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1.
Breast Cancer ; 31(2): 228-233, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38012337

RESUMO

OBJECTIVE: Various efforts have been made to improve the accuracy of breast cancer screening. This study aimed to report differences in the contribution of ultrasonography to cancer screening assessments of dense and non-dense breasts. METHODS: The participants in this study were 29,640 Japanese women in their 40 s who underwent breast cancer screening at the Iwate Cancer Society between 2018 and 2021. This included women who chose mammography alone or mammography with adjunctive ultrasonography (overall assessment). They were classified into two groups according to the breast density in mammography: dense breasts and non-dense breasts. Recall rate, breast cancer detection rate, and positive predictive value of the two screening-type groups were evaluated for each breast density group. RESULTS: Of the 29,640 women analyzed, 18,861 (63.6%) underwent mammography alone and 10,779 (36.3%) were by overall assessments. The number of women recalled was higher in the overall assessment group than in the mammography-alone group (2.9% vs. 1.9%, p < 0.01). The proportion of women in whom breast cancer was detected was higher in the overall assessment group than in the mammography-alone group (0.31% [n = 33] vs. 0.15% [n = 28], p < 0.01). For non-dense breasts, there were no significant differences in either the recall rate or the breast cancer detection rate between those who underwent mammography alone and those who underwent overall assessment. Conversely, for dense breasts, the recall rate after mammography alone was lower than that after overall assessment (1.8% vs. 3.8%, p < 0.01), and the breast cancer detection rate was higher after overall assessment than after mammography alone (0.40% vs. 0.18%, p < 0.01). CONCLUSION: We found the benefits of adjunctive ultrasonography with mammography to differ depending on breast density. This could be used to tailor the selection of screening modalities to individuals.


Assuntos
Densidade da Mama , Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/diagnóstico por imagem , Ultrassonografia Mamária , Mamografia , Ultrassonografia , Detecção Precoce de Câncer , Programas de Rastreamento
2.
Bioorg Med Chem ; 22(21): 5891-901, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25284253

RESUMO

Non-secosteroidal vitamin D receptor (VDR) ligands are promising candidates for many clinical applications. We recently developed novel non-secosteroidal VDR agonists based on p-carborane (an icosahedral carbon-containing boron cluster) as a hydrophobic core structure. Here, we report the design, synthesis and biological evaluation of carborane-based vitamin D analogs bearing various substituents at the diol moiety. Among the synthesized compounds, methylene derivative 31 exhibited the most potent vitamin D activity, which was comparable to that of the natural hormone, 1α,25(OH)2D3. This compound is one of the most potent non-secosteroidal VDR agonists reported to date, and is a promising lead for development of novel drug candidates.


Assuntos
Boranos/química , Vitamina D/análogos & derivados , Boranos/síntese química , Boranos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Desenho de Fármacos , Células HL-60 , Humanos , Ligantes , Ligação Proteica , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Relação Estrutura-Atividade , Vitamina D/síntese química , Vitamina D/farmacologia
3.
Bioorg Med Chem Lett ; 24(18): 4515-4519, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25149512

RESUMO

Vitamin D receptor (VDR), a nuclear receptor for 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3, 1), is a promising target for multiple clinical applications. We recently developed non-secosteroidal VDR ligands based on a carbon-containing boron cluster, 1,12-dicarba-closo-dodecaborane (p-carborane), and examined the binding of one of them to VDR by means of crystallographic analysis. Here, we utilized that X-ray structure to design novel p-carborane-based tetraol-type vitamin D analogs, and we examined the biological activities of the synthesized compounds. Structure-activity relationship study revealed that introduction of an ω-hydroxyalkoxy functionality enhanced the biological activity, and the configuration of the substituent significantly influenced the potency. Among the synthesized compounds, 4-hydroxybutoxy derivative 9a exhibited the most potent activity, which was equal to that of the secosteroidal vitamin D analog, 19-nor-1α,25-dihydroxyvitamin D3 (2).


Assuntos
Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Desenho de Fármacos , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Compostos de Boro/química , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Vitamina D/química
4.
Bioorg Med Chem ; 22(4): 1227-35, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24486205

RESUMO

1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure-activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure-activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.


Assuntos
Boranos/química , Vitamina D/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Células HL-60 , Humanos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Vitamina D/síntese química , Vitamina D/farmacologia , Vitaminas/síntese química , Vitaminas/farmacologia
5.
Bioorg Med Chem Lett ; 22(4): 1756-60, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22285943

RESUMO

Vitamin D receptor (VDR) is a nuclear receptor for 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)), and is an attractive target for multiple clinical applications. We recently developed novel non-secosteroidal VDR ligands bearing a hydrophobic p-carborane cage, thereby establishing the utility of this spherical hydrophobic core structure for development of VDR ligands. Here, we synthesized two series of novel non-secosteroidal VDR ligands with different spherical hydrophobic cores, that is, bicyclo[2.2.2]octane derivatives and p-carborane derivatives, and compared their biological activities in order to examine the difference between the interactions of the C-H hydrocarbon surface and the B-H carborane surface with the receptor. Carborane derivatives exhibited more potent differentiation-inducing activity toward HL-60 cells than did the corresponding bicyclo[2.2.2]octane derivatives. These results suggest that the hydrophobic carborane cage may interact more efficiently than the hydrocarbons with the hydrophobic surface of VDR. This finding further supports the view that carborane structure is a promising option for drug development.


Assuntos
Boranos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ligantes , Receptores de Calcitriol/agonistas , Boranos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células HL-60 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Receptores de Calcitriol/química
6.
J Am Chem Soc ; 133(51): 20933-41, 2011 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-22066785

RESUMO

We report here the design and synthesis of a novel vitamin D receptor (VDR) agonist whose hydrophobic core structure is p-carborane (1,12-dicarba-closo-dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability and a characteristically hydrophobic B-H surface). This carborane-based VDR ligand exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure analysis provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation. These results indicate that the spherical B-H surface of carborane can function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups on the alkyl chains to the appropriate positions for interaction with the VDR binding site, despite the entropic disadvantage of the flexible structure. We suggest that carborane structure is a promising option in the design of novel drug candidates.


Assuntos
Compostos de Boro/química , Compostos de Boro/farmacologia , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Domínio Catalítico , Diferenciação Celular/efeitos dos fármacos , Desenho de Fármacos , Células HL-60 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Modelos Moleculares , Ligação Proteica , Receptores de Calcitriol/química
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