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BACKGROUND: Ehlers-Danlos syndrome (EDS) is a rare inherited connective tissue disease characterized by hyperextensibility of the skin and joints and tissue fragility of the skin and blood vessels, Vascular EDS is the most severe form of EDS, with abnormal arterial fragility. There have been no reports of breast cancer occurring in patients with vascular EDS. Here, we report here a very rare case of breast cancer in a patient with vascular EDS. CASE PRESENTATION: A 46-year-old woman with vascular EDS underwent partial left mastectomy and sentinel lymph node biopsy for left breast cancer (cStage 0) detected by medical examination. The final pathological diagnosis was invasive ductal carcinoma of the breast (pStage IA) [hormone receptor-positive, HER2 score 2 equivocal (FISH-positive), Ki-67LI 18%, luminal-HER2 type]. BluePrint was submitted as an aid in determining the postoperative treatment strategy, BluePrint Molecular Subtype HER2-type. However, the 10-year breast cancer mortality risk using Predict was low (5%). After consultation with the patient, the decision was made to administer postoperative radiation to the preserved breast along with hormone therapy only. There was no delay in postoperative wound healing, and the patient was free of metastatic recurrence for 9 months after surgery. CONCLUSION: We performed surgery, postoperative radiotherapy, and hormonal therapy in a breast cancer patient with vascular EDS without major complications.
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BACKGROUND: Invasive lobular carcinoma (ILC) is distinct from invasive ductal carcinoma (IDC) in terms of their hormonal microenvironments that may require different therapeutic strategies. We previously reported that selective estrogen receptor modulator (SERM) function requires F-box protein 22 (Fbxo22). Here, we investigated the role of Fbxo22 as a potential biomarker contributing to the resistance to endocrine therapy in ILC. METHODS: A total of 302 breast cancer (BC) patients including 150 ILC were recruited in the study. Fbxo22 expression and clinical information were analyzed to elucidate whether Fbxo22 negativity could be a prognostic factor or there were any correlations among clinical variables and SERM efficacy. RESULTS: Fbxo22 negativity was significantly higher in ILC compared with IDC (58.0% vs. 27.0%, P < 0.001) and higher in postmenopausal patients than premenopausal patients (64.1% vs. 48.2%, P = 0.041). In the ILC cohort, Fbxo22-negative patients had poorer overall survival (OS) than Fbxo22-positive patients, with 10-year OS rates of 77.4% vs. 93.6% (P = 0.055). All patients treated with SERMs, Fbxo22 negativity resulted in a poorer outcome, with 10-year OS rates of 81.3% vs. 92.3% (P = 0.032). In multivariate analysis regarding recurrence-free survival (RFS) in ILC patients, Fbxo22 status was independently predictive of survival as well as lymph node metastasis. CONCLUSION: Fbxo22 negativity significantly impacts on survival in BC patients with IDC and ILC, and the disadvantage was enhanced among ILC postmenopausal women or patients treated with SERMs. The findings suggest that different therapeutic strategies might be needed according to the different histopathological types when considering adjuvant endocrine therapy.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma Lobular/patología , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Carcinoma Ductal de Mama/patología , Resultado del Tratamiento , Microambiente TumoralRESUMEN
Albumin is an attractive component for the development of biomaterials applied as biomedical implants, including drug carriers and tissue engineering scaffolds, because of its high biocompatibility and low immunogenicity. Additionally, albumin-based gelators facilitate cross-linking reactions under mild conditions, which maintains the high viability of encapsulated living cells. In this study, we synthesized albumin derivatives to undergo gelation under physiological conditions via the peroxidase-catalyzed formation of cross-links. Albumin was modified with phenolic hydroxyl groups (Alb-Ph-OH) using carbodiimide chemistry, and the effect of degree of substitution on gelation was investigated. Various properties of the Alb-Ph-OH hydrogels, namely the gelation time, swelling ratio, pore size, storage modulus, and enzymatic degradability, were easily controlled by adjusting the degree of substitution and the polymer concentration. Moreover, the viability of cells encapsulated within the Alb-Ph-OH hydrogel was high. These results demonstrate the potential applicability of Alb-Ph-OH hydrogels as cell-encapsulating materials for biomedical applications, including tissue engineering.
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Encapsulación Celular , Hidrogeles , Hidrogeles/química , Andamios del Tejido/química , Ingeniería de Tejidos/métodos , AlbúminasRESUMEN
BACKGROUND: NASH is an increasingly common cause of chronic liver disease and can progress to cirrhosis and HCC. Although exercise suppresses inflammation during acute hepatitis, its impact on the progression of chronic liver disease remains unclear. Here, we investigated the effects of exercise on disease progression and intrahepatic immune cell composition in a mouse model of NASH. METHOD: Mice were assigned to 4 groups: 2 control groups (normal diet) and 2 NASH groups (western diet and low-dose carbon tetrachloride injection). One of each group remained sedentary and one was exercised on a treadmill for 12 weeks (60 min/d, 5 times/wk). All mice were then analyzed for liver histomorphology, steatosis, inflammation, and fibrosis; liver, adipose tissue, and skeletal muscle expression of genes related to metabolism and inflammation; and intrahepatic immune cell composition. RESULT: Compared with the normal diet mice, NASH mice exhibited enhanced liver steatosis, inflammation, and fibrosis; upregulated expression of liver lipogenesis-related and inflammation-related genes; and increased frequencies of intrahepatic F4/80 int CD11b hi bone marrow-derived macrophages and programmed death receptor-1 (PD-1) + CD8 + T cells. Expression of inflammatory cytokines and the frequencies of bone marrow-derived macrophages and PD-1 + CD8 + T cells correlated positively with liver steatosis, inflammation, and fibrosis. Exercise was shown to reduce NASH-induced hepatic steatosis, liver inflammation, and fibrosis; induce alterations in metabolism-related genes and inflammatory cytokines in the liver; and suppress accumulation of liver bone marrow-derived macrophages and PD-1 + CD8 + T cells. In addition, we showed that exercise induced increased expression of IL-15 in muscle and its deficiency exacerbated the pathology of NASH. CONCLUSIONS: Exercise alters the intrahepatic immune cell profile and protects against disease progression in a mouse model of NASH.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Receptor de Muerte Celular Programada 1 , Neoplasias Hepáticas/patología , Inflamación , Fibrosis , Citocinas/metabolismo , Progresión de la EnfermedadRESUMEN
[Purpose] This study aimed to clarify the relationship between one-eye visual deprivation; thus, interfering with stereoscopic perception, and movement and obtain insights on the influence of visual perception on movement to step over obstacles. [Participants and Methods] Participants were 25 healthy individuals. There were two conditions of visual perception (stationary and approaching conditions) and two additional conditions of binocular and monocular visions. Under the four conditions, participants were asked to step over an obstacle immediately after a 90° turn while walking. Distance between the foot and obstacle, foot pressure distribution, and stance phase time were measured. [Results] Toe clearance was lower in the approaching condition than that in the binocular stationary condition. The trajectory length ratio was greater in the approaching condition than that in the stationary condition, and heel-ground contact, metatarsal-ground contact, and stance times were all shorter in the binocular condition. Additionally, heel contact, midfoot contact, metatarsal contact, and stance times were shorter in the approaching condition than that in the stationary condition. [Conclusion] In walking with a 90° turn, the binocular approaching condition provided more visual information and positively affected motor control of movements to step over an obstacle.
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[Purpose] The purpose of this study was to clarify whether the presence of obstructions changes the crossing motion during walking based on the visual perception of obstacles. [Participants and Methods] We included 25 healthy university students as the participants in this study. They were asked to step over obstacles while walking under two conditions i.e., with obstruction and without obstruction. We analyzed the distance between the foot and obstacle (clearance), trajectory of foot pressure movement and distribution as measured by a foot pressure distribution measurement system, and stance phase time. [Results] No significant differences were found between the two conditions for either clearance or foot pressure distribution. In other words, no difference in crossing motion was observed after visual recognition of the obstacle, both in the presence or absence of the obstruction. [Conclusion] The results suggest that no differences exist in the accuracy of recognizing visual information about an obstacle through different mechanisms of selective visual attention.
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The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients.
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18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.
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Aminoácidos/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Expresión Génica , Transportador de Aminoácidos Neutros Grandes 1/fisiología , Anciano , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Metabolismo Energético/genética , Femenino , Glucosa/metabolismo , Humanos , Transportador de Aminoácidos Neutros Grandes 1/genética , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Células MCF-7 , Persona de Mediana Edad , Terapia Neoadyuvante , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
Our previous study demonstrated that downregulation of transcription factor Specificity protein (Sp) 1 suppresses the malignant potentials of A549 human lung cancer cell line with the reduced ß4-galactosylation of highly branched N-glycans on cell surface glycoproteins. The reduced ß4-galactosylation was brought about by the decreased expression of the ß4-galactosyltransferase 1 (ß4GalT1) gene. Herein, we examined whether the reduced ß4-galactosylation by decreasing the ß4GalT1 gene expression suppresses the malignant potentials of A549 cells. In the ß4GalT1-downregulated cells, the ß4-galactosylation of highly branched N-glycans was reduced in several glycoproteins such as lysosome-associated membrane protein-1 and E-cadherin. The anchorage-independent growth and migratory ability of the ß4GalT1-downregulated cells decreased when compared with the control cells. Furthermore, the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) decreased in the ß4GalT1-downregulated cells. These results indicate that downregulation of the ß4GalT1 gene decreases the ß4-galactosylation of highly branched N-glycans and the phosphorylation of p44/42 MAPK, and suppresses the malignant potentials of A549 cells.
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Galactosiltransferasas/genética , Regulación Neoplásica de la Expresión Génica , Células A549 , Movimiento Celular , Regulación hacia Abajo , Galactosiltransferasas/metabolismo , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Polisacáridos/metabolismo , Interferencia de ARNRESUMEN
The molecular mechanisms by which environmental light conditions affect cerebellar development are incompletely understood. We showed that circadian disruption by light-at-night induced Purkinje cell death through pineal allopregnanolone (ALLO) activity during early life in chicks. Light-at-night caused the loss of diurnal variation of pineal ALLO synthesis during early life and led to cerebellar Purkinje cell death, which was suppressed by a daily injection of ALLO. The loss of diurnal variation of pineal ALLO synthesis induced not only reduction in pituitary adenylate cyclase-activating polypeptide (PACAP), a neuroprotective hormone, but also transcriptional repression of the cerebellar Adcyap1 gene that produces PACAP, with subsequent Purkinje cell death. Taken together, pineal ALLO mediated the effect of light on early cerebellar development in chicks.
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Encéfalo/crecimiento & desarrollo , Ritmo Circadiano , Luz , Glándula Pineal/fisiología , Pregnanolona/metabolismo , Animales , Encéfalo/citología , Células COS , Muerte Celular , Pollos , Chlorocebus aethiops , Masculino , Estimulación Luminosa , Células de Purkinje/citologíaRESUMEN
Salmon migrate upstream against an opposing current in their natal river. However, the molecular mechanisms that stimulate upstream migratory behavior are poorly understood. Here, we show that 7α-hydroxypregnenolone (7α-OH PREG), a newly identified neuronal modulator of locomotion, acts as a key factor for upstream migration in salmon. We first identified 7α-OH PREG and cytochrome P450 7α-hydroxylase (P4507α), a steroidogenic enzyme producing 7α-OH PREG, in the salmon brain and then found that 7α-OH PREG synthesis in the brain increases during upstream migration. Subsequently, we demonstrated that 7α-OH PREG increases upstream migratory behavior of salmon. We further found that 7α-OH PREG acts on dopamine neurons in the magnocellular preoptic nucleus during upstream migration. Thus, 7α-OH PREG stimulates upstream migratory behavior through the dopaminergic system in salmon. These findings provide new insights into the molecular mechanisms of fish upstream migration.