Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models cannot support ...development of human innate immune cells, including myeloid cells and natural killer (NK) cells. Here we describe two mouse strains called MITRG and MISTRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked into their respective mouse loci. The human cytokines support the development and function of monocytes, macrophages and NK cells derived from human fetal liver or adult CD34(+) progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MITRG and MISTRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this ...end, nonobese diabetic (NOD).Cg‐PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems humanized NSG (HuNSG). HuNSG mice received human leukocyte antigen partially matched tumor implants from patient‐ derived xenografts PDX; non‐small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple‐negative breast cancer (TNBC) or from a TNBC cell line‐derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune‐engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+T cells, as demonstrated by antibody‐mediated depletion. Thus, tumor‐bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.—Wang, M., Yao, L.‐C., Cheng, M., Cai, D., Martinek, J., Pan, C.‐X., Shi, W., Ma, A.‐H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD‐1‐targeted cancer immunotherapy. FASEB J. 32,1537‐1549 (2018). www.fasebj.org
Main Recommendations
ESGE recommends the use of a graded pneumatic dilation protocol in achalasia, starting with a 30-mm dilation and followed by a 35-mm dilation at a planned interval of 2 – 4 ...weeks, with a subsequent 40-mm dilation when there is insufficient relief, over both a single balloon dilation procedure or the use of a larger balloon from the outset.
Strong recommendation, high quality of evidence, level of agreement 100 %.
ESGE recommends being cautious in treating spastic motility disorders other than achalasia with peroral endoscopic myotomy (POEM).
Strong recommendation, very low quality of evidence, level of agreement 87.5 %.
ESGE recommends against the routine use of botulinum toxin injections to treat patients with non-achalasia hypercontractile esophageal motility disorders (Jackhammer esophagus, distal esophageal spasm). However, if, in individual patients, endoscopic injection of botulinum toxin is chosen, ESGE recommends performing injections into four quadrants of the lower esophageal sphincter and in the lower third of the esophagus.
Strong recommendation, low quality of evidence, level of agreement 78.6 %.
ESGE recommends that endoscopic pylorus-directed therapy should be considered only in patients with symptoms suggestive of gastroparesis in combination with objective proof of delayed gastric emptying using a validated test, and only when medical therapy has failed.
Strong recommendation, very low quality of evidence, level of agreement 100 %.
ESGE recommends against the use of botulinum toxin injection in the treatment of unselected patients with gastroparesis.
Strong recommendation, high quality of evidence, level of agreement 92.9 %.
ESGE recommends consideration of gastric peroral endoscopic myotomy (G-POEM) in carefully selected patients only, because it is an emerging procedure with limited data on effectiveness, safety, and durability. G-POEM should be performed in expert centers only, preferably in the context of a clinical trial.
Strong recommendation, low quality of evidence, level of agreement 100 %.
The paper deals with ancient methods of astronavigation and their potential use in finding geographical locations in Ptolemy's Geographike Hyphegesis. Further, it describes the systematic errors in ...these methods and suggests how to correct them. The results include a new map which compares the locations of Ptolemy's sites after removing the errors with their real locations. Subsequently, significant ancient locations according to Ptolemy's list of noteworthy cities are identified on the map. In some cases, we presume that they were located on the map using astronavigation. The results of this Study imply that Ptolemy may have adopted a comparatively regular network of points from some older authors which was the basis of his extensive work.
Main Recommendations
ESGE suggests flexible endoscopic treatment over open surgical treatment as first-line therapy for patients with a symptomatic Zenker’s diverticulum of any size.
Weak ...recommendation, low quality of evidence, level of agreement 100 %.
ESGE recommends that emerging treatments for Zenker’s diverticulum, such as Zenker’s peroral endoscopic myotomy (Z-POEM) and tunneling, be considered as experimental; these treatments should be offered in a research setting only.
Strong recommendation, low quality of evidence, level of agreement 100 %.
ESGE recommends against the widespread clinical use of transoral incisionless fundoplication (TIF) as an alternative to proton pump inhibitor (PPI) therapy or antireflux surgery in the treatment of gastroesophageal reflux disease (GERD), because of the lack of data on the long-term outcomes, the inferiority of TIF to fundoplication, and its modest efficacy in only highly selected patients. TIF may have a role for patients with mild GERD who are not willing to take PPIs or undergo antireflux surgery.
Strong recommendation, moderate quality of evidence, level of agreement 92.8 %.
ESGE recommends against the use of the Medigus ultrasonic surgical endostapler (MUSE) in clinical practice because of insufficient data showing its effectiveness and safety in patients with GERD. MUSE should be used in clinical trials only.
Strong recommendation, low quality evidence, level of agreement 100 %.
ESGE recommends against the use of antireflux mucosectomy (ARMS) in routine clinical practice in the treatment of GERD because of the lack of data and its potential complications.
Strong recommendation, low quality evidence, level of agreement 100 %.
ESGE recommends endoscopic cecostomy only after conservative management with medical therapies or retrograde lavage has failed.
Strong recommendation, low quality evidence, level of agreement 93.3 %.
ESGE recommends fixing the cecum to the abdominal wall at three points (using T-anchors, a double-needle suturing device, or laparoscopic fixation) to prevent leaks and infectious adverse events, whatever percutaneous endoscopic cecostomy method is used.
Strong recommendation, very low quality evidence, level of agreement 86.7 %.
ESGE recommends considering endoscopic decompression of the colon in patients with Ogilvie’s syndrome that is not improving with conservative treatment.
Strong recommendation, low quality evidence, level of agreement 93.8 %.
ESGE recommends prompt endoscopic decompression if the cecal diameter is > 12 cm and if the Ogilvie’s syndrome exists for a duration of longer than 4 – 6 days.
Strong recommendation, low quality evidence, level of agreement 87.5 %.
Protein complex Arp2/3 has a conserved role in the nucleation of branched actin filaments. It is constituted of seven subunits, including actin-like subunits ARP2 and ARP3 plus five other subunits ...called Arp2/3 Complex Component 1 to 5, which are not related to actin. Knock-out plant mutants lacking individual plant ARP2/3 subunits have a typical phenotype of distorted trichomes, altered pavement cells shape and defects in cell adhesion. While knock-out mutant Arabidopsis plants for most ARP2/3 subunits have been characterized before, Arabidopsis plant mutants missing ARPC1 and ARPC3 subunits have not yet been described. Using CRISPR/Cas9, we generated knock-out mutants lacking ARPC1 and ARPC3 subunits. We confirmed that the loss of ARPC1 subunits results in the typical ARP2/3 mutant phenotype. However, the mutants lacking ARPC3 subunits resulted in plants with surprisingly different phenotypes. Our results suggest that plant ARP2/3 complex function in trichome shaping does not require ARPC3 subunit, while the fully assembled complex is necessary for the establishment of correct cell adhesion in the epidermis.
Proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is diagnosed in at least one-third of patients with suspected eosinophilic esophagitis (EoE). We aimed to evaluate the durability ...and factors influencing long-term efficacy of PPI therapy.
Retrospective multicenter cohort study of patients with PPI-REE who had at least 12 months of follow-up. PPI therapy was tapered to the lowest dose, which maintained clinical remission. Primary outcomes were the proportion of patients with loss of histological response (<15 eos/HPF) and predictors of loss of response. CYP2C19 polymorphisms were determined from blood samples in a subset of patients.
Seventy-five PPI-REE patients were included (mean follow-up 26 months (12-85)), of whom fifty-five (73%) had sustained histological remission on low-dose PPI therapy. Loss of response was significantly higher in those patients with a CYP2C19 rapid metabolizer genotype (36% vs. 6%, P = 0.01) and with rhinoconjunctivitis (40% vs. 13%, P = 0.007). On the multivariate analysis, a CYP2C19 rapid metabolizer genotype (odds ratio (OR) 12.5; 95% confidence interval (CI): 1.3-115.9) and rhinoconjunctivitis (OR 8.6; 95% CI: 1.5-48.7) were independent predictors of loss of response. Among relapsing patients, eosinophilia was limited to the distal esophagus in 14/20 (70%). Nine of ten relapsers, with distal eosinophilia, all showing a CYP2C19 rapid metabolizer genotype, regained histological remission after PPI dose intensification.
Most PPI-REE patients remain in long-term remission on low-dose PPI therapy. CYP2C19 rapid metabolizer genotypes and rhinoconjunctivitis were independent predictors of loss of response to PPI, but patients frequently responded to PPI dose escalation.
Circadian clocks are timing devices that rhythmically adjust organism's behavior, physiology, and metabolism to the 24-h day-night cycle. Eukaryotic circadian clocks rely on several interlocked ...transcription-translation feedback loops, where protein stability is the key part of the delay between transcription and the appearance of the mature proteins within the feedback loops. In bilaterian animals, including mammals and insects, the circadian clock depends on a homologous set of proteins. Despite mostly conserved clock components among the fruit fly
and mammals, several lineage-specific differences exist. Here we have systematically explored the evolution and sequence variability of insect DBT proteins and their vertebrate homologs casein kinase 1 delta (CKIδ) and epsilon (CKIε), dated the origin and separation of CKIδ from CKIε, and identified at least three additional independent duplications of the CKIδ/ε gene in
,
, and
. We determined conserved regions in DBT specific to Diptera, and functionally tested a subset of those in
. Replacement of Lysine K224 with acidic residues strongly impacts the free-running period even in heterozygous flies, whereas homozygous mutants are not viable. K224D mutants have a temperature compensation defect with longer free-running periods at higher temperatures, which is exactly the opposite trend of what was reported for corresponding mammalian mutants. All DBTs of dipteran insects contain the NKRQK motif at positions 220-224. The occurrence of this motif perfectly correlates with the presence of BRIDE OF DOUBLETIME, BDBT, in Diptera. BDBT is a non-canonical FK506-binding protein that physically interacts with
DBT. The phylogeny of FK506-binding proteins suggests that BDBT is either absent or highly modified in non-dipteran insects. In addition to
analysis of DBT/CKIδ/ε evolution and diversity, we have identified four novel casein kinase 1 genes specific to the
genus
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