Endoscopic ultrasound-guided immunotherapy

AbstractAnti-tumoral endoscopic ultrasound-guided fine-needle injection (EUS-FNI), with its minimally invasive access for anti-tumoral agent delivery, is the most exciting field of intervention EUS. Pancreatic cancer is regarded as a systemic disease even if imaging modalities reveal no visible metastasis. From that perspective, immunological therapy is performed. To date, several reports have described immunotherapy under EUS-guidance. The first report of EUS-FNI intended for immunotherapy for advanced pancreatic cancer was published in 2000. In that study, an allogeneic mixed-lymphocyte culture was injected into tumors of eight patients with unresectable local pancreatic adenocarcinoma. The study of dendritic cells (DCs) for cancer has continued to develop in recent years. Actually, DCs are potent antigen-presenting cells for the induction of primary T-cell dependent immune response. When injected intratumorally, DCs acquire and process tumor antigens in situ, migrate to regional lymphoid organs, and initiate a strong tumor-specific immune response. To date, three reports have described EUS-FNI of DCs into pancreatic cancer: two for unresectable and one for pre-surgical operations. Every study has indicated the feasibility and safety. Furthermore, these reports showed that EUS-guided DCs injection might be an important option for treating advanced pancreatic cancer. EUS-guided immunotherapy is a very exciting field in interventional EUS for obstinate cancers

Surface Phenotype Changes and Increased Response to Oxidative Stress in CD4+CD25high T Cells

Conversion of CD4+CD25+FOXP3+ T regulatory cells (Tregs) from the immature (CD45RA+) to mature (CD45RO+) phenotype has been shown during development and allergic reactions. The relative frequencies of these Treg phenotypes and their responses to oxidative stress during development and allergic inflammation were analysed in samples from paediatric and adult subjects. The FOXP3lowCD45RA+ population was dominant in early childhood, while the percentage of FOXP3highCD45RO+ cells began increasing in the first year of life. These phenotypic changes were observed in subjects with and without asthma. Further, there was a significant increase in phosphorylated ERK1/2 (pERK1/2) protein in hydrogen peroxide (H2O2)-treated CD4+CD25high cells in adults with asthma compared with those without asthma. Increased pERK1/2 levels corresponded with increased Ca2+ response to T cell receptor stimulation. mRNA expression of peroxiredoxins declined in Tregs from adults with asthma. Finally, CD4+CD25high cells from paediatric subjects were more sensitive to oxidative stress than those from adults in vitro. The differential Treg sensitivity to oxidative stress observed in children and adults was likely dependent on phenotypic CD45 isoform switching. Increased sensitivity of Treg cells from adults with asthma to H2O2 resulted from a reduction of peroxiredoxin-2, -3, -4 and increased pERK1/2 via impaired Ca2+ response in these cells

The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses.

The motoneural control of skeletal muscle contraction requires the neuromuscular junction (NMJ), a midmuscle synapse between the motor nerve and myotube. The formation and maintenance of NMJs are orchestrated by the muscle-specific receptor tyrosine kinase (MuSK). Motor neuron-derived agrin activates MuSK via binding to MuSK\u27s coreceptor Lrp4, and genetic defects in agrin underlie a congenital myasthenic syndrome (an NMJ disorder). However, MuSK-dependent postsynaptic differentiation of NMJs occurs in the absence of a motor neuron, indicating a need for nerve/agrin-independent MuSK activation. We previously identified the muscle protein Dok-7 as an essential activator of MuSK. Although NMJ formation requires agrin under physiological conditions, it is dispensable for NMJ formation experimentally in the absence of the neurotransmitter acetylcholine, which inhibits postsynaptic specialization. Thus, it was hypothesized that MuSK needs agrin together with Lrp4 and Dok-7 to achieve sufficient activation to surmount inhibition by acetylcholine. Here, we show that forced expression of Dok-7 in muscle enhanced MuSK activation in mice lacking agrin or Lrp4 and restored midmuscle NMJ formation in agrin-deficient mice, but not in Lrp4-deficient mice, probably due to the loss of Lrp4-dependent presynaptic differentiation. However, these NMJs in agrin-deficient mice rapidly disappeared after birth, and postsynaptic specializations emerged ectopically throughout myotubes whereas exogenous Dok-7-mediated MuSK activation was maintained. These findings demonstrate that the MuSK activator agrin plays another role essential for the postnatal maintenance, but not for embryonic formation, of NMJs and also for the postnatal, but not prenatal, midmuscle localization of postsynaptic specializations, providing physiological and pathophysiological insight into NMJ homeostasis. Proc Natl Acad Sci U S A 2014 Nov 18; 111(46):16556-16561

Agenesis of the Gallbladder in Monozygotic Twin Sisters

Agenesis of the gallbladder, a rare anomaly, is generally regarded as an organogenic failure. Several reports suggest that this congenital defect is inherited but that supposition remains controversial. We described agenesis of the gallbladder in identical twins. A 21-year-old female presented with a history of acute pain in the epigastrium and right hypochondrium. Various imaging modalities showed “gallbladder agenesis.” Moreover, her older identical twin sister had also no visualized gallbladder in imaging modalities. This case report strongly suggested that agenesis of the gallbladder would be caused by a genetic abnormality

Agenesis of the Gallbladder in Monozygotic Twin Sisters

Agenesis of the gallbladder, a rare anomaly, is generally regarded as an organogenic failure. Several reports suggest that this congenital defect is inherited but that supposition remains controversial. We described agenesis of the gallbladder in identical twins. A 21-year-old female presented with a history of acute pain in the epigastrium and right hypochondrium. Various imaging modalities showed "gallbladder agenesis." Moreover, her older identical twin sister had also no visualized gallbladder in imaging modalities. This case report strongly suggested that agenesis of the gallbladder would be caused by a genetic abnormality

The Role of Endoscopic Ultrasound for Esophageal Varices

Esophageal varices are caused by the development of collateral circulation in the esophagus as a result of portal hypertension. It is important to administer appropriate preventive treatment because bleeding varices can be fatal. Esophageal varices have complex and diverse hemodynamics, and there are various variations for each case. Endoscopic ultrasound (EUS) can estimate the hemodynamics of each case. Therefore, observation by EUS in esophageal varices provides useful information, such as safe and effective treatment selection, prediction of recurrence, and appropriate follow-up after treatment. Although treatment for the esophagogastric varices can be performed without EUS imaging, understanding the local hemodynamics of the varices using EUS prior to treatment will lead to more safe and effective treatment. EUS observation is an indispensable tool for thorough variceal care

Participation of th17 and treg cells in pediatric bronchial asthma

The immune response plays an important role in the development of allergic diseases. It is established that a complex network of various immunocytes such as Th2, non-Th2 (Th17), and regulatory T (Treg) participate in allergic reactions. In this study, we examined the frequencies of Th17 cells (IL-17-positive cells) and Treg cells (FOXP3-positive cells) in the peripheral blood and elucidated their participation in pediatric allergic diseases such as bronchial asthma and food allergies. Our study included 35 subjects, 27 with allergic diseases (19 with asthma and 8 with food allergies) and 8 were controls (without any allergic diseases); their age ranged from 1 to 13 years. The frequency of Th17 cells (IL-17-positive cells) among the CD4+T cells in the peripheral blood was 2.33 ± 1.29% in patients with bronchial asthma, 1.53 ± 1.34% in those with food allergies, and 1.50 ± 0.809% in controls. These results indicated that only the patients with bronchial asthma had a trend towards a higher frequency of Th17 cells (p = 0.1558). The ratio of Th17 cells to Treg cells did not show any statistical correlation among the patients with bronchial asthma. However, when we excluded the patients with a severe type of asthma, we could obtain an inverse trend between the ratio of Th17 cells to Treg cells (p = 0.1655). This study suggested that Th17 cells and Treg cells participate in pediatric allergic reactions such as bronchial asthma