Photoimmunotherapy targeting biliary-pancreatic cancer with humanized anti-TROP2 antibody.

Photoimmunotherapy (PIT) is a new type of tumor-specific treatment utilizing monoclonal antibody (mAb)-photosensitizer conjugates and near-infrared (NIR) light irradiation. One potential PIT target, the type I transmembrane protein TROP2, is expressed at high levels in many cancers, including pancreatic carcinoma (PC) and cholangiocarcinoma (CC), in which its expression is correlated with poor prognosis and tumor aggressiveness. In this study, we assessed the efficacy of PIT utilizing newly developed humanized anti-TROP2 mAb conjugated to the photosensitizer IR700 (TROP2-IR700) for PC and CC. Immunohistochemistry on PC and CC tissue microarrays confirmed that TROP2 is overexpressed in about half of PC and CC specimens. Using cultured PC and CC cells, TROP2-IR700 localized TROP2-specific and target-specific cell killing was observed after NIR light irradiation. In addition, TROP2-IR700 was localized to mouse xenograft tumors expressing TROP2 after intravenous injection. PC and CC xenograft tumor growth was significantly inhibited by TROP2-targeted PIT relative to controls. The efficacy of TROP2-targeted PIT in vitro and against xenografted tumors in vivo suggests promise as a therapy for human PC and CC, both of which currently have dismal prognoses and limited therapeutic options.

Cytochrome P450 genes play central roles in transcriptional response by keratinocytes to a high-voltage alternating current electric field.

The endogenous electric field (EF) of skin wounds plays an important role in the biological processes that underlie wound healing. Treatments that modulate wound-EFs promote healing. However, the mechanism(s) that underlie this effect remain unclear. Agilent-based microarrays were used to determine the transcriptomes of the keratinocyte line HaCaT, normal human dermal fibroblasts, and the human dermal endothelial cell line HMEC-1 before and after high-voltage alternating current (AC)-EF (14,000 V, 90 Hz) treatment. The keratinocytes had the most genes whose transcription was altered by EF. They included the cytochrome P450 (CYP) genes CYP1A1 and CYP1B1, HMOX1, EREG, DUSP5, and SLC7A11 (all upregulated), and DOCK8, ABCC6, and CYP26A1 (all downregulated). As shown by transcriptional-network analysis, all three CYP genes played central roles in the EF-induced changes in keratinocyte transcriptome. To the best of our knowledge, this is the first study that demonstrates that CYP genes play a key role in the transcriptional responses of human keratinocytes to EF treatment. Further investigations into the effects of EF on wound healing, aging, and regenerative medicine are likely to yield promising results.

Prior Direct Oral Anticoagulant Therapy is Related to Small Infarct Volume and No Major Artery Occlusion in Patients With Stroke and Non-Valvular Atrial Fibrillation.

Background The aims of the present study were to investigate the relationships between prior direct oral anticoagulant ( DOAC ) therapy and infarct volume and the site of arterial occlusion in patients with acute ischemic stroke and non-valvular atrial fibrillation. Methods and Results From March 2011 through November 2016, consecutive patients with acute ischemic stroke in the middle cerebral artery territory and non-valvular atrial fibrillation were recruited. The infarct volume was assessed semi-automatically using initial diffusion-weighted imaging, and the arterial occlusion site was evaluated on magnetic resonance angiography. The effect of prior DOAC treatment on the site of arterial occlusion was assessed by multivariate ordinal logistic regression analysis. A total of 330 patients (149 women; median age 79 [quartiles 71-86] years; median National Institutes of Health Stroke Scale score 11 [4-21]) were enrolled. Of these, 239 were on no anticoagulant, 40 were undertreated with a vitamin K antagonist ( VKA ), 22 were sufficiently treated with VKA ( PT - INR ≥1.6), and 29 were on a DOAC before the acute ischemic stroke. The infarct volume on admission differed among the groups (median 14.5 [2.0-59.8] cm3 in patients with no anticoagulation, 24.8 [2.1-63.0] in undertreated VKA , 1.3 [0.3-13.5] in sufficient VKA , and 2.3 [0.5-21.0] in DOAC , P=0.001). Multivariate analysis showed that prior DOAC treatment was independently and negatively associated with more proximal artery occlusion (odds ratio [OR] 0.34, P=0.015), compared with no anticoagulant. Conclusions DOAC treatment before the event was associated with smaller infarct volume and decreased risk of greater proximal artery occlusion in acute ischemic stroke patients with non-valvular atrial fibrillation, compared with no anticoagulation.

Effect of Kampo medicine "Dai-kenchu-to" on microbiome in the intestine of the rats with fast stress.

PURPOSE: Diversity of gut microbiome has been recently reported to be lost in inflammatory bowel disease. We have previously reported that the Dai-kenchu-to (DKT) prevented the bacterial translocation through suppression of cytokine and apoptosis in rat's fast stress model. The aim of this study was to evaluate the effect of DKT on maintenance of microbial diversity in rat's intestine with inflammation. METHOD: Wister rats were received the fast stress for 5 days. In DKT group, rats were administered with DKT (300 mg/kg/day) during the fast stress (DKT-group). The gut microbiomes were analyzed at before- and after- fast stress, and the effect of DKT for on microbial diversities of the gut were evaluated by the PCR-clone library method targeting the 16 S ribosomal RNA gene. RESULT: In Control-group, Erysipelotrichaceae increased to 86% in after fast stress, OTU of before-fast stress was 111 and after fast stress was only 9 (changing rate: 58%). The diversity of microbiome was severely decreased. On the other hand, in DKT-group, diversity of microbiome was kept after fast stress (Lachnospiraceae: Ruminococcaceae: Coriobacteriales 54%, 22%, 5%), Operational taxonomic units of before fast stress was 52 and after fast stress was 55 (changing rate: 6%). Family Lachnospiraceae which includes butyrate-producing Clostridia (Clostridium IV and XIVa). CONCLUSION: DKT prevented the reduction of diversity of microbiome in rat's fast stress model. Our data suggested the new anti-inflammatory mechanism of DKT through gut microbiome.