Difamilast ointment in adult patients with atopic dermatitis: A phase 3 randomized, double-blind, vehicle-controlled trial.

BACKGROUND: Difamilast is a selective phosphodiesterase 4 inhibitor. Phosphodiesterase 4 is involved in cytokine production linked with inflammatory disorders, including atopic dermatitis. OBJECTIVE: To demonstrate the superiority of difamilast ointment 1% to vehicle in adult Japanese patients with atopic dermatitis. METHODS: In this phase 3, randomized, double-blind trial, patients aged 15-70 years with an investigator global assessment score of 2 or 3 received topical difamilast ointment 1% (n = 182) or a vehicle (n = 182) twice daily for 4 weeks. RESULTS: The success rate in investigator global assessment score at week 4 (primary endpoint)-the percentage of patients achieving an investigator global assessment score of 0 or 1 with ≥2-grade improvement-was significantly higher with 1% difamilast than with the vehicle (38.46% vs 12.64%, respectively, P < .0001). The success rates in ≥50%, ≥75%, and ≥90% improvement in overall eczema area and severity index score at week 4 followed the same trend. Difamilast at 1% provided significant mean percent improvement from baseline in overall eczema area and severity index score versus vehicle from week 1 to 4. Treatment-emergent adverse events were mostly mild or moderate and less frequent with difamilast. LIMITATIONS: Study treatment was limited to 4 weeks. CONCLUSION: Difamilast ointment 1% demonstrated superiority to the vehicle and favorable safety in adult Japanese patients with atopic dermatitis.

Biocompatible and Na+-sensitive thin-film transistor for biological fluid sensing.

In this study, we develop a Na+-sensitive thin-film transistor (TFT) for a biocompatible ion sensor and investigate its cytotoxicity. A transparent amorphous oxide semiconductor composed of amorphous In-Ga-Zn-oxide (a-InGaZnO) is utilized as a channel of the Na+-sensitive TFT, which includes an indium tin oxide (ITO) film as the source and drain electrodes and a Ta2O5 thin-film gate, onto which a Na+-sensitive membrane is coated. As one of the Na+-sensitive membranes, the polyvinyl chloride (PVC) membrane with bis(12-crown-4) as the ionophore used on the TFT sensors shows good sensitivity and selectivity to changes in Na+ concentration but has high cytotoxicity owing to the leaching of its plasticizer to the solution; the plasticizer is added to solve and entrap the ionophore in the PVC membrane. On the other hand, a plasticizer-free Na+-sensitive membrane, the fluoropolysilicone (FPS) membrane with the bis(12-crown-4) ionophore, also reduces cell viability owing to the leaching of the ionophore. However, the FPS membrane with calix[4]arene as the ionophore on the gate of TFT sensors exhibits not only favorable electrical properties but also the lack of cytotoxicity. Thus, considering structural flexibility of TFTs, a platform based on TFT sensors coated with the Na+-sensitive FPS membrane containing calix[4]arene is suitable as a biocompatible Na+ sensing system for the continuous monitoring of ionic components in biological fluids such as sweat and tears.

Comparative effectiveness of angioembolization versus open surgery in patients with blunt splenic injury.

The effectiveness and safety of transcatheter splenic artery embolization (SAE) compared to those of open surgery in patients with blunt splenic injury (BSI) remain unclear. This retrospective cohort-matched study utilized data from the Japan Trauma Data Bank recorded between 2004 and 2019. Patients with BSI who underwent SAE or open surgery were selected. A propensity score matching analysis was used to balance the baseline covariates and compare outcomes, including all-cause in-hospital mortality and spleen salvage. From 361,706 patients recorded in the data source, this study included 2,192 patients with BSI who underwent SAE or open surgery. A propensity score matching analysis was used to extract 377 matched pairs of patients. The in-hospital mortality rates (SAE, 11.6% vs. open surgery, 11.2%, adjusted relative risk (aRR): 0.64; 95% confidence interval [CI]: 0.38-1.09, p = 0.10) were similar in both the groups. However, spleen salvage was significantly less achieved in the open surgery group than in the SAE group (SAE, 87.1% vs. open surgery, 32.1%; aRR: 2.84, 95%CI: 2.29-3.51, p < 0.001). Survival rates did not significantly differ between BSI patients undergoing SAE and those undergoing open surgery. Nonetheless, SAE was notably associated with a higher likelihood of successful spleen salvage.

Ultrasensitive enzyme-linked immunosorbent assay for the detection of MPT64 secretory antigen to evaluate Mycobacterium tuberculosis viability in sputum.

OBJECTIVES: This study examined Mycobacterium tuberculosis (MTB)-secreted MPT64 as a surrogate of bacterial viability for the diagnosis of active pulmonary TB (PTB) and for follow-up treatment. METHODS: In this proof-of-concept prospective study, 50 PTB patients in the Tokyo metropolitan region, between 2017 and 2018, were consecutively included and 30 healthy individuals were also included. Each PTB patient submitted sputum on days 0, 14 and 28 for diagnosis and follow-up, and each healthy individual submitted one sputum sample. The following were performed: smear microscopy, Xpert MTB/RIF, MGIT and solid culture, and MPT64 detection on the sputum samples. Ultrasensitive ELISA (usELISA) was used to detect MPT64. The receiver operating characteristic analyses for diagnosis and follow-up revealed the optimal cut-off value of MPT64 absorbance for detecting culture positivity at multiple intervals. RESULTS: The sensitivity of MPT64 for diagnosing PTB was 88.0% (95% CI 75.7-95.5) and the specificity was 96.7% (95% CI 82.8-99.9). The specificity of MPT64 for predicting negative culture results on day 14 was 89.5% (95% CI 66.9-98.7). The sensitivity of MPT64 for predicting positive culture results on day 28 was 81.0% (95% CI 58.1-94.6). CONCLUSIONS: This study revealed that MPT64 is useful for diagnosing active PTB in patients and predicting treatment efficacy at follow-up.

Ductal carcinoma in situ: correlation between FDG-PET/CT and histopathology.

PURPOSE: The aim of this study was to determine if any correlation exists between tumor cell density and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET)/CT) for pure or predominant ductal carcinoma in situ (DCIS). MATERIALS AND METHODS: Subjects in this retrospective review comprised 11 patients who underwent FDG-PET/CT for DCIS. Pathological tumor cell density and FDG-PET/CT images were compared. A tumor background count density ratio of >1.5 was defined as the detectable range for DCIS. RESULTS: Pathological density of disease was high in eight patients, intermediate in one, and low in two. In all eight patients with a detectable intraductal component on PET/CT, the density of disease was classified as high. In three patients undetected by PET/CT, the density of disease was classified as intermediate or low. On statistical analysis, the correlation between the density of disease and tumor background count density ratio (TBCDR) on PET/CT was significant (<0.05), whereas the nuclear grade and Van Nuys grade were not significant. In the eight patients detected by PET/CT, the discrepancy between histopathological mapping and FDG-PET/CT mapping was >20 mm in four patients and represented underestimation in four patients who showed low density of disease in the peripheral area. CONCLUSIONS: Tumor cell density of intraductal carcinoma appears strongly correlated to detection by FDG-PET/CT.

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication.

ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy.

The Effect of 5-Aminolevulinic Acid on Cytochrome P450-Mediated Prodrug Activation.

Of late, numerous prodrugs are widely used for therapy. The hemeprotein cytochrome P450 (CYP) catalyzes the activation of prodrugs to form active metabolites. Therefore, the activation of CYP function might allow the use of lower doses of prodrugs and decrease toxicity. We hypothesized that the addition of 5-aminolevulinic acid (ALA), a precursor in the porphyrin biosynthetic pathway, enhances the synthesis of heme, leading to the up-regulation of CYP activity. To test this hypothesis, we treated a human gastric cancer cell line with ALA and determined the effect on CYP-dependent prodrug activation. For this purpose, we focused on the anticancer prodrug tegafur, which is converted to its active metabolite 5-fluorouracil (5-FU) mainly by CYP2A6. We show here that ALA increased CYP2A6-dependent tegafur activation, suggesting that ALA elevated CYP activity and potentiated the activation of the prodrug.