CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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Dipeptidyl peptidase-4 expression in pancreatic tissue from patients with congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is caused by unregulated insulin release and leads to hyperinsulinaemic-hypoglycaemia (HH). Glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY) and the enzyme; dipeptidyl peptidase-4 (DPP-4) all regulate appetite and glucose homeostasis. These proteins have been identified as possible contributors to HH but the mechanism remains poorly understood. We aimed to look at the expression pattern of pancreatic DPP-4 in children with focal and diffuse CHI (FCHI and DCHI, respectively). Using immunohistochemistry; we determined DPP-4 expression patterns in the pancreas of CHI patients. DPP-4 was found to be expressed in the pancreatic β, α and δ-cells in and around the focal area. However, it was predominantly co-localised with β-cells in the paediatric tissue samples. Additionally, proliferating β-cells expressed DPP-4 in DCHI, which was absent in the FCHI pancreas. Insulin was found to be present in the exocrine acini and duct cells of the DCHI pancreas suggestive of exocrine to endocrine transdifferentiation. Furthermore, 6 medically-unresponsive DCHI pancreatic samples showed an up-regulation of total pancreatic DPP-4 expression. In conclusion; the expression studies have shown DPP-4 to be altered in HH, however, further work is required to understand the underlying role for this enzyme.     

Predictors of Treatment Outcomes in ANCA-Associated Vasculitis with Severe Kidney Failure

Background and objectives

In ANCA-associated GN, severe renal dysfunction portends a poor prognosis for renal recovery and patient survival. This study evaluated the prognostic factors affecting renal and patient outcomes in patients presenting with severe kidney failure to guide immunosuppressive therapy.

Design, setting, participants, & measurements

This study retrospectively evaluated clinical and histopathologic characteristics of 155 patients who underwent biopsy between October 1985 and February 2011 (median eGFR at presentation, 7.1 ml/min per 1.73 m²; 87% required hemodialysis), all treated with immunosuppressive medications. Three outcomes of interest were measured: patient survival, renal survival, and treatment response (defined as dialysis-free survival without active vasculitis by 4 months after biopsy). Competing risk, Cox, and logistic regression analyses were conducted for each outcome measure.

Results

Within 4 months after biopsy, treatment response was attained in 51% of patients, 35% remained on dialysis, and 14% died. In a competing risk analysis, estimated cumulative incidence rates of ESRD and disease-related mortality were 26% and 17% at 1 year and 32% and 28% at 5 years, respectively. Cyclophosphamide therapy and treatment response by 4 months were independently associated with patient and renal survival, adjusting for the percentage of normal glomeruli, histopathologic chronicity index score, and baseline clinical characteristics. Only 5% of patients still dialysis dependent at 4 months subsequently recovered renal function. Low chronicity index score (odds ratio [OR], 1.16; 95% confidence interval [95% CI], 1.04 to 1.30, per unit decrease) and baseline eGFR>10 ml/min per 1.73 m² (OR, 2.77; 95% CI, 1.09 to 7.01) were significantly associated with treatment response by 4 months. Among cyclophosphamide-treated patients, the likelihood of treatment response was >14% even with highest chronicity index score and eGFR<10 ml/min per 1.73 m².

Conclusions

Although low baseline renal function and severe renal scarring are associated with lower treatment response rate, no “futility” threshold could be identified. Conversely, continued immunosuppressive therapy beyond 4 months is unlikely to benefit patients who remain dialysis dependent.     

TLR2 engagement on CD4+ T cells enhances effector functions and protective responses to Mycobacterium tuberculosis

We have previously demonstrated that mycobacterial lipoproteins engage TLR2 on human CD4⁺ T cells and upregulate TCR‐triggered IFN‐γ secretion and cell proliferation in vitro. Here we examined the role of CD4⁺ T‐cell‐expressed TLR2 in Mycobacterium tuberculosis (MTB) Ag‐specific T‐cell priming and in protection against MTB infection in vivo. Like their human counterparts, mouse CD4⁺ T cells express TLR2 and respond to TLR2 costimulation in vitro. This Th1‐like response was observed in the context of both polyclonal and Ag‐specific TCR stimulation. To evaluate the role of T‐cell TLR2 in priming of CD4⁺ T cells in vivo, naive MTB Ag85B‐specific TCR transgenic CD4⁺ T cells (P25 TCR‐Tg) were adoptively transferred into Tlr2^?/? recipient C57BL/6 mice that were then immunized with Ag85B and with or without TLR2 ligand Pam₃Cys‐SKKKK. TLR2 engagement during priming resulted in increased numbers of IFN‐γ‐secreting P25 TCR‐Tg T cells 1 week after immunization. P25 TCR‐Tg T cells stimulated in vitro via TCR and TLR2 conferred more protection than T cells stimulated via TCR alone when adoptively transferred before MTB infection. Our findings indicate that TLR2 engagement on CD4⁺ T cells increases MTB Ag‐specific responses and may contribute to protection against MTB infection.     

Cognitive processing load across a wide range of listening conditions: Insights from pupillometry

The pupil response to speech masked by interfering speech was assessed across an intelligibility range from 0% to 99% correct. In total, 37 participants aged between 18 and 36 years and with normal hearing were included. Pupil dilation was largest at intermediate intelligibility levels, smaller at high intelligibility, and slightly smaller at very difficult levels. Participants who reported that they often gave up listening at low intelligibility levels had smaller pupil dilations in these conditions. Participants who were good at reading masked text had relatively large pupil dilation when intelligibility was low. We conclude that the pupil response is sensitive to processing load, and possibly reflects cognitive overload in difficult conditions. It seems affected by methodological aspects and individual abilities, but does not reflect subjective ratings.     

Routine application of a novel MLPA-based first-line screening test uncovers clinically relevant copy number aberrations in haematological malignancies undetectable by conventional cytogenetics

Objective

The presence of numerical and/or structural chromosomal abnormalities is a frequent finding in clonal hematopoietic malignant disease, typically diagnosed through routine karyotyping and/or fluorescent in situ hybridization (FISH) analysis. Recently, the application of array comparative genomic hybridization (aCGH) has uncovered many new cryptic genomic copy number imbalances, most of which are now recognized as clinically useful markers of haematological malignancies. In view of the limitations of both FISH and aCGH techniques, in terms of their routine application as a first line screening test, we designed a new multiple ligation-dependent probe amplification (MLPA) probemix for use in addition to classic karyotype analysis.

Methods

A novel MLPA probemix was developed to interrogate copy number changes involving chromosomal regions: 2p23-24 (MYCN, ALK), 5q32-34 (MIR145A, EBF1, MIR146A), 6q21-27, 7p12.2 (IKZF1), 7q21-36, 8q24.21 (MYC), 9p24 (JAK2 V617F point mutation), 9p21.3 (CDKN2A/2B), 9p13.2 (PAX5), 10q23 (PTEN), 11q22.3 (ATM), 12p13.2 (ETV6), 13q14 (RB1, MIR15A, DLEU2, DLEU1), 17p13.1 (TP53), and 21q22.1 (RUNX1/AML1) and was applied to DNA extracted from 313 consecutive bone marrow patient samples, referred for routine karyotype analysis.

Results

More than half of the samples originated from newly investigated patients. We discovered clinically relevant genomic aberrations, involving a total of 24 patients (8%) all with a normal karyotype, which would have remained undiagnosed.

Discussion

Our data clearly indicate that routine application of this MLPA screening panel, as an adjunct to karyotype analysis, provides a sensitive, robust, rapid and low-cost approach for uncovering clinically important genomic abnormalities, which would have otherwise remained undetected.     

Patterns of cortical input to the primary motor area in the marmoset monkey

In primates the primary motor cortex (M1) forms a topographic map of the body, whereby neurons in the medial part of this area control movements involving trunk and hindlimb muscles, those in the intermediate part control movements involving forelimb muscles, and those in the lateral part control movements of facial and other head muscles. This topography is accompanied by changes in cytoarchitectural characteristics, raising the question of whether the anatomical connections also vary between different parts of M1. To address this issue, we compared the patterns of cortical afferents revealed by retrograde tracer injections in different locations within M1 of marmoset monkeys. We found that the entire extent of this area is unified by projections from the dorsocaudal and medial subdivisions of premotor cortex (areas 6DC and 6M), from somatosensory areas 3a, 3b, 1/2, and S2, and from posterior parietal area PE. While cingulate areas projected to all subdivisions, they preferentially targeted the medial part of M1. Conversely, the ventral premotor areas were preferentially connected with the lateral part of M1. Smaller but consistent inputs originated in frontal area 6DR, ventral posterior parietal cortex, the retroinsular cortex, and area TPt. Connections with intraparietal, prefrontal, and temporal areas were very sparse, and variable. Our results demonstrate that M1 is unified by a consistent pattern of major connections, but also shows regional variations in terms of minor inputs. These differences likely reflect requirements for control of voluntary movement involving different body parts. J. Comp. Neurol. 522:811–843, 2014. © 2013 Wiley Periodicals, Inc.     

Patterns of afferent input to the caudal and rostral areas of the dorsal premotor cortex (6DC and 6DR) in the marmoset monkey

Corticocortical projections to the caudal and rostral areas of dorsal premotor cortex (6DC and 6DR, also known as F2 and F7) were studied in the marmoset monkey. Both areas received their main thalamic inputs from the ventral anterior and ventral lateral complexes, and received dense projections from the medial premotor cortex. However, there were marked differences in their connections with other cortical areas. While 6DR received consistent inputs from prefrontal cortex, area 6DC received few such connections. Conversely, 6DC, but not 6DR, received major projections from the primary motor and somatosensory areas. Projections from the anterior cingulate cortex preferentially targeted 6DC, while the posterior cingulate and adjacent medial wall areas preferentially targeted 6DR. Projections from the medial parietal area PE to 6DC were particularly dense, while intraparietal areas (especially the putative homolog of LIP) were more strongly labeled after 6DR injections. Finally, 6DC and 6DR were distinct in terms of inputs from the ventral parietal cortex: projections to 6DR originated preferentially from caudal areas (PG and OPt), while 6DC received input primarily from rostral areas (PF and PFG). Differences in connections suggest that area 6DR includes rostral and caudal subdivisions, with the former also involved in oculomotor control. These results suggest that area 6DC is more directly involved in the preparation and execution of motor acts, while area 6DR integrates sensory and internally driven inputs for the planning of goal‐directed actions. They also provide strong evidence of a homologous organization of the dorsal premotor cortex in New and Old World monkeys. J. Comp. Neurol. 522:3683–3716, 2014. © 2014 Wiley Periodicals, Inc.