Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency recently found to be associated with mutations of DOCK8. Clinically, this disorder is characterized beside recurrent ...bacterial complications, in particular by an unusual susceptibility to extensive cutaneous viral complications and by a high risk for squamous cell carcinoma. Here, we report on lasting control over the disorder in two patients by hematopoietic cell transplantation (HCT). Both patients were suffering from extensive long-lasting cutaneous viral complications, in particular from disfiguring molluscum contagiosum infections, when treated at the age of 10 and 17 years. Donors were matched unrelated, and conditioning was carried out with a combination of fludarabine, melphalan and BM-targeted radioimmunotherapy. Both patients developed stable, full donor cell chimerism, with the exception of persistent low-IgA serum levels and the exception of normal immune functions. Over the course of several months, cutaneous manifestations of viral disease resolved completely and both patients remain clinically well and free of infectious complications at 4 and 2 years, respectively, after transplantation. This represents the first report indicating HCT to be curative in patients with AR-HIES, which should be considered early before life-threatening complications develop, which include malignancies.
CD147 (basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDACs) which is associated with poor prognosis in many malignancies. The ...role of CD147 in pancreatic cancer, however, remains elusive.
Silencing of CD147 by RNA interference (RNAi) reduced the proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for the function and expression of the monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time reverse transcription-PCR (RT-PCR) as well as immunohistology. MCT1 and MCT4 are the natural transporters of lactate, and MiaPaCa2 cells exhibited a high rate of lactate production, which is characteristic for the Warburg effect, an early hallmark of cancer that confers a significant growth advantage. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 expression. CD147 silencing inhibited the expression and function of MCT1 and MCT4 and resulted in an increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer cell growth in a dose-dependent fashion. In vivo, knock-down of CD147 in MiaPaCa2 cells by inducible short hairpin RNA (shRNA)-mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM assay) and inhibited tumourigenicity in a xenograft model in nude mice.
The function of CD147 as an ancillary protein that is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression with the malignant potential of pancreatic cancer cells exhibiting the Warburg effect.
Claudin-4 has been identified as an integral constituent of tight junctions and has been found to be highly expressed in pancreatic cancer. The aim of the present study was to elucidate the effect of ...claudin-4 on growth and metastatic potential in pancreatic cancer cells, as well as the regulation of claudin-4 by oncogenic pathways. Claudin-4 was stably overexpressed in SUIT-2 pancreatic cancer cells, and its effect on invasion and growth in vitro was examined by using two-chamber invasion assays, soft agar assays, and fluorescence-activated cell sorter analysis. Claudin-4 localization was characterized by light and electron microscopy, and pulmonary colonization was analyzed in vivo after injection of claudin-4 overexpressing cells into the tail vein of nude mice. Overexpression of claudin-4 was associated with significantly reduced invasive potential in vitro and inhibited colony formation in soft agar assays. In vivo, tail vein-injected claudin-4 overexpressing cells formed significantly less pulmonary metastases in comparison with mock-transfected cells. These effects were not caused by changes in proliferation, cell cycle progression, or matrix metalloproteinase gelatinolytic activity, but were paralleled by increased cell contact formation. Moreover, proinvasive transforming growth factor beta was able to down-regulate claudin-4 in PANC-1 cells. Inhibition of Ras signaling by using dominant-negative Ras and specific inhibitors of both downstream effectors mitogen-activated protein/extracellular signal-regulated kinase kinase and phosphatidylinositol 3'-kinase also decreased claudin-4 expression. Our findings identify claudin-4 as a potent inhibitor of the invasiveness and metastatic phenotype of pancreatic cancer cells, and as a target of the transforming growth factor beta and Ras/Raf/extracellular signal-regulated kinase pathways.
Hadron production (
π
±
, proton,
Λ
,
K
S
0
,
K
±
) in
π
-
+
C
and
π
-
+
W
collisions is investigated at an incident pion beam momentum of
1.7
GeV
/
c
. This comprehensive set of data measured with ...HADES at SIS18/GSI significantly extends the existing world data on hadron production in pion induced reactions and provides a new reference for models that are commonly used for the interpretation of heavy-ion collisions. The measured inclusive differential production cross-sections are compared with state-of-the-art transport model (GiBUU, SMASH) calculations. The (semi-) exclusive channel
π
-
+
A
→
Λ
+
K
S
0
+
X
, in which the kinematics of the strange hadrons are correlated, is also investigated and compared to a model calculation. Agreement and remaining tensions between data and the current version of the considered transport models are discussed.
A feasibility study has been performed in order to investigate the performance of the HADES detector to measure the electromagnetic decays of the hyperon resonances
Σ
(
1385
)
0
,
Λ
(
1405
)
and
...Λ
(
1520
)
as well as the production of double strange baryon systems
Ξ
-
and
Λ
Λ
in p + p reactions at a beam kinetic energy of
4.5
GeV
. The existing HADES detector will be upgraded by a new Forward Detector, which extends the detector acceptance into a range of polar angles that plays a crucial role for these investigations. The analysis of each channel is preceded by a consideration of the production cross-sections. Afterwards the expected signal count rates using a target consisting of either liquid hydrogen or polyethylene are summarized.
At energies below sNN≈2.55GeV, strange quarks cannot be produced in binary nucleon-nucleon collisions because of the higher production threshold of the lightest hadrons carrying strangeness. Hence, ...the investigation of sub-threshold strangeness production in heavy-ion collisions is one of the most promising probes, to access the properties of the created system, as the missing energy must be provided by the latter one. For the first time, a nearly complete set of strange particles has been reconstructed in the 40% most central Au+Au collisions at sNN=2.42GeV. The data sample includes multi-differential representations of charged and neutral particles containing strangeness (K±, Ks0, ϕ, Λ). To achieve a better understanding of strangeness production the properties of the short-lived resonances have to be investigated. The first steps in this direction are presented here, including the reconstruction of baryon resonances using a new iterative technique, comparison to microscopic transport model calculations and interpretation of the pion transverse momentum distribution.
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