DSP-0509, a TLR7 agonist, exerted synergistic anti-tumor immunity combined with various immune therapies through modulating diverse immune cells in cancer microenvironment.

Toll-like receptor 7 (TLR7) acts as a crucial component of the innate immune system. Upon TLR7 binding to its ligand, myeloid cells, including dendritic cells (DCs) and macrophages, are activated and play vital roles in initiating adaptive immunity. Consequently, TLR7 agonists have been employed in cancer immunotherapy.

TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation.

Background: TLR7 is a key player in the antiviral immunity. TLR7 signaling activates antigen-presenting cells including DCs and macrophages. This activation results in the adaptive immunity including T cells and B cells.

Effectiveness of self-sampling human papillomavirus test on precancer detection and screening uptake in Japan: The ACCESS randomized controlled trial.

Japan is lagging in cervical cancer prevention. The effectiveness of a self-sampling human papillomavirus (HPV) test, a possible measure to overcome this situation, has not yet been evaluated. A randomized controlled trial was performed to evaluate the effectiveness of a self-sampling HPV test on detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and screening uptake.

Acceptability of self-sampling human papillomavirus test for cervical cancer screening in Japan: A questionnaire survey in the ACCESS trial.

Purpose: In terms of medical policy for cervical cancer prevention, Japan lags far behind other industrialized countries. We initiated a randomized controlled trial to evaluate the self-sampling human papillomavirus (HPV) test as a tool to raise screening uptake and detection of pre-cancer. This study was conducted to explore the acceptability and preference of self-sampling using a subset of the data from this trial.

DSP-0509, a systemically available TLR7 agonist, exhibits combination effect with immune checkpoint blockade by activating anti-tumor immune effects.

TLR7 is an innate immune receptor that recognizes single-stranded RNAs, and its activation leads to anti-tumor immune effects. Although it is the only approved TLR7 agonist in cancer therapy, imiquimod is allowed to be administered with topical formulation. Thus, systemic administrative TLR7 agonist is expected in terms of expanding applicable cancer types.

Implementation of a self-sampling HPV test for non-responders to cervical cancer screening in Japan: secondary analysis of the ACCESS trial.

A self-sampling human papillomavirus (HPV) test could improve the morbidity and mortality of cervical cancer in Japan. However, its effectiveness and feasibility have not been demonstrated sufficiently. Hence, we launched a randomized controlled trial, which is ongoing, and report the results of a secondary analysis.

Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy.

Strategies to augment anti-cancer immune responses have recently demonstrated therapeutic utility. To date clinical success has been achieved through targeting co-inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1. However, approaches that target co-activatory pathways are also being actively being developed.

TLR7 tolerance is independent of the type I IFN pathway and leads to loss of anti-tumor efficacy in mice.

Systemic administration of small molecule toll-like receptor (TLR)-7 agonists leads to potent activation of innate immunity and to the generation of anti-tumor immune responses. However, activation of TLRs with small molecule agonists may lead to the induction of TLR tolerance, defined as a state of hyporesponsiveness to subsequent agonism, which may limit immune activation, the generation of anti-tumor responses and clinical response. Our data reveal that dose scheduling impacts on the efficacy of systemic therapy with the selective TLR7 agonist, 6-amino-2-(butylamino)-9-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (DSR-6434).

Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors.

We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity.

Poor pregnancy outcome following assisted reproductive technology among women operated on for bilateral endometriomas.

Purpose: To determine the first line of infertility treatment for managing patients with unilateral or bilateral ovarian endometriomas.

Methods: We evaluated pregnancy outcome in patients who had received ovarian surgery for unilateral (Group U, = 47) or bilateral endometriomas (Group B, = 38) and aspiration with or without alcohol fixation for unilateral (Group u, = 37) or bilateral endometriomas (Group b, = 22). Subsequently, 64 of these women, excluding 29 dropouts, underwent assisted reproductive technology.

Elective cryopreservation of all day 5 blastocysts is more effective than using day 6 blastocysts for improving pregnancy outcome in stimulated cycles.

To evaluate the efficacy of cryopreservation of all blastocysts for future transfers in stimulated cycles. We carried out fresh blastocyst transfer cycles on day 5 ( = 290) or day 6 ( = 119) and thawed blastocyst transfer cycles that were frozen on day 5 ( = 136), day 6 ( = 71) or day 6 electively ( = 21). We retrospectively compared the clinical outcome of fresh blastocyst transfers with thawed blastocyst transfers according to the day of blastocyst transfer or freezing.

Beneficial effect of long zona dissection on frozen-thawed blastocysts at a young age.

To assess the appropriateness of assisted hatching using long zona dissection of human frozen-thawed blastocysts at the time of warming, especially in women over 35 years of age or with repeated implantation failures. Of 177 frozen-thawed blastocyst transfer cycles, 89 control cycles had an intact zona and 88 cycles had assisted hatching using long zona dissection of human thawed blastocyst at the time of warming. These two groups were further subdivided by age to a total of four subgroups: ≤34 years (assisted hatching,  = 39; controls,  = 39) and ≥35 years (assisted hatching,  = 49; controls,  = 50).

Two-dimensional differential gel electrophoresis of rat heart proteins in ischemia and ischemia-reperfusion.

Ischemia-reperfusion injury occurs in acute myocardial infarction, cardiopulmonary bypass surgery, and heart transplantation. However the precise mechanisms still remain unclear. In order to identify proteins that are involved in ischemia-reperfusion injury, we compared precipitated 100,000g fractions of normal, ischemic, and ischemic-reperfused rat hearts using two-dimensional (2D) difference gel electrophoresis (2D-DIGE).

Reduction of myocardial infarct size by SM-197378, a novel Na+/H+ exchange inhibitor, in rabbits.

The effects of SM-197378, 2-[[[amino(imino)methyl]amino]carbonyl]-1-methyl-4-trifluoromethyl-1H-indol-7-yl=hydrogen=sulfate monohydrate, a novel potent Na+/H+exchange inhibitor, on heart injury were studied using a rabbit model involving 30 min of myocardial ischemia and 5 h of reperfusion. Intravenous administration of SM-197378 before ischemia reduced the infarct size by approximately 30-50% in a dose-dependent manner. This anti-necrotic effect was achieved without significant hemodynamic changes.

Reduction of myocardial infarct size by SM-198110, a novel Na+/H+ exchange inhibitor, in rabbits.

The effects of 3-[2-({[amino(imino)methyl]amino}carbonyl)-4-chloro-1H-indol-1-yl]-1-propanesulphonic acid monohydrate (SM-198110), a novel potent Na+/H+ exchange inhibitor, and cariporide (Hoe642), another Na+/H+ exchange inhibitor, were studied in a myocardial ischaemia and reperfusion injury model. Anaesthetized rabbits were subjected to occlusion of the coronary artery for 30 min followed by reperfusion for 5 h. SM-198110 or cariporide was administered before ischaemia and before reperfusion.

Differences in the effects of Na+-H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts.

The protective effects of the Na+-H+ exchange (NHE) inhibitors SM-198110 (2-[[(aminoiminomethyl) amino] carbonyl]-4-chloro-1H-indole-1-propanesulfonic acid monohydrate) and SM-197378 (N-(aminoiminomethyl)-1-methyl-7-(sulfooxy)-4-(trifluoromethyl)-1H-indole-2-carboxamide monohydrate) were investigated in perfused Langendorff guinea-pig hearts subjected to ischemia (40 min) and reperfusion (40 min). The recovery of left ventricular developed pressure (LVDP) from ischemia by reperfusion was 39.0% in the control, while in the hearts pretreated with SM-198110 or SM-197378 (10(-7) M), it was about 100%.

Proteomic analysis of rat heart in ischemia and ischemia-reperfusion using fluorescence two-dimensional difference gel electrophoresis.

Ischemia-reperfusion injury is a major complication occurring in acute myocardial infarction, cardiopulmonary bypass surgery, and heart transplantation. The aim of this study was to identify proteins that were involved in ischemia-reperfusion injury using fluorescence two-dimensional difference gel electrophoresis. We compared the 100,000 x g precipitate fractions of normal, ischemic and ischemia-reperfused rat hearts and detected six spots which changed more than two-fold in expression level and two additional spots related to these spots.

Correlation between body composition and efficacy of lateral wedged insoles for medial compartment osteoarthritis of the knee.

Objective: To investigate anthropometric measures that closely correlate with symptomatic relief of osteoarthritis (OA) of the knee in response to lateral wedged insole use.

Methods: Seventy-one patients with medial compartment knee OA were treated with insoles with subtalar strapping or insoles with talonavicular strapping. Randomization was performed according to birth date.

Protective effect of Na+ /H+ exchange inhibitor, SM-20550, on impaired mitochondrial respiratory function and mitochondrial Ca2+ overload in ischemic/reperfused rat hearts.

The aim of this study was to investigate whether a selective Na+/H+ exchange inhibitor, SM-20550, can modulate the mitochondrial respiratory function and mitochondrial Ca2+ content in isolated rat hearts subjected to 40 min of ischemia and 20 min of reperfusion. SM-20550 (10, 100 nM) was administered for 5 min prior to ischemia and for 20 min during the reperfusion period. At 20 min after reperfusion, treatment with SM-20550 (10, 100 nM) improved the recovery of left ventricular developed pressure and suppressed the rise in left ventricular end-diastolic pressure.

Effects of SM-20550, a new Na(+)/H(+) exchange inhibitor, on survival and infarct size in rat myocardial infarction.

The effect of a novel potent Na(+)/H(+) exchange inhibitor, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid], on survival after myocardial infarction was studied. Anesthetized rats underwent occlusion of the coronary artery (30 min) followed by reperfusion (14 days). SM-20550 was administered intravenously before ischemia (1-day treatment group) or before ischemia and on the 2 days following (3-day treatment group).

Effect of an orally active Na+/H+ exchange inhibitor, SMP-300, on experimental angina and myocardial infarction models in rats.

The effects of SMP-300, an orally active, potent, and selective Na+/H+ exchange inhibitor, were evaluated and compared with those of nifedipine, propranolol, and nicorandil on three experimental angina models and on myocardial infarction in rats. SMP-300 (0.1-1 mg/kg, p.