Unprecedented inequivalent metal coordination environments in a mixed-ligand dicobalt complex

Bimetallic complexes of the transition metals containing mixed diimine and dithiolate ligands are of fundamental interest on account of their intriguing electronic properties. Almost always, such complexes are isolated as species in which both the metal centers are in identical coordination environments - this means that the two metals often have identical redox properties. In contrast, mixed-diimine/dithiolate bimetallic complexes of the first row transition metals where the two metals are in dissimilar coordination environments are exceedingly rare, and are only known for nickel. Herein, we report the first ever example of a mixed-diimine/dithiolate dicobalt complex where the two cobalt centers are in different coordination environments. The synthesis of this compound is straightforward, and produces a complex in which the two cobalt centers display very different redox properties

Validation of a multifactorial risk factor model used for predicting future caries risk with nevada adolescents

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to measure the validity and reliability of a multifactorial Risk Factor Model developed for use in predicting future caries risk in Nevada adolescents in a public health setting.</p> <p>Methods</p> <p>This study examined retrospective data from an oral health surveillance initiative that screened over 51,000 students 13-18 years of age, attending public/private schools in Nevada across six academic years (2002/2003-2007/2008). The Risk Factor Model included ten demographic variables: exposure to fluoridation in the municipal water supply, environmental smoke exposure, race, age, locale (metropolitan vs. rural), tobacco use, Body Mass Index, insurance status, sex, and sealant application. Multiple regression was used in a previous study to establish which significantly contributed to caries risk. Follow-up logistic regression ascertained the weight of contribution and odds ratios of the ten variables. Researchers in this study computed sensitivity, specificity, positive predictive value (PVP), negative predictive value (PVN), and prevalence across all six years of screening to assess the validity of the Risk Factor Model.</p> <p>Results</p> <p>Subjects' overall mean caries prevalence across all six years was 66%. Average sensitivity across all six years was 79%; average specificity was 81%; average PVP was 89% and average PVN was 67%.</p> <p>Conclusions</p> <p>Overall, the Risk Factor Model provided a relatively constant, valid measure of caries that could be used in conjunction with a comprehensive risk assessment in population-based screenings by school nurses/nurse practitioners, health educators, and physicians to guide them in assessing potential future caries risk for use in prevention and referral practices.</p

Current and future therapeutic approaches for the treatment of follicular lymphoma

Introduction: Recent advances in prognostication as well as management of Follicular Lymphoma (FL) are moving to personalized approach. Areas covered: Prognostic scores as well as consolidated and innovative therapeutic approaches are evaluated according to the various presentation modalities. For asymptomatic, low-tumor burden FL, a \u2018watch and wait\u2019 policy is currently the first-choice approach, although possible alternatives are discussed. Early stage FL may be treated with local radiotherapy although the role of minimal residual disease in possible additional agents should be determined. The first line treatment for symptomatic FL is chemo-immunotherapy followed by two years maintenance therapy with anti-CD20 monoclonal antibodies. A deeper knowledge of FL biology has opened new perspectives regarding the timing of therapy and has offered new targets for the development of novel agents that aim to change the therapeutic scenario of FL management. Expert commentary: The introduction of novel agents could question the incurability of FL and change the therapeutic goal from prolonging the complete remission state to eradicating the disease in young/fit patients, as well as improving quality of life in elderly/unfit patients. In the near future, combining new biologic agents and adoptive cell therapies could help in achieving these aims

IDH1R132, IDH2R140 and IDH2R172 in AML: different genetic landscapes correlate with outcome and may influence targeted treatment strategies

Introduction: In AML, IDH mutations can be found at a frequency of 7% for IDH1 and 10% for IDH2 . Precision medicine aims at specifically targeting different gene mutations. Novel drugs which inhibit mutated IDH activity, such as AG-120 (for IDH1), AG-221 (for IDH2) or AG-881 (for IDH1 and 2), are currently tested in clinical trials to assess whether they confer better prognosis and overall survival to patients that carry these mutations. Aim: To comprehensively investigate the genetics and prognosis of de novo AML with IDH1 R132, IDH2 R140, and IDH2 R172 mutations. Patients and Methods: In a cohort of 306 de novo AML patients (pts) - all IDH1 or IDH2 mutated - cytomorphology and cytogenetics were available. The cohort comprised 141 females and 165 males, the median age was 65 yrs (range: 21-90 yrs). In all pts a 25-gene panel was investigated by next generation sequencing: ASXL1, BCOR, CALR, CBL, CEBPA, CSNK1A1, DNMT3A, ETV6, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, and ZRSR2 . FLT3 -ITD and KMT2A -PTD were analyzed by gene scan. All pts were treated with intensive standard chemotherapy. Overall survival (OS) analyses were performed in comparison to a FAB and MRC (Grimwade et al., Blood 2010;116(3):354-365) matched IDH wild type (wt) reference cohort (n=540). Results: In total,106 pts (35%) were mutated in IDH1 R132, 166 (54%) in IDH2 R140 and 34 (11%) in IDH2 R172. Regarding amino acidic substitutions, IDH1 R132 was dominated by the R132H substitution in 44 (41%) and the R132C in 39 cases (37%); IDH2 R140 was largely skewed towards the R140Q substitution which occurred in 92% of cases; IDH2 R172 showed R172K in 32 cases (94%) and R172W in 2 cases (6%). The majority of pts had mutations in two (n=148, 44%) or three (n=78, 23%) of the other 24 analyzed genes (range: 0-6), while only six pts (2%) showed no additional mutations. Among FAB classification, 144 pts (47%) were classified as M1 and 94 (31%) as M2; this rather immature phenotype was most prominent in IDH1 mutated pts with an even higher percentage of M1 (64%) and less of M2 (22%). AML M3 was not present in this cohort at all, indicating a specific occurrence of IDH mutations in distinct AML types. Cytogenetic analyses revealed that 227 pts (74%) had a normal karyotype, 79 (26%) showed an aberrant karyotype with only 6 pts (2%) having a complex karyotype. This is also reflected by a high number of pts in the intermediate MRC group (n=285), while only 6 and 15 pts were grouped to the favorable MRC or adverse MRC group, respectively. Most frequently IDH mutated pts were also mutated in NPM1 (49%), followed by DNMT3A (40%), SRSF2 (29%), FLT3 -ITD (21%), ASXL1 (16%), NRAS (15%), RUNX1 (15%), and KMT2A -PTD(13%). All other analyzed genes were mutated in <10% of cases. Of note, no IDH2 R172 mutated patient carried a NPM1 mutation, but 63% and 50% of pts mutated in IDH1 R132 and IDH2 R140 (p<0.001). This was also true for NRAS with 18% and 17% of pts mutated in IDH1 R132 and IDH2 R140 (p=0.001). FLT3 was mutated rarely in patients with IDH2 R172 (5%) compared to those with mutations in IDH1 R132 (28%) or IDH2 R140 (32%; p=0.001). In contrast BCOR was often mutated in IDH2 R172 mutated pts (32%) compared to 5% and 7% of pts mutated in IDH1 R132 and IDH2 R140 (p<0.001). SRSF2 was frequently mutated in IDH2 R140 mutated pts (43%; p<0.001) compared to pts mutated in IDH1 R132 (13%) and IDH2 R172 (8%). ASXL1 mutations were rare in IDH1 R132 mutated pts (8%; p=0.007) compared to 22% and 16% in IDH2 R140 and R172 mutated pts. Overall survival analysis did not show significant differences between IDH1 and IDH2 mutated and IDH wt pts. However, when separating IDH1 R132, IDH2 R140, and IDH2 R172 mutated pts, the latter group showed a better prognosis (median OS not reached) compared to all others (median OS: 28 months; p=0.040; Fig. 1). Other worse prognostic factors in IDH mutated pts were higher white blood cell count (WBC) and age, or ASXL1, DNMT3A, SRSF2, and TP53 mutations. NPM1 mutations showed a favorable impact. In multivariate analyses, only IDH R172 mutation, WBC, and age remained independent prognostic factors. Conclusions: AML pts with IDH1 R132, IDH2 R140, and IDH2 R172 mutations differ in their morphological and genetic patterns. This translates into a more favorable outcome for IDH2 R172 mutated pts. Therefore, IDH mutated AML need further molecular subclassification to define prognosis and select optimal targeted treatment strategies accordingly