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1.
Rinsho Ketsueki ; 64(3): 193-197, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-37019672

RESUMO

All-trans retinoic acid (ATRA) is used as standard induction therapy for acute promyelocytic leukemia (APL), but it is contraindicated for patients on hemodialysis. We present a case of a patient with APL on hemodialysis, intubated, and with marked disseminated intravascular coagulation (DIC) who was successfully treated with ATRA. A 49-year-old man was transferred to our hospital and admitted into the intensive care unit due to renal dysfunction, DIC, and pneumonia. Promyelocytes were noted in the peripheral blood, and he was diagnosed with APL after bone-marrow examination. Because of renal dysfunction, only Ara-C was used but with a reduced dose. The patient's condition improved, and he was extubated and withdrawn from dialysis on the 5th day of hospitalization. The patient suffered from APL syndrome during induction therapy, which necessitated ATRA withdrawal and steroid administration. Remission was achieved after induction therapy, and the patient is currently on maintenance therapy. There are few cases of patients with APL on hemodialysis who were treated with ATRA; hence, it is necessary to review the treatment plan for these patients.


Assuntos
Injúria Renal Aguda , Leucemia Promielocítica Aguda , Masculino , Humanos , Pessoa de Meia-Idade , Leucemia Promielocítica Aguda/tratamento farmacológico , Indução de Remissão , Tretinoína/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Diálise Renal
2.
Breast Cancer Res Treat ; 196(2): 255-266, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36087189

RESUMO

PURPOSE: The prognosis of HER2-positive breast cancer has improved with the development of anti-HER2 therapies. In order to further improve the prognosis of HER2-positive breast cancer, it is essential to elucidate the cells that survive during the therapy (drug-tolerant persister DTP). METHODS: Of the 2022 breast cancer patients operated at our institution during 2004-2018, 240 (12%) had HER2-positive breast cancer. Neo-adjuvant chemotherapy including trastuzumab (Tr-NAC) was administered to 94 of them. Forty-six of them were complete remission (CR), and 48 were non-CR. After 6.9 ± 3.7 years of follow-up, all 46 CR cases showed no recurrence (Cohort A), and 48 non-CR cases were divided into 31 cases with no recurrence (Cohort B) and 17 cases with recurrence (Cohort C). In addition to clinical backgrounds, we compared genomic profiles for 27 patients (Cohort A; 15/48, B; 7/31, and C; 5/17) who consented to genomic analysis. RESULTS: Genomic abnormalities of TP53 and PIK3CA were frequently observed in biopsy samples pre Tr-NAC, but we found no differences between CR (Cohort A) and non-CR (Cohorts B + C). Then, we examined both of pre and post Tr-NAC samples of Cohort B (7) and C (5) to see the relationship between recurrence and genomic abnormalities. TP53 mutations were significantly more prevalent in Cohort C (5/5, 100%) than cohort B (3/7, 43%) in the surgical sample after treatment (p = 0.04). PyClone analysis of TP53 mutations showed that the cellular frequency of TP53 clones increased in 4 of 5 patients in Cohort C and none of B. On the other hand, we found no enhancement of PIK3CA mutant clones in Cohort C. CONCLUSIONS: The DTP after Tr-NAC associated with subsequent relapse had TP53 mutations, suggesting that overcoming DTP with TP53 mutations is the most important clinical challenge. TRIAL REGISTRATION: Not applicable.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/genética , Células Clonais/metabolismo , Células Clonais/patologia , Proteína Supressora de Tumor p53/genética
3.
Gan To Kagaku Ryoho ; 49(1): 85-87, 2022 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-35046370

RESUMO

We present 2 cases of carcinoma en cuirasse, an uncommon clinical manifestation of metastatic cutaneous breast cancer. Case 1, a 70-year-old woman, presented with diffuse erythematous, indurated skin lesions that covered her entire anterior chest wall. Skin biopsy revealed tumor cells in the dermis which were ER and PgR positive and HER2 negative. CT showed pleural and pericardial effusion which led to a final diagnosis of cutaneous metastasis from breast cancer. Fulvestrant monotherapy was initiated and maintained a good clinical effect for 40 months. She died of multiple liver metastasis after 53 months from her first visit. Case 2 was a 71-year-old woman, with a 24 month history of a left breast tumor that gradually accompanied erythematous skin indurations and erosion, which spread to her entire left chest wall and contralateral breast. Following skin biopsy and CT, she was diagnosed to have triple negative breast cancer with multiple lymph node and cutaneous metastasis. After 4 cycles of EC, capecitabine was administrated and her skin lesions improved rapidly, including the lymph nodes. She is currently alive after 12 months since her first visit and under chemotherapy against new cutaneous metastasis.


Assuntos
Neoplasias da Mama , Carcinoma , Neoplasias Cutâneas , Idoso , Mama , Neoplasias da Mama/tratamento farmacológico , Feminino , Fulvestranto , Humanos , Neoplasias Cutâneas/tratamento farmacológico
4.
Allergol Int ; 70(2): 223-228, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33248880

RESUMO

BACKGROUND: This study was aimed at evaluating the efficacy and safety of oral immunotherapy (OIT) in children with severe cow's milk allergy. METHODS: The subjects comprised 28 children (aged 3-12 years) with allergic symptoms that were induced by ≤ 10 mL of cow's milk in an oral food challenge test (OFC). The subjects were randomly allocated to the treatment group (n = 14) and control group (n = 14); the former received rush immunotherapy for 2 weeks, followed by a gradual increase of cow's milk volume to 100 mL for 1 year, and the latter completely eliminated cow's milk for 1 year. Both groups underwent an OFC with 100 mL of cow's milk after 1 year. RESULTS: The treatment group had significantly higher rates of a negative OFC [7/14 (50%) vs. 0/14 (0%), p < 0.01] compared with the control group. The cow's milk-specific IgE level significantly decreased in the treatment group (p < 0.01) but not in the control group (p = 0.63). During the study period, adrenaline was required in 6/14 patients (43%) of the treatment group and in 0/14 patients (0%) of the control group. Long follow-up data were available at the 2-year point after the study for 8 in the treatment group and 7 (87.5%) of these continued to ingest milk (>100 mL). CONCLUSIONS: The effect of immunotherapy was 50%, but the incidence of adverse events was not low. Further studies focusing on safety is necessary to standardize OIT for cow's milk allergy.


Assuntos
Dessensibilização Imunológica , Hipersensibilidade a Leite/terapia , Leite/efeitos adversos , Administração Oral , Alérgenos/administração & dosagem , Alérgenos/efeitos adversos , Animais , Criança , Pré-Escolar , Dessensibilização Imunológica/efeitos adversos , Método Duplo-Cego , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoglobulina E/sangue , Japão , Leucócitos Mononucleares/imunologia , Masculino , Leite/imunologia , Hipersensibilidade a Leite/sangue , Hipersensibilidade a Leite/genética , Hipersensibilidade a Leite/imunologia
5.
Nature ; 497(7450): 490-3, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23644455

RESUMO

Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.


Assuntos
Remodelação Óssea , Osso e Ossos/inervação , Osso e Ossos/metabolismo , Semaforina-3A/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Osso e Ossos/anatomia & histologia , Diferenciação Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Tamanho do Órgão , Osteoblastos/citologia , Osteoblastos/metabolismo , Semaforina-3A/deficiência , Semaforina-3A/genética , Células Receptoras Sensoriais/citologia
6.
Biol Pharm Bull ; 41(1): 147-150, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29081457

RESUMO

Alternative plasticizers have become more popular due to health concerns about phthalate esters. We demonstrated that phthalate esters enhanced skin sensitization to fluorescein isothiocyanate (FITC) in mouse contact hypersensitivity models. Alternative plasticizers have not been well studied as to their effect on the immune system. We previously found that diisopropyl adipate (DIPA), an aliphatic dicarboxylic acid ester, enhanced skin sensitization to FITC. Sebacate esters are also widely used as alternative plasticizers. Here we tested diisopropyl sebacate (DIPS), which has the same alcohol with an aliphatic dicarboxylic acid of longer chain, using BALB/c mice. The results showed that DIPS facilitated skin sensitization to FITC and increased FITC-presenting dendritic cell trafficking from the skin to draining lymph nodes. Furthermore, DIPS activated transient receptor potential ankyrin 1 (TRPA1). The latter feature has been commonly observed for phthalate esters and DIPA, which have adjuvant effects. In summary, the adjuvant effect of a sebacate ester was demonstrated in a mouse model.


Assuntos
Adjuvantes Imunológicos/toxicidade , Ácidos Decanoicos/toxicidade , Dermatite de Contato/imunologia , Fluoresceína-5-Isotiocianato/administração & dosagem , Plastificantes/toxicidade , Animais , Células CHO , Cálcio/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Cricetulus , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Dermatite de Contato/etiologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos Endogâmicos BALB C , Canal de Cátion TRPA1/genética
7.
Heart Vessels ; 33(6): 615-622, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29204682

RESUMO

We evaluated the impact of pharmacist-led heart failure (HF) drug recommendations during hospitalization for hospitalized patients with HF. Hospitalized patients with HF were retrospectively reviewed. Patients were hospitalized before (n = 208, non-intervention group) or after (n = 170, intervention group) the launch of the HF multidisciplinary team (HFMDT) approach with pharmacist-led HF medication optimization. There were no significant group differences in patient background characteristics at admission. Patients with HF with reduced ejection fraction who were not on beta blockers or angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACE-I/ARB) at admission were significantly more likely to be on beta blockers at the time of discharge in the intervention group (73.3 vs 96.3%, P = 0.027) compared to those in non-intervention group; however, the change in ACE-I/ARB prescriptions was not significant (53.3 vs 63.3%, P = 0.601). The proportion of patients on any drug with recommendations against its use in patients with HF did not change from admission to discharge in the non-intervention group (21.2 vs. 20.2%, P = 0.855), but was significantly reduced in the intervention group (22.9 vs. 12.9%, P = 0.005). There were no group differences in the in-hospital all-cause mortality (non-intervention, 3.4%; intervention, 2.4%; P = 0.761) or length of hospital stay (median: non-intervention, 13 days; intervention, 14 days; P = 0.508). Pharmacist-led HF drug recommendations during hospitalization as part of a HFMDT approach for hospitalized patients with HF can increase beta blocker prescriptions and decrease non-preferred drug prescriptions.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/tendências , Equipe de Assistência ao Paciente , Farmacêuticos , Idoso , Fármacos Cardiovasculares/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
8.
Gan To Kagaku Ryoho ; 45(9): 1343-1346, 2018 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-30237378

RESUMO

A 73-year-old woman noticed a mass in her right breast about 1 year ago and consulted our hospital for an enlarged mass of about 10 cm in diameter.She was diagnosed with locally advanced triple negative breast cancer, and we initiated S-1 treatment as neoadjuvant chemotherapy.After 4 chemotherapy courses, computed tomography showed that the primary tumor had shrunk.Therefore, right mastectomy and axillary dissection were performed, and UFT was administered after surgery.She is currently alive with no recurrence 18 months after surgery.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Idoso , Combinação de Medicamentos , Feminino , Humanos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia
9.
Microbiol Immunol ; 61(1): 34-41, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28111794

RESUMO

Although antimicrobial products are essential for treating diseases caused by bacteria, antimicrobial treatment selects for antimicrobial-resistant (AMR) bacteria. The aim of this study was to determine the effects of administration of first-generation cephalosporins on development of resistant Escherichia coli in dog feces. The proportions of cephalexin (LEX)-resistant E. coli in fecal samples of three healthy dogs treated i.v. with cefazolin before castration and then orally with LEX for 3 days post-operation (PO) were examined using DHL agar with or without LEX (50 µg/mL). LEX-resistant E. coli were found within 3 days PO, accounted for 100% of all identified E. coli 3-5 days PO in all dogs, and were predominantly found until 12 days PO. LEX-resistant E. coli isolates on DHL agar containing LEX were subjected to antimicrobial susceptibility testing, pulsed-field gel electrophoresis (PFGE) genotyping, ß-lactamase typing and plasmid profiling. All isolates tested exhibited cefotaxime (CTX) resistance (CTX minimal inhibitory concentration ≥4 µg/mL). Seven PFGE profiles were classified into five groups and three ß-lactamase combinations (blaCMY-4 -blaTEM-1 , blaTEM-1 -blaCTX-M-15 and blaTEM-1 -blaCTX-M-15 -blaCMY-4 ). All isolates exhibited identical PFGE profiles in all dogs on four days PO and subsequently showed divergent PFGE profiles. Our results indicate there are two selection periods for AMR bacteria resulting from the use of antimicrobials. Thus, continuing hygiene practices are necessary to prevent AMR bacteria transfer via dog feces after antimicrobial administration.


Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Doenças do Cão/microbiologia , Infecções por Escherichia coli/veterinária , Escherichia coli/efeitos dos fármacos , Fezes/microbiologia , Animais , DNA Bacteriano/genética , Cães , Farmacorresistência Bacteriana Múltipla , Eletroforese em Gel de Campo Pulsado/métodos , Escherichia coli/enzimologia , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/transmissão , Proteínas de Escherichia coli/genética , Genótipo , Masculino , Testes de Sensibilidade Microbiana , beta-Lactamases/genética
10.
New Phytol ; 206(3): 1013-1023, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25628228

RESUMO

Plastid gene expression (PGE) is one of the signals that regulate the expression of photosynthesis-associated nuclear genes (PhANGs) via GENOMES UNCOUPLED1 (GUN1)-dependent retrograde signaling. We recently isolated Arabidopsis sugar-inducible cotyledon yellow-192 (sicy-192), a gain-of-function mutant of plastidic invertase, and showed that following the treatment of this mutant with sucrose, the expression of PhANGs as well as PGE decreased, suggesting that the sicy-192 mutation activates a PGE-evoked and GUN1-mediated retrograde pathway. To clarify the relationship between the sicy-192 mutation, PGE, and GUN1-mediated pathway, plastid and nuclear gene expression in a double mutant of sicy-192 and gun1-101, a null mutant of GUN1 was studied. Plastid-encoded RNA polymerase (PEP)-dependent PGE was markedly suppressed in the sicy-192 mutant by the sucrose treatment, but the suppression as well as cotyledon yellow phenotype was not mitigated by GUN1 disruption. Microarray analysis revealed that the altered expression of nuclear genes such as PhANG in the sucrose-treated sicy-192 mutant was largely dependent on GUN1. The present findings demonstrated that the sicy-192 mutation alters nuclear gene expression with sucrose treatment via GUN1, which is possibly followed by inhibiting PEP-dependent PGE, providing a new insight into the role of plastid sugar metabolism in nuclear gene expression.


Assuntos
Proteínas de Arabidopsis/fisiologia , Arabidopsis/genética , Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica de Plantas , Plastídeos/enzimologia , beta-Frutofuranosidase/fisiologia , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mutação , Nitrogênio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fotossíntese/genética , Transdução de Sinais , Sacarose/metabolismo , Sacarose/farmacologia , beta-Frutofuranosidase/genética , beta-Frutofuranosidase/metabolismo
11.
Arch Biochem Biophys ; 575: 61-8, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25906744

RESUMO

The chloroplastic fructose-1,6-bisphosphatase (FBPase) is a late-limiting enzyme in the Calvin cycle. In the present study, we isolated and characterized the cDNAs encoding two types of chloroplastic FBPase isoforms (EgFBPaseI and II) from Euglena gracilis. The Km values of recombinant EgFBPaseI and EgFBPaseII for fructose 1,6-bisphosphate (Fru 1,6-P2) were 165 ± 17 and 2200 ± 200 µM, respectively. The activity of EgFBPaseI was inhibited by 1mM H2O2 and recovered when incubated with DTT. The activity of EgFBPaseII was resistant to concentrations of H2O2 up to 1mM, which was distinct from those of EgFBPaseI and spinach chloroplastic FBPase. The suppression of EgFBPaseI gene expression by gene silencing markedly decreased photosynthetic activity and inhibited cell growth. The results of the present study clearly demonstrated that EgFBPaseI played a critical role in photosynthesis in Euglena chloroplasts.


Assuntos
Cloroplastos/enzimologia , Euglena gracilis/enzimologia , Frutose-Bifosfatase/metabolismo , Sequência de Aminoácidos , Frutose-Bifosfatase/química , Frutose-Bifosfatase/genética , Dados de Sequência Molecular , Filogenia , Interferência de RNA , Homologia de Sequência de Aminoácidos
12.
Biol Pharm Bull ; 38(7): 1054-62, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25959058

RESUMO

Due to health concerns about phthalate esters, the use of alternative plasticizers is being considered. Phthalate esters enhance skin sensitization to fluorescein isothiocyanate (FITC) in mouse models. We have demonstrated that phthalate esters stimulate transient receptor potential ankyrin 1 (TRPA1) cation channels expressed on sensory neurons. We also found a correlation between TRPA1 activation and the enhancing effect on FITC-induced contact hypersensitivity (CHS) when testing various types of phthalate esters. Here we investigated the effects of an alternative plasticizer, diisopropyl adipate (DIA). Activation of TRPA1 by DIA was demonstrated by calcium mobilization using Chinese hamster ovary cells expressing TRPA1 in vitro. The effect of DIA was inhibited by a TRPA1-specific antagonist, HC-030031. The presence of DIA or dibutyl phthalate (DBP; positive control) during skin sensitization of BALB/c mice to FITC augmented the CHS response, as revealed by the level of ear-swelling. The enhancing effect of DIA was inhibited by in vivo pretreatment with HC-030031. FITC-presenting CD11c(+) dendritic cell (DC)-trafficking to draining lymph nodes was facilitated both by DIA and by DBP. DBP and DIA were similarly active in the enhancement of interferon-γ production by draining lymph nodes, but the effect on interleukin-4 production was weaker with DIA. Overall, DIA activated TRPA1 and enhanced FITC-induced CHS, as DBP did. The adjuvant effects of adipate esters may need to be considered because they are used as ingredients in cosmetics and drug formulations topically applied to the skin.


Assuntos
Adipatos/farmacologia , Adjuvantes Imunológicos/farmacologia , Dermatite de Contato/imunologia , Plastificantes/farmacologia , Canais de Potencial de Receptor Transitório/imunologia , Acetanilidas/farmacologia , Animais , Células CHO , Cálcio/metabolismo , Cricetulus , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Dermatite de Contato/etiologia , Feminino , Fluoresceína-5-Isotiocianato , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos Endogâmicos BALB C , Purinas/farmacologia , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genética
13.
Biosci Biotechnol Biochem ; 79(12): 1957-64, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26214137

RESUMO

Euglena gracilis has the ability to accumulate a storage polysaccharide, a ß-1,3-glucan known as paramylon, under aerobic conditions. Under anaerobic conditions, E. gracilis cells degrade paramylon and synthesize wax esters. Cytosolic fructose-1,6-bisphosphatase (FBPase) appears to be a key enzyme in gluconeogenesis and position branch point of carbon partitioning between paramylon and wax ester biosynthesis. We herein identified and characterized cytosolic FBPase from E. gracilis. The Km and Vmax values of EgFBPaseIII were 16.5 ± 1.6 µM and 30.4 ± 7.2 µmol min(-1) mg protein(-1), respectively. The activity of EgFBPaseIII was not regulated by AMP or reversible redox modulation. No significant differences were observed in the production of paramylon in transiently suppressed EgFBPaseIII gene expression cells by RNAi (KD-EgFBPaseIII); nevertheless, FBPase activity was markedly decreased in KD-EgFBPaseIII cells. On the other hand, the growth of KD-EgFBPaseIII cells was slightly higher than that of control cells.


Assuntos
Citosol/enzimologia , Euglena gracilis/citologia , Frutose-Bifosfatase/metabolismo , Sequência de Aminoácidos , Biomassa , Euglena gracilis/enzimologia , Euglena gracilis/genética , Euglena gracilis/metabolismo , Frutose-Bifosfatase/química , Frutose-Bifosfatase/genética , Glucanos/biossíntese , Dados de Sequência Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
14.
Nat Med ; 13(10): 1234-40, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17873881

RESUMO

Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu-/-) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu-/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Absorciometria de Fóton , Animais , Densidade Óssea/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Imuno-Histoquímica , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Modelos Biológicos , Neuropeptídeos/análise , Neuropeptídeos/genética , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Fatores Sexuais , Sistema Nervoso Simpático/metabolismo , Tomografia Computadorizada por Raios X
15.
Yakugaku Zasshi ; 144(6): 685-690, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38825477

RESUMO

Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL) is unclear. In this study, we evaluated the effects of edema caused by administration of DTX on HRQOL in patients with early-stage breast cancer. We prospectively investigated patients diagnosed with early-stage breast cancer (stage I-III) who received 4 cycles of DTX as preoperative or postoperative chemotherapy between September 2021 and December 2022 at Yamanashi Prefectural Central Hospital. The circumference of each extremity was measured at each administration of DTX, and limb edema was evaluated by Common Terminology Criteria for Adverse Events version 5.0. HRQOL was evaluated using SF-12 version 2, which has a range of 0-100 (national standard, 50), and compared between the presence and absence of grade 2 or higher edema and between before and after administration of DTX. Twenty patients met the eligibility criteria and were included in the study. There was no difference in the HRQOL score according to whether grade 2 limb edema was present. The median HRQOL summary scores before and after administration of DTX were 51.1 and 50.8 (p=0.763), respectively, for mental health, 52.6 and 49.4 (p=0.005) for physical health, and 38.9 and 37.5 (p=1.000) for role/social health. We found no direct effect of DTX-induced limb edema on HRQOL in patients with early-stage breast cancer. However, HRQOL summary scores indicated that administration of DTX reduced physical health in these patients.


Assuntos
Neoplasias da Mama , Docetaxel , Edema , Qualidade de Vida , Humanos , Docetaxel/efeitos adversos , Docetaxel/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Edema/induzido quimicamente , Edema/etiologia , Idoso , Estadiamento de Neoplasias , Adulto , Extremidades , Antineoplásicos/efeitos adversos , Assistência Perioperatória
16.
Int Cancer Conf J ; 13(3): 193-198, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38962040

RESUMO

A 61-year-old woman with BRCA2 pathogenic variant had been treated for 20 years and showed dynamic changes in the genomic profile of her metachronous bilateral breast cancer and metastases. She underwent right breast conservation surgery at age 42-Genome 1, lung metastasis and left axillary lymph node metastasis at age 51, partial excision under local anesthesia for left breast cancer at age 53-Genome 2, left axillary lymph node dissection was added 6 month later-Genome 3. Then, olaparib was administered, and subsequently, left mastectomy was performed for the recurrence of left breast cancer at age 59-Genome 4. Genomic profile of the tumor was analyzed at four points (Genome 1-3 were analyzed by in house breast cancer panel, and Genome 4 was analyzed by Foundation One CDx). Two interesting findings emerged from these analyses. First, the genomic profile revealed that the left axillary lymph node metastasis, considered histologically from right breast cancer, was a metastasis from the left breast cancer. The second finding is that as the disease progressed, mutation profile became more diverse. The profile of the left breast cancer removed after olaparib and other treatments showed reversion mutation of BRCA2 and was diagnosed as tumor mutation burden high. Subsequent response to pembrolizumab was favorable.

17.
Development ; 137(7): 1159-67, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20181744

RESUMO

Chondrocyte differentiation is strictly regulated by various transcription factors, including Runx2 and Runx3; however, the physiological role of Runx1 in chondrocyte differentiation remains unknown. To examine the role of Runx1, we generated mesenchymal-cell-specific and chondrocyte-specific Runx1-deficient mice [Prx1 Runx1(f/f) mice and alpha1(II) Runx1(f/f) mice, respectively] to circumvent the embryonic lethality of Runx1-deficient mice. We then mated these mice with Runx2 mutant mice to obtain mesenchymal-cell-specific or chondrocyte-specific Runx1; Runx2 double-mutant mice [Prx1 DKO mice and alpha1(II) DKO mice, respectively]. Prx1 Runx1(f/f) mice displayed a delay in sternal development and Prx1 DKO mice completely lacked a sternum. By contrast, alpha1(II) Runx1(f/f) mice and alpha1(II) DKO mice did not show any abnormal sternal morphogenesis or chondrocyte differentiation. Notably, Runx1, Runx2 and the Prx1-Cre transgene were co-expressed specifically in the sternum, which explains the observation that the abnormalities were limited to the sternum. Histologically, mesenchymal cells condensed normally in the prospective sternum of Prx1 DKO mice; however, commitment to the chondrocyte lineage, which follows mesenchymal condensation, was significantly impaired. In situ hybridization analyses demonstrated that the expression of alpha1(II) collagen (Col2a1 - Mouse Genome Informatics), Sox5 and Sox6 in the prospective sternum of Prx1 DKO mice was severely attenuated, whereas Sox9 expression was unchanged. Molecular analyses revealed that Runx1 and Runx2 induce the expression of Sox5 and Sox6, which leads to the induction of alpha1(II) collagen expression via the direct regulation of promoter activity. Collectively, these results show that Runx1 and Runx2 cooperatively regulate sternal morphogenesis and the commitment of mesenchymal cells to become chondrocytes through the induction of Sox5 and Sox6.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Morfogênese/fisiologia , Esterno/embriologia , Animais , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Cartilagem/citologia , Cartilagem/fisiologia , Diferenciação Celular , Linhagem da Célula , Condrócitos/citologia , Condrócitos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Regulação da Expressão Gênica no Desenvolvimento , Células HeLa , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Camundongos Knockout , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Esterno/anormalidades , Esterno/anatomia & histologia , Esterno/metabolismo , Transgenes
18.
Dermatology ; 227(1): 26-30, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23942189

RESUMO

Nakajo-Nishimura syndrome (NNS) is a very rare hereditary autoinflammatory disorder that generally has its onset in infancy with pernio-like rashes and gradually develops into partial lipodystrophy. A distinct homozygous PSMB8 mutation encoding an immunoproteasome subunit has recently been identified as its genetic cause. Here, we report a new case of a patient with NNS who developed exudative erythemas on his face and extremities at 2 months of age, along with high fever, elevated serum hepatic aminotransferase levels and hepatosplenomegaly. Massive infiltration of inflammatory cells was observed histologically in the dermis and subcutis without apparent leukocytoclastic vasculitis. These symptoms improved with oral corticosteroids but recurred periodically, and a thin angular face with long clubbed fingers gradually developed. Identification of the PSMB8 mutation finalized the diagnosis of NNS at 5 years of age. Understanding a variety of clinicopathological features at the developmental stages is necessary to make an early diagnosis of NNS.


Assuntos
Eritema Nodoso/diagnóstico , Eritema Nodoso/genética , Dedos/anormalidades , Complexo de Endopeptidases do Proteassoma/genética , Anti-Inflamatórios/uso terapêutico , Betametasona/uso terapêutico , Pré-Escolar , Fármacos Dermatológicos/uso terapêutico , Eritema Nodoso/tratamento farmacológico , Hepatomegalia/complicações , Humanos , Masculino , Metotrexato/uso terapêutico , Mutação , Esplenomegalia/complicações
19.
Ann Diagn Pathol ; 17(1): 99-103, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22784439

RESUMO

Approximately half a century has passed since asbestos was first reported to be the main cause of malignant mesothelioma; yet the incidence of this disease continues to increase worldwide. Twenty percent of cases occur without prior asbestos exposure, and in these patients, malignant peritoneal mesothelioma is more common than malignant pleural mesothelioma. Here, we report the cytomorphologic and immunohistochemical features of 2 cases of malignant peritoneal mesothelioma where there was no history of asbestos exposure. Ascitic cytology showed that most cells were isolated and that clusters were rarely observed, but the findings were consistent with malignant mesothelioma in both cases. Immunohistochemical analysis for epithelial membrane antigen, calretinin, vimentin, ß-catenin, melan-A, glucose transporter-1, cytokeratin CAM5.2, Wilms tumor antigen-1, D2-40, CD146, progesterone receptor, estrogen receptor, and cytokeratin 5/6 was indicative of malignant mesothelioma. In malignant mesothelioma without prior asbestos exposure, the etiology and prognostic significance is still unclear. Further study is needed to clarify this point.


Assuntos
Amianto , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mesotelioma/metabolismo , Mesotelioma/patologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Idoso , Calbindina 2 , Humanos , Neoplasias Pulmonares/etiologia , Masculino , Mesotelioma/etiologia , Mesotelioma Maligno , Mucina-1/metabolismo , Neoplasias Peritoneais/etiologia , Peritônio/metabolismo , Peritônio/patologia , Proteína G de Ligação ao Cálcio S100/metabolismo , Vimentina/metabolismo
20.
J Toxicol Pathol ; 26(1): 61-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23723570

RESUMO

Uterine deciduomas were found in two female virgin rats, a 15-week-old Lewis rat and a 7-week-old Sprague-Dawley rat. The firm white nodules were located at the base of unilateral uterine horns and were approximately 6 mm and 4 mm in diameter. Histopathologically, the nodules were composed of three areas, each with a distinct type of proliferating cells: large epithelioid decidual cells with round nuclei, prominent nucleoli and abundant eosinophilic cytoplasm (antimesometrial region); compact spindle-shaped cells with oval nuclei and vacuolar cytoplasm (transitional region); and pleomorphic and spiny cells with round to oval nuclei and compact eosinophilic cytoplasm (mesometrial region). These cells proliferated in sheet-like arrangements and transformed into the other types of cells located in surrounding regions. Immunohistochemically, proliferating cells in all regions were strongly positive for proliferating cell nuclear antigen. The proliferating cells were positive for vimentin, and large decidual cells were positive for common acute lymphoblastic leukemia antigen 10, a marker of uterine interstitial cells. Large decidual cells were positive for α-smooth muscle actin and desmin, suggesting differentiation into muscular cells. Progesterone receptor was expressed in all cell types; however, estrogen receptor α was not expressed in the antimesometrial region. These extremely rare tumor-like nodules represent nonneoplastic lesions referred as decidual reactions of endometrial interstitial cells, and their biological behavior is that of a space-occupying benign tumor in young rats. Our cases might provide information as a historical control in toxicity and pharmacological studies in rats.

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