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BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aß) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aß and Aß-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aß-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aß-induced AD pathology. Therefore, inhibiting the Aß-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aß-PirB interaction and Aß-induced dendritic spine elimination. METHODS: The inhibitory role of LOTUS against Aß-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aß-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron. RESULTS: We found that LOTUS inhibits the binding of Aß to PirB overexpressed in Cos7 cells. In addition, we found that Aß-induced dephosphorylation of cofilin and Aß-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aß-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aß binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aß to LilrB2 in a similar manner. CONCLUSIONS: This study implied that LOTUS improved Aß-induced synapse elimination by suppressing Aß-PirB interaction in rodents and inhibited Aß-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aß-induced AD pathologies.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Proteínas de Ligação ao Cálcio , Receptores Imunológicos , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Imunoglobulinas/metabolismo , Camundongos Transgênicos , Doenças Neurodegenerativas/metabolismo , Receptores Imunológicos/metabolismo , Proteínas de Ligação ao Cálcio/metabolismoRESUMO
Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin-associated axonal growth inhibitor with binding to both receptors of Nogo receptor-1 (NgR1) and paired immunoglobulin-like receptor (PIR)-B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1-mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR-B functions in neurons remains unknown. In this study, protein-protein interactions analyses found that LOTUS binds to PIR-B and abolishes Nogo-binding to PIR-B completely. Reverse transcription-polymerase chain reaction and immunocytochemistry revealed that PIR-B is expressed in dorsal root ganglions (DRGs) from wild-type and Ngr1-deficient mice (male and female). In these DRG neurons, Nogo induced growth cone collapse and neurite outgrowth inhibition, but treatment with the soluble form of LOTUS completely suppressed them. Moreover, Nogo-induced growth cone collapse and neurite outgrowth inhibition in Ngr1-deficient DRG neurons were neutralized by PIR-B function-blocking antibodies, indicating that these Nogo-induced phenomena were mediated by PIR-B. Our data show that LOTUS negatively regulates a PIR-B function. LOTUS thus exerts an antagonistic action on both receptors of NgR1 and PIR-B. This may lead to an improvement in the defective regeneration of axons following injury.
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Axônios/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Receptor Nogo 1/antagonistas & inibidores , Receptores Imunológicos/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Axônios/metabolismo , Células COS , Células Cultivadas , Chlorocebus aethiops , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor Nogo 1/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Receptores Imunológicos/metabolismoRESUMO
Nogo receptor type 1 (NgR1) is known to inhibit neuronal regeneration in the CNS. Previously, we have shown that lateral olfactory tract usher substance (LOTUS) interacts with NgR1 and inhibits its function by blocking its ligand binding. Therefore, LOTUS is expected to have therapeutic potential for the promotion of neuronal regeneration. However, it remains unknown whether the soluble form of LOTUS (s-LOTUS) also has an inhibitory action on NgR1 function as a candidate for therapeutic agents. Here, we show that s-LOTUS inhibits NgR1-mediated signaling by inhibiting the molecular interaction between NgR1 and its coreceptor, p75 neurotrophin receptor (p75NTR). In contrast to the membrane-bound form of LOTUS, s-LOTUS did not block ligand binding to NgR1. However, we identified p75NTR as a novel LOTUS binding partner and found that s-LOTUS suppressed the interaction between p75NTR and NgR1. s-LOTUS inhibited myelin-associated inhibitor (MAI)-induced RhoA activation in murine cortical neurons. Functional analyses revealed that s-LOTUS inhibited MAI-induced growth cone collapse and neurite outgrowth inhibition in chick DRG neurons. In addition, whereas olfactory bulb neurons of lotus-KO mice are sensitive to MAI due to a lack of LOTUS expression, treatment with s-LOTUS inhibited MAI-induced growth cone collapse in these neurons. Finally, we observed that s-LOTUS promoted axonal regeneration in optic nerve crush injury of mice (either sex). These findings suggest that s-LOTUS inhibits NgR1-mediated signaling, possibly by interfering with the interaction between NgR1 and p75NTR Therefore, s-LOTUS may have potential as a therapeutic agent for neuronal regeneration in the damaged CNS.SIGNIFICANCE STATEMENT Nogo receptor type 1 (NgR1) is a receptor well known to inhibit neuronal regeneration in the CNS. Because the membrane-bound form of lateral olfactory tract usher substance (LOTUS) antagonizes NgR1 through a cis-type molecular interaction between LOTUS and NgR1, the soluble form of LOTUS (s-LOTUS) is expected to be a therapeutic agent for neuronal regeneration. In our present study, we show that s-LOTUS inhibits the interaction between NgR1 and p75NTR, NgR1 ligand-induced RhoA activation, growth cone collapse, and neurite outgrowth inhibition and promotes axonal regeneration. Our results indicate that s-LOTUS inhibits NgR1-mediated signaling through a trans-type molecular interaction between LOTUS and NgR1 and, therefore, s-LOTUS may have therapeutic potential for neuronal regeneration.
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Proteínas de Ligação ao Cálcio/metabolismo , Receptor Nogo 1/efeitos dos fármacos , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Embrião de Galinha , Feminino , Cones de Crescimento/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Associada a Mielina/antagonistas & inibidores , Compressão Nervosa , Regeneração Nervosa/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptor Nogo 1/metabolismo , Bulbo Olfatório/citologia , Bulbo Olfatório/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTPRESUMO
BACKGROUND: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. METHODS: CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. RESULTS: Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CONCLUSIONS: CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.
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Proteínas de Ligação ao Cálcio/líquido cefalorraquidiano , Meningite/líquido cefalorraquidiano , Meningite/diagnóstico , Receptor Nogo 1/antagonistas & inibidores , Receptor Nogo 1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores/líquido cefalorraquidiano , Feminino , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
An adverse effect associated with the administration of carbapenems is central nervous system (CNS) toxicity, with higher brain concentrations of carbapenems being linked to an increased risk of seizures. However, the pharmacokinetics and brain penetration of carbapenems have not yet been examined. Thus, the aim of this in vivo investigation was to determine the pharmacokinetics and brain penetration of carbapenems in mice. Blood samples and brain tissue samples were obtained 10, 20, 30, 60, and 120 min after the subcutaneous administration of carbapenems (91 mg/kg). We obtained the following values for the pharmacokinetic parameters of carbapenems in mice: 1.20-1.71 L/h/kg for CLtotal/F, 1.41-2.03 h(-1) for Ke, 0.34-0.51 h for T1/2, 0.66-0.95 L/kg for Vss/F, 0.49-0.73 h for MRT, 83.46-110.58 µg/mL for Cmax, plasma, and 0.28-0.83 µg/g for Cmax, brain tissue. The AUC0-∞ of the carbapenems tested in plasma were in the following order: doripenem > meropenem > biapenem > imipenem, and in brain tissue were: imipenem > doripenem > meropenem > biapenem. The degrees of brain tissue penetration, defined as the AUC0-∞, brain tissue/fAUC0-∞, plasma ratio, were 0.016 for imipenem, 0.004 for meropenem, 0.002 for biapenem, and 0.008 for doripenem. The results of the present study demonstrated that, of the carbapenems examined, imipenem penetrated brain tissue to the greatest extent.
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Antibacterianos/farmacocinética , Química Encefálica/efeitos dos fármacos , Encéfalo/metabolismo , Carbapenêmicos/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/análise , Carbapenêmicos/administração & dosagem , Carbapenêmicos/análise , Injeções Subcutâneas , CamundongosRESUMO
Axon growth inhibitors such as Nogo proteins, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), and B lymphocyte stimulator (BLyS) commonly bind to Nogo receptor-1 (NgR1), leading to enormous restriction of functional recovery after damage to the adult central nervous system. Recently, we found that lateral olfactory tract usher substance (LOTUS) antagonizes NgR1-mediated Nogo signaling. However, whether LOTUS exerts antagonism of NgR1 when bound by the other three ligands has not been determined. Overexpression of LOTUS together with NgR1 in COS7 cells blocked the binding of MAG, OMgp, and BLyS to NgR1. In cultured dorsal root ganglion neurons in which endogenous LOTUS is only weakly expressed, overexpression of LOTUS suppressed growth cone collapse and neurite outgrowth inhibition induced by these three NgR1 ligands. LOTUS suppressed NgR1 ligand-induced growth cone collapse in cultured olfactory bulb neurons, which endogenously express LOTUS. Growth cone collapse was induced by NgR1 ligands in lotus-deficient mice. These data suggest that LOTUS functions as a potent endogenous antagonist for NgR1 when bound by all four known NgR1 ligands, raising the possibility that LOTUS may protect neurons from NgR1-mediated axonal growth inhibition and thereby may be useful for promoting neuronal regeneration as a potent inhibitor of NgR1.
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Proteínas de Ligação ao Cálcio/metabolismo , Regulação da Expressão Gênica/genética , Cones de Crescimento/fisiologia , Proteínas da Mielina/metabolismo , Neurônios/citologia , Análise de Variância , Animais , Fator Ativador de Células B/metabolismo , Células COS , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Embrião de Galinha , Chlorocebus aethiops , Gânglios Espinais/citologia , Camundongos , Camundongos Transgênicos , Mutação/genética , Proteínas da Mielina/genética , Glicoproteína Associada a Mielina/metabolismo , Proteínas Nogo , Glicoproteína Oligodendrócito-Mielina/metabolismo , Ligação Proteica/genética , TransfecçãoRESUMO
Neurite outgrowth is a crucial process for organizing neuronal circuits in neuronal development and regeneration after injury. Regenerative failure in the adult mammalian central nervous system (CNS) is attributed to axonal growth inhibitors such as the Nogo protein that commonly binds to Nogo receptor-1 (NgR1). We previously reported that lateral olfactory tract usher substance (LOTUS) functions as an endogenous antagonist for NgR1 in forming neuronal circuits in the developing brain and improving axonal regeneration in the adult injured CNS. However, another molecular and cellular function of LOTUS remains unknown. In this study, we found that cultured retinal explant neurons extend their neurites on the LOTUS-coating substrate. This action was also observed in cultured retinal explant neurons derived from Ngr1-deficient mouse embryos, indicating that the promoting action of LOTUS on neurite outgrowth may be mediated by unidentified LOTUS-binding protein(s). We therefore screened the binding partner(s) of LOTUS by using a liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis and pull-down assay showed that LOTUS interacts with Teneurin-4 (Ten-4), a cell adhesion molecule. RNAi knockdown of Ten-4 inhibited neurite outgrowth on the LOTUS substrate in retinoic acid (RA)-treated Neuro2A cells. Furthermore, a soluble form of Ten-4 attenuates the promoting action on neurite outgrowth in cultured retinal explant neurons on the LOTUS substrate. These results suggest that LOTUS promotes neurite outgrowth by interacting with Ten-4. Our findings may provide a new molecular mechanism of LOTUS to contribute to neuronal circuit formation in development and to enhance axonal regeneration after CNS injury.
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Crescimento Neuronal , Animais , Crescimento Neuronal/efeitos dos fármacos , Camundongos , Neuritos/metabolismo , Neuritos/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Receptor Nogo 1/metabolismo , Humanos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Retina/metabolismoRESUMO
Although dyslipidemia in the brain has been implicated in neurodegenerative disorders, the molecular mechanisms underlying its pathogenesis have been largely unclear. PDZD8 is a lipid transfer protein and mice deficient in PDZD8 (PDZD8-KO mice) manifest abnormal accumulation of cholesteryl esters (CEs) in the brain due to impaired lipophagy, the degradation system of lipid droplets. Here we show the detailed mechanism of PDZD8-dependent lipophagy. PDZD8 transports cholesterol to lipid droplets (LDs), and eventually promotes fusion of LDs and lysosomes. In addition, PDZD8-KO mice exhibit growth retardation, hyperactivity, reduced anxiety and fear, increased sensorimotor gating, and impaired cued fear conditioned memory and working memory. These results indicate that abnormal CE accumulation in the brain caused by PDZD8 deficiency affects emotion, cognition and adaptive behavior, and that PDZD8 plays an important role in the maintenance of brain function through lipid metabolism.
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Proteínas Adaptadoras de Transdução de Sinal , Encéfalo , Dislipidemias , Animais , Camundongos , Encéfalo/fisiopatologia , Cognição , Dislipidemias/complicações , Medo , Metabolismo dos Lipídeos , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, in Fig. 4 on p. 650, the same ßactin bands had apparently been used to show the experimental effects of the proteasome inhibitor MG132 on cFLIP in HSC2 cells in Fig. 4A, and the effects of MG132 on IAPs in HSC3 cells in Fig. 4B. In addition, for the fourth lane in the gel showing the effects of MG132 on cFLIP in HSC3 cells, this should have been labelled as '+MG132 / +TRAIL' (not as '/'). Upon contacting the authors in relation to this matter, they could only admit that errors had been made in the preparation of the figure; moreover, they no longer had access to the original data owing to the time that has elapsed since the publication of the paper, and it would be impossible for them to now repeat this experiment. After having considered this matter and in conjunction with a request made by the authors, the Editor of Oncology Reports has decided that this paper should be retracted from the publication. Both the Editor and the authors apologize to the readership for any inconvenience caused. [Oncology Reports 25: 645652, 2011; DOI: 10.3892/or.2010.1127].
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Sciatic hernia is a rare type of pelvic floor hernia. The herniated tissue can include the ureter, small and large bowel, and ovary, among other tissues. Only a few cases of laparoscopic treatment for a sciatic hernia with small-bowel incarceration have been reported. We report our experience using a laparoscopic approach for treatment of sciatic hernia in an 83-year-old woman and review the literature on sciatic hernias. The patient was referred to our hospital complaining of constipation and abdominal bloating. Computed tomography (CT) scanning showed a right sciatic hernia containing the small bowel. Laparoscopic repair of the sciatic hernia was performed using a self-fixating mesh. The patient was discharged after an uneventful postoperative course and has not developed abdominal bloating or constipation postoperatively. In conclusion, a sciatic hernia was successfully repaired using a laparoscopic trans-preperitoneal approach and ProGrip Self-Fixating Mesh.
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Laparoscopia , Telas Cirúrgicas , Feminino , Humanos , Adulto , Idoso de 80 Anos ou mais , Hérnia/diagnóstico por imagem , Laparoscopia/métodos , Pelve , Constipação IntestinalRESUMO
Myelin-derived axon growth inhibitors, such as Nogo, bind to Nogo receptor-1 (NgR1) and thereby limit the action of axonal regeneration after injury in the adult central nervous system. Recently, we have found that cartilage acidic protein-1B (Crtac1B)/lateral olfactory tract usher substance (LOTUS) binds to NgR1 and functions as an endogenous NgR1 antagonist. To examine the functional domain of LOTUS in the antagonism to NgR1, analysis using the deletion mutants of LOTUS was performed and revealed that the carboxyl-terminal region (UA/EC domain) of LOTUS bound to NgR1. The UA/EC fragment of LOTUS overexpressed together with NgR1 in COS7 cells abolished the binding of Nogo66 to NgR1. Overexpression of the UA/EC fragment in cultured chick dorsal root ganglion neurons suppressed Nogo66-induced growth cone collapse. These findings suggest that the UA/EC region is a functional domain of LOTUS serving for an antagonistic action to NgR1.
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Proteínas de Ligação ao Cálcio/metabolismo , Proteínas da Mielina/metabolismo , Receptores de Superfície Celular/metabolismo , Actinas/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Embrião de Galinha , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Cones de Crescimento/metabolismo , Camundongos , Proteínas da Mielina/antagonistas & inibidores , Receptor Nogo 1 , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Superfície Celular/antagonistas & inibidoresRESUMO
INTRODUCTION: Glaucoma is a leading cause of irreversible blindness and ripasudil was the first Rho kinase inhibitor approved as antiglaucoma medication. Here we present the final analysis of the ROCK-J study, a large-scale post-marketing surveillance study to evaluate the long-term safety and effectiveness of ripasudil in Japanese patients with glaucoma or ocular hypertension in a real-word clinical setting. METHODS: ROCK-J was a 24-month, prospective, open-label, observational study that included ripasudil-naïve patients with glaucoma or ocular hypertension who were initiating treatment with ripasudil according to the Japanese approved indication between June 1, 2015 and April 30, 2017. The primary safety endpoint was the incidence of adverse drug reactions (ADRs) (including blepharitis, plus assessment of its background factors); the primary efficacy endpoint was change in intraocular pressure (IOP) from baseline to 24 months. RESULTS: A total of 3374 Japanese patients with glaucoma or ocular hypertension were evaluated for safety and 3178 for effectiveness of ripasudil over a mean 524.5-day observational period. Overall, 853 (25.3%) patients experienced adverse drug reactions; the most common were blepharitis (8.6%), conjunctival hyperemia (8.5%), and conjunctivitis (6.3%). Multivariate analyses demonstrated that patients were more likely to experience the ADR blepharitis with ripasudil treatment if they were female (hazard ratio [HR] 1.307; p = 0.040), had comorbid or a previous history of blepharitis (HR 2.178; p = 0.001), or had a history of allergy to pollen (HR 1.645; p = 0.003) or medication (HR 2.276; p < 0.001). IOP decreased significantly from baseline with ripasudil; the least-squares mean ± standard error change in IOP from baseline to 24 months was - 2.6 ± 0.1 mmHg (p < 0.001). Significant IOP changes were seen in four types of glaucoma, namely primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, and secondary glaucoma, and ocular hypertension. CONCLUSION: Ripasudil was safe and effective as an antiglaucoma medication with no new safety signals identified and significant reductions in IOP maintained over 24 months of treatment.
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Blefarite , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Glaucoma de Ângulo Aberto , Glaucoma , Hipertensão Ocular , Anti-Hipertensivos/uso terapêutico , Blefarite/induzido quimicamente , Blefarite/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Feminino , Glaucoma/tratamento farmacológico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Pressão Intraocular , Isoquinolinas , Hipertensão Ocular/induzido quimicamente , Hipertensão Ocular/tratamento farmacológico , Soluções Oftálmicas/uso terapêutico , Estudos Prospectivos , Sulfonamidas , Resultado do Tratamento , Quinases Associadas a rhoRESUMO
BACKGROUND: Esophageal gastrointestinal stromal tumors (E-GISTs) are often diagnosed early due to complaints such as dysphagia and are rarely found to be huge in size. Here, we report the treatment of a case of huge E-GIST successfully resected by minimally invasive surgery after neoadjuvant imatinib therapy. CASE PRESENTATION: An 86-year-old male patient with a 3-month history of dysphagia was referred to our hospital because of a suspected mediastinal tumor on chest X-ray. The chest computed tomography scan revealed a huge solid tumor, of about 100 mm in diameter, protruding into the left thoracic cavity. Histopathological examination results of fine-needle aspiration biopsy under endoscopic ultrasonography revealed a c-kit and CD34-positive esophageal gastrointestinal stromal tumor. The patient received neoadjuvant therapy with imatinib (400 mg/day) to reduce the size of the tumor and prevent rupture during resection. After 28 days of oral administration of imatinib, the tumor size decreased. However, the patient refused to continue treatment with imatinib and therefore underwent mediastino-laparoscopic transhiatal esophagectomy. We successfully resected the tumor completely with mediastino-laparoscopic surgical techniques. Esophageal reconstruction was performed using a gastric tube in the posterior sternal route. After an uneventful postoperative course, the patient was discharged postoperative day 14. Immunohistochemical findings of the resected specimen showed that the tumor cells were positive for c-kit, DOG-1 and CD34 and negative for smooth muscle actin and S100. CONCLUSIONS: Hybrid surgical procedure utilizing mediastino-laparoscopy might be useful for high-risk patient with esophageal tumors.
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BACKGROUND: Few reports have examined dental arch morphology (DAM) after dental implant placement in cleft patients and its actual state is unclear. OBJECTIVE: To analyze the presence of changes in DAM and influencing factors in cleft lip and/or palate (CLP) patients who receive implant treatment in the alveolar cleft region. METHODS: Subjects comprised 20 CLP patients in whom maxillary dental arch width (DAW) was evaluated before and after implant treatment based on computed tomography data. First, widths between the canines (W3), between the first premolars (W4), between the second premolars (W5), and between the first molars (W6) were measured before and after surgery. Changes in distance were analyzed using the Wilcoxon signed-rank test, revealing a significant increase in W6. Analysis of Co-Variance was performed with the difference in W6 after implant treatment as the response variable, and the following six items as explanatory variables: sex; cleft type; age at alveolar bone graft; time to implantation after bone grafting; number of implants; and time after completion of the observation period. RESULTS: The reduction in W6 was larger in the order of complete bilateral CLP, complete unilateral CLP, and unilateral cleft lip and alveolus, and the change decreased with an increasing number of implants. CONCLUSIONS: Implant treatment of the alveolar cleft region may result in a slight reduction in width of the dental arch after treatment completion.
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Fenda Labial , Fissura Palatina , Implantes Dentários , Fenda Labial/diagnóstico por imagem , Fenda Labial/cirurgia , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/cirurgia , Arco Dental/diagnóstico por imagem , Arco Dental/cirurgia , Humanos , Maxila/diagnóstico por imagem , Maxila/cirurgiaRESUMO
AIMS/INTRODUCTION: Tofogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3-year prospective observational post-marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J-STEP/LT]). MATERIALS AND METHODS: This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. RESULTS: Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion-related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were -0.68 ± 1.34% (n = 6,158, P < 0.0001) and -3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively. CONCLUSIONS: J-STEP/LT, a 3-year, prospective, observational, post-marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus.
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Compostos Benzidrílicos/uso terapêutico , Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Padrões de Prática Médica/normas , Vigilância de Produtos Comercializados/métodos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glicemia/análise , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
PURPOSE: Long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) remain unsatisfactory despite advances in combination of treatment modalities. SCCHN is characterized by locoregional spread and it is clinically accessible, making it an attractive target for intratumoral biological therapies. EXPERIMENTAL DESIGN: OBP-301 is a type 5 adenovirus that contains the replication cassette in which the human telomerase reverse transcriptase promoter drives expression of the E1 genes. OBP-401 contained the replication cassette and the green fluorescent protein (GFP) gene. The antitumor effects of OBP-301 were evaluated in vitro by the sodium 30-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay and in vivo in an orthotopic xenograft model. Virus spread into the lymphatics was also orthotopically assessed by using OBP-401. RESULTS: Intratumoral injection of OBP-301 resulted in the shrinkage of human SCCHN tumors orthotopically implanted into the tongues of BALB/c nu/nu mice and significantly recovered weight loss by enabling oral ingestion. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Moreover, whole-body fluorescent imaging revealed that intratumorally injected OBP-401 could visualize the metastatic lymph nodes, indicating the ability of the virus to traffic to the regional lymphatic area and to selectively replicate in neoplastic lesions, resulting in GFP expression and cell death in metastatic lymph nodes. CONCLUSIONS: These results illustrate the potential of telomerase-specific oncolytic viruses for a novel therapeutic and diagnostic approach, termed theranostics, for human SCCHN.
Assuntos
Adenoviridae/genética , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Telomerase/genética , Animais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS/INTRODUCTION: This subanalysis aimed to assess the safety and effectiveness of tofogliflozin by using data from the Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly to categorize elderly Japanese patients with type 2 diabetes mellitus by the number of concomitant oral antidiabetic drugs (OADs) and insulin use at baseline. MATERIALS AND METHODS: Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly is a 1-year prospective, observational and multicenter post-marketing study that enrolled all patients with type 2 diabetes mellitus aged ≥65 years who started tofogliflozin during the first 3 months after its launch in May 2014 in Japan. RESULTS: The safety and effectiveness analysis sets included 1,497 and 1,422 patients, respectively. Overall, 18.10 and 2.20% of the patients experienced adverse drug reactions (ADRs) and serious ADRs, respectively. ADRs of special interest in the total, 0 OAD, one OAD, two OADs, three or more OADs and insulin groups occurred in 12.22, 10.04, 12.35, 13.32, 11.27 and 14.91% of patients, respectively. Volume depletion-related events were the most frequently observed ADRs of special interest. Hypoglycemia occurred in 1.07% of patients. Overall, glycated hemoglobin and bodyweight were significantly decreased, but the estimated glomerular filtration rate was not significantly changed. CONCLUSIONS: Our finding suggests that tofogliflozin could be safely and effectively used in elderly Japanese patients with type 2 diabetes mellitus, irrespective of the number of OADs and the use of insulin.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Povo Asiático , Peso Corporal , Feminino , Taxa de Filtração Glomerular , Hemoglobinas Glicadas/análise , Humanos , Japão , Masculino , Vigilância de Produtos Comercializados , Estudos ProspectivosRESUMO
AIMS/INTRODUCTION: Due to the paucity of tofogliflozin data, we assessed the safety and effectiveness of tofogliflozin among Japanese patients with type 2 diabetes mellitus in the clinical setting, stratifying the patients by age, sex, estimated glomerular filtration (eGFR) rate and body mass index. We report the results of a 12-month interim analysis. MATERIALS AND METHODS: This was a 3-year prospective, observational and multicenter post-marketing study (Japanese Study of tofogliflozin with type 2 diabetes mellitus Patients/Long Term). RESULTS: Out of 6,897 patients enrolled, the safety and effectiveness analysis populations consisted of 6,712 and 6,449 patients, respectively. During 12 months, adverse drug reactions and their incidence were 9.12 and 0.88%, respectively. The incidence of hypoglycemia was 0.67%. Polyuria/pollakiuria occurred more frequently in patients aged ≥65 years than in patients aged <65 years. Women experienced higher rates of urinary tract and genital infection than men. The lowest eGFR subgroup experienced maximum volume depletion-related events. Cardiovascular and cerebrovascular disorders occurred in 0.55% of the patients. Glycated hemoglobin (HbA1c) and bodyweight significantly decreased by -0.76% and -2.73 kg, respectively, from baseline to the last observation carried forward (P < 0.0001). Except for the lowest eGFR subgroup, other eGFR subgroups showed significantly decreased HbA1c values. All eGFR subgroups showed significantly decreased bodyweight, and all body mass index subgroups showed significantly decreased HbA1c and bodyweight. CONCLUSIONS: Our interim 12-month data suggest that tofogliflozin could be used safely and effectively in Japanese patients with type 2 diabetes mellitus, as tofogliflozin was well tolerated with low hypoglycemia risk, and significantly improved HbA1c and bodyweight.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Biomarcadores/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Vigilância de Produtos Comercializados/estatística & dados numéricos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glicemia/análise , Diabetes Mellitus Tipo 2/patologia , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Prognóstico , Estudos ProspectivosRESUMO
AIMS/INTRODUCTION: Tofogliflozin is a potent and highly selective sodium-glucose cotransporter 2 inhibitor, and is currently used to treat patients with type 2 diabetes mellitus. We designed a 3-year study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness in routine clinical practice. The 3- and 12-month interim analysis showed tofogliflozin was well-tolerated, safe and clinically effective. Here, we report the results of the 24-month interim analysis. MATERIALS AND METHODS: This is a 3-year prospective, observational and multicenter post-marketing study (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term). RESULTS: Of the 6,897 patients enrolled, 6,712 and 6,461 patients were analyzed for the safety and effectiveness of tofogliflozin, respectively. During the 24-month observation period, the incidence rates of adverse drug reactions (ADRs) and serious adverse drug reactions were 11.25 and 1.21%, respectively. As to adverse drug reactions of special interest, the incidence rates of hypoglycemia, polyuria/pollakiuria, volume depletion-related events, urinary tract infections and genital infection were 0.83, 1.28, 1.46, 1.18 and 1.62%, respectively. Renal disorders, and cardiovascular and cerebrovascular disorders occurred in 0.63 and 0.76% of the patients, respectively. Glycated hemoglobin A1c and bodyweight decreased significantly by -0.70% (P < 0.0001) and -2.95 kg (P < 0.0001), respectively, from baseline to week 104 (last observation carried forward). CONCLUSIONS: Significant safety concerns have not been observed, and clinical benefit including a long-term reduction in glycated hemoglobin A1c over a 104-week (24 months) observation period with weight loss was suggested in this 24-month interim analysis of the 3-year Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term in routine clinical practice.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Resultado do Tratamento , Redução de Peso/efeitos dos fármacosRESUMO
The adult mammalian central nervous system (CNS) rarely recovers from injury. Myelin fragments contain axonal growth inhibitors that limit axonal regeneration, thus playing a major role in determining neural recovery. Nogo receptor-1 (NgR1) and its ligands are among the inhibitors that limit axonal regeneration. It has been previously shown that the endogenous protein, lateral olfactory tract usher substance (LOTUS), antagonizes NgR1-mediated signaling and accelerates neuronal plasticity after spinal cord injury and cerebral ischemia in mice. However, it remained unclear whether LOTUS-mediated reorganization of descending motor pathways in the adult brain is physiologically functional and contributes to functional recovery. Here, we generated LOTUS-overexpressing transgenic (LOTUS-Tg) rats to investigate the role of LOTUS in neuronal function after damage. After unilateral pyramidotomy, motor function in LOTUS-Tg rats recovered significantly compared to that in wild-type animals. In a retrograde tracing study, labeled axons spanning from the impaired side of the cervical spinal cord to the unlesioned hemisphere of the red nucleus and sensorimotor cortex were increased in LOTUS-Tg rats. Anterograde tracing from the unlesioned cortex also revealed enhanced ipsilateral connectivity to the impaired side of the cervical spinal cord in LOTUS-Tg rats. Moreover, electrophysiological analysis showed that contralesional cortex stimulation significantly increased ipsilateral forelimb movement in LOTUS-Tg rats, which was consistent with the histological findings. According to these data, LOTUS overexpression accelerates ipsilateral projection from the unlesioned cortex and promotes functional recovery after unilateral pyramidotomy. LOTUS could be a future therapeutic option for CNS injury.