Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small ...biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.
The borylamino-diborata-allyl anion Shere, Henry T. W; Liu, Han-Ying; Neale, Samuel E ...
Chemical science,
05/2024, Letnik:
15, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Reactions of β-diketiminato alkaline earth alkyldiboranate derivatives (BDI)Ae{pinBB(R)pin} (BDI = HC{(Me)CNDipp}
2
; Dipp = 2,6-i-Pr
2
C
6
H
3
; Ae = Mg, R =
n
-Bu or Ae = Ca, R =
n
-hexyl) with
t
...-BuNC provide access to the respective group 2 derivatives of unprecedented diborata-allyl, {(pinB)
2
CNBpin(
t
-Bu)}
−
, anions. Although the necessary mode of B-C bond cleavage implicated in these transformations could not be elucidated, further studies of the reactivity of magnesium triboranates toward isonitriles delivered a more general and rational synthetic access to analogous anionic moieties. Extending this latter reactivity to a less symmetric triboranate variant also provided an isomeric Mg-C-bonded dibora-alkyl species and sufficient experimental insight to prompt theoretical evaluation of this reactivity. DFT calculations, thus, support a reaction pathway predicated on initial RNC attack at a peripheral boron centre and the intermediacy of such dibora-alkyl intermediates.
Reactions of alkaline earth alkyldiboranate and triboranate derivatives with organic isonitriles provides access to unprecedented diborata-allyl anions.
Molecular β‐diketiminato (BDI) calcium hydride and n‐hexyl derivatives are shown to display contrasting reactivities toward bis(pinacolato)diboron (B2pin2). Whereas the dimeric constitution of the ...calcium hydride is retained during formation of an unusual diborane(6) dianion, the initially dimeric organocalcium reagent is converted to a calcium diboranate monomer, (BDI)Ca{pinB‐Bpin(n‐hex)}. Attempts to effect heterolysis of the B−B bond of this latter species in a manner reminiscent of a previously reported magnesium system were unsuccessful and resulted in either dismutation to the homoleptic β‐diketiminate, (BDI)2Ca, or, in the case of organic nitriles, the generation of N‐donor adduct derivatives, (BDI)Ca(NCR){pinB‐Bpin(n‐hex)} (R=t‐Bu, i‐Pr, o‐tol). This latter reactivity again contrasts with the previously reported behaviour of an analogous magnesium diboranate, observations that are rationalised by density functional theory (DFT) calculations to be effectively a consequence of the larger radius and lower resultant steric congestion, of the third‐row group 2 cation.
The behavior of the potassium alumanyl, {SiNDipp}AlK2 ({SiNDipp} = {CH2SiMe2N(Dipp)}2; Dipp = 2,6-i-Pr2C6H3), toward organic nitriles has been investigated. In common with earlier studies of the ...reactivity of charge neutral Al(I) species with multiply bonded small molecules, it is suggested that the initial step in all the reactions involves 2 + 1 cycloaddition and the generation of an η2–CN–Al alumina azacyclopropane unit. In the cases of o- and m-tolyl-substituted aryl nitriles, this species is too kinetically labile to allow its isolation and undergoes C–C coupling via immediate Al–C/CN insertion to yield the alumina diazabutadiene derivatives. In contrast, the increased steric profile of alkyl nitriles imposes a marked influence on the nature of the products formed. Consistent with the proposed sequential pathway, reaction of {SiNDipp}AlK2 with t-BuCN provides an isolable alumina cyclopropane species that is kinetically resistant to onward reaction with a further nitrile equivalent. While reduction in the alkyl nitrile steric demands by use of i-PrCN again facilitates C–C bond formation, the crowding of the Al center by the resultant alumina-diazabutadienediide moiety appears to be beyond the limit of kinetic viability, resulting in an unusual 2-fold C–H to N–H isomerization from one of the C-iso-propyl substituents and the isolation of a 1-alumina-2,5-diazabutadiene structure.
To evaluate the utility of a point of care lung ultrasound (POC-LUS) on patient management in the Neonatal Intensive Care Unit (NICU).
A retrospective cohort study of neonates who had POC-LUS from ...2016 to 2020 in two-level III NICUs in Winnipeg, Manitoba, Canada. The primary outcome was the change in clinical management. The analysis aims mainly to describe the implementation process of the POC-LUS program.
A total of 956 neonates underwent 4076 POC-LUS studies during the study period. The number of POC-LUS studies increased significantly every year, from 316 (in 2016) to 1257 (in 2020) (p < 0.001). POC-LUS resulted in a change in clinical management following 2528 POC-LUS studies (62%), while it supported continuing the same management in 1548 studies (38%).
POC-LUS in Manitoba increased since its inception and led to an alteration in the clinical management in a significant proportion of patients who received the service.
Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.
We created a genetic risk score ...(GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study.
Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 95% CI 0.80-0.87, p = 6.0 x 10-21; AAA OR 0.76 95% CI 0.68-0.86, p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 95% CI 0.71-0.97, p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 95% CI 0.78-0.93, p = 5.0 x 10-04).
Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.
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