Electric shock causes a fleeing-like persistent behavioral response in the nematode Caenorhabditis elegans.

Behavioral persistency reflects internal brain states, which are the foundations of multiple brain functions. However, experimental paradigms enabling genetic analyses of behavioral persistency and its associated brain functions have been limited. Here, we report novel persistent behavioral responses caused by electric stimuli in the nematode Caenorhabditis elegans. When the animals on bacterial food are stimulated by alternating current, their movement speed suddenly increases 2- to 3-fold, persisting for more than 1 minute even after a 5-second stimulation. Genetic analyses reveal that voltage-gated channels in the neurons are required for the response, possibly as the sensors, and neuropeptide signaling regulates the duration of the persistent response. Additional behavioral analyses implicate that the animal's response to electric shock is scalable and has a negative valence. These properties, along with persistence, have been recently regarded as essential features of emotion, suggesting that C. elegans response to electric shock may reflect a form of emotion, akin to fear.

Detailed analysis of social support and proactive coping with depressive symptoms in Japanese HIV-infected individuals.

The aim of this study was to determine the association of the type of social support and proactive coping with depressive symptoms (DS) in Japanese people living with human immunodeficiency virus (PLHIV), in order to select effective psychosocial care or intervention. Questionnaires were anonymously collected from randomly recruited participants. The questionnaire included items on demographic characteristics, HIV treatment-related factors, DS, social support, and coping. Hierarchical binary logistic regression was used to identify factors associated with DS. A total of 564 patients completed the questionnaire and 207 (37%) patients reported DS. Demographic factors, such as drug-use-related disorders [adjusted odds ratio (AOR) 7.21, 95% confidence interval (95%CI) 1.95-26.70], unemployment (AOR 3.06, 95%CI 1.50-6.27) and younger age (AOR 0.96, 95%CI 0.94-0.99) were significantly associated with DS. With regard to coping, higher levels of instrumental support seeking (AOR 1.09, 95%CI 1.01-1.18), lower levels of proactive coping (AOR 0.91, 95%CI 0.87-0.96) and lower levels of emotional support seeking (AOR 0.82, 95%CI 0.72-0.92) were significantly associated with DS. Our results highlight the need for psychosocial care to enhance or compensate proactive coping and emotional support seeking abilities in DS. Healthcare workers should pay attention to the mental health of young unemployed PLHIV with drug-use-related disorders.

Carcinoembryonic antigen as a specific glycoprotein ligand of rBC2LCN lectin on pancreatic ductal adenocarcinoma cells.

The rBC2LCN lectin, known as a stem cell marker probe that binds to an H type 3 fucosylated trisaccharide motif, was recently revealed to also bind to pancreatic ductal adenocarcinoma (PDAC) cells. A lectin-drug conjugate was generated by fusing rBC2LCN with a cytocidal toxin, and it showed a strong anticancer effect in in vitro and in vivo PDAC models. However, it is unclear which molecules are carrier proteins of rBC2LCN on PDAC cells. In this study, we identified a rBC2LCN-positive glycoprotein expressed in PDAC. Tumor lysates of PDAC patient-derived xenografts (PDXs) were coprecipitated with rBC2LCN lectin and analyzed by liquid chromatography-mass spectrometry. A total of 343 proteins were initially identified. We used a web-based database to select five glycoproteins and independently evaluated their expression in PDAC by immunohistochemistry (IHC). Among them, we focused on carcinoembryonic antigen 5 (CEA) as the most cancer-specific carrier protein in PDAC, as it showed the most prominent difference in expression rate between PDAC cells (74%) and normal pancreatic duct cells (0%, P > .0001). rBC2LCN lectin and CEA colocalization in PDAC samples was confirmed by double-staining analysis. Furthermore, rBC2LCN-precipitated fractions were blotted with an anti-CEA polyclonal antibody (pAb), and CEA pAb-precipitated fractions were blotted with rBC2LCN lectin. The results demonstrate that CEA is in fact a ligand of rBC2LCN lectin.

Lectin drug conjugate therapy for colorectal cancer.

Drug resistance represents an obstacle in colorectal cancer (CRC) treatment because of its association with poor prognosis. rBC2LCN is a lectin isolated from Burkholderia that binds cell surface glycans that have fucose moieties. Because fucosylation is enhanced in many types of cancers, this lectin could be an efficient drug carrier if CRC cells specifically present such glycans. Therefore, we examined the therapeutic efficacy and toxicity of lectin drug conjugate therapy in CRC mouse xenograft models. The affinity of rBC2LCN for human CRC cell lines HT-29, LoVo, LS174T, and DLD-1 was assessed in vitro. The cytocidal efficacy of a lectin drug conjugate, rBC2LCN-38 kDa domain of pseudomonas exotoxin A (PE38) was evaluated by MTT assay. The therapeutic effects and toxicity for each CRC cell line-derived mouse xenograft model were compared between the intervention and control groups. LS174T and DLD-1 cell lines showed a strong affinity for rBC2LCN. In the xenograft model, the tumor volume in the rBC2LCN-PE38 group was significantly reduced compared with that using control treatment alone. However, the HT-29 cell line showed weak affinity and poor therapeutic efficacy. No significant toxicities or adverse responses were observed. In conclusion, we demonstrated that rBC2LCN lectin binds CRC cells and that rBC2LCN-PE38 significantly suppresses tumor growth in vivo. In addition, the efficacy of the drug conjugate correlated with its binding affinity for each CRC cell line. These results suggest that lectin drug conjugate therapy has potential as a novel targeted therapy for CRC cell surface glycans.

High-Pressure Synthesis and Crystal Structure of the Sulfur-Richest Chromium Sulfide CrS3 Composed of Cr(III) and Disulfide Ions.

The new binary chromium sulfide CrS3 has been synthesized by reaction of Cr3S4 and sulfur mixtures at 800 °C and 13 GPa. CrS3 crystallizes in an orthorhombic unit cell with a = 4.6742(7) Å, b = 5.7315(8) Å, c = 10.603(2) Å, and V = 284.873(4) Å3. It has a novel structure composed of Cr2S10 edge-shared octahedral dimers, which share all of their corners to form a three-dimensional structure. All of the sulfur atoms form S22- disulfide ions with a S-S distance of 2.063(5) or 2.068(8) Å. The structure of CrS3 is a derivative of the crystal structure of marcasite FeS2, in which one in three metal sites of the marcasite structure is vacant in the CrS3 structure.

Neurocognitive dysfunction and brain FDG-PET/CT findings in HIV-infected hemophilia patients and HIV-infected non-hemophilia patients.

This single-institution cross-sectional study aimed to grasp the prevalence and features of neurocognitive dysfunction in HIV-infected hemophilia patients in Japan. We conducted neuropsychological tests and medical examinations in 56 HIV-infected hemophilia patients who received outpatient treatment at the AIDS Clinical Center, National Center for Global Health and Medicine. A total of 388 HIV-infected non-hemophilia patients who received outpatient treatment at the same institution were included as a control group. To investigate sites responsible for neurocognitive dysfunction in HIV-infected hemophilia patients using brain FDG-PET/CT scans, the accumulation of FDG in each brain region was compared. Approximately 50% of HIV-infected hemophilia patients had neurocognitive dysfunction. The prevalence of asymptomatic neurocognitive impairment was high (34%). Neurocognitive dysfunction was associated with educational level in HIV-infected hemophilia patients. In the symptomatic group, hemophilic arthropathy and history of cerebrovascular disorders were associated with neurocognitive dysfunction. Left temporal lobe function was reduced in the symptomatic group.

Novel Pancreatic Cancer Therapy Targeting Cell Surface Glycans by Liposomes Modified with rBC2LCN Lectin.

INTRODUCTION: Since the outermost layer of cancer cells is covered with various glycans, targeting these groups may serve as an effective strategy in cancer therapy. We previously reported that fucosylated glycans are specifically expressed on pancreatic cancer cells, and that a protein specifically binding to these glycans, namely rBC2LCN lectin, is a potential guiding drug carrier. In the present study, a novel type of glycan-targeting nanoparticle was developed by modifying the surface of doxorubicin-containing liposomes with rBC2LCN lectin. The efficiency and specificity of this formulation, termed Lec-Doxosome, were examined in vitro and in vivo in human pancreatic cancer models. METHODS: Lec-Doxosome was prepared by a post-insertion method based on the insertion of rBC2LCN lectin into the liposomal surface via a lipid linker. The in vitro cellular binding, uptake, and cytotoxicity of Lec-Doxosome were compared with the corresponding parameters in the unmodified liposomes by applying to human pancreatic cancer cell line (Capan-1) with affinity for rBC2LCN lectin. For the in vivo assay, Lec-Doxosome was intravenously injected once per week for a total of 3 weeks into mice bearing subcutaneous tumors. RESULTS: The in vitro application of Lec-Doxosome resulted in a 1.2- to 1.6-fold higher intracellular doxorubicin accumulation and a 1.5-fold stronger cytotoxicity compared with the respective rates of accumulation and cytotoxicity in the unmodified liposomes. In vivo, Lec-Doxosome reduced the mean tumor weight (368 mg) compared with that in mice treated with unmodified liposomes (456 mg), without causing any additional adverse events. CONCLUSION: It was demonstrated from the results obtained herein that rBC2LCN lectin is a potent modifier, as a means for boosting the efficiency of nanoparticles in the targeting of cancer cell surface glycans.

Retrocolic Gastrojejunostomy After Pancreaticoduodenectomy: A Satisfactory Delayed Gastric-Emptying Rate.

OBJECTIVES: Delayed gastric emptying (DGE) is a critical complication after pancreaticoduodenectomy (PD). Antecolic gastrojejunostomy has long been adopted as standard procedure because it is thought to reduce DGE. However, we have used retrocolic gastrojejunostomy (retro-GJ) for more than 10 years and have not observed high DGE rates. We aimed to clarify whether our retro-GJ approach produced comparable outcomes in preventing DGE. METHODS: A total of 211 patients who underwent pylorus-resecting PD with retro-GJ at our institution between 2005 and 2016 were retrospectively analyzed. The incidence rate of DGE and the length of postoperative hospital stay were assessed. RESULTS: The overall incidence of DGE with our retro-GJ procedure was 13% (n = 28), and the rate of clinically relevant DGE (grade B or C based on the International Study Group of Pancreatic Surgery criteria) was 4% (n = 8). The median postoperative hospital stay was 17 days (interquartile range, 13-25 days). Major complications (Clavien-Dindo grade ≥III) occurred in 37% (n = 79) of patients and were not associated with the occurrence of clinically relevant DGE (P = 0.47). CONCLUSIONS: Our retro-GJ approach after PD with gastrojejunostomy, which involves careful positioning at the left-sided inframesocolic point, satisfactorily prevents DGE.

Stool filling of an intestinal duplication cyst at the ileocecal valve triggers colonic intussusception: a case report.

BACKGROUND: Intestinal duplication, a congenital malformation, is considered a rare condition, particularly in adults. Although it affects young children, a minority of patients remains asymptomatic until adulthood. Here, we describe a case of an intestinal duplication cyst that caused intussusception by a unique mechanism. CASE PRESENTATION: A 19-year-old man was admitted to our hospital for intermittent abdominal pain. Computed tomography revealed colonic intussusception induced by a nodular mass in the ileocecal region. Urgent ileocecal resection was performed because of the risk of colonic ischemia. The resected material comprised a stool-filled noncommunicating cyst that protruded into the enteric lumen at the ileocecal valve. Histological analyses revealed that the inner wall of the cyst was lined with colonic mucosa and that the muscle layer of the cyst was shared with that of the original enteric wall; furthermore, the cyst had a vestige of an opening site in the wall. We concluded that the cyst was an intestinal duplication that poured stool into its lumen through the tiny orifice, thereby triggering intussusception. CONCLUSIONS: The present case suggests that stool-pouring can cause intussusception into the space of an intestinal duplication lesion.

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin-Drug Conjugate (LDC).

Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL = 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments. Mol Cancer Ther; 17(1); 183-95. ©2017 AACR.

Chicken antibody against a restrictive epitope of prion protein distinguishes normal and abnormal prion proteins.

Recently, we reported the application of a recombinant chicken IgY monoclonal antibody, Ab3-15, against mammalian prion protein (PrP), for the diagnosis of bovine spongiform encephalopathy in cattle. In this study, we have characterized a soluble, single-chain variable fragment (scFv) form of this antibody, sphAb3-15 using brain homogenates from mice. This sphAb3-15 antibody recognized denatured forms of both PrP(C) and PrP(Sc), and PrP(Sc) after PK-treatment, on Western blotting. In sandwich ELISAs, on dot blots and by immunoprecipitation, sphAb3-15 efficiently bound to PrP from normal brain homogenates, but weakly bound PrP from scrapie-infected brain homogenates. These results suggest that sphAb3-15 selectively recognizes PrP(C) under native conditions and that the epitope recognized by sphAb3-15 may undergo conformational changes during the conversion of PrP(C) into PrP(Sc).

Development of recombinant chicken IgY from single chain fragment of variable region for diagnosis of BSE.

We generated two recombinant chicken IgYs, designated Ab3-15 and Ab4-19, against mammalian prion protein (PrP) from the single chain fragment of variable region (scFv) antibodies. These two antibodies recognized PrP(Sc) from bovine spongiform encephalopathy (BSE) in cattle and were more sensitive than the corresponding scFv antibodies. These antibodies also recognized PrP(Sc) from other scrapie-infected mammals. These results indicate that Ab3-15 and Ab4-19 are useful for diagnosis of BSE as well as other prion diseases.