Organoaluminium complexes derived from Anilines or Schiff bases for ring opening polymerization of epsilon-caprolactone, delta-valerolactone and rac-lactide

Reaction of R¹R²CHN=CH(3,5-tBu₂C₆H₂-OH-2) (R¹ = R² = Me L¹H; R¹ = Me, R² = Ph L²H; R¹ = R2 = Ph L³H) with one equivalent of R³3Al (R³ = Me, Et) afforded [(L¹-³)AlR³₂] (L¹, R³ = Me 1, R³ = Et 2; L², R³ = Me 3, R³ = Et 4; L³ R³ = Me 5, R³ = Et 6); complex 1 has been previously reported. Use of the N,O-ligand derived from 2,2/-diphenylglycine afforded either 5 or a by-product [Ph₂NCH₂(3,5-tBu₂C₆H₂-O-2)AlMe₂] (7). The known Schiff base complex [2-Ph₂PC₆H4CH₂(3,5-tBu₂C₃H₂-O-2)AlMe₂] (8) and the product of the reaction of 2-diphenylphosphinoaniline 1-NH₂,2-PPh₂C₆H4 with Me3Al, namely {Ph₂PC₆H4N[(Me₂Al)₂mu-Me](mu-Me₂Al)} (9) were also isolated. For structural and catalytic comparisons, complexes resulting from interaction of Me₃Al with diphenylamine or benzhydrylamine, namely {Ph₂N[(Me₂Al)2mu-Me]} (10) and [Ph₂CHNH(mu-Me₂Al)]₂·MeCN (11), were prepared. The molecular structures of the Schiff pro-ligands derived from Ph₂CHNH₂ and 2,2/-Ph2C(CO₂H)(NH₂), together with complexes 5, 7 and 9 - 11·MeCN were determined. All complexes have been screened for their ability to ring opening polymerization (ROP) epsilon-caprolactone, delta-valerolactone or rac-lactide, in the presence of benzyl alcohol, with or without solvent present. The co-polymerization of epsilon-caprolactone with rac-lactide has also been studied

Organoaluminium complexes derived from anilines or Schiff bases for the ring-opening polymerization of ε-Caprolactone, δ-Valerolactone and rac-Lactide

Reaction of R1R2CHN=CH(3,5-tBu2C6H2-OH-2) (R1 = R2 = Me L1H; R1 = Me, R2 = Ph L2H; R1 = R2 = Ph L3H) with slightly greater than one equivalent of R33Al (R3 = Me, Et) afforded the complexes [(L1–3)AlR32] (L1, R3 = Me 1, R3 = Et 2; L2, R3 = Me 3, R3 = Et 4; L3 R3 = Me 5, R3 = Et 6); complex 1 has been previously reported. Use of the N,O-ligand derived from 2,2′-diphenylglycine afforded either 5 or the byproduct [Ph2NCH2(3,5-tBu2C6H2-O-2)AlMe2] (7). The known Schiff base complex [2-Ph2PC6H4CH2(3,5-tBu2C6H2-O-2)AlMe2] (8) and the product of the reaction of 2-diphenylphosphinoaniline 1-NH2,2-PPh2C6H4 with Me3Al, namely {Ph2PC6H4N[(Me2Al)2µ-Me](µ-Me2Al)} (9), were also isolated. For structural and catalytic comparisons, complexes resulting from the interaction of Me3Al with diphenylamine (or benzhydrylamine), namely {Ph2N[(Me2Al)2µ-Me]} (10) and [Ph2CHNH(µ-Me2Al)]2·MeCN (11), were prepared. The molecular structures of the Schiff proligands derived from Ph2CHNH2 and 2,2′-Ph2C(CO2H)(NH2), together with those of complexes 5, 7 and 9–11·MeCN were determined; 5 contains a chelating imino/phenoxide ligand, whereas 7 contains the imino function outside of the metallocyclic ring. Complex 9 contains three nitrogen-bound Al centres, two of which are linked by a methyl bridge, whilst the third bridges the N and P centres. In 10, the structure resembles 9 with a bridging methyl group, whereas the introduction of the extra carbon in 11 results in the formation of a dimer. All complexes have been screened for their ability to promote the ring-opening polymerization (ROP) ε-caprolactone, δ-valerolactone or rac-lactide, in the presence of benzyl alcohol, with or without solvent present. Reasonable conversions were achievable at room temperature for ε-caprolactone when using complexes 7, 9 and 12, whilst at higher temperatures (80–110 °C), all complexes produced good (> 65 %) to quantitative conversions over periods as short as 3 min, albeit with poor control. In the absence of solvent, conversions were nearly quantitative at 80 °C in 5 min with better agreement between observed and calculated molecular weight (Mn). For rac-lactide, conversions were typically in the range 71–86 % at 110 °C in 12 h, with poor control affording atactic polylactide (PLA), whilst for δ-valerolactone more forcing conditions (12–24 h at 110 °C) were required for high conversion. Co-polymerization of ε-caprolactone with rac-lactide afforded co-polymers with appreciable lactide content (35–62.5 %); the reverse addition was ineffective, affording only (polycaprolactone) PCL

Extracellular vesicle-enriched miRNA profiles across pregnancy in the MADRES cohort

Publisher: Public Library of ScienceInternational audienceMicroRNA (miRNA) circulating in plasma have been proposed as biomarkers for a variety of conditions and diseases, including complications during pregnancy. During pregnancy, about 15–25% of maternal plasma exosomes, a small size-class of EVs, are hypothesized to originate in the placenta, and may play a role in communication between the fetus and mother. However, few studies have addressed changes in miRNA over the course of pregnancy with repeated measures, nor focused on diverse populations. We describe changes in miRNA in early and late pregnancy from the MADRES cohort of primarily low-income Hispanic women based in Los Angeles, CA. miRNA derived from extracellular-vesicles (EVs) were isolated from maternal blood plasma samples collected in early and late pregnancy. In this study, we identified 64 of 130 detectable miRNA which significantly increased with gestational age at the time of collection (GA), and 26 which decreased with GA. Possible fetal sex-specific associations were observed for 30 of these 90 significant miRNA. Predicted gene targets for miRNA significantly associated with GA were identified using MirDIP and were found to be enriched for Gene Ontology categories that included energetic and metabolic processes but were underrepresented in immune-related categories. Circulating EV-associated miRNA during pregnancy are likely important for maternal-fetal communication, and may play roles in supporting and maintaining a healthy pregnancy, given the changing needs of the fetus

Oral contraceptives and postmenopausal hormones and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers and noncarriers: the WECARE Study

The potential effects of oral contraceptive (OC) and postmenopausal hormone (PMH) use are not well understood among BRCA1 or BRCA2 (BRCA1/2) deleterious mutation carriers with a history of breast cancer. We investigated the association between OC and PMH use and risk of contralateral breast cancer (CBC) in the WECARE (Women's Environment, Cancer, and Radiation Epidemiology) Study. The WECARE Study is a population-based case-control study of 705 women with asynchronous CBC and 1,398 women with unilateral breast cancer, including 181 BRCA1/2 mutation carriers. Risk-factor information was assessed by telephone interview. Mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing in all participants. Outcomes, treatment, and tumor characteristics were abstracted from medical records. Ever use of OCs was not associated with risk among noncarriers (RR = 0.87; 95% CI = 0.66-1.15) or BRCA2 carriers (RR = 0.82; 95% CI = 0.21-3.13). BRCA1 carriers who used OCs had a nonsignificant greater risk than nonusers (RR = 2.38; 95% CI = 0.72-7.83). Total duration of OC use and at least 5 years of use before age 30 were associated with a nonsignificant increased risk among mutation carriers but not among noncarriers. Few women had ever used PMH and we found no significant associations between lifetime use and CBC risk among carriers and noncarriers. In conclusion, the association between OC/PMH use and risk of CBC does not differ significantly between carriers and noncarriers; however, because carriers have a higher baseline risk of second primaries, even a potential small increase in risk as a result of OC use may be clinically relevant

Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2.

PURPOSE: Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS: In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed. RESULTS: Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance. CONCLUSION: The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation

Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study

Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers. The WECARE Study is a population-based multi-center case-control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers. None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65-2.65 and 0.53, 95% CI 0.19-1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers. For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. (c) 2010 Wiley-Liss, Inc

Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study.

ObjectiveReproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers.MethodsThe WECARE Study is a population-based multi-center case-control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers.ResultsNone of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65-2.65 and 0.53, 95% CI 0.19-1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers.ConclusionFor two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers

Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer.

Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutations in BRCA1 and BRCA2, it is critical to determine the effectiveness of standard adjuvant therapies in preventing CBC in mutation carriers. The WECARE study is a matched, case-control study of 708 women with CBC as cases and 1,399 women with unilateral breast cancer (UBC) as controls, including 181 BRCA1/BRCA2 mutation carriers. Interviews and medical record reviews provided detailed information on risk factors and breast cancer therapy. All study participants were screened for BRCA1 and BRCA2 mutations using denaturing high-performance liquid chromatography (DHPLC) to detect genetic variants in the coding and flanking regions of the genes. Conditional logistic regression was used to compare the risk of CBC associated with chemotherapy and tamoxifen in BRCA1/BRCA2 mutation carriers and non-carriers. Chemotherapy was associated with lower CBC risk both in non-carriers (RR = 0.6 [95% CI: 0.5-0.7]) and carriers (RR = 0.5 [95% CI: 0.2-1.0]; P value = 0.04). Tamoxifen was associated with a reduced CBC risk in non-carriers (RR = 0.7 [95% CI: 0.6-1.0]; P value = 0.03). We observed a similar but non-significant reduction associated with tamoxifen in mutation carriers (RR = 0.7 [95% CI: 0.3-1.8]). The tests of heterogeneity comparing carriers to non-carriers did not provide evidence for a difference in the associations with chemotherapy (P value = 0.51) nor with tamoxifen (P value = 0.15). Overall, we did not observe a difference in the relative risk reduction associated with adjuvant treatment between BRCA1/BRCA2 mutation carriers and non-carriers. However, given the higher absolute CBC risk in mutation carriers, the potentially greater impact of adjuvant therapy in reducing CBC risk among mutation carriers should be considered when developing treatment plans for these patients

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood–brain barrier and exhibits potent activity against glioblastoma

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood–brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380)