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BACKGROUND: Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death-ligand 1 (PD-L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD-L1 expression who received MONO or COMB as a first-line treatment. Here, we report updated data and evaluate the long-term outcomes. METHODS: We performed a retrospective multicenter study of 298 patients with NSCLC and high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff. RESULTS: In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0-1). At the prolonged data cutoff, the median follow-up was 20.2 (range: 0.1-41.4) months. The median progression-free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow-up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO. CONCLUSIONS: COMB may be effective as a first-line treatment for NSCLC with high PD-L1 expression in a selected subset of patients.
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Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/metabolismo , Feminino , Idoso , Antígeno B7-H1/metabolismo , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Resultado do Tratamento , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
Background/Aim: Radium-223 treatment reduces the risk of death in patients with metastatic castration-resistant prostate cancer (CRPC). This study analyzed the prognostic factors in patients treated with radium-223 dichloride. Patients and Methods: Patients who received radium-223 dichloride were retrospectively analyzed. Prostate-specific antigen (PSA) response and alkaline phosphatase (ALP) decline rates were analyzed. Overall survival (OS) was evaluated using Kaplan-Meier curves, and prognostic factors for OS were assessed using Cox proportional hazards analysis. Results: Fifty-six patients were included in the study. The five-year OS rate in patients after diagnosis of CRPC was 62.2% [95% confidence interval (CI)=27.55-112.45], while the five-year OS rate in patients at the initiation of radium-223 treatment was 21.3% (95%CI=17.20-36.79). Six patients (11.1%) had a >50% PSA decline rate, and 10 (17.9%) had a >50% ALP decline rate. Cox proportional hazards analysis showed that PSA levels at the initiation of radium-223 treatment [hazard ratio (HR)=1.00; 95%CI=1.00-1.00; p=0.0054] and Gleason Pattern (GP) 5 (HR=5.42; 95%CI=1.08-27.27; p=0.0400) were associated with OS. Patients with GP 5 had a significantly poorer prognosis compared with patients with a GP ≤4. Early administration of radium-223 as a first- or second-line treatment was not associated with OS compared with late administration of radium-223 as a third-line or later treatment. Conclusion: GP 5 and high PSA levels at radium-223 initiation were associated with worse OS. Radium-223 as first- or second-line treatment was not associated with OS. Therefore, a treatment strategy for CRPC based on GP 5 is needed.
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Background/Aim: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. Patients and Methods: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. Results: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. Conclusion: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.
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Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205).
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Brentuximab Vedotin , Antígeno Ki-1 , Neoplasias Cutâneas , Humanos , Brentuximab Vedotin/administração & dosagem , Brentuximab Vedotin/uso terapêutico , Masculino , Pessoa de Meia-Idade , Antígeno Ki-1/imunologia , Antígeno Ki-1/análise , Feminino , Idoso , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/imunologia , Estudos Prospectivos , Japão , Adulto , Idoso de 80 Anos ou mais , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Micose Fungoide/imunologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/patologia , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Imunoconjugados/administração & dosagem , Imunoconjugados/uso terapêutico , Imunoconjugados/efeitos adversos , Resultado do Tratamento , População do Leste AsiáticoRESUMO
Unsaturated cyclic terpenes often exhibit instability due to the proximation of C=C bonds in the cyclic skeleton, leading to nonenzymatic degradation. In this study, the crystalline sponge (CS) method was employed for the X-ray conformational analysis of a minute amount of oily and cyclic terpene compound, (+)-germacrene D-4-ol, which was produced by a terpene synthase OILTS under inâ vitro conditions. The CS method revealed a reactive conformation of the cyclic terpene with proximal double bonds. Under weakly acidic inâ vivo conditions, OILTS gave four pseudo-natural products or artifacts. The CS method also elucidated the structures of these degraded compounds, proposing a degradation mechanism triggered by the transannular reactions.
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Daphnane diterpenoids were recognized for their extensive range of potent biological activities. In the present study, phytochemical investigation including LC-MS/MS analysis resulted in the identification of five daphnane diterpenoid orthoesters (1-5). Among the five daphnane diterpenoids, two previously unreported compounds, daphnepedunins I and J (2 and 4) were isolated from Daphne pedunculata. The structure of new compounds was elucidated with extensive physicochemical and spectroscopic analyses. Their structure was characterized by the presence of an unusual odd-numbered aliphatic chain connected to an orthoester. The isolated compounds were evaluated for their anti-HIV activity against HIV-1 infection of MT4 cells, and the results indicated that compound 1 showed the most potent anti-HIV activity with an IC50 value of 0.82 nM.
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Polysaccharides have gained attention as valuable supplements and natural medicinal resources, particularly for their anti-tumor properties. Their low toxicity and potent anti-tumor effects make them promising candidates for cancer prevention and treatment. The tumor microenvironment is crucial in tumor development and offers potential avenues for novel cancer therapies. Research indicates that polysaccharides can positively influence the tumor microenvironment. However, the structural complexity of most anti-tumor polysaccharides, often heteropolysaccharides, poses challenges for structural analysis. To enhance their pharmacological activity, researchers have modified the structure and properties of natural polysaccharides based on structure-activity relationships, and they have discovered that many polysaccharides exhibit significantly enhanced anti-tumor activity after chemical modification. This article reviews recent strategies for targeting the tumor microenvironment with polysaccharides and briefly discusses the structure-activity relationships of anti-tumor polysaccharides. It also summarises the main chemical modification methods of polysaccharides and discusses the impact of chemical modifications on the anti-tumor activity of polysaccharides. The review aims to lay a theoretical foundation for the development of anti-tumor polysaccharides and their derivatives.
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Neoplasias , Polissacarídeos , Microambiente Tumoral , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/uso terapêuticoRESUMO
OILTS is a viral class I terpene synthase found from the giant virus Orpheovirus IHUMI-LCC2. It exhibits a unique structure and demonstrates high plasticity to metal cofactors, allowing it to biosynthesize different cyclic terpene frameworks. Notably, while OILTS produces only (+)-germacrene D-4-ol with the most common cofactor, Mg2+, it also biosynthesizes a different cyclic terpene, (+)-cubebol, with Mn2+, Co2+, or Ni2+, presenting a rare instance of cofactor-dependent enzyme catalysis. This is the first report of (+)-cubebol biosynthesis, to our knowledge. In addition, OILTS can uptake Zn2+ as a cofactor, which is uncommon among ordinary terpene synthases. These findings suggest that OILTS's functional plasticity may benefit the virus in diverse host environments, highlighting potential evolutionary implications.
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Alquil e Aril Transferases , Alquil e Aril Transferases/metabolismo , Alquil e Aril Transferases/química , Metais/química , Metais/metabolismo , Zinco/metabolismo , Zinco/química , Terpenos/metabolismo , Terpenos/química , Níquel/química , Níquel/metabolismo , Magnésio/metabolismo , Magnésio/química , Proteínas Virais/metabolismo , Proteínas Virais/químicaRESUMO
Introduction: Inflammatory myofibroblastic tumors are borderline malignant soft tissue tumors primarily affecting the lungs and pelvic organs. This report presents a rare case of an inflammatory myofibroblastic tumor originating from the prostate gland in a young male. Case presentation: A 20-year-old man developed gross hematuria and dysuria, revealing a prostatic mass. Pathological examination of a biopsy displayed spindle-shaped myofibroblast proliferation and an infiltrate of inflammatory cells, leading to a diagnosis of inflammatory myofibroblastic tumor. Following fertility preservation measures, the patient underwent a robot-assisted laparoscopic total prostatectomy with bilateral nerve sparing, resulting in a postoperative diagnosis of inflammatory myofibroblastic tumor. No recurrence was observed in subsequent imaging, and urinary continence was maintained. Conclusion: Surgical resection appears effective in managing inflammatory myofibroblastic tumors of the prostate. This case underscores the importance of complete tumor resection due to the significant recurrence risk associated with inflammatory myofibroblastic tumors. Radical total prostatectomy emerges as a potential treatment strategy for prostate originating inflammatory myofibroblastic tumors.
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Bent ligands bridged by heteroatoms have drawn significant interest as supramolecular coordination architectures. Traditionally, divalent group 16 elements are preferred over trivalent group 15 elements because of the anticipated steric hindrance. In this study, we explore metal-organic frameworks (MOFs) based on dipyridinoarsoles (DPAs), 4,4'-bipyridines bridged with an arsenic atom. An MOF with methyl-substituted DPA collapsed upon solvent removal, whereas that with phenyl-substituted DPA demonstrated breathing behavior due to guest molecule adsorption/desorption. In contrast, MOFs using the phosphorus analogue dipyridinophosphole exhibit inferior adsorption and lack breathing behavior. This is the first study to investigate the interplay among substituents, bridging elements, and dynamic behavior in MOFs using bent group 15 ligands.
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Daphnepedunins G (1) and H (2) with unusual macrocyclic 3,4-seco-daphnane orthoester structure were isolated from Daphne pedunculata. Their structures were determined by physicochemical and spectroscopic analyses combined with synthetic methods, including methyl esterification, derivatization reaction using a chiral anisotropic agent, and biomimetic conversion. Compounds 1 and 2 along with their methyl esters 1a and 2a were evaluated for anti-HIV activity, among which 1a and 2a exhibited potent activity with IC50 values of 1.08 and 1.17 µM, respectively.
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Daphne , Diterpenos , Thoracica , Animais , Daphne/química , Diterpenos/química , Estrutura MolecularRESUMO
PURPOSE: This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer. METHODS AND MATERIALS: This study was conducted at 37 hospitals on men aged 40 to 79 years, with stage T2c-3a, prostate-specific antigen >20 ng/mL, or Gleason score >7, who received 6 months of ADT combined with iodine-125 brachytherapy followed by EBRT. After stratification, patients were randomly assigned to either no further treatment (short arm) or 24 months of adjuvant ADT (long arm). According to the Phoenix definition of failure, the primary endpoint was the cumulative incidence of biochemical progression. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific mortality, overall survival, and grade 3+ adverse events. An intention-to-treat analysis was conducted using survival estimates determined using competing risk analyses. RESULTS: Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P = .65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P = .62) and 1.2 versus 0.6% (P = .62), respectively. CONCLUSIONS: Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.
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Braquiterapia , Radioisótopos do Iodo , Neoplasias da Próstata , Masculino , Humanos , Braquiterapia/métodos , Antagonistas de Androgênios/uso terapêutico , Androgênios , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Antígeno Prostático EspecíficoRESUMO
The occurrence of macrocyclic daphnane orthoesters (MDOs) with a 1-alkyl group originating from a C14 aliphatic chain is extremely limited in the plant kingdom and has only been isolated from Edgeworthia chrysantha. In the present study, LC-ESI-MS/MS analysis was performed on different parts of E. chrysantha, including flower buds, flowers, leaves, and stems, and resulted in the identification of seven MDOs in all the four plant parts, including two previously unreported compounds 1 and 7. Further LC-MS guided isolation was carried out to afford compounds 1 and 7, and their structures were determined by various spectroscopic analyses. These compounds were also evaluated for anti-HIV activity, thus expanding insights into the structure-activity relationships for MDOs.
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Diterpenos , Thymelaeaceae , Cromatografia Líquida , Espectrometria de Massa com Cromatografia Líquida , Espectrometria de Massas em Tandem , Estrutura Molecular , Thymelaeaceae/químicaRESUMO
The Industries need techniques for the rapid structure analysis of amino acid derivatives. The amino acid derivatives are sometimes produced as impurities in the industrial production processes, and cause toxicity problems. Herein, we report the crystalline sponge (CS) method analysis of variety of amino acids using a formyl group installed CS crystal. Most amino acids possess a primary amino group, which can form Schiff-base with the formyl group under mild conditions. Thus, the formyl group installed CS crystal can efficiently capture the amino acids via Schiff-base formation. We successfully analyzed derivatives of 18 proteogenic amino acids, 6 non-proteogenic amino acids, and 4 dipeptides using the formyl group installed CS. We thus believe that the protocols shown in this study would serve the need of the industries.
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The Arctic Ocean is facing dramatic environmental and ecosystem changes. In this context, an international multiship survey project was undertaken in 2020 to obtain current baseline data. During the survey, unusually low dissolved oxygen and acidified water were found in a high-seas fishable area of the western (Pacific-side) Arctic Ocean. Herein, we show that the Beaufort Gyre shrinks to the east of an ocean ridge and forms a front between the water within the gyre and the water from the eastern (Atlantic-side) Arctic. That phenomenon triggers a frontal northward flow along the ocean ridge. This flow likely transports the low oxygen and acidified water toward the high-seas fishable area; similar biogeochemical properties had previously been observed only on the shelf-slope north of the East Siberian Sea.
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Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has emerged as a powerful tool for the rapid identification of compounds within natural resources. Daphnane diterpenoids, a class of natural compounds predominantly found in plants belonging to the Thymelaeaceae and Euphorbiaceae families, have attracted much attention due to their remarkable anticancer and anti-HIV activities. In the present study, the presence of daphnane diterpenoids in Wikstroemia indica, a plant belonging to the Thymelaeaceae family, was investigated by LC-MS/MS analysis. As a result, 21 daphnane diterpenoids (1-21) in the stems of W. indica were detected. Among these, six major compounds (12, 15, 17, 18, 20, and 21) were isolated and their structures were unequivocally identified through a comprehensive analysis of the MS and NMR data. For the minor compounds (1-11, 13, 14, 16, and 19), their structures were elucidated by in-depth MS/MS fragmentation analysis. This study represents the first disclosure of structurally diverse daphnane diterpenoids in W. indica, significantly contributing to our understanding of bioactive diterpenoids in plants within the Thymelaeaceae family.
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BACKGROUND: Oral formulations are not suitable for demented patients with dysphagia, those refuse to take tablets, or those with drug compliance problem. However, only oral formulations of donepezil hydrochloride are approved for the treatment of severe Alzheimer's disease in Japan. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of long-term application of a 55.0âmg transdermal donepezil patch switched from a 10âmg oral donepezil hydrochloride tablet, for the treatment of patients with severe Alzheimer's disease. METHODS: A 52-week, multicenter, open-label, uncontrolled (phase III) study (jRCT2080224612) was conducted in Japan between April 2019 and August 2021. A 10âmg donepezil hydrochloride tablet was administered once a day for four weeks; a 55.0âmg donepezil patch was then applied once a day for 52 weeks in patients with severe Alzheimer's disease. RESULTS: Of 64 patients received the patch, 45 completed the 52-week period. The overall discontinuation rate was 29.7% (19/64). Among the 19 patients discontinued, six patients 9.4% (6/64) discontinued due to adverse events. The incidence of adverse events at application sites was 67.2% (43/64), including application site erythema 29.7% (19/64), application site pruritus 25.0% (16/64), and contact dermatitis 20.3% (13/64). Adverse events were mild and did not increase with time, demonstrating a favorable safety profile. Cognitive function, measured using the Mini-Mental State Examination, was maintained for up to 24 weeks. CONCLUSIONS: Adverse events were considered manageable in a clinical setting. The long-term application of a 55.0âmg donepezil patch once a day was feasible treatment in patients with severe Alzheimer's disease.
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Doença de Alzheimer , Humanos , Donepezila/uso terapêutico , Doença de Alzheimer/psicologia , Inibidores da Colinesterase/efeitos adversos , Piperidinas/efeitos adversos , Indanos/efeitos adversos , Resultado do Tratamento , Comprimidos/uso terapêuticoRESUMO
Metal-organic frameworks (MOFs) are potential candidates for the platform of the solid acid; however, no MOF has been reported that has both aqueous ammonium stability and a strong acid site. This manuscript reports a highly stable MOF with a cation exchange site synthesized by the reaction between zirconium and mellitic acid under a high concentration of ammonium cations (NH4+). Single-crystal XRD analysis of the MOF revealed the presence of four free carboxyl groups of the mellitic acid ligand, and the high first association constant (pKa1) of one of the carboxyl groups acts as a monovalent ion-exchanging site. NH4+ in the MOF can be reversibly exchanged with proton (H+), sodium (Na+), and potassium (K+) cations in an aqueous solution. Moreover, the uniform nanospace of the MOF provides the acid site for selective NH4+ recovery from the aqueous mixture of NH4+ and Na+, which could solve the global nitrogen cycle problem. The solid acid nature of the MOF also results in the proton conductivity reaching 1.34 × 10-3 S cm-1 at 55 °C by ion exchange from NH4+ to H+.
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PURPOSE: We evaluated the treatment outcomes of different prostate volumes (PVs), <15 cc, 15-20 cc, and > 20 cc, in patients with prostate cancer who underwent permanent seed implantation (PI) ± external beam radiation therapy ± hormone therapy in a national Japanese prospective cohort study (J-POPS). METHODS AND MATERIALS: Of the 6721 patients in J-POPS from 2005 to 2011, 6652 were included in the analysis population. We categorized the patients into the following three PV groups: <15 cc, 15-20 cc, and > 20 cc. We evaluated the effect of PV on biochemical freedom from failure (bFFF), prostate cancer-specific mortality (PCSM), and all-cause mortality (ACM) using the Phoenix definition and Cox proportional hazard models. RESULTS: The median follow-up period was 60.0 months. Patients in each PV group was 491 (7.4%), 1118 (16.8%), and 5043 (75.8%), respectively. No difference was observed in bFFF (94.7%, 96.2%, and 95.7%, p = 0.407), PCSM (99.8%, 99.7%, and 99.8%, p = 0.682), and ACM (98.2%, 96.7%, and 97.2%, p = 0.119) at 5 years for each PV group. In univariate and multivariate analyses, PV was not associated with bFFF, PCSM, ACM, or grade 2 toxicity. The percentage of positive biopsies was the single most significant predictor for all treatment outcomes. CONCLUSIONS: Our results obtained by analyzing a very large Japanese prospective database showed no difference in treatment outcomes according to PV (<15 cc, 15-20 cc, and Ë20 cc). Our study confirmed that PI in small prostates (even < 15 cc) remains an effective treatment option.
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Pharmacological intervention of circadian rhythms is a potentially useful approach for ameliorating various health problems caused by disturbed circadian rhythms including sleep disorder and metabolic diseases. To find compounds that affect circadian rhythms, we screened mushroom extracts using mouse cells expressing the luciferase gene under the control of the mouse Bmal1 promoter. The culture filtrate extract from the basidiomycete Cyclocybe erebia enhanced the oscillation of bioluminescence caused by the expression of the luciferase gene and prolonged the period of bioluminescence. Bioassay-guided fractionation of the extract resulted in purification of compounds 1 and 2. Spectroscopic analyses along with single-crystal X-ray diffraction analysis, revealed that these compounds were diterpenoids with a unique skeleton and a fused ring system comprising 3-, 7-, and 5-membered rings. Compounds 1 and 2 were named cyclocircadins A and B, respectively. These findings suggested that natural diterpenoids could be a source of compounds with the activity affecting circadian rhythms.