Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant

The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls.As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010.10:g.43582056T?>?C; genotype TT, OR?=?17.31, P?=?1.462?×?10^?21). Previously published associations in variants in SEMA (rs11766001, NC_000007.13:g.84145202A?>?C; allele C, OR?=?2.268, P?=?0.009533) and NRG1 (rs4541858, NC_000008.10:g.32410309A?>?G; allele G, OR?=?1.567, P?=?0.015; rs7835688, NC_000008.10:g.32411499G?>?C; allele C, OR?=?1.567, P?=?0.015) were also replicated in the genome-wide association analysis. Sequencing revealed a total of 12 exonic RET rare variants. Of these, eight amino acid changing rare variants and two frameshift variants caused or possibly caused Hirschsprung disease.Only a minority of the Hirschsprung disease cases (9/30 familial; 7/75 sporadic) carried one of the rare variants. Excluding the rare variant carriers from the genome-wide association analysis did not appreciably change the association of rs2435357 with Hirschsprung disease. We estimate that approximately two thirds of the sporadic cases may be statistically attributed to the recessive action of the common non-coding RET variants. Thus, even though most cases do not carry rare RET variants, combinations of rare variants and the common non-coding RET variant cause the majority of the cases in our population.     

Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses

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Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement

We describe the postmortem findings of a 47-year-old man with Fabry disease, an X-linked glycolipid storage disorder, who was on enzyme replacement therapy with recombinant α-galactosidase A for more than 2 years. The patient had widespread atherosclerotic coronary artery disease that culminated in a massive acute myocardial infarction. Atherosclerotic lesions were seen in the right and left coronary systems, aorta, and the basilar artery. Typical Fabry cardiomyopathy and glomerular nephropathy were found. With the exception of vascular endothelial cells, extensive glycolipid storage deposits were seen in all vascular and nonvascular cells and organ systems. We conclude that, at least in this patient, repeated infusions with α-galactosidase A over a prolonged period did not appreciably clear storage material in cells other than vascular endothelial cells. These findings also illustrate accelerated atherosclerosis in susceptible patients with Fabry disease.     

N2 event-related potential correlates of response inhibition in an auditory Go/Nogo task.

The aim of this study was to investigate the event-related potential correlates of response inhibition in the N2 time window, specifically in the auditory modality. A paired tone Go/Nogo paradigm elicited an enhanced fronto-central negativity in the Nogo condition, which was accompanied by a concurring inferior fronto-temporal positivity. In contrast to most previous studies our data provide evidence for a fronto-central Nogo-N2 component in the auditory modality.     

Pentraxin‐3 is upregulated in the central nervous system during MS and EAE,but does not modulate experimental neurological disease

Pentraxin‐3 (PTX3), an acute‐phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2‐mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti‐inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3‐deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation.     

Induced arginine transport via cationic amino acid transporter‐1 is necessary for human T‐cell proliferation

Availability of the semiessential amino acid arginine is fundamental for the efficient function of human T lymphocytes. Tumor‐associated arginine deprivation, mainly induced by myeloid‐derived suppressor cells, is a central mechanism of tumor immune escape from T‐cell‐mediated antitumor immune responses. We thus assumed that transmembranous transport of arginine must be crucial for T‐cell function and studied which transporters are responsible for arginine influx into primary human T lymphocytes. Here, we show that activation via CD3 and CD28 induces arginine transport into primary human T cells. Both naïve and memory CD4⁺ T cells as well as CD8⁺ T cells specifically upregulated the human cationic amino acid transporter‐1 (hCAT‐1), with an enhanced and persistent expression under arginine starvation. When hCAT‐1 induction was suppressed via siRNA transfection, arginine uptake, and cellular proliferation were impaired. In summary, our results demonstrate that hCAT‐1 is a key component of efficient T‐cell activation and a novel potential target structure to modulate adaptive immune responses in tumor immunity or inflammation.     

Patterns of Pretreatment Diagnostic Assessment in Patients Treated with Stereotactic Body Radiation Therapy (SBRT) for Non-Small Cell Lung Cancer (NSCLC): Special Characteristics in the COVID Pandemic and Influence on Outcomes

The pandemic raised a discussion about the postponement of medical interventions for non-small cell lung cancer (NSCLC). We analyzed the characteristics of pretreatment diagnostic assessment in the pandemic and the influence of diagnostic assessment on outcomes. A total of 96 patients with stereotactic body radiation therapy (SBRT) for NSCLC were included. The number of patients increased from mean 0.9 (2012–2019) to 1.45 per month in the COVID era (p < 0.05). Pandemic-related factors (contact reduction, limited intensive care unit resources) might have influenced clinical decision making towards SBRT. The time from pretreatment assessment (multidisciplinary tumor board decision, bronchoscopy, planning CT) to SBRT was longer during the COVID period (p < 0.05). Reduced services, staff shortage, or appointment management to mitigate infection risks might explain this finding. Overall survival, progression-free survival, locoregional progression-free survival, and distant progression-free survival were superior in patients who received a PET/CT scan prior to SBRT (p < 0.05). This supports that SBRT guidelines advocate the acquisition of a PET/CT scan. A longer time from PET/CT scan/conventional staging to SBRT (<10 vs. ≥10 weeks) was associated with worse locoregional control (p < 0.05). The postponement of diagnostic or therapeutic measures in the pandemic should be discussed cautiously. Patient- and tumor-related features should be evaluated in detail.     

Reduced anoctamin 7 (ANO7) expression is a strong and independent predictor of poor prognosis in prostate cancer

Objective:Anoctamin 7(ANO7)is a calcium2+-dependent chloride ion channel protein.Its expression is restricted to prostate epithelial cells.The exact function is unknown.This study aimed to analyze ANO7 expression and its clinical significance in prostate cancer(PCa).Methods:ANO7 expression was assessed by immunohistochemistry in 17,747 clinical PCa specimens.Results:ANO7 was strongly expressed in normal prostate glandular cells but often less abundant in cancer cells.ANO7 staining was interpretable in 13,594 cancer tissues and considered strong in 34.4%,moderate in 48.7%,weak in 9.3%,and negative in 7.6%.Reduced staining was tightly linked to adverse tumor features[high classical and quantitative Gleason grade,lymph node metastasis,advanced tumor stage,high Ki67 labeling index,positive surgical margin,and early biochemical recurrence(P<0.0001 each)].The univariate Cox hazard ratio for prostate-specific antigen(PSA)recurrence after prostatectomy in patients with negative vs.strong ANO7 expression was 2.98(95%confidence interval 2.61–3.38).The prognostic impact was independent of established pre-or postoperatively available parameters(P<0.0001).Analysis of annotated molecular data showed that low ANO7 expression was linked to TMPRSS2:ERG fusions(P<0.0001),elevated androgen receptor expression(P<0.0001),as well as presence of 9 of 11 chromosomal deletions(P<0.05 each).A particularly strong association of low ANO7 expression with phosphatase and tensin homolog(PTEN)deletion may indicate a functional relationship with the PTEN/AKT pathway.Conclusions:These data identify reduced ANO7 protein expression as a strong and independent predictor of poor prognosis in PCa.ANO7 measurement,either alone or in combination,might provide clinically useful prognostic information in PCa.