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1.
Article in English | MEDLINE | ID: mdl-38387735

ABSTRACT

BACKGROUND: There are few clinical and radiographic studies of coracoclavicular (CC) ligament reconstruction in chronic acromioclavicular (AC) joint dislocation. Additionally, reported AC joint reduction rates vary. HYPOTHESIS: Arthroscopically assisted double-bundle semitendinosus tendon autografts with CC and AC ligament reconstruction for AC joint reconstruction provide AC joint stability and improved function at the final visit. METHODS: In this retrospective study of prospectively collected data, 21 patients surgically treated for chronic AC joint dislocation (Rockwood III-V) were assessed clinically and radiographically preoperatively, and at day 1, 3 months, 12 months, and at a final visit (>24 months) postoperatively. Clinical assessments included Constant and American Shoulder and Elbow Surgeons scores. The CC vertical distance (CCD) on the affected and unaffected sides [CCD ratio (%)] on the anterosuperior view were measured. AC joint vertical reduction loss was defined as an increase in the CCD ratio of >25%. Horizontal AC joint instability was evaluated on axillary views. Pearsons' correlation coefficients were generated to examine the relationships among postoperative clinical scores, CCD ratio, interval from injury to surgery, and age at the time of surgery. RESULTS: Twenty-one shoulders in 21 patients (mean age, 40.0 years at the time of surgery; 16 men, 5 women) were evaluated with a mean 31.7-month follow-up period. The mean Constant scores, American Shoulder and Elbow Surgeons scores, and CCD ratios significantly improved from preoperatively to the final visit (57.4 ± 10.1, 49.1 ± 12.1, 101.6 ± 64.1 preoperatively; 89.6 ± 5.3, 96.5 ± 4.2, 9.9 ± 34.5 at the final visit, respectively [P < .001 for all]). Vertical AC and horizontal AC joint instability were observed in 4 shoulders (19.0%) and in 1 shoulder (4.8%), respectively. However, there was no significant correlation between the increase in CCD and clinical scores at the final visit (Constant score; r = 0.179, P = .438: American Shoulder and Elbow Surgeons score; r = -0.260, P = .256) or the interval from injury to surgery (r = 0.099, P = .669) or age at the time of surgery (r = 0.019, P = .935). No clinical complications were associated with clinical symptoms. CONCLUSIONS: Patients who underwent the index procedure achieved significant improvement in shoulder function without complications related clinical symptom after a mean follow-up interval of 31.7 months. In contrast, the rates of total ACJ instability in the vertical and horizontal planes were unsatisfactory but compatible with those in previous studies.

2.
Cell Death Dis ; 14(9): 642, 2023 Sep 29.
Article in English | MEDLINE | ID: mdl-37773170

ABSTRACT

Differentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1, a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.

3.
Cancer Sci ; 114(7): 2920-2930, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37142416

ABSTRACT

Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.


Subject(s)
Brain Neoplasms , Glioblastoma , Glioma , Humans , Mice , Animals , Glioblastoma/pathology , Pentamidine/pharmacology , Pentamidine/therapeutic use , Brain Neoplasms/pathology , Cell Proliferation , Cell Line, Tumor , Glioma/pathology , Apoptosis , Xenograft Model Antitumor Assays
4.
Biochem Biophys Res Commun ; 621: 74-79, 2022 09 17.
Article in English | MEDLINE | ID: mdl-35810594

ABSTRACT

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes. Although various therapeutic approaches have been developed, refractoriness of chemotherapy and relapse cause a poor prognosis of the disease and further therapeutic strategies are required. Here, we report that Ras homolog enriched in brain (RHEB), a critical regulator of mTOR complex 1 activity, is a potential target for T-ALL therapy. In this study, we established an sgRNA library that comprehensively targeted mTOR upstream and downstream pathways, including autophagy. CRISPR/Cas9 dropout screening revealed critical roles of mTOR-related molecules in T-ALL cell survival. Among the regulators, we focused on RHEB because we previously found that it is dispensable for normal hematopoiesis in mice. Transcriptome and metabolic analyses revealed that RHEB deficiency suppressed de novo nucleotide biosynthesis, leading to human T-ALL cell death. Importantly, RHEB deficiency suppressed tumor growth in both mouse and xenograft models. Our data provide a potential strategy for efficient therapy of T-ALL by RHEB-specific inhibition.


Subject(s)
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Ras Homolog Enriched in Brain Protein , Animals , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Ras Homolog Enriched in Brain Protein/genetics , Ras Homolog Enriched in Brain Protein/metabolism , Signal Transduction , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/metabolism
5.
Ann Med Surg (Lond) ; 79: 103965, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35860109

ABSTRACT

Introduction: and importance: Tumor localization is vital in the surgical management of nonpalpable breast cancer. Various localization methods exist, each with their own disadvantages. Therefore, we need to investigate the optimal method of diagnosis for this condition. Case presentation: A 66-year-old woman presented to our facility with a microcalcification detected on screening mammography (MMG). The lesion was neither palpable nor detectable on ultrasonography (US). Three-dimensional stereotactic biopsy using MMG revealed ductal carcinoma in situ. The precise tumor location was needed to perform breast-conserving surgery. Clinical discussion: Our hospital did not have radioisotope imaging; hence, wire placement would have been difficult for this lesion location. To aid in localization, indocyanine green (ICG) and fluorescence imaging were used. ICG was injected preoperatively using stereotactic MMG, which enabled clear visualization of the lesion. Then, an accurate resection was performed. The patient was discharged without any complications 2 days after surgery. Conclusion: The findings of this case report suggest that stereotactic MMG-guided ICG can be useful in localizing breast cancer tumors that are nonpalpable and undetectable by US.

6.
Cancer Sci ; 113(8): 2716-2726, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35657693

ABSTRACT

Lysosomes function as the digestive system of a cell and are involved in macromolecular recycling, vesicle trafficking, metabolic reprogramming, and progrowth signaling. Although quality control of lysosome biogenesis is thought to be a potential target for cancer therapy, practical strategies have not been established. Here, we show that lysosomal membrane integrity supported by lysophagy, a selective autophagy for damaged lysosomes, is a promising therapeutic target for glioblastoma (GBM). In this study, we found that ifenprodil, an FDA-approved drug with neuromodulatory activities, efficiently inhibited spheroid formation of patient-derived GBM cells in a combination with autophagy inhibition. Ifenprodil increased intracellular Ca2+ level, resulting in mitochondrial reactive oxygen species-mediated cytotoxicity. The ifenprodil-induced Ca2+ elevation was due to Ca2+ release from lysosomes, but not endoplasmic reticulum, associated with galectin-3 punctation as an indicator of lysosomal membrane damage. As the Ca2+ release was enhanced by ATG5 deficiency, autophagy protected against lysosomal membrane damage. By comparative analysis of 765 FDA-approved compounds, we identified another clinically available drug for central nervous system (CNS) diseases, amoxapine, in addition to ifenprodil. Both compounds promoted degradation of lysosomal membrane proteins, indicating a critical role of lysophagy in quality control of lysosomal membrane integrity. Importantly, a synergistic inhibitory effect of ifenprodil and chloroquine, a clinically available autophagy inhibitor, on spheroid formation was remarkable in GBM cells, but not in nontransformed neural progenitor cells. Finally, chloroquine dramatically enhanced effects of the compounds inducing lysosomal membrane damage in a patient-derived xenograft model. These data demonstrate a therapeutic advantage of targeting lysosomal membrane integrity in GBM.


Subject(s)
Glioblastoma , Glioma , Autophagy , Chloroquine/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioma/drug therapy , Glioma/metabolism , Humans , Lysosomes/metabolism , Macroautophagy
7.
Foot Ankle Surg ; 28(1): 25-29, 2022 Jan.
Article in English | MEDLINE | ID: mdl-33574007

ABSTRACT

BACKGROUND: The purpose of this study was to investigate the second-look arthroscopic evaluation after osteochondral autogenous transfer (OAT) for osteochondral lesion of the talar dome (OLT) with the criteria of the International Cartilage Repair Society (ICRS). METHODS: Ten patients (twelve ankles) with OLT underwent OAT with osteotomy of the medial malleolus. Clinical outcomes were evaluated using the American Orthopedic Foot & Ankle Society (AOFAS) ankle-hindfoot scale. The condition of the transplanted cartilage was evaluated at the time of second-look arthroscopy using the ICRS Cartilage Repair Assessment. RESULTS: The AOFAS ankle-hindfoot scale was significantly improved from 65.1 ± 1.9 points before surgery to 98.1 ± 2.8 points at the time of second-look arthroscopy (p < 0.01). The ICRS Cartilage Repair Assessment was 11.4 points on average (9-12 points). CONCLUSIONS: The OAT for OLT is considered to be a useful treatment even if invasion by medial malleolus osteotomy is added. LEVEL OF EVIDENCE: Level IV, Case series.


Subject(s)
Cartilage, Articular , Talus , Ankle Joint/surgery , Arthroscopy , Cartilage , Cartilage, Articular/surgery , Humans , Osteotomy , Talus/surgery , Tibia , Treatment Outcome
8.
Mol Brain ; 14(1): 160, 2021 10 29.
Article in English | MEDLINE | ID: mdl-34715888

ABSTRACT

Songbirds are one of the few animal taxa that possess vocal learning abilities. Different species of songbirds exhibit species-specific learning programs during song acquisition. Songbirds with open-ended vocal learning capacity, such as the canary, modify their songs during adulthood. Nevertheless, the neural molecular mechanisms underlying open-ended vocal learning are not fully understood. We investigated the singing-driven expression of neural activity-dependent genes (Arc, Egr1, c-fos, Nr4a1, Sik1, Dusp6, and Gadd45ß) in the canary to examine a potential relationship between the gene expression level and the degree of seasonal vocal plasticity at different ages. The expression of these genes was differently regulated throughout the critical period of vocal learning in the zebra finch, a closed-ended song learner. In the canary, the neural activity-dependent genes were induced by singing in the song nuclei throughout the year. However, in the vocal motor nucleus, the robust nucleus of the arcopallium (RA), all genes were regulated with a higher induction rate by singing in the fall than in the spring. The singing-driven expression of these genes showed a similar induction rate in the fall between the first year juvenile and the second year adult canaries, suggesting a seasonal, not age-dependent, regulation of the neural activity-dependent genes. By measuring seasonal vocal plasticity and singing-driven gene expression, we found that in RA, the induction intensity of the neural activity-dependent genes was correlated with the state of vocal plasticity. These results demonstrate a correlation between vocal plasticity and the singing-driven expression of neural activity-dependent genes in RA through song development, regardless of whether a songbird species possesses an open- or closed-ended vocal learning capacity.


Subject(s)
Canaries/genetics , Gene Expression Regulation/physiology , Learning/physiology , Nerve Tissue Proteins/biosynthesis , Seasons , Vocalization, Animal/physiology , Aging/physiology , Animals , Canaries/physiology , Male , Nerve Tissue Proteins/genetics , Neural Pathways/physiology
9.
Am J Sports Med ; 49(13): 3656-3668, 2021 11.
Article in English | MEDLINE | ID: mdl-34623941

ABSTRACT

BACKGROUND: In shoulders with irreparable massive rotator cuff tears (RCTs) with high-grade fatty degeneration (Goutallier stage 3 or 4) of the supraspinatus tendon and low-grade fatty degeneration (Goutallier stage 1 or 2) of the infraspinatus tendon (ISP), arthroscopic patch grafting (PG) has been reported as superior to partial repair (PR) regarding the ISP retear rate at short-term to midterm follow-up. However, the longer term outcomes are unclear. PURPOSE: To compare clinical and structural outcomes in the PG and PR groups at a minimum of 7 years postoperatively. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: We evaluated 24 patients in the PG group and 24 patients in the PR group. We primarily used the Constant score for clinical outcomes and performed magnetic resonance imaging for structural outcomes in the PG and PR groups. The risk factors for a retear of the ISP were identified by univariate and multivariate (forward stepwise selection method) logistic regression analyses. We primarily compared values at midterm follow-up (<4 years) with values at the final follow-up (minimum 7 years) for each patient. RESULTS: The mean midterm and final follow-up times for the PG group were 41.0 and 95.1 months, respectively, compared with 35.7 and 99.3 months, respectively, for the PR group. We found significant differences for the midterm and final follow-up Constant total scores in the PG and PR groups (midterm follow-up: 79.1 vs 69.9, respectively [P = .001]; final follow-up: 76.0 vs 65.3, respectively [P = .006]) and in the Constant strength scores (midterm follow-up: 14.6 vs 8.5, respectively [P < .001]; final follow-up: 13.1 vs 8.3, respectively [P = .001]). Treatment group (PR) was a significant predictor of an ISP retear in the logistic regression analysis (odds ratio, 3.545; P = .043). CONCLUSION: Patients with low-grade massive RCTs treated with PG or PR improved significantly in terms of clinical outcomes at the midterm and final follow-up time points. However, Constant scores were significantly better in the PG group at the final follow-up.


Subject(s)
Rotator Cuff Injuries , Rotator Cuff , Arthroscopy , Autografts , Fascia , Follow-Up Studies , Humans , Rotator Cuff/surgery , Rotator Cuff Injuries/surgery , Treatment Outcome
10.
Sci Rep ; 11(1): 1666, 2021 01 18.
Article in English | MEDLINE | ID: mdl-33462315

ABSTRACT

Autophagy is a cellular degradation system contributing to homeostasis of tissue stem cells including haematopoietic stem cells (HSCs). It plays pleiotropic roles in HSC characteristics throughout life, but its stage-specific roles in HSC self-renewal are unclear. To investigate the effects of Atg5 deletion on stage-specific HSC functions, we compared the repopulating capacity of HSCs in Atg5f/f;Vavi-cre mice from postnatal day (P) 0-7 weeks of age. Interestingly, Atg5 deficiency led to no remarkable abnormality in the HSC self-renewal capacity at P0, but significant defects at P7, followed by severe defects. Induction of Atg5 deletion at P5 by tamoxifen administration to Atg5f/f;Rosa26-Cre-ERT2 mice resulted in normal haematopoiesis, including the HSC population, until around 1 year, suggesting that Atg5 in the early neonatal period was critical for haematopoiesis in adults. Mitochondrial oxidative stress was increased by Atg5 loss in neonatal HSC/progenitor cells. Although p62 had accumulated in immature bone marrow cells of Atg5f/f;Vavi-cre mice, p62 deletion did not restore defective HSC functions, indicating that Atg5-dependent haematopoietic regulation in the developmental period was independent of p62. This study proposes a critical role of autophagy in HSC protection against harsh environments in the early neonatal stage, which is essential for healthy long-term haematopoiesis.


Subject(s)
Autophagy-Related Protein 5/metabolism , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Sequestosome-1 Protein/metabolism , Animals , Animals, Newborn , Autophagy/physiology , Autophagy-Related Protein 5/genetics , Disease Models, Animal , Female , Hematopoietic Stem Cells/pathology , Male , Mice , Mice, Knockout , Oxidative Stress/physiology
11.
Cartilage ; 13(1_suppl): 1156S-1164S, 2021 12.
Article in English | MEDLINE | ID: mdl-32911970

ABSTRACT

OBJECTIVE: Treatments for steroid-induced osteonecrosis of the knee remains challenging, and there has not been sufficient evidence to support joint preservation surgery. This study evaluated long-term outcomes of osteochondral autologous transplantation (OAT) for steroid-induced osteonecrosis of the knee. DESIGN: This retrospective case series included patients who underwent OAT for steroid-induced osteonecrosis of the knee from 1998 to 2008. The survivorship and need for secondary surgery were evaluated, and the clinical outcome was evaluated with the International Knee Documentation Committee (IKDC) subjective score. Preoperative and final Kellgren-Lawrence (KL) grade of the femorotibial and patellofemoral joints were individually evaluated. RESULTS: Fourteen knees of 10 patients whose mean age was 32.5 (95%CI 26.4-38.6) years were included and followed for 14.0 (12.4-15.7) years. The mean lesion size of 6.9 (5.3-8.5) cm2 was repaired using 4 median (minimum 2, maximum 5) osteochondral plugs. No revision surgeries were performed for transplanted osteochondral plugs. The IKDC subjective score improved from 32.9 (24.5-41.3) to 74.2 (61.9-88.5) (P < 0.001). Knee flexion was improved at the final follow-up, and Seiza sitting was finally possible in 9 knees in 7 patients. Although the osteoarthritic change did not progress in femorotibial joint, patellofemoral joint showed early osteoarthritic changes at the final follow-up (mean KL grade: 0.8 [0.5-1.1]). CONCLUSIONS: Prosthetic joint replacement was successfully avoided for at least the first decade by OAT in young patients with steroid-induced osteonecrosis of the knee. The progression of KL grade of the patellofemoral joint is of concern.


Subject(s)
Bone Transplantation , Glucocorticoids/adverse effects , Intra-Articular Fractures , Knee Joint/surgery , Osteonecrosis/surgery , Transplantation, Autologous , Adult , Female , Follow-Up Studies , Humans , Male , Middle Aged , Osteonecrosis/chemically induced , Osteonecrosis/diagnosis , Retrospective Studies , Steroids , Survivorship , Treatment Outcome
13.
J Oral Maxillofac Surg ; 78(8): 1397-1402, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32386974

ABSTRACT

PURPOSE: Differentiating between bilateral condylar resorption (CR) and mandibular hypoplasia (MH) can be challenging owing to the difficulty in chronological observation and establishing standardized measurements. The purpose of the present study was to assess whether temporomandibular joint (TMJ) function can distinguish between CR and MH and clarify the essential diagnostic imaging tools for CR. MATERIALS AND METHODS: We performed a cross-sectional study of patients with mandibular retrognathia. The primary predictor variables were a clinical dysfunction score for the TMJ, mandibular plane angle (MPA), SNA angle, SNB angle, and cortical erosion score in the condylar heads. The demographic variables were age, anterior disc displacement, and previous orthodontic treatment. The anatomic variable was the condylar height (CH). The primary outcome variable was the disease status (CR or MH). The patients were divided into the CR group and MH group. The patients with CR were selected on the basis of a CH value of less than 22 mm. TMJ function was assessed using the Helkimo clinical dysfunction index. The CH on panoramic radiographs was measured using the Kjellberg method. The MPA, SNA angle, and SNB angle were analyzed using cephalometric analysis. Cortical erosion in the condylar head was assessed using computed tomography and magnetic resonance imaging. RESULTS: A total of 23 female participants were enrolled in the present study. The average clinical dysfunction score for the TMJ was 4.4 in the CR group and 0.4 in the MH group (P < .05). The average MPA was 41.2° in the CR group and 35.5° in the MH group (P < .05). CONCLUSIONS: The present investigation has shown that assessing TMJ function and analyzing MPA using a cephalometric radiograph can differentiate CR from MH.


Subject(s)
Joint Dislocations , Temporomandibular Joint Disorders/diagnostic imaging , Cephalometry , Cross-Sectional Studies , Female , Humans , Magnetic Resonance Imaging , Mandibular Condyle/diagnostic imaging , Temporomandibular Joint , Temporomandibular Joint Disc/diagnostic imaging
14.
Curr Pharm Des ; 26(36): 4675-4684, 2020.
Article in English | MEDLINE | ID: mdl-32348209

ABSTRACT

BACKGROUND: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes. PURPOSE: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications. METHODS: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis. RESULTS: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter. CONCLUSION: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.


Subject(s)
Brain Neoplasms , Glioblastoma , Pharmaceutical Preparations , Brain Neoplasms/drug therapy , Cell Line, Tumor , Drug Resistance, Neoplasm , Glioblastoma/drug therapy , Humans , Palmitic Acids , Xenograft Model Antitumor Assays
15.
Commun Chem ; 3(1): 183, 2020 Dec 07.
Article in English | MEDLINE | ID: mdl-36703437

ABSTRACT

Metabolic syndrome is associated with obesity, hypertension, and dyslipidemia, and increased cardiovascular risk. Therefore, quick and accurate measurements of specific metabolites are critical for diagnosis; however, detection methods are limited. Here we describe the synthesis of pillar[n]arenes to target 1-methylnicotinamide (1-MNA), which is one metabolite of vitamin B3 (nicotinamide) produced by the cancer-associated nicotinamide N-methyltransferase (NNMT). We found that water-soluble pillar[5]arene (P5A) forms host-guest complexes with both 1-MNA and nicotinamide, and water-soluble pillar[6]arene (P6A) selectively binds to 1-MNA at the micromolar level. P6A can be used as a "turn-off sensor" by photoinduced electron transfer (detection limit is 4.38 × 10-6 M). In our cell-free reaction, P6A is used to quantitatively monitor the activity of NNMT. Moreover, studies using NNMT-deficient mice reveal that P6A exclusively binds to 1-MNA in crude urinary samples. Our findings demonstrate that P6A can be used as a biosensor to quantify 1-MNA in crude biological samples.

16.
Sci Rep ; 9(1): 10049, 2019 07 11.
Article in English | MEDLINE | ID: mdl-31296906

ABSTRACT

Cancer stem cells are associated with chemoresistance and rapid recurrence of malignant tumors, including glioblastoma (GBM). Although temozolomide (TMZ) is the most effective drug treatment for GBM, GBM cells acquire resistance and become refractory to TMZ during treatment. Therefore, glioma stem cell (GSC)-targeted therapy and TMZ-enhancing therapy may be effective approaches to improve GBM prognosis. Many drugs that suppress the signaling pathways that maintain GSC or enhance the effects of TMZ have been reported. However, there are no established therapies beyond TMZ treatment currently in use. In this study, we screened drug libraries composed of 1,301 existing drugs using cell viability assays to evaluate effects on GSCs, which led to selection of kenpaullone, a kinase inhibitor, as a TMZ enhancer targeting GSCs. Kenpaullone efficiently suppressed activity of glycogen synthase kinase (GSK) 3ß. Combination therapy with kenpaullone and TMZ suppressed stem cell phenotype and viability of both GSCs and glioma cell lines. Combination therapy in mouse models significantly prolonged survival time compared with TMZ monotherapy. Taken together, kenpaullone is a promising drug for treatment of GBM by targeting GSCs and overcoming chemoresistance to TMZ.


Subject(s)
Benzazepines/therapeutic use , Brain Neoplasms/drug therapy , Chemotherapy, Adjuvant/methods , Glioblastoma/drug therapy , Glycogen Synthase Kinases/metabolism , Indoles/therapeutic use , Neoplastic Stem Cells/pathology , Protein Kinase Inhibitors/therapeutic use , Animals , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Survival , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Glioblastoma/pathology , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Mice , Neoplastic Stem Cells/drug effects , Signal Transduction , Temozolomide/therapeutic use , Xenograft Model Antitumor Assays
17.
In Vivo ; 33(4): 1067-1079, 2019.
Article in English | MEDLINE | ID: mdl-31280194

ABSTRACT

BACKGROUND/AIM: Biocompatibility of a novel and more stable hydroxyapatite (HA)-dispersed titanium (Ti)-based composite was investigated, using the mouse osteoblast precursor cell line MC3T3-E1. MATERIALS AND METHODS: Surface of powders and plates was observed by scanning electron microscopy. Distribution of calcium and phosphorus on the surface of the composite was evaluated by an electron beam microanalyzer. Crystal structure was analyzed by X-ray diffractometer. Cell viability was determined by WST-1 assay. RESULTS: HA was stable against the compressive force, shearing stress and sintering heat at 800°C, but it slightly decomposed at 1100°C. With the increase of HA in the composites, the adhesion/proliferation of MC3T3-E1 cells was reduced. The growth inhibition by HA does not seem to be due to materials released from the plate, but rather to the contact to the surface of the plate. Sintering of the HA plate at 1100°C increased the number of attached viable cells. On the other hand, culturing on the synthesized calcium phosphate (apatite containing carbonic acid) increased the number of attached cells to a greater extent. CONCLUSION: HA inhibits the growth of osteoblastic cells, but sintering at 1100°C changes the surface properties of the composite so as to stimulate cell growth.


Subject(s)
Biocompatible Materials , Cell Adhesion , Durapatite , Osteoblasts/metabolism , Titanium , Animals , Biocompatible Materials/chemistry , Cell Culture Techniques , Cell Line , Cell Proliferation , Cell Survival , Durapatite/chemistry , Materials Testing , Mice , Microscopy, Electron, Scanning , Osteoblasts/cytology , Osteoblasts/ultrastructure , Spectrum Analysis , Surface Properties , Titanium/chemistry
18.
Gan To Kagaku Ryoho ; 46(5): 907-911, 2019 May.
Article in Japanese | MEDLINE | ID: mdl-31189813

ABSTRACT

Red Cross Pharmaceutical Association conducted a questionnaire-based survey to evaluate the status of implementation of pharmaceutical intervention as well as personal counseling for outpatients with cancer undergoing chemotherapy. Based on the survey results from 93 hospitals across the country, it was found that pharmacists performed an intervention on outpatients receiving chemotherapy in 68 hospitals(73.1%)and conducted personal counseling for outpatients with cancer in 48 hospitals(51.6%). Out of the 68 hospitals, 20 did not conduct personal counseling for outpatients with cancer. This was attributable to the fact that 14 hospitals did not have a qualified pharmacist, 3 did not have sufficient manpower, and 3 did not have the required system. The results of a logistic regression analysis showed that the number of pharmacists significantly affected implementation of pharmaceutical intervention as well as personal counseling for outpatients with cancer undergoing chemotherapy(p=0.042, p=0.023, respectively). The pharmacists can receive a fee for medical services only after conducting personal counseling for outpatients with cancer undergoing chemotherapy. However, in hospitals with a small number of pharmacists, they could not claim their fees owing to lack of manpower. This survey found that lack of manpower is currently the most important issue.


Subject(s)
Neoplasms , Red Cross , Counseling , Humans , Pharmacists , Surveys and Questionnaires
19.
Orthop J Sports Med ; 7(4): 2325967119838249, 2019 Apr.
Article in English | MEDLINE | ID: mdl-31041329

ABSTRACT

BACKGROUND: The presence of delamination and a larger rotator cuff tear (RCT) size have been associated with poorer outcomes in rotator cuff repair. Therefore, we developed a new surgical procedure, arthroscopic lamina-specific double-row fixation (ALSDR), for the repair of large delaminated RCTs. PURPOSE: To investigate the clinical outcomes, magnetic resonance imaging findings, and satisfaction with several variables after ALSDR for large delaminated RCTs. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 30 active patients (mean age, 59.1 years) undergoing ALSDR were assessed by a numeric rating scale (NRS; 0-10) for pain, surgery, work, and exercise as well as American Shoulder and Elbow Surgeons (ASES), Constant, and Simple Shoulder Test (SST) scores at a mean of 65.9 months postoperatively. Rotator cuff integrity was determined by magnetic resonance imaging. The Spearman correlation coefficient (ρ) was used to determine the correlation between clinical and NRS scores. RESULTS: Five patients (16.7%) had a retear. Each of the postoperative functional and NRS scores except the NRS work score was significantly better in the healed shoulders than in the shoulders with a retear (P < .001). The NRS pain score showed a significant negative correlation with ASES, Constant, and SST scores (ρ = -0.775, -0.668, and -0.742, respectively; P < .001 for all). The NRS surgery score had a positive correlation with Constant and SST scores (ρ = 0.393 [P = .032] and ρ = 0.456 [P = .011], respectively). The NRS work score had a positive correlation with ASES, Constant, and SST scores (ρ = 0.382 [P = .037], ρ = 0.386 [P = .035], and ρ = 0.414 [P = .023], respectively). The NRS exercise score had a positive correlation with ASES, Constant, and SST scores (ρ = 0.567 [P = .001], ρ = 0.511 [P = .004], and ρ = 0.639 [P < .001], respectively). CONCLUSION: Our results showed that there was a significant correlation between clinical and NRS scores. The results indicate that ALSDR can provide a high degree of functionality and can be a useful alternative treatment for active patients with large delaminated RCTs.

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