Chemokines and their receptors control the emigration of leukocytes during inflammation. The role of the RANTES (regulated on activation normal T-cell expressed and secreted) receptors CCR1 and CCR5 in the selective recruitment of monocytes, T(H)1-like T-cell clones, and peripheral T cells enriched for CD45RO(+) "memory" cells were tested in a system in which arrest under flow conditions is triggered by RANTES immobilized to activated endothelium. With the use of selective nonpeptide receptor antagonists or blocking antibodies, it was found that the RANTES-induced arrest of these cells was mediated predominantly by CCR1. In contrast, CCR5 mainly contributed to the spreading in shear flow, and both CCR1 and CCR5 supported transendothelial chemotaxis toward RANTES. The data in this study reveal specialized roles of apparently redundant receptors in distinct steps of leukocyte trafficking and suggest that not all receptors currently used to define mononuclear cell subsets are involved in their direct recruitment from the circulation.

With the unprecedented developments in deep learning, automatic segmentation of main abdominal organs (i.e., liver, kidney, and spleen) seems to be a solved problem as the state-of-the-art (SOTA) methods have achieved comparable results with inter-observer variability on existing benchmark datasets. However, most of the existing abdominal organ segmentation benchmark datasets only contain single-center, single-phase, single-vendor, or single-disease cases, thus, it is unclear whether the excellent performance can generalize on more diverse datasets. In this paper, we present a large and diverse abdominal CT organ segmentation dataset, termed as AbdomenCT-1K, with more than 1000 (1K) CT scans from 11 countries, including multi-center, multi-phase, multi-vendor, and multi-disease cases. Furthermore, we conduct a large-scale study for liver, kidney, spleen, and pancreas segmentation, as well as reveal the unsolved segmentation problems of the SOTA method, such as the limited generalization ability on distinct medical centers, phases, and unseen diseases. To advance the unsolved problems, we build four organ segmentation benchmarks for fully supervised, semi-supervised, weakly supervised, and continual learning, which are currently challenging and active research topics. Accordingly, we develop a simple and effective method for each benchmark, which can be used as out-of-the-box methods and strong baselines. We believe the introduction of the AbdomenCT-1K dataset will promote the future in-depth research towards clinical applicable abdominal organ segmentation methods. Moreover, the datasets, codes and trained models of baseline methods will be publicly available.

Several microbes have been suspected as pathogenetic factors in schizophrenia. We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. Our aim here was to analyze frequencies of three types of Chlamydiaceae in schizophrenic patients (n = 72), random controls (n = 225) and hospital-patient controls (n = 36), together with HLA-A genotypes. Patients were diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders-IV. Blood samples were collected at the beginning of hospitalization and analyzed with Chlamydiaceae species-specific polymerase chain reaction (PCR). Control panels consisted of randomly selected volunteers and hospitalized, non-schizophrenic patients. We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P = 1.39 Â 10 À10 , odds ratio (OR) = 9.43), especially with Chlamydophila psittaci (P = 2.81 Â 10 À7, OR = 24.39). Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P = 8.03 Â 10 À5 , OR = 50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype.

Destruction of cancer cells by cytotoxic T lymphocytes depends on immunogenic tumor peptides generated by proteasomes and presented by human leukocyte antigen (HLA) molecules. Functional differences arising from alleles of immunoproteasome subunits have not been recognized so far. We analyzed the genetic polymorphism of the immunoproteasome subunits LMP2 and LMP7 and of the transporters associated with antigen processing (TAP1 and TAP2) in two independently collected panels of colorectal carcinoma patients (N 1 ¼ 112, N 2 ¼ 62; controls, N ¼ 165). High risk of colon cancer was associated with the LMP7-K/Q genotype (OR ¼ 8.10, P ¼ 1.10 Â 10 À11) and low risk with the LMP7-Q/Q genotype (OR ¼ 0.10, P ¼ 5.97 Â 10 -13 ). The basis for these distinct associations of LMP7 genotypes was functionally assessed by IFN-g stimulation of colon carcinoma cell lines (N ¼ 10), followed by analyses of mRNA expression of HLA class I, TAP1, TAP2, and LMP7, with real-time PCR. Whereas induction of HLA-B, TAP1, and TAP2 was comparable in all cell lines, transcript amounts of LMP7-Q increased 10-fold, but of LMP7-K only 3.8-fold. This correlated with a reduced transcript stability of LMP7-K (t1 2 % 7 minutes) compared with LMP7-Q (t1 2 % 33 minutes). In addition, LMP7-Q/Q colon carcinoma cells increased (the peptide based) HLA class I surface expression significantly after IFN-g stimulation, whereas LMP7-Q/K and LMP7-K/K carcinoma cells showed minimal (<20%) changes. These results suggest that the presence of LMP7-K can reduce the formation of immunoproteasomes and thus peptide processing, followed by reduced peptide-HLA presentation, a crucial factor in the immune response against cancer. Cancer Res; 71(23); 7145-54. Ó2011 AACR.

The viral CC chemokine macrophage inhibitory protein-II (vMIP-II) encoded by human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, however, its ability to control the initial recruitment of specific leukocyte subtypes from the peripheral circulation has not been fully clarified. Here we show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated human microvascular endothelium (HMVEC) under flow conditions. The internalization of the receptors CCR1 and CCR5 that mediate arrest and transmigration of these cells in response to RANTES was prevented by vMIP-II, supporting its role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered the firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as confirmed by its down-regulation. Immunohistochemical analysis of HHV-8-associated Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear cell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes over Th1-type CXCR3(+)/CCR5(+) leukocytes, indicating that as a CCR3 agonist vMIP-II can drive a Th2-type immune response in vivo. Thus, our data provide evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and thereby facilitating evasion from cytotoxic reactions.

In previous studies we found that several Neurotransmitters and Neuropeptides among them: Glutamate, Dopamine, Gonadotropin-releasing-hormone (GnRH) I and II, Somatostatin, CGRP and Neuropeptide Y, can each by itself, at low physiological concentration (~10 nM) bind its receptors in human T cells and trigger several key T cell functions. These findings showed that the nervous system, via Neurotransmitters and Neuropeptides, can 'talk' directly to the immune system, and stimulate what we coined 'Nerve-Driven Immunity': immune responses dictated by the nervous system. In various human cancers, the immune system of the patients, and their T cells in particular, are not functioning well enough against the cancer due to several reasons, among them the suppressive effects on the immune system induced by: (1) the cancer itself, (2) the chemotherapy and radiotherapy, (3) the ongoing/chronic stress, anxiety, depression and pain felt by the cancer patients. In Head and Neck Cancer (HNC), 5-year survival rate remains below 50%, primarily because of local recurrences or second primary tumors. Two-thirds of HNC patients are diagnosed at advanced clinical stage and have significantly poorer prognosis. Most HNC patients have multiple severe immunological defects especially in their T cells. A major defect in T cells of patients with HNC or other types of cancer is low CD3zeta expression that correlates with poor prognosis, decreased proliferation, apoptotic profile, abnormal cytokine secretion and poor abilities of destructing cancer cells. T cells of cancer patients are often also unable to migrate properly towards the tumor. In this study we asked if Glutamate, Dopamine or GnRH-II can augment the spontaneous migration, chemotactic migration and towards autologous HNC migration, and also increase CD3zeta and CD3epsilon expression, of peripheral T cells purified from the blood of five HNC patients. These HNC patients had either primary tumor or recurrence, and have been already treated by surgery and/or radiotherapy and/or chemotherapy without satisfactory outcomes. We found that Glutamate, Dopamine and GnRH-II, each by itself, at 10 nM, and during 30 min incubation only with the peripheral T cells of the HNC patients increased substantially their: (1) spontaneous migration (up to 4.4 fold increase), (2) chemotactic migration towards the key chemokine SDF-1 (up to 2.3 fold increase), (3) migration towards the autologous HNC tumor removed surgically ~48 h earlier in a pre-planned operation (up to 3.5 fold increase). Each of the Neurotransmitters even 'allowed' the T cells of one HNC patient to overcome completely the suppressive anti-migration effect of his autologous tumor, (4) cell surface CD3zeta expression (up to 4.3 fold increase), (5) cell surface CD3epsilon expression (up to 1.9 fold increase). If the absolutely essential larger scale subsequent studies would validate our present findings, Glutamate, Dopamine and GnRH-II could be used for a completely novel indication: adoptive T cell immunotherapy for some patients with ...

No abstract

Glioma is a severe disease of the central nervous system. Although previous studies have identified the important role of the immune response in association with tumor intervention, it is still unknown whether PU.1, a transcription factor known for its role in myeloid differentiation and immune responses, is involved in the progression of glioma. In the present study, we found a significant increase in SPI1, the gene that encodes PU.1, in samples from patients with glioma. Through genotype-phenotype association analysis several candidate factors that may mediate the role of PU.1 in glioma were identified. To further validate the association between PU.1 and glioma we found that the expression of BTK, a potential target of PU.1, was also upregulated in patients with glioma. We also demonstrated that various biological pathways could be involved in PU.1-associated glioma by analyzing these potential targets in the Reactome database. These results provide evidence that PU.1 could serve a role in the progress of glioma through its transcriptional targets in multiple signaling pathways. Therefore, in addition to its role in hematopoietic linage development and leukemia, PU.1 appears to be involved in the regulation of glioma and potentially in other malignant cancers.