no auxiliary preparation features. Strain gauges provided the force (Kgs) that resulted in electric currency disrupt at the crown/die interface, thus providing data regarding the force required for slight crown micromovement (2 microm). Data between control and experimental groups were compared using the Mann-Whitney U test (alpha=.05). RESULTS: Proximal grooves, proximal boxes, buccolingual grooves, occlusal inclined planes, and occlusal isthmuses were not effective at increasing a crown's resistance to dislodgement when the tooth preparation lacked resistance. The only crown modification that offered enhanced resistance form when compared with the control group was the reduced TOC in the cervical half of the axial wall. CONCLUSION: Within the limitations of this in vitro study the crown preparation modification that significantly enhanced the resistance form of a compromised tooth preparation was reducing the TOC at the cervical aspect of the axial wall. Placing auxiliary retentive features such as grooves and boxes into a compromised tooth preparation (2.5 mm occlusocervical dimension and 20-degree TOC) was not effective when these retentive features possessed the same 20-degree TOC as the prepared axial walls.     

Clinical complications with implants and implant prostheses

The purpose of this article is to identify the types of complications that have been reported in conjunction with endosseous root form implants and associated implant prostheses. A Medline and an extensive hand search were performed on English-language publications beginning in 1981. The searches focused on publications that contained clinical data regarding success/failure/complications. The complications were divided into the following 6 categories: surgical, implant loss, bone loss, peri-implant soft tissue, mechanical, and esthetic/phonetic. The raw data were combined from multiple studies and means calculated to identify trends noted in the incidences of complications. The most common implant complications (those with a greater than a 15% incidence) were loosening of the overdenture retentive mechanism (33%), implant loss in irradiated maxillae (25%), hemorrhage-related complications (24%), resin veneer fracture with fixed partial dentures (22%), implant loss with maxillary overdentures (21%), overdentures needing to be relined (19%), implant loss in type IV bone (16%), and overdenture clip/attachment fracture (16%). It was not possible to calculate an overall complications incidence for implant prostheses because there were not multiple clinical studies that simultaneously evaluated all or most of the categories of complications. Although the implant data had to be obtained from different studies, they do indicate a trend toward a greater incidence of complications with implant prostheses than single crowns, fixed partial dentures, all-ceramic crowns, resin-bonded prostheses, and posts and cores.