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Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. We aimed to clarify whether perioperative exercise capacity was related to long-term survival in hepatocellular carcinoma patients with chronic liver injury undergoing hepatectomy. One hundred-six patients with hepatocellular carcinoma underwent pre- and postoperative cardiopulmonary exercise testing to determine their anaerobic threshold, defined as the point between carbon dioxide production and oxygen consumption per unit of time. Testing involved 35 items including blood biochemistry analysis, in-vivo component analysis, dual-energy X-ray absorptiometry, and cardiopulmonary exercise testing preoperatively and 6 months postoperatively. We classified patients with anaerobic threshold ≥ 90% 6 months postoperatively compared with the preoperative level as the maintenance group (n = 78) and patients with anaerobic threshold < 90% as the decrease group (n = 28). Five-year recurrence-free survival rates were 39.9% vs. 9.9% (maintenance vs. decrease group) (hazard ratio: 1.87 [95% confidence interval: 1.12-3.13]; P = 0.018). Five-year overall survival rates were maintenance: 81.9%, and decrease: 61.7% (hazard ratio: 2.95 [95% confidence interval: 1.37-6.33]; P = 0.006). Multivariable Cox proportional hazards models showed that perioperative maintenance of anaerobic threshold was an independent prognostic indicator for both recurrence-free- and overall survival. Although the mean anaerobic threshold from preoperative to postoperative month 6 decreased in the exercise-not-implemented group, the exercise-implemented group experienced increased anaerobic threshold, on average, at postoperative month 6. The significant prognostic factor affecting postoperative survival for chronic liver injury patients with HCC undergoing hepatectomy was maintenance of anaerobic threshold up to 6 months postoperatively.

Fusarium sporotrichioides strain M-1-1, originally deposited as Fusarium solani IFO 9955 in 1974 and later moved to NBRC, is known for producing T-2 toxin. In addition to NRRL 3299, which was used in the United States to study T-2 toxin biosynthesis, NBRC 9955 has been extensively used for trichothecene research in Japan. To facilitate and accurately document studies on trichothecene biosynthesis using NBRC 9955, its phylogenetic classification and trichothecene metabolite profiles were determined. As anticipated, NBRC 9955 was classified as F. sporotrichioides, which exhibited a more distant phylogenetic relationship to other strains within the same species. Time-course TLC analyses demonstrated the accumulation of various deacetylated trichothecenes in yeast extract-rich liquid media during the late growth stages. Conversely, an increase in 3-O-acetylation of T-2 toxin was observed at late stages when cultivated in micronutrient-poor synthetic liquid medium. Northern blot analysis revealed that Tri8 expression halted in cultures with the synthetic medium, which accounts for the growth stage-dependent 3-O-acetylation observed. On a brown rice flour solid medium, the fungal strain produced mixtures of T-2 toxin, neosolaniol, HT-2 toxin, and their 3-O-acetyl derivatives. These results highlight the risk of underestimating the levels of toxic trichothecene metabolites when using the standard contamination monitoring protocols.

Members of the IRAK family of kinases mediate Toll-like receptor (TLR) signaling. Here we show that IRAK2 was essential for sustaining TLR-induced expression of genes encoding cytokines and activation of the transcription factor NF-κB, despite the fact that IRAK2 was dispensable for activation of the initial signaling cascades. IRAK2 was activated 'downstream' of IRAK4, like IRAK1, and TLR-induced cytokine production was abrogated in the absence of both IRAK1 and IRAK2. Whereas the kinase activity of IRAK1 decreased within 1 h of TLR2 stimulation, coincident with IRAK1 degradation, the kinase activity of IRAK2 was sustained and peaked at 8 h after stimulation. Thus, IRAK2 is critical in late-phase TLR responses, and IRAK1 and IRAK2 are essential for the initial responses to TLR stimulation.

Background Various tubes may be fixed to the skin by ligation using silk sutures after gastrointestinal surgery. We investigated the effects of a skin substitute, “Nonaht®,” on pain and skin inflammation at the fixation sites of various tubes. Methods The effects of tubes (abdominal drains, small intestinal feeding tubes, and bile duct drainage tubes) fixed in place using either silk sutures or Nonaht were compared for 1–3 months. Results The median pain scores at the fixation site when abdominal drains were removed were 1.0 with silk sutures and 0 with Nonaht ( p  < 0.001). Scarring at the fixation site at postoperative month (POM) 1 occurred in 13 of 28 cases in the silk suture group and in no cases in the Nonaht group ( p  < 0.001). The median pain scores at the fixation site with long-term tubes on postoperative day (POD) 14 and POM 1 were 2.0 and 1.0, respectively, with silk sutures, and none at all time points with Nonaht ( p  < 0.001). Scarring at the fixation site at POM 3 occurred in all 10 cases in the silk suture group and in no cases in the Nonaht group ( p  < 0.001). Conclusions Patients with conventional skin fixation of tubes using silk sutures were continuously aware of pain at the fixation site and developed skin damage and subsequent scar formation, especially for tubes inserted for ≥ 1 month. The use of Nonaht may reduce the incidence of dermatitis and wound infections at tube fixation sites, thereby promoting early postoperative recovery.

Lactosomes™ are biocompatible nanoparticles that can be used for cancer tissue imaging and drug delivery. Lactosomes are polymeric micelles formed by the self-assembly of biodegradable amphiphilic block copolymers composed of hydrophilic polysarcosine and hydrophobic poly-L-lactic acid chains. The particle size can be controlled in the range of 20 to 100 nm. Lactosomes can also be loaded with hydrophobic imaging probes and photosensitizers, such as indocyanine green. Indocyanine green-loaded lactosomes are stable for long-term circulation in the blood, allowing for accumulation in cancer tissues. Such lactosomes function as a photosensitizer, which simultaneously enables fluorescence diagnosis and photodynamic therapy. This review provides an overview of lactosomes with respect to molecular design, accumulation in cancer tissue, and theranostics applications. The use of lactosomes can facilitate the treatment of cancers in unresectable tissues, such as glioblastoma and head and neck cancers, which can lead to improved quality of life for patients with recurrent and unresectable cancers. We conclude by describing some outstanding questions and future directions for cancer theranostics with respect to clinical applications.

DNA vaccines induce adaptive immune responses mainly via induction of type-I interferon. This paper shows that this occurs by a mechanism that is independent of the activation of nucleic acid binding Toll-like receptors. B and CD4 + T cell responses require activation of the TBK pathway in hematopoietic cells, whereas TBK1 in non-hematopoietic cells is critical for the activation of CD8 + T cells. Successful vaccines contain not only protective antigen(s) but also an adjuvant component that triggers innate immune activation and is necessary for their optimal immunogenicity 1 , 2 . In the case of DNA vaccines 3 , this consists of plasmid DNA; however, the adjuvant element(s) as well as its intra- and inter-cellular innate immune signalling pathway(s) leading to the encoded antigen-specific T- and B-cell responses remain unclear. Here we demonstrate in vivo that TANK-binding kinase 1 (TBK1), a non-canonical IκB kinase, mediates the adjuvant effect of DNA vaccines and is essential for its immunogenicity in mice. Plasmid-DNA-activated, TBK1-dependent signalling and the resultant type-I interferon receptor-mediated signalling was required for induction of antigen-specific B and T cells, which occurred even in the absence of innate immune signalling through a well known CpG DNA sensor—Toll-like receptor 9 (TLR9) or Z-DNA binding protein 1 (ZBP1, also known as DAI, which was recently reported as a potential B-form DNA sensor 4 ). Moreover, bone-marrow-transfer experiments revealed that TBK1-mediated signalling in haematopoietic cells was critical for the induction of antigen-specific B and CD4 + T cells, whereas in non-haematopoietic cells TBK1 was required for CD8 + T-cell induction. These data suggest that TBK1 is a key signalling molecule for DNA-vaccine-induced immunogenicity, by differentially controlling DNA-activated innate immune signalling through haematopoietic and non-haematopoietic cells.

Purpose and background For the past decade, there have been few chemotherapy options for unresectable biliary tract cancer (BTC). Recently, however, combination therapy with gemcitabine and cisplatin plus S-1 (GCS) has been identified as a promising strategy. This retrospective study analyzes the clinical results of GCS therapy and subsequent conversion surgery (CS). Method We analyzed the clinical data of 60 consecutive patients who received GCS therapy for unresectable upper BTC at our university hospital during the 5 years between September, 2018 and December, 2022. Results All patients received GCS therapy as first-line chemotherapy. The response rate was 33.9% and subsequent CS was performed in 35.0%. Of the patients who underwent CS, 81% required more than bisectionectomy of the liver with extrahepatic bile duct resection. The median overall survival of the patients who received GCS therapy and underwent subsequent CS was significantly longer than that of the patients who received GCS therapy alone (28.0 months vs. 12.4 months, respectively; p  < 0.001). A decrease in the CA19-9 level 1 month after chemotherapy and RECIST PR were independent positive predictors of CS, whereas unresectable gallbladder cancer and pretreatment ALBI grade 3 were negative predictors of CS. Conclusion GCS therapy and subsequent CS may contribute to the longer term survival of patients with unresectable upper BTC.

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses 1 , 2 . The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition 3 , 4 , 5 , 6 , 7 . In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue 3 . Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified 8 , the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 ( MDA5 -/- ) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I -/- and MDA5 -/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.

The trichothecene biosynthesis in Fusarium begins with the cyclization of farnesyl pyrophosphate to trichodiene, followed by subsequent oxygenation to isotrichotriol. This initial bicyclic intermediate is further cyclized to isotrichodermol (ITDmol), a tricyclic precursor with a toxic trichothecene skeleton. Although the first cyclization and subsequent oxygenation are catalyzed by enzymes encoded by Tri5 and Tri4, the second cyclization occurs non-enzymatically. Following ITDmol formation, the enzymes encoded by Tri101, Tri11, Tri3, and Tri1 catalyze 3-O-acetylation, 15-hydroxylation, 15-O-acetylation, and A-ring oxygenation, respectively. In this study, we extensively analyzed the metabolites of the corresponding pathway-blocked mutants of Fusarium graminearum. The disruption of these Tri genes, except Tri3, led to the accumulation of tricyclic trichothecenes as the main products: ITDmol due to Tri101 disruption; a mixture of isotrichodermin (ITD), 7-hydroxyisotrichodermin (7-HIT), and 8-hydroxyisotrichodermin (8-HIT) due to Tri11 disruption; and a mixture of calonectrin and 3-deacetylcalonectrin due to Tri1 disruption. However, the ΔFgtri3 mutant accumulated substantial amounts of bicyclic metabolites, isotrichotriol and trichotriol, in addition to tricyclic 15-deacetylcalonectrin (15-deCAL). The ΔFgtri5ΔFgtri3 double gene disruptant transformed ITD into 7-HIT, 8-HIT, and 15-deCAL. The deletion of FgTri3 and overexpression of Tri6 and Tri10 trichothecene regulatory genes did not result in the accumulation of 15-deCAL in the transgenic strain. Thus, the absence of Tri3p and/or the presence of a small amount of 15-deCAL adversely affected the non-enzymatic second cyclization and C-15 hydroxylation steps.

Recent meta-analyses concluded that antibiotic prophylaxis is not warranted in low-risk laparoscopic cholecystectomy. However, most trials in the meta-analyses had a relatively small sample size and were statistically underpowered. In addition, many of the trials mentioned potential cost savings owing to the elimination of prophylactic antibiotics. However, no trial has statistically estimated the cost effectiveness. To evaluate the results of meta-analyses, we conducted a randomized controlled trial on the role of prophylactic antibiotics in low-risk laparoscopic cholecystectomy with an adequate sample size. From March 2007 to May 2013, at the Department of Surgery, Kansai Medical University, patients who were scheduled for elective laparoscopic cholecystectomy were randomly assigned to one of two arms: those who were and were not administered prophylactic antibiotics. The primary endpoint was the occurrence of postoperative infections and secondary endpoints were postoperative hospital stay and medical costs. During the study period, 518 patients were assigned to the Antibiotics group and 519 to the No antibiotics group. Occurrences of surgical site infections, distant infections and overall infections were significantly lower in the Antibiotics group than in the No antibiotics group (0.8 vs. 3.7%, p = 0.001, OR: 0.205 (95%CI: 0.069 to 0.606); 0.4 vs. 3.1%, p = 0.0004, OR: 0.122 (95%CI: 0.028 to 0.533); 1.2 vs. 6.7%; p<0.0001, OR: 0.162 (95%CI: 0.068 to 0.389), respectively). The postoperative hospital stay was significantly shorter in the Antibiotics group (mean, SD: 3.69±1.56 vs. 4.07±3.00; p = 0.01) and the postoperative medical costs were significantly lower in the Antibiotics group (mean, SD: $766±341 vs. 832±670; p = 0.047). Multivariable analysis showed that independent risk factors for postoperative infectious complications were no prophylactic antibiotics (p<0.0001) and age 65 or older (p = 0.006). Perioperative administration of prophylactic antibiotics should be recommended in laparoscopic cholecystectomy to prevent postoperative infectious complications and to reduce medical costs. UMIN Clinical Trials Registry UMIN000003749.