Background
Delta-like ligand 3 (DLL3), a member of the Notch pathway, has been identified as a potential therapeutic target as it is highly expressed in small cell lung cancer (SCLC), a subtype ...accounting for 15% of lung cancer cases.
Objective
A systematic literature review (SLR) was conducted to understand the prevalence and prognostic impact of DLL3 expression on survival of patients with SCLC and treatment response.
Patients and Methods
Systematic literature searches were conducted across multiple databases to capture studies of any SCLC population that evaluated DLL3 expression. Specific outcomes of interest included prevalence of DLL3 expression, method of expression analysis, and impact on outcome, including treatment response and survival (overall, progression-free, disease-free) according to varying levels of DLL3 expression/positivity. Standard risk of bias tools were used to evaluate study quality.
Results
Among the 30 included studies, the most common DLL3 testing method was immunohistochemistry (
N
= 26, 86.7%). For comparability, results focused on the 13 (22.3%) studies that used the Ventana DLL3 (SP347) immunohistochemistry assay. The prevalence of DLL3 positivity ranged from 80.0–93.5% for studies using a threshold of ≥ 1% of tumor cells (
N
= 4) and 58.3–91.1% for studies with a ≥ 25% threshold (
N
= 4). DLL3 expression was generally categorized as high using cutoffs of ≥ 50% (prevalence range: 45.8–79.5%;
N
= 6) or ≥ 75% (prevalence range: 47.3–75.6%;
N
= 5) of cells with positivity. Two studies used an H-score of ≥ 150 to define high DLL3 expression with prevalence ranging from 33.3–53.1%. No consistent associations were seen between DLL3 expression level and patient age, sex, smoking history, or disease stage. Two studies reported change in DLL3 expression category (high versus low) before and after chemotherapy. No statistically significant differences were reported between DLL3 expression groups and survival (overall, progression-free, or disease-free) or treatment response.
Conclusions
There is a high prevalence of DLL3 expression in SCLC. Further research and analytical methods may help to characterize different populations of patients with SCLC based on DLL3 expression. While no significant prognostic factor in the included studies was identified, additional cohort studies using standardized methodology, with longer follow-up, are needed to better characterize any potential differences in patient survival or response by DLL3 expression level in SCLC.
Seasonal influenza vaccines elicit antibody responses that can prevent infection, but their efficacy is reduced in the elderly. While a subset of elderly individuals can still mount sufficient ...vaccine-induced antibody responses, little is known about the properties of the vaccine-induced antibody repertoires in elderly as compared to young responders. To gain insights into the effects of aging on influenza vaccine-induced antibody responses, we used flow cytometry and a cell-barcoding method to sequence antibody heavy and light chain gene pairs expressed by individual blood plasmablasts generated in response to influenza vaccination in elderly (aged 70–89) and young (aged 20–29) responders. We found similar blood plasmablast levels in the elderly and young responders seven days post vaccination. Informatics analysis revealed increased clonality, but similar heavy chain V(D)J gene usage in the elderly as compared to young vaccine responders. Although the elderly responders exhibited decreased antibody sequence diversity and fewer consequential mutations relative to young responders, recombinant antibodies from elderly responders bound a broader range of influenza strain HAs. Thus elderly influenza vaccine responders mount plasmablast responses with restricted diversity but with an increased breadth of binding across influenza strains. Our results suggest that the ability to generate plasmablast responses encoding cross-strain binding antibodies likely represents a mechanism important to vaccine responses in the elderly.
Objectives In 2008, a new set of penicillin breakpoints was published in the CLSI revised guideline, M100-S18, to define the susceptibility of non-meningeal isolates of Streptococcus pneumoniae. The ...impact of the change is studied and discussed. Methods Laboratory data on pneumococcal isolates collected from Chang Gung Memorial Hospital during 2000–07 were analysed using the original and modified penicillin CLSI breakpoints. Results A total of 3729 non-duplicate isolates were identifed, including 43 (1.2%) meningeal isolates showing high rates of penicillin (79.1%) and ceftriaxone (34.9%) resistance. For non-meningeal isolates, penicillin non-susceptibility was reduced significantly from 75.1% (72.4% in 2000–03 increasing to 77.4% in 2004–07) to 16% (28.6% in 2000 decreasing to 2.4% in 2007) if the modified breakpoints were applied. However, isolates for which penicillin MICs were 1–2 mg/L increased significantly from 34.2% in 2000 to 59.8% in 2007. Ceftriaxone non-susceptibility also increased significantly from 2.8% before 2005 to 18.4% thereafter. A quarter (25.7%) of the pneumococcal isolates were recovered from patients <10 years old. Higher resistance to penicillin (89.8% versus 70.4%; or 19.1% versus 13.2% by the modified breakpoints) or ceftriaxone (11.1% versus 5.8%) was found among these isolates, compared with those from older patients. Conclusions With the implementation of the new breakpoints, clinicians may continue to use penicillin for the treatment of non-meningeal pneumococcal infections in preference to other drug classes. However, as isolates with borderline penicillin MICs are increasing, continued surveillance of pneumococcal susceptibility to penicillin will be needed.
The innate immune response of mucosal epithelial cells during pathogen invasion plays a central role in immune regulation in the gut. Toxoplasma gondii is a protozoan intracellular parasite that is ...usually transmitted through oral infection. Although much of the information on immunity to T. gondii has come from i.p. infection models, more recent studies have revealed the importance of studying immunity following infection through the natural peroral route. Oral infection studies have identified many of the key players in the intestinal response; however, they have relied on responses detected days to weeks following infection. Much less is known about how the gut epithelial layer senses and reacts during initial contact with the pathogen. Given the importance of epithelial cells during pathogen invasion, this study uses an in vitro approach to isolate the key players and examine the early response of intestinal epithelial cells during infection by T. gondii. We show that human intestinal epithelial cells infected with T. gondii elicit rapid MAPK phosphorylation, NF-kappaB nuclear translocation, and secretion of IL-8. Both ERK1/2 activation and IL-8 secretion responses were shown to be MyD88 dependent and TLR2 was identified to be involved in the recognition of the parasite regardless of the parasite genotype. Furthermore, we were able to identify additional T. gondii-regulated genes in the infected cells using a pathway-focused array. Together, our findings suggest that intestinal epithelial cells were able to recognize T. gondii during infection, and the outcome is important for modulating intestinal immune responses.
Compartmentalization of nucleic acid sensing TLR9 has been implicated as a mechanism to prevent recognition of self nucleic acid structures. Furthermore, recognition of CpG DNA in different endosomal ...compartments leads to the production of the proinflammatory cytokine TNF-α, or type I IFN. We previously characterized a tyrosine-based motif at aa 888-891 in the cytoplasmic tail of TLR9 important for appropriate intracellular localization. In this article, we show that this motif is selectively required for the production of TNF, but not IFN. In response to CpG DNA stimulation, the proteolytically processed 80-kDa fragment is tyrosine phosphorylated. Although Y888 is not itself phosphorylated, the structure of this motif is necessary for both TLR9 phosphorylation and TNF-α production in response to CpG DNA. We conclude that bifurcation in TLR9 signaling is regulated by a critical tyrosine motif in the cytoplasmic tail.
Objectives Mycobacterium kansasii causes a variety of infections. Although previous reports on the prognosis of antimicrobial therapy have been mostly satisfactory, problems involving treatment ...failure or relapse have been encountered. The purpose of this study was to establish a relationship between the clinical treatment outcomes of M. kansasii infections and bacterial drug susceptibility, and their clonality. Methods A total of 37 M. kansasii clinical isolates and clinical information on 34 patients were retrospectively collected in a tertiary medical centre in Taiwan. Bacterial drug susceptibility was determined by the microdilution method. The phylogenetic relationship was analysed by PFGE analysis. Results Results of PFGE typing revealed a major cluster (cluster I) and eight other divergent patterns. Two/three strains leading to treatment failure were also multidrug resistant and belonged to cluster I. Conclusions A relationship between high drug resistance and genetic relatedness of some M. kansasii strains was established. This was associated with clinical treatment failure.
It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals, and thus ...high-resolution technologies are likely required. We used cytometry by time-of-flight and next-generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related precancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 precancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T-cell, B-cell, and natural killer-cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0% ± 0.7% (mean ± SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27(+)) and naïve (CD24(lo)CD38(+)) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells.
We investigated the changing trend of various toxigenic Clostridium difficile isolates at a 3 500-bed hospital in Taiwan. Genetic relatedness and antimicrobial susceptibility of toxigenic C. ...difficile isolates were also examined.
A total of 110 non-repeat toxigenic C. difficile isolates from different patients were collected between 2002 and 2007. Characterization of the 110 toxigenic isolates was performed using agar dilution method, multilocus variable-number tandem-repeat analysis (MLVA) genotyping, tcdC genotyping, and toxinotyping.
Among the 110 toxigenic isolates studied, 70 isolates harbored tcdA and tcdB (A⁺B⁺) and 40 isolates harbored tcdB only (A⁻B⁺). The annual number of A⁺B⁺ isolates considerably increased over the 6-year study (P = 0.055). A total of 109 different MLVA genotypes were identified, in which A⁺B⁺ isolates and A⁻B⁺ isolates were differentiated into two genetic clusters with similarity of 17.6%. Twenty-four (60%) of the 40 A⁻B⁺ isolates formed a major cluster, MLVA-group 1, with a similarity of 85%. Seven (6.4%) resistant isolates were identified, including two metronidazole-resistant and five vancomycin-resistant isolates.
This study indicated a persistence of a MLVA group 1 A⁻B⁺ isolates and an increase of A⁺B⁺ isolates with diverse MLVA types. Moreover, C. difficile isolates with antimicrobial resistance to metronidazole or vancomycin were found to have emerged. Continuous surveillance is warranted to understand the recent situation and control the further spread of the toxigenic C. difficile isolates, especially among hospitalized patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
1 Division of Cardiology, Department of Internal Medicine, Chang Gung University College of Medicine, Taipei, Taiwan, ROC
2 Division of Infectious Diseases, Chang Gung Memorial Hospital, Chang Gung ...University College of Medicine, Taipei, Taiwan, ROC
3 Department of Clinical Pathology and Department of Medical Biotechnology and Laboratory Science, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan, ROC
4 Division of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, ROC
Correspondence Pao-Hsien Chu pchu{at}adm.cgmh.org.tw
Received 3 July 2007
Accepted 24 October 2007
We report a case of Neisseria elongata endocarditis with thalamic septic embolization and subsequent brain abscess formation, which to the best of our knowledge has never been reported in the literature. The brain abscess completely resolved after a surgical repair of the infected mitral valve and an additional 4 weeks of antimicrobial therapy. Based on a review of all previous reports of N. elongata endocarditis, including ours, this will remind physicians that invasive N. elongata infections should be managed and followed up cautiously, as surgical intervention is often required.
Abbreviations: CRP, C-reactive protein; CT, computed tomography; ER, emergency room; MRI, magnetic resonance imaging.
PDF
