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Abstract Background Nonresectable gastric cancer develops rapidly; thus, monitoring disease progression especially in patients receiving nivolumab as late-line therapy is important. Biomarkers may facilitate the evaluation of nivolumab treatment response. Herein, we assessed the utility of serum-based inflammatory indicators for evaluating tumor response to nivolumab. Methods This multicenter retrospective cohort study included 111 patients treated with nivolumab monotherapy for nonresectable advanced or recurrent gastric cancer from October 2017 to October 2021. We measured changes in the C-reactive protein (CRP)-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in serum from baseline to after the fourth administration of nivolumab. Furthermore, we calculated the area under the receiver operating characteristic curves (AUC ROCs) for CAR, PLR, and NLR to identify the optimal cutoff values for treatment response. We also investigated the relationship between clinicopathologic factors and disease control (complete response, partial response, and stable disease) using the chi-squared test. Results The overall response rate (complete and partial response) was 11.7%, and the disease control rate was 44.1%. The median overall survival (OS) was 14.0 (95% CI 10.7‒19.2) months, and the median progression-free survival (PFS) was 4.1 (95% CI 3.0‒5.9) months. The AUC ROCs for CAR, PLR, and NLR before nivolumab monotherapy for patients with progressive disease (PD) were 0.574 (95% CI, 0.461‒0.687), 0.528 (95% CI, 0.418‒0.637), and 0.511 (95% CI, 0.401‒0.620), respectively. The values for changes in CAR, PLR, and NLR were 0.766 (95% CI, 0.666‒0.865), 0.707 (95% CI, 0.607‒0.807), and 0.660 (95% CI 0.556‒0.765), respectively. The cutoff values for the treatment response were 3.0, 1.3, and 1.4 for CAR, PLR, and NLR, respectively. The PFS and OS were significantly longer when the treatment response values for changes in CAR, PLR, and NLR were below these cutoff values (CAR: OS, p

Abstract Background The da Vinci™ Surgical System, recognized as the leading surgical robotic platform globally, now faces competition from a growing number of new robotic surgical systems. With the expiration of key patents, innovative entrants have emerged, each offering unique features to address limitations and challenges in minimally invasive surgery. The hinotori™ Surgical Robot System (hinotori), developed in Japan and approved for clinical use in November 2022, represents one such entrant. This study demonstrates initial insights into the application of the hinotori in robot-assisted surgeries for patients with rectal neoplasms. Methods The present study, conducted at a single institution, retrospectively reviewed 28 patients with rectal neoplasms treated with the hinotori from November 2022 to March 2024. The surgical technique involved placing five ports, including one for an assistant, and performing either total or tumor-specific mesorectal excision using the double bipolar method (DBM). The DBM uses two bipolar instruments depending on the situation, typically Maryland bipolar forceps on the right and Fenestrated bipolar forceps on the left, to allow precise dissection, hemostasis, and lymph node dissection. Results The study group comprised 28 patients, half of whom were male. The median age was 62 years and the body mass index stood at 22.1 kg/m2. Distribution of clinical stages included eight at stage I, five at stage II, twelve at stage III, and three at stage IV. The majority, 26 patients (92.9%), underwent anterior resection using a double stapling technique. There were no intraoperative complications or conversions to other surgical approaches. The median operative time and cockpit time were 257 and 148 min, respectively. Blood loss was 15 mL. Postoperative complications were infrequent, with only one patient experiencing transient ileus. A median of 18 lymph nodes was retrieved, and no positive surgical margins were identified. Conclusions The introduction of the hinotori for rectal neoplasms appears to be safe and feasible, particularly when performed by experienced robotic surgeons. The double bipolar method enabled precise dissection and hemostasis, contributing to minimal blood loss and effective lymph node dissection.

Abstract Background This study aimed to investigate the effect of the use of new lithotomy stirrups-2 on the pressure dispersal on lower limbs, which may lead to the prevention of well-leg compartment syndrome (WLCS) and deep venous thrombosis (DVT), which are the most commonly associated adverse events with laparoscopic and robot-assisted rectal surgery. Methods A total of 30 healthy participants were included in this study. The pressure (mmHg) applied on various lower limb muscles when using conventional lithotomy stirrups-1 and new type stirrups-2 was recorded in various lithotomy positions; 1) neutral position, 2) Trendelenburg position (15°) with a 0° right inferior tilt, and 3) Trendelenburg position (15°) with a 10° right inferior tilt. Using a special sensor pad named Palm Q®, and the average values were compared between two types of stirrups. Results The use of new lithotomy stirrups-2 significantly reduced the pressure applied on the lower limb muscles in various lithotomy positions compared with the use of lithotomy stirrups-1. The most pressured lower limb muscle when using both lithotomy stirrups was the central soleus muscle, which is the most common site for the development of WLCS and DVT. In addition, when using the conventional lithotomy stirrups-1, the pressure was predominantly applied to the proximal soleus muscle; however, when using lithotomy stirrups-2, the pressure was shifted to the more distal soleus muscle. Conclusion These results suggest that the new lithotomy stirrups-2 is useful in reducing the pressure load on leg muscles, especially on the proximal to central soleus, and may reduce the incidence of WLCS and DVT after rectal surgery performed in the lithotomy position. Further clinical studies are needed to determine whether the use of lithotomy stirrups-2 prevents these complications in various clinical settings.

Abstract Aim Lenvatinib mesylate (LEN) is an oral tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events. This study was aimed at investigating the incidence of LEN‐induced palmar‐planter erythrodysesthesia syndrome (PPES) and its relationship with patient demographics by analyzing clinical laboratory data of LEN‐treated patients with HCC. Methods This was a single‐centre, retrospective study of patients with HCC who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration. Results Overall, 75 patients with HCC were enrolled. LEN‐induced PPES was found in 48.0% (36/75 patients). In these patients, alkaline phosphatase (ALP), γ‐Glutamyl transpeptidase (γ‐GTP) and monocytes (MONO) were significantly high (ALP: p = 1.32 × 10−3, γ‐GTP: p = 4.25 × 10−3 and MONO: p = 0.013). The cut off values of ALP, γ‐GTP and MONO for LEN‐induced PPES were estimated at 573 U/L, 89 U/L, and 310 counts/μL, respectively. In the multivariate analysis, γ‐GTP and MONO were independent risk factors for LEN‐induced PPES. Conclusions High γ‐GTP and high MONO were risk factors for LEN‐induced PPES.

Abstract Background Hydrocele of the canal of Nuck (HCN) is a rare disease, and its indications for laparoscopic surgery are not well-established. Case presentation A 53-year-old woman was referred to our hospital due to an uncomfortable thumb-sized inguinal mass. Preoperative computed tomography scan and magnetic resonance imaging revealed a hydrocele extending from the abdominal cavity around the left deep inguinal ring via the inguinal canal to the subcutaneous space. The patient was diagnosed with HCN protruding into the abdominal cavity and extending to the subcutaneous space. Laparoscopy can easily access the hydrocele protruding into the abdominal cavity. Furthermore, laparoscopic hernioplasty can be superior to the anterior approach for females. Hence, laparoscopic surgery was performed. After transecting the round ligament of the uterus, a tense 3-cm hydrocele was dissected with it. In order to approach the hydrocele distal to the deep inguinal ring, the transversalis fascia was incised medially to the inferior epigastric vessels. The subcutaneously connected hydrocele was excised from the incision. Then, the enlarged deep inguinal ring was reinforced using a mesh with the laparoscopic transabdominal preperitoneal approach. The patient was discharged 2 days postoperatively. Laparoscopic resection can be more effective for a hydrocele protruding into the abdominal cavity as it facilitates an easy access to the hydrocele. Moreover, laparoscopic resection of a hydrocele extending from the inguinal canal to the subcutaneous space via a transversalis fascia incision can be safer, with low risk of injury to the inferior epigastric vessels. The incised transversalis fascia and the enlarged deep inguinal ring due to the HCN were simultaneously repaired with the laparoscopic transabdominal preperitoneal repair. There are two reports on laparoscopic resection via a transversalis fascia incision for HCNs located between the inguinal canal and the subcutaneous space, which does not require intraperitoneal hydrocelectomy. However, this is the first report on laparoscopic resection of large HCNs protruding into the abdominal cavity and extending beyond the inguinal canal into the subcutaneous space via intraperitoneal hydrocelectomy and a transversalis fascia incision. Conclusions Laparoscopic surgery with transversalis fascia incision can be useful for HCNs extending from the abdominal cavity to the subcutaneous space.

Abstract Background Although most duodenal carcinomas are pathological adenocarcinomas, a small number of cases have been reported of adenosquamous carcinoma, characterized by variable combinations of two malignant components: adenocarcinoma and squamous cell carcinoma. However, owing to the small number of cases of non-ampullary duodenal adenosquamous carcinoma, there have been no reported cases of emergency pancreaticoduodenectomy for gastrointestinal hemorrhage due to non-ampullary duodenal adenosquamous carcinoma. Case presentation A 66-year-old Japanese male presented to the referring hospital with a chief complaint of abdominal pain, diarrhea, and dark urine that had persisted for 1 month. The patient was referred to our hospital because of liver dysfunction on a blood examination. Laboratory results of the blood on the day of admission showed that total and direct bilirubin levels (12.0 mg/dl and 9.6 mg/dl) were markedly increased. An endoscopic retrograde biliary drainage tube was inserted for the treatment of obstructive jaundice, and imaging studies were continuously performed. Contrast-enhanced computed tomography and endoscopy revealed an ill-defined lesion involving the second portion of the duodenum, predominantly along the medial wall, and measuring 60 mm in diameter. No metastases were observed by positron emission tomography. Pancreaticoduodenectomy was planned based on the pathological findings of poorly differentiated adenocarcinoma. However, 2 days before the scheduled surgery, the patient experienced hemorrhagic shock with melena. Owing to poor hemostasis after endoscopic treatment and poor control of hemodynamic circulation despite blood transfusion, radiological embolization and hemostasis were attempted but were incomplete. An emergency pancreaticoduodenectomy was performed after embolizing the route from the gastroduodenal artery and pseudoaneurysm area to reduce bleeding. The operation was completed using an anterior approach without Kocherization or tunneling due to the huge tumor. The operation time was 4 h and 32 min, and blood loss was 595 mL The pathological diagnosis was adenosquamous carcinoma. The postoperative course was uneventful with 17 day hospital stay and the patient is currently well, with no signs of recurrence 9 months after surgery. Conclusions This report presents an extremely rare case of successful emergency pancreaticoduodenectomy for gastrointestinal hemorrhage caused by non-ampullary duodenal adenosquamous carcinoma.

BackgroundInterleukin (IL)-17-producing γδT (γδT17) cells mediate inflammatory responses in barrier tissues. Dysregulated γδT17 cell activation can lead to the overproduction of IL-17 and IL-22 and the development of inflammatory diseases, including psoriasis. IL-23 and IL-1β are known to synergistically activate γδT17 cells, but the regulatory mechanisms of γδT17 cells have not been fully elucidated. This study aimed to reveal the contribution of the inflammatory cytokine tumor necrosis factor-like ligand 1A (TL1A) to γδT17 cell activation and psoriasis development.MethodsAnti-TL1A antibody was injected into an imiquimod (IMQ)-induced murine psoriasis model. TL1A receptor expression was analyzed in splenic and dermal γδT cells. γδT cells were tested for cytokine production in vitro and in vivo under stimulation with IL-23, IL-1β, and TL1A. TL1A was applied to a psoriasis model induced by intradermal IL-23 injection. Mice deficient in γδT cells were intradermally injected with IL-23 plus TL1A to verify the contribution of TL1A-dependent γδT-cell activation to psoriasis development.ResultsNeutralization of TL1A attenuated γδT17 cell activation in IMQ-treated skin. TL1A induced cytokine production by splenic γδT17 cells in synergy with IL-23. Dermal γδT17 cells constitutively expressed a TL1A receptor at high levels and vigorously produced IL-22 upon intradermal IL-23 and TL1A injection but not IL-23 alone. TL1A exacerbated the dermal symptoms induced by IL-23 injection in wild-type but not in γδT cell–deficient mice.ConclusionThese findings suggest a novel regulatory mechanism of γδT cells through TL1A and its involvement in psoriasis pathogenesis as a possible therapeutic target.

Mycobacterium bovis bacilli Calmette-Guerin (BCG) is a licensed vaccine against tuberculosis. It requires attenuated live bacteria to be effective, possibly because actively secreted proteins play a critical role in inducing anti-tuberculosis immunity. BCG also functions as an effective adjuvant. Moreover, the effects of BCG components as adjuvants are not important as those of attenuated live BCG, which is used in cancer immunotherapy. However, the BCG secreted proteins have not been paid attention in anticancer immunity. To understand mycobacterial secreted proteins’ function, we investigate immune responses to BCG culture filtrate proteins (CFP). Here, CFP strongly induce both antigen-specific CD4+ T cells and specific CD8+ T cells, which may be functional cytotoxic T lymphocytes (CTLs). In this study, we clearly demonstrate that CFP acts as an adjuvant for CTL induction against specific co-administered proteins and propose CFP as a new protein adjuvant. The CTL response shows potent anticancer effects in mice. These findings could provide insight into the contribution of mycobacterial secreted proteins in both anticancer and antimycobacterial immunity.

Abstract Background Intravascular papillary endothelial hyperplasia (IPEH), also known as Masson's tumor, is a benign, non-neoplastic vascular lesion that is characterized by reactive proliferation of papillary endothelial cells associated with a thrombus. These lesions typically develop in the vascular regions of the head and neck, oral cavity, or extremities; however, other organ systems have been affected. IPEH in the gastrointestinal tract is rare, with only a few cases reported to date. Thus, the pathogenesis and clinical features of IPEH in the gastrointestinal tract are not entirely understood. Moreover, the local excision of certain subtypes of IPEH can be curative; this makes timely diagnosis essential. We present the case of a patient with IPEH in the cecum that was discovered while investigating the cause of severe anemia. Case presentation A 29-year-old woman visited a general practitioner (GP) with the complaint of abdominal pain. She was diagnosed with acute appendicitis and was prescribed antibiotics. After treatment, her abdominal pain disappeared. However, she was found to be severely anemic (hemoglobin level, 6.5 g/dl). To determine the cause of her anemia, the GP referred her to our hospital for further examination and treatment. Computed tomography scan revealed cecal wall thickening. Further, a lower gastrointestinal endoscopy revealed a 2-cm raised mass-like lesion in the cecum. This lesion was pathologically identified as an inflammatory granuloma. The cause of her anemia was determined to be bleeding from the lesion in the cecum. She underwent laparoscopic ileocecal resection. Histopathological examination of the surgical specimen revealed a spongy structure comprising many small papillary fibrous tissues lined by a typical monolayer endothelium. Further, immunohistochemical analysis showed that the cells of the endothelium monolayer expressed CD31, CD34. The Ki-67 labeling index was

Abstract The use of an adjuvant in vaccination is thought to be effective for enhancing immune responses to various pathogens. We genetically constructed a live attenuated simian human immunodeficiency virus (SHIV) to express the adjuvant molecule Ag85B (SHIV-Ag85B). SHIV-Ag85B could not be detected 4 weeks after injection in cynomolgus macaques, and strong SHIV-specific T cell responses were induced in these macaques. When the macaques in which SHIV-Ag85B had become undetectable were challenged with pathogenic SHIV89.6P at 37 weeks after SHIV-Ag85B had become undetectable, SHIV89.6P was not detected after the challenge. Eradication of SHIV89.6P was confirmed by adoptive transfer experiments and CD8-depletion studies. The SHIV-Ag85B-inoculated macaques showed enhancement of Gag-specific monofunctional and polyfunctional CD8+ T cells in the acute phase of the pathogenic SHIV challenge. The results suggest that SHIV-Ag85B elicited strong sterile immune responses against pathogenic SHIV and that it may lead to the development of a vaccine for AIDS virus infection.

We had reported the novel concept of “caudal approach in laparoscopic liver resection” in 2013. In the first report, the caudal approach of laparoscopic transection–first posterior sectionectomy without prior mobilization of the liver in the left lateral position was described. Thereafter, 10 complex laparoscopic extended posterior sectionectomies with combined resection of the right hepatic vein or diaphragm were performed using the same approach. In the present study, the short-term outcomes of these cases and 42 cases of laparoscopic sectionectomies or hemi-hepatectomies (excluding left lateral sectionectomy) were compared. There was no statistically significant difference between the groups in terms of patients’ backgrounds, diseases for resection, preoperative liver function, tumor number and size, as well as outcomes, operation time, intraoperative blood loss, morbidity, conversion to laparotomy, and post-operative hospital stay. Even complex laparoscopic extended posterior sectionectomy was safely performed using this procedure. This approach has the technical benefits of acquiring a well-opened transection plane between the resected liver fixed to the retroperitoneum and the residual liver sinking to the left with the force of gravity during parenchymal transection, and less bleeding from the right hepatic vein due to its higher position than the inferior vena cava. Furthermore, it has an oncological benefit similar to that of the anterior approach in open liver resection, even in posterior sectionectomy. The detailed procedure and general conceptual benefits of the caudal approach to laparoscopic liver resection for repeated multimodal treatment for hepatocellular carcinoma are described.

Antipsychotics are often the first-line treatment for behavioral and psychological symptoms of dementia. However, the potential anticholinergic effects of antipsychotics could counteract the therapeutic effects of cholinesterase inhibitors used to treat dementia. We investigated the inhibitory effects of 26 antipsychotics on [N-Methyl-3H]scopolamine specific binding in mouse cerebral cortex. At 10−5 M, chlorpromazine, levomepromazine, prochlorperazine, timiperone, zotepine, pimozide, blonanserin, olanzapine, quetiapine, and clozapine inhibited [N-Methyl-3H]scopolamine binding by > 45%. Furthermore, the pKi values of chlorpromazine, levomepromazine, zotepine, olanzapine, and clozapine overlapped with their clinically achievable blood concentrations. Therefore, the anticholinergic properties of these antipsychotics could attenuate the effects of cholinesterase inhibitors. Keywords: Antipsychotics, Anticholinergic effect, Mouse cerebral cortex

Abstract Background Since both the antibacterial effects and common adverse effects of colistin are concentration-dependent, determination of the most appropriate dosage regimen and administration method for colistin therapy is essential to ensure its efficacy and safety. We aimed to establish a rapid and simple high-performance liquid chromatography (HPLC)-based system for the clinical determination of colistin serum concentrations. Methods Extraction using a solid-phase C18 cartridge, derivatisation with 9-fluorenylmethyl chloroformate, and elution with a short reversed-phase Cl8 column effectively separated colistin from an internal standard. The HPLC apparatus and conditions were as follows: analytical column, Hydrosphere C18; sample injection volume, 50 μL; column temperature, 40 °C; detector, Shimadzu RF-5300 fluorescence spectrophotometer (excitation wavelength, 260 nm; emission wavelength, 315 nm); mobile phase, acetonitrile/tetrahydrofuran/distilled water (50,14,20, v/v/v); flow-rate, 1.6 mL/min. Results The calibration curves obtained for colistin were linear in the concentration range of 0.10–8.0 μg/mL. The regression equation was y = 0.6496× − 0.0141 (r 2 = 0.9999). The limit of detection was ~ 0.025 μg/mL, and the assay intra- and inter-day precisions were 0.87–3.74% and 1.97–6.17%, respectively. The analytical peaks of colistin A, colistin B, and the internal standard were resolved with adequate peak symmetries, and their retention times were approximately 8.2, 6.8, and 5.4 min, respectively. Furthermore, the assay was successfully applied to quantify the plasma colistin levels of a haemodialysis patient. Conclusion The assay is a simple, rapid, accurate, selective, clinically applicable HPLC-based method for the quantification of colistin in human plasma.

The incidence of infections with nontuberculous mycobacteria (NTM) has been increasing worldwide. The emergence of multidrug-resistant NTM is a serious clinical concern, and a vaccine for NTM has not yet been developed. We previously developed a new recombinant Bacillus Calmette–Guérin (rBCG) vaccine encoding the antigen 85B (Ag85B) protein of Mycobacterium kansasii—termed rBCG-Mkan85B—which was used together with a booster immunization with plasmid DNA expressing the same M. kansasii Ag85B gene (DNA-Mkan85B). We reported that rBCG-Mkan85B/DNA-Mkan85B prime–boost immunization elicited various NTM strain-specific CD4+ and CD8+ T cells and induced Mycobacterium tuberculosis-specific immunity. In this study, to investigate the protective effect against M. kansasii infection, we challenged mice vaccinated with a rBCG-Mkan85B or rBCG-Mkan85B/DNA-Mkan85B prime–boost strategy with virulent M. kansasii. Although BCG and rBCG-Mkan85B immunization each suppressed the growth of M. kansasii in the mouse lungs, the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination reduced the bacterial burden more significantly. Moreover, the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination induced antigen-specific CD4+ and CD8+ T cells. Our data suggest that rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination effectively enhances antigen-specific T cells. Our novel rBCG could be a potential alternative to clinical BCG for preventing various NTM infections.

High-temperature stress during the grain-filling stage reduces grain quality of rice, and this is a serious problem in Japan, especially in the Kyushu region. To solve this problem, various heat-tolerant cultivars have been bred, such as ‘Nikomaru’, ‘Kumasannochikara’, ‘Genkitsukushi’, ‘Sagabiyori’, and ‘Otentosodachi’. When cultivated under high temperature after flowering, these heat-tolerant cultivars had lower percentages of chalky grains than in the heat-sensitive cultivar ‘Hinohikari’. All the heat-tolerant cultivars markedly decreased the nonstructural carbohydrate content in the stem under the high temperature compared to control condition during early grain-filling stage, which is considered to be a common trait of heat tolerance. Notably, ‘Sagabiyori’, ‘Genkitsukushi’, and ‘Nikomaru’ maintained a nucellar epidermis at 17 days after flowering (DAF) under high temperature, whereas the nucellar epidermis disappeared in ‘Hinohikari’. In addition, the expression of AGPS2b, thought to be a rate-limiting enzyme in starch synthesis, in ‘Kumasannochikara’, ‘Otentosodachi’, and ‘Nikomaru’ did not decrease under high temperature, whereas ‘Hinohikari’, ‘Sagabiyori’, and ‘Genkitsukushi’ could not maintain expression of the gene at 17 DAF. Moreover, the expression of Amy3E, a starch-degradation-related gene considered to induce grain chalkiness, in ‘Kumasannochikara’ at 17 DAF was not increased by high temperature. These results suggest that the heat-stress-tolerant cultivars have various mechanisms for dealing with high-temperature stress.

The fluoroquinolone antibiotic ciprofloxacin has been reported to block delayed rectifier K+ channels at much higher concentrations than those at which it exerts its bactericidal activity. In this study using the halothane-anesthetized guinea pig, we assessed whether ciprofloxacin has a proarrhythmic activity. Ciprofloxacin at a clinically relevant dose of 3 mg/kg, i.v. did not affect any electrocardiographic parameters. At 10 mg/kg, it prolonged the QT interval and the duration of the monophasic action potential of the ventricle under sinus rhythm and constant ventricular pacing (n = 6). The extents of its effects on the ventricular repolarization phase were comparable to those of another fluoroquinolone antibiotic moxifloxacin at a clinically relevant dose of 3 mg/kg (n = 6). Meanwhile, the PR interval and QRS width were also increased by ciprofloxacin at 10 mg/kg, suggesting that the drug inhibited cardiac K+ channels as well as Na+ and Ca2+ channels in vivo. These results suggest that ciprofloxacin exerted a multi-ion channel–blocking action in the heart within the supra-therapeutic dose range. Therefore, careful observation may be necessary for patients with heart disease receiving a higher dose of ciprofloxacin in order to prevent the emergence of resistance. Keywords:: ciprofloxacin, fluoroquinolone antibiotic, QT interval, monophasic action potential

Many epidemiological studies have suggested that the recent increase in prevalence and severity of allergic diseases such as asthma is inversely correlated with Mycobacterium bovis bacillus Calmette Guerin (BCG) vaccination. However, the underlying mechanisms by which mycobacterial components suppress allergic diseases are not yet fully understood. Here we showed the inhibitory mechanisms for development of allergic airway inflammation by using highly purified recombinant Ag85B (rAg85B), which is one of the major protein antigens secreted from M. tuberculosis. Ag85B is thought to be a single immunogenic protein that can elicit a strong Th1-type immune response in hosts infected with mycobacteria, including individuals vaccinated with BCG. Administration of rAg85B showed a strong inhibitory effect on the development of allergic airway inflammation with induction of Th1-response and IL-17and IL-22 production. Both cytokines induced by rAg85B were involved in the induction of Th17-related cytokine-production innate immune cells in the lung. Administration of neutralizing antibodies to IL-17 or IL-22 in rAg85B-treated mice revealed that IL-17 induced the infiltration of neutrophils in BAL fluid and that allergen-induced bronchial eosinophilia was inhibited by IL-22. Furthermore, enhancement of the expression of genes associated with tissue homeostasis and wound healing was observed in bronchial tissues after rAg85B administration in a Th17-related cytokine dependent manner. The results of this study provide evidence for the potential usefulness of rAg85B as a novel approach for anti-allergic effect and tissue repair other than the role as a conventional TB vaccine.

OBJECTIVE: Obesity is a major risk factor for cardiovascular disease. Recent evidence demonstrates that dysregulation of fat-derived hormones, also known as adipokines, is linked with the pathogenesis of obesity-related disorders including coronary artery disease (CAD). Here, we investigated whether circulating level of an adipokine C1q/TNF-related protein (CTRP) 1 is associated with the prevalence of CAD. METHODS AND RESULTS: Consecutive 76 male CAD patients were enrolled from inpatients that underwent coronary angiography. Sixty four healthy male subjects served as controls. Plasma CTRP1 concentration was determined by enzyme-linked immunosorbent assay. CTRP1 levels were correlated positively with systolic blood pressure (BP) and triglyceride levels, and negatively with HDL cholesterol levels in all subjects. Plasma levels of CTRP1 were significantly higher in CAD patients than in control subjects (CAD: 443.3±18.6 ng/ml, control: 307.8±21.5 ng/ml, p

Obese states characterized by chronic inflammation are closely linked to the development of metabolic dysfunction. We identified adipolin/CTRP12 as an insulin-sensitizing and anti-inflammatory adipokine. Although obese conditions down-regulate adipolin expression, its molecular mechanism is largely unknown. Here we show that the transcriptional regulator Krüppel-like factor (KLF) 15 is involved in the regulation of adipolin expression in adipocytes. White adipose tissue from diet-induced obese (DIO) mice showed decreased expression of KLF9 and KLF15 among several KLFs, which was accompanied by reduced expression of adipolin. In cultured 3T3L1 adipocytes, treatment with TNFα significantly reduced the mRNA levels of KLF9, KLF15 and adipolin. Adenovirus-mediated overexpression of KLF15 but not KLF9 reversed TNFα-induced reduction of adipolin expression in adipocytes. Conversely, gene targeting ablation of KLF15 attenuated adipolin expression in adipocytes. Expression of KLF15 but not KLF9 enhanced the promoter activity of adipolin in HEK293 cells. Pretreatment of 3T3L1 adipocytes with the JNK inhibitor SP600125, but not p38 MAPK inhibitor SB203580 blocked the inhibitory effects of TNFα on adipolin and KLF15 expression. These data suggest that adipose inflammation under conditions of obesity suppresses adipolin expression via JNK-dependent down-regulation of KLF15 in adipocytes.

Mycobacterium bovis bacille Calmette-Guérin (BCG) is the only available vaccine for tuberculosis (TB). Although this vaccine is effective in controlling infantile TB, BCG-induced protective effects against pulmonary diseases in adults have not been clearly demonstrated. Recombinant BCG (rBCG) technology has been extensively applied to obtain more potent immunogenicity of this vaccine, and several candidate TB vaccines have currently reached human clinical trials. On the other hand, recent progress in the improvement of the BCG vector, such as the codon optimization strategy and combination with viral vector boost, allows us to utilize this bacterium in HIV vaccine development. In this paper, we review recent progress in rBCG-based vaccine studies that may have implications in the development of novel vaccines for controlling global infectious diseases in the near future.

In epithelial tissues, intercellular adhesion structures are formed between adjacent cells via intercellular adhesion factors, such as zonula occludens (ZO-1), to maintain the structure and function of tissues and organs, thereby contributing to homeostasis. Epithelial cells are polarized into apical and basal regions by tight junctions (TJs), a type of intercellular adhesion structure, and thus, their intracellular organelles are asymmetrically distributed. Normal epithelial cells maintain their cellular function by controlling cytoskeletal reorganization, motility, and division by maintaining asymmetry in their intracellular organelles. Among the features common to many cancer tissues are abnormalities in cell polarity and intercellular adhesion. Lung adenocarcinoma consists of a mixture of five different histologic types that can be distinguished in the same section: lepidic, papillary, acinar, micropapillary, and solid patterns. Therefore, it is often difficult to accurately assess histological images because the staining differs according to the histological types. In the present study, we evaluated ZO-1 staining based on histological features observed in a single section and examined its relationship to clinicopathological features. In non-tumor areas, ZO-1 was expressed on the plasma membrane and in the cytoplasm of normal alveolar epithelial cells. However, in tumor areas, ZO-1 staining was mainly localized in the cytoplasm and on the plasma membrane only in a few cells. ZO-1-negative cases tended to have poorer prognoses in all histological types, with a poorer prognosis in the solid pattern. These results suggest that ZO-1 expression in solid-pattern lung adenocarcinoma may be a useful prognostic marker. [ABSTRACT FROM AUTHOR]