Biomedical subjects

Takashi Nomura

Publications and source records attributed to Takashi Nomura.

At least 19 recordsLinked to original sources

PubMed2026

A multicenter phase II trial of ramucirumab plus irinotecan for early recurrence of gastric cancer during or after adjuvant chemotherapy with docetaxel plus S-1 therapy: the RAMIEL trial (OGSG1901).

BACKGROUND: There is currently no established chemotherapy regimen for early recurrence of pathological stage III gastric cancer (GC) following adjuvant chemotherapy with docetaxel plus S-1 (DS) after D2 gastrectomy. We aimed to evaluate the efficacy and safety of ramucirumab plus irinotecan in patients with GC who experienced early recurrence during or within 6 months after DS adjuvant chemotherapy. METHODS: This prospective, open-label, multicenter phase II trial enrolled eligible patients treated at 25 centers of the Osaka Gastrointestinal Cancer Chemotherapy Study Group in Japan. Patients received ramucirumab (8 mg/kg) and irinotecan (150 mg/m2) every 2 weeks. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size was set at 40 based on a threshold median OS of 7 months and an expected median OS of 11 months, with a one-sided alpha error of 0.05 and a power of 0.80. RESULTS: Between November 2019 and July 2023, 43 patients were enrolled, and 39 were included in the analysis after excluding three ineligible patients and one who did not initiate protocol treatment. The median OS was 15.9 months (95% CI: 8.8-42.0; p = 0.003). The median PFS was 5.5 months (95% CI: 3.9-8.1), and the ORR was 38.5%. Grade  ≥ 3 adverse events, including neutropenia (25.6%) and hypertension (25.6%), were observed in more than 20% of patients. CONCLUSION: Ramucirumab plus irinotecan demonstrated promising efficacy and manageable toxicity in patients with early recurrence of GC following adjuvant DS therapy. TRIAL REGISTRATION: This study was prospectively registered in the Japan Registry of Clinical Trials (jRCTs05119071, October 6, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs051190071 ).

Docetaxel↗

PubMed2007

T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.

This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17-secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell-derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-gamma deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-gamma deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA.

Animals↗

PubMed2006

Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H+/K+-ATPase-reactive TCR transgenic mouse.

Autoimmunity is often accompanied by the development of ectopic lymphoid tissues in the target organ, and these tissues have been believed to have close relevance to the severity of the disease. However, the true relationship between the extent of such lymphoid structures and the intensity or type of immune responses mediated by self-reactive T cells has remained unclear. In the present study, we generated transgenic mice expressing TCR from an autoimmune gastritis (AIG)-inducing Th1 cell clone specific for one of the major stomach self-Ags, H(+)/K(+)-ATPase alpha subunit. The transgenic mice spontaneously develop massive lymphoid neogenesis with a highly organized tissue structure in the gastric mucosa, demonstrating Ag-specific, T cell-mediated induction of the lymphoid tissues. Nevertheless, the damage of surrounding tissue and autoantibody production were considerably limited compared with those in typical AIG induced by neonatal thymectomy. Such a moderate pathology is likely due to the locally restricted activation and Th2 skewing of self-reactive T cells, as well as the accumulation of naturally occurring regulatory T cells in the target organ. Altogether, the findings suggest that lymphoid neogenesis in chronic autoimmunity does not simply correlate with the destructive response; rather, the overall activation status of the T cell network, i.e., the balance of self-reactivity and tolerance, in the local environment has an impact.

Adoptive Transfer↗

PubMed2006

CSF orexin levels of Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration.

Excessive daytime sleepiness has been widely accepted as a common problem not only in Parkinson's disease (PD) but also in other related disorders. Lowered excretion of orexin A (hypocretin 1) into the cerebrospinal fluid (CSF) is known to play a pathological role in narcolepsy and secondary hypersomnia due to hypothalamic dysfunction. Although the levels of CSF orexin in PD have been previously examined, the results have been controversial, and no systematic investigation of CSF orexin excretion has been conducted on PD related disorders. In this study, orexin was measured in CSF collected by lumbar puncture in 62 patients with PD, 13 patients with dementia with Lewy bodies (DLB), 16 patients with progressive supranuclear palsy (PSP), and 7 patients with corticobasal degeneration (CBD). Levels of CSF orexin (mean+/-SD pg/ml) were 302+/-38 in PD, 297+/-48 in DLB, 258+/-37 in PSP, 246+/-90 in CBD. The occurrence of low orexin levels (<or=110pg/ml) was rare in both PD and DLB, and orexin levels were significantly lower in the PSP and CBD groups compared to PD (PSP: p<0.001, CBD: p<0.05). Orexin levels were inversely correlated with duration of morbidity in PSP but not in the other conditions studied. These findings suggest that loss of orexin neurons or impaired orexin neurotransmission might exist as a part of the neurodegeneration associated with advanced PSP with long duration of morbidity.

Aged↗

PubMed2006

Clinical characteristics of Restless legs syndrome in patients with Parkinson's disease.

To assess the characteristics, clinical significance and pathology of Restless legs syndrome (RLS) in patients with Parkinson's disease (PD), we studied clinical backgrounds, RLS symptoms, polysomnographic (PSG) variables and therapeutic outcomes in 13 PD patients with RLS (pRLS), and compared them with those of 22 idiopathic RLS patients (iRLS). In all but one pRLS patient, RLS symptoms arose within 5 years of PD onset. pRLS patients had a lower prevalence of family history of RLS, and the age at onset was higher than in iRLS subjects. Scores for the severity scale established by the International Restless Legs Syndrome Study Group (IRLS), the Pittsburgh Sleep Quality Index, and the suggested immobilization test did not differ between groups. However, the periodic limb movements index measured by polysomnogram was smaller in pRLS subjects. After RLS treatment, symptoms improved significantly in both groups; however, pRLS subjects showed higher IRLS scores despite receiving similar doses of RLS medications. The severity of RLS before treatment was quite similar between the two groups, but the response to treatment could be poorer in pRLS than in iRLS. Thus, degeneration of the diencephalospinal dopaminergic pathway due to PD itself and physiological aging could overlap in the pathology of pRLS.

Age of Onset↗

PubMed2006

Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis.

Naturally occurring CD25(+)CD4(+) regulatory T cells (Tregs) actively engage in the maintenance of immunologic self-tolerance and immunoregulation. They specifically express the transcription factor Forkhead box P3 (Foxp3) as a master control molecule for their development and function. Although several cell-surface molecules have been reported as Treg-specific markers, such as CD25, glucocorticoid-induced TNFR family-related gene/protein and CTL-associated molecule-4, they are also expressed on activated T cells derived from CD25(-)CD4(+) naive T cells. To identify Treg-specific molecules controlled by Foxp3, we performed DNA microarray analysis by comparing the following pairs of cell populations: fresh CD25(+)CD4(+) T cells versus fresh CD25(-)CD4(+) T cells, activated CD25(+)CD4(+) T cells versus activated CD25(-)CD4(+) T cells and retrovirally Foxp3-transduced CD25(-)CD4(+) T cells versus mock-transduced CD25(-)CD4(+) T cells. We found that the Gpr83, Ecm1, Cmtm7, Nkg7, Socs2 and glutaredoxin genes are predominantly transcribed in fresh and activated natural Treg as well as in Foxp3-transduced cells, while insulin-like 7, galectin-1, granzyme B and helios genes are natural Treg specific but Foxp3 independent. G protein-coupled receptor 83 (Gpr83) expression on the cell surface of natural Treg was confirmed by staining with Gpr83-specific antibody. Retroviral transduction of either group of genes in CD25(-)CD4(+) T cells failed to confer in vitro suppressive activity. Thus, there are several genes that are expressed in a highly Treg-specific fashion. Some of these genes are controlled by Foxp3, and others are not. These genes, in particular, Gpr83, Ecm1 and Helios, could potentially be used as specific markers for natural Treg.

Animals↗

PubMed2006

Spontaneous development of autoimmune arthritis due to genetic anomaly of T cell signal transduction: Part 1.

A point mutation of the gene encoding ZAP-70, a key signal transduction molecule in T cells, results in spontaneous development of T cell-mediated autoimmune arthritis in mice homozygous for the mutation. The genetic anomaly alters differentiation and selection of T cells in the thymus, leading to thymic production of arthritogenic autoimmune T cells. The arthritogenic T cells persist in the periphery and elicit arthritis when activated by microbial agents that stimulate innate immunity. This model is instrumental in understanding how genetic variations in T cell signal transduction, together with environmental influences, contribute to the development of autoimmune disease.

Animals↗

PubMed2006

A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether: synthesis and structure-activity relationships.

A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and its analogues were prepared, and their antibacterial activities and pharmacokinetic properties were evaluated. We found that the introduction of an (R)-alkyl group between the amide and iminoether groups could improve the pharmacokinetic properties while maintaining the activity against erythromycin-resistant Streptococcus pneumoniae. Among the ketolides prepared with the (R)-alkyl group, compound 5p with an N-(3-quinoxalin-6-yl-propyl)-propionamide moiety was found to have in vivo efficacy comparable to CAM with potent in vitro antibacterial activities against the key respiratory pathogens including Haemophilus influenzae and erythromycin-resistant S. pneumoniae.

Acetamides↗

PubMed2006

Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease.

To explore the clinical significance of restless legs syndrome (RLS) in Parkinson's disease (PD) and the causal relationship between these two disorders, we made a comparison of both the prevalence of RLS and the severity of sleep disturbance manifested on the Pittsburg Sleep Quality Index (PSQI) between patients with PD (n=165) and age- and sex-matched control subjects (n=131). The prevalence of RLS diagnosed by clinical interview was significantly higher in PD patients than in control subjects (12% vs. 2.3%). PSQI score was significantly higher in PD patients with RLS than in both patients without RLS and controls. However, PSQI score was not statistically different between the latter two groups. Among the PD patients with RLS, only 2 had a positive family history of RLS. Only 3 PD patients had requested treatment for the disorder. Our results emphasize the etiological link between RLS and PD in a Japanese cohort, and the existence of RLS is thought to be one of the most important factors aggravating sleep disturbance in PD, despite the low RLS severity.

Aged↗

PubMed2006

Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease.

Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.

Animals↗

PubMed2006

Preparation and characterization of polypeptide-stabilized gold nanoparticles.

Helical polypeptides have a highly rigid conformation. In order to control self-assembling structure in nanoscale, the rigidity of the stabilizing molecules, which is working as scaffolds, is highly important. Furthermore, the molecular lengths of polypeptides can be readily controlled by using their unique polymerization methods. In this study, we have used helical polypeptides as the stabilizing reagent of metal nanoparticles. As for rigid helical polypeptides, poly(gamma-benzyl-L-glutamate) (PBLG) was selected, and was synthesized by N-carboxylic acid anhydride (NCA) polymerization. Preparation of helical polypeptide-stabilized gold nanoparticles using a two-phase reduction process from the corresponding metal salts with NaBH4 is therefore introduced. PBLG itself did not have good stabilizing ability for metal nanoparticles and a terminal attaching ligand was indispensable for nanoparticle stabilization and, for this purpose, lipoic acid was selected. It is estimated that lipoic acid functionalized polypeptide molecules were attached perpendicularly to the particle surface by lipoic acid group. The size and structure, as well as assembling will be discussed in this manuscript.

Drug Stability↗

PubMed2005

9-Oxime-3-ketolides: modification at the C-11,12-diol moiety and antibacterial activities against key respiratory pathogens.

In the search for new types of ketolide antibiotics active against key respiratory pathogens including erythromycin-resistant strains, we conducted an extensive study on the modification at the C-11,12-diol moiety of 9-oxime-3-ketolide derivatives. Among the derivatives prepared, compound 6 with carbonate at the C-11,12 position was found to have potent antibacterial activities against erythromycin-resistant Staphylococcus aureus as well as other erythromycin-susceptible strains.

Anti-Bacterial Agents↗

PubMed2005

Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells.

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4+ and CD8+ T cells, including interferon (IFN)-gamma-secreting cells, infiltrated regressing tumors. Tumor-specific IFN-gamma-secreting CD4+ and CD8+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-gamma-intact mice but not IFN-gamma-deficient mice. Furthermore, coadministration of anti-GITR and anti-CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg-specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg-mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-gamma, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.

Animals↗

PubMed2005

A new type of ketolides bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether synthesis and structure-activity relationships.

A new type of ketolides, bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and a cyclic carbonate at the C-11,12 position was prepared and the antibacterial activities of the compounds were evaluated. Some of the derivatives showed potent antibacterial activity against both Haemophilus influenzae and Streptococcus pneumoniae, which are clinically important respiratory tract pathogens. Among the derivatives prepared, compound 5s with a quinolin-4-yl moiety was found to have potent and well-balanced activity against S. pneumoniae and H. influenzae including erythromycin-resistant strains.

Acetamides↗

PubMed2005

A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice.

A combination of genetic and environmental factors can cause autoimmune disease in animals. SKG mice, which are genetically prone to develop autoimmune arthritis, fail to develop the disease under a microbially clean condition, despite active thymic production of arthritogenic autoimmune T cells and their persistence in the periphery. However, in the clean environment, a single intraperitoneal injection of zymosan, a crude fungal beta-glucan, or purified beta-glucans such as curdlan and laminarin can trigger severe chronic arthritis in SKG mice, but only transient arthritis in normal mice. Blockade of Dectin-1, a major beta-glucan receptor, can prevent SKG arthritis triggered by beta-glucans, which strongly activate dendritic cells in vitro in a Dectin-1-dependent but Toll-like receptor-independent manner. Furthermore, antibiotic treatment against fungi can prevent SKG arthritis in an arthritis-prone microbial environment. Multiple injections of polyinosinic-polycytidylic acid double-stranded RNA also elicit mild arthritis in SKG mice. Thus, specific microbes, including fungi and viruses, may evoke autoimmune arthritis such as rheumatoid arthritis by stimulating innate immunity in individuals who harbor potentially arthritogenic autoimmune T cells as a result of genetic anomalies or variations.

Animals↗

PubMed2005

Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.

Animals↗

PubMed2005

The significance of the intraoperative repeated dosing of antimicrobials for preventing surgical wound infection in colorectal surgery.

PURPOSE: It is widely accepted that antimicrobial prophylaxis is useful for the prevention of surgical wound infection, especially in colorectal surgery. While many reports support the finding that the first dose should be administered immediately before surgery, there is less evidence concerning the ideal timing for the second dose. The purpose of this study is to examine the significance of intraoperative repeated dosing. METHODS: A surgical series of 131 patients with primary colorectal cancer was retrospectively analyzed for 14 parameters, including the protocols of antimicrobial administration to determine the clinical risk factors for surgical wound infection. RESULTS: The overall surgical wound infection rate of the 131 patients was 16.0% (21/131). When the operation finished within 4 h after the first dose (n = 29), wound infection was observed in only one patient (3.4%). In a prolonged operation exceeding 4 h after the first dose, the surgical wound infection rates were 8.5% and 26.5%, respectively, for those with (n = 47) and without (n = 49) intraoperative repeated dosing, which were significantly different based on both a univariate analysis (P = 0.031) and a multivariate analysis (P = 0.0079). CONCLUSION: Intraoperative repeated antimicrobial dosing is therefore recommended to prevent the surgical wound infection for prolonged colorectal surgery.

Aged↗

PubMed2005

Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains.

We describe here the sequence of the Plasmodium vivax mdr1 gene from 10 different isolates differing in chloroquine sensitivity. The deduced amino acid sequence of PvMDR1 shares more than 70% similarity with other malarial MDR proteins and it displays consensus motifs of an ABC family transporter including two transmembrane domains and two ATP binding cassettes. Similarity and dendrogram analyses revealed that sequences could be grouped according to their geographical origin. Within each geographical group however, no correlation was found between chloroquine resistance and specific mutations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗