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Objective. The levels of vitamin D, trace elements, and glucose and lipid metabolism in psoriasis were evaluated, and their value in disease diagnosis and severity evaluation was explored. Methods. In this study, the serum trace elements, blood glucose, and blood lipid indexes of 360 patients with psoriasis and 500 healthy subjects were compared and analyzed. Results. The results of 25-(OH) D3, Cu/Zn, and HDL-C in patients with psoriasis were significantly different from those in the control group. With the aggravation of the disease, Psoriasis Area and Severity Index (PASI) was positively correlated with 25-(OH) D3 and HDL-C and negatively correlated with Cu/Zn. The AUC of the three indexes for the diagnosis of psoriasis was 0.899, 0.675, and 0.848, respectively. Conclusion. There are metabolic abnormalities of 25-(OH) D3, Cu/Zn, and HDL-C in patients with psoriasis, and paying attention to these indicators is conducive to the diagnosis of disease.

Sand waves near the shelf break in the northern South China Sea have not previously been described in detail due to the lack of high-resolution bathymetric data. Their occurrence, however, is important for understanding sand transport and dispersal in the northern South China Sea. Here, using recent bathymetric data, side-scan image, bottom current measurements, and sediment samples collected in 2010 and 2016, we document the distribution, geometry, and mobility of sand waves in five regions along the shelf break of the northern South China Sea. Results show that the sand waves have distinctly different distribution patterns, geometries, and migration behaviors above and below the 145 m isobath. Sand waves at depths greater than 145 m are larger and steeper, and mostly occur on slopes steeper than 0.5°. Their crest lines are aligned parallel to the isobaths and their migration direction is toward the southeast (seaward). In comparison, the sand waves on the gentler sloping seabed at water depths

In order to help users select a reliable service in the open and complicated network, an autonomous dynamic trust management system is put forward based on collaborative recommendation mechanism and uncertainty analysis of satisfaction data. Any user in the network can store and update autonomously his trust table which contains direct interaction experience, find easily the reliable referrers according to collaborative recommendation, and collect valuable trust data and calculate the satisfaction and its reliability based on uncertainty analysis. Then the direct, recommended and self-recommended trusts can be calculated and finally be used to compute the global trust which will help the user to make a trust decision. A complicated network environment which includes quite a part of malicious nodes is built for investigating the robustness and effectiveness of the trust system. The experimental results show that the quality of service selection can be improved with the increase of interaction; the system can keep stable even though there are 50% malicious nodes initially in the network or a large number of malicious nodes join the network after stability; the system can resist the collusion attack more effectively and has lower computation and storage overhead than contrastive models.

The inflammatory response and apoptosis are key factors in cerebral ischemia-reperfusion injury. The severity of the inflammatory reaction and apoptosis has an important impact on the prognosis of stroke. The ultrasmall superparamagnetic iron oxide particle has provided an effective magnetic resonance molecular imaging method for dynamic observation of the cell infiltration process in vivo. The aims of the present study were to investigate the inflammatory response of cerebral ischemia-reperfusion injury in mice using ferumoxytol-enhanced magnetic resonance imaging, and to observe the dynamic changes of inflammatory response and apoptosis. In the present study a C57BL/6n mouse cerebral ischemia-reperfusion model was established by blocking the right middle cerebral artery with an occluding suture. Subsequently, the mice were injected with ferumoxytol via the tail vein, and magnetic resonance scanning was performed at corresponding time points to observe the signal changes. Furthermore, blood samples were used to measure the level of serum inflammatory factors, and histological staining was performed to assess the number of iron-swallowing microglial cells and apoptotic cells. The present results suggested that there was no significant difference in the serum inflammatory factors tumor necrosis factor-α and interleukin 1β between the middle cerebral artery occlusion (MCAO) and MCAO + ferumoxytol groups injected with ferumoxytol and physiological saline. The lowest signal ratio in the negative enhancement region was decreased 24 h after reperfusion in mice injected with ferumoxytol. The proportion of iron-swallowing microglial cells and TUNEL-positive cells were the highest at 24 h after reperfusion, and decreased gradually at 48 and 72 h after reperfusion. Therefore, the present results indicated that ferumoxytol injection of 18 mg Fe/kg does not affect the inflammatory response in the acute phase of cerebral ischemia and reperfusion. Ferumoxytol-enhanced magnetic resonance imaging can be used as an effective means to monitor the inflammatory response in the acute phase of cerebral ischemia-reperfusion injury. Furthermore, it was found that activation of the inflammatory response and apoptosis in the acute stage of cerebral ischemia-reperfusion injury is consistent.

Uric acid nephropathy (UAN) is one of the most common metabolic diseases and leads to kidney damage. This study aimed to evaluate the effect of Weicao capsule on renal injury of UAN rats and to examine whether the mechanism was associated with induction of autophagy and degradation of nucleotide binding oligomerization domain (Nod)-like receptor (NLR) protein 3 (NLRP3) inflammasome. Sixty Sprague-Dawley rats were randomly allocated into 6 groups: Control, Model, Allopurinol, and Weicao (0.55/1.1/2.2 g/kg) group. The data showed activation of renal NLRP3 inflammasome in UAN rats, with elevation in serum levels of interleukin (IL)-1β and IL-18, and subsequent deterioration of renal injury. Fortunately, Weicao had a markedly therapeutic effect on UAN rats, including improving renal function-related indexes, ameliorating hyperuricemia-related inflammation, decreasing crystals in renal tissue and alleviating renal interstitial fibrosis. Additionally, Weicao exerted anti-proliferative and anti-apoptosis effects on rat renal tubular epithelial cell NRK-52E in macrophages from UAN rats. Our investigation into the mechanism revealed that Weicao suppressed the activated NLRP3 inflammasome. Furthermore, Weicao induced autophagy, as evidenced by a dose-dependent increase in levels of renal autophagy-related proteins in UAN rats. Moreover, autophagy inhibitor 3-MA and NLRP3 activator ATP blocked the effect of Weicao on autophagy induction and NLRP3 inflammasome degradation. In conclusion, Weicao had similar effects as allopurinol and exerted anti-inflammatory and renal-protective effect in a concentration-dependent manner in UAN rats, most likely through increasing autophagy and NLRP3 degradation. Our study provides new insight into the underlying mechanism of Weicao in the treatment of UAN.

Understanding the link between deglacial sea-level jumps and abrupt climate change may provide crucial insights into future ice-climate feedbacks. However, much ambiguity remains surrounding many of the last deglacial meltwater pulses. Here, we present a complete sedimentary succession from the inner shelf of the East China Sea, which has clearly documented multiple abrupt rises in the deglacial sea level. The results suggest that the postglacial sedimentary sequence, resting on a late Pleistocene basement of stiff clay, formed during a three-stage process marked by characteristic lithology and foraminiferal fauna. The abrupt shifts in the sedimentary facies indicate that seawater firstly intruded into the inner shelf just before the onset of the slowdown in sea-level rise caused by the Younger Dryas cooling event and changed the inner shelf into a tidal flat environment, as demonstrated by the sudden appearance of both planktonic foraminifera and typical brackish-water species of benthic foraminifera. Meltwater pulse 1B (MWP-1B) is depicted by a sharp upward transition to a nearshore subtidal environment at 11.62 kyr. This episode of sea-level rise induced the initial flooding of the inner shelf, which is well documented by the sudden reduction in brackish-water foraminifera species and evident increase in inner-shelf benthic species. The prominent sea-level rise at approximately 7.54 kyr was responsible for the shift to stable inner shelf conditions and resulted in the maximum flooding of the inner shelf area, initiating subsequent formation of the alongshore mud wedge. Additionally, obvious peaks in both the benthic foraminifer abundance and the marine algae concentration at approximately 8.13 kyr confirm the previously identified sea-level jump at approximately 8.2 kyr, which coincides with the weakening of the Asian monsoon demonstrated by the peak grain size in our record, further indicating its apparent connection to the 8.2 kyr climatic reversal.

Cerebral ischemic injury has been the leading cause of death and long term disability in the world because of the lack of successful therapies to it, leading to neurological and behavioral deficits. The present study aims to investigate the effects of combined preconditioning (PC) with hypoxia and GYKI-52466 (GYKI) on cerebral ischemic injury and to explore the mechanism. The results showed that combined preconditioning with hypoxia and GYKI-52466 increased the survival rate of cerebral ischemia rats, alleviated the neurological deficit, increased the object recognition and social recognition memory of rats and suppressed the inflammatory reaction induced by cerebral ischemia. Further experiments found that preconditioning with hypoxia and GYKI-52466 significantly increased the HIF-1α and eNOS expression as well as eNOS activity, while inhibitors of HIF-1α and eNOS abolished the protective effects of hypoxia+GYKI PC on neurological deficit. Taken together, these results indicate that combined preconditioning with hypoxia and GYKI-52466 is effective to prevent cerebral ischemia injury, while HIF-1α and eNOS may be involved in the mechanism.

To reconstruct the productivity changes for the last 10 500 a in the northeastern East China Sea (ECS), biogenic compounds (such as carbonate, organic carbon and opal), marine micropaleontological fossils (planktonic foraminifera, benthic foraminifera, radiolarian and silicoflagellate) and the compositional characters of benthic foraminifera fauna analyses were carried out on a sediment core DOC082 obtained from the western slope of Okinawa Trough (29 degrees 13.93'N, 128 degrees 08.53' E; 1 128 m water depth). The long-term changes of biogenic and micropaleontological proxies display some similarities through the last 10 500 a, which show three different phases: lower values are recorded during the early and middle Holocene (before about 4 000 a BP), followed by an abrupt and remarkable increase at about 4 000 a BP, the late Holocene (after about 3 000 a BP) is characterized by continuously high values. The multi-proxy data of paleoproductivity and percents of benthic foraminifera genera (Uvigerina and Bulimina) show that during the early and middle Holocene (10 500-4 000 a BP) productivity was relatively low with a sudden and distinct increase at about 4 000 a BP, and the late Holocene (3 400-0 a BP) is marked by significantly higher productivity. Also, the radiolarian-based sea surface temperature (SST) records reveal a distinct decline in SST in the late Holocene after 3 200 a BP, very different from the early and middle Holocene. For the last 3 000 a, the enhanced biological productivity and distinctly lower SST indicate a major change of oceanographic conditions in the northeastern ECS. These marine environmental anomalies are consistent with other paleoclimatic records for the late Holocene in the Chinese continent and its surrounding regions. After analyzing the mechanisms of modern productivity and SST changes in the northeastern ECS, and based on the climatic anomalies in the Chinese continent and variations in the Kuroshio Current during modern El Nino periods, we suggest that the anomalous environmental conditions in the northeastern ECS may imply intensified El Nino activity during the late Holocene.

Hacs1, a SH3 and SAM domain-containing adaptor protein, is up-regulated by IL-4 in activated B cells and strongly expressed in dendritic cells. To elucidate the function of Hacs1 in immune regulation, we generated Hacs1(-/-) mice by deletion of the SH3 and SAM domains. Hacs1(-/-) mice were viable and fertile and had normal bone marrow B-cell development and normal splenic T- and B-cell populations. However, adult Hacs1(-/-) mice had increased peritoneal B1a cells (IgM(+)CD5(+)). On immunization with T-cell-independent antigen TNP-Ficoll, Hacs1(-/-) mice had increased production of anti-TNP IgM and IgG3. Purified splenic B cells from Hacs1(-/-) mice showed increased cell proliferation on BCR (B-cell receptor) stimulation. We further demonstrate that the Hacs1(-/-) B cells had increased global tyrosine phosphorylation, including tyrosine kinases Lyn and Akt. Both T-helper type 1 (T(h)1) and T-helper type 2 (T(h)2) humoral responses were enhanced in Hacs1(-/-) mice. In vitro bone marrow-derived Hacs1(-/-) dendritic cells showed increased IL-12 production on stimulation with ovalbumin (OVA). This study suggests that Hacs1 is an immunoinhibitory adaptor that might be a useful target for immune suppression therapy.-Wang, D., Stewart, A. K., Zhuang, L., Zhu, Y., Wang, Y., Shi, C., Keating, A., Slutsky, A., Zhang, H., Wen, X.-Y. Enhanced adaptive immunity in mice lacking the immunoinhibitory adaptor Hacs1.

The morphology of the beach backshore and foreshore at Huiquan Bay, Qingdao, China, is characterized by a single intertidal sandbar system with a spring tide range of 4.59 m. The beach was measured with a laser total station of Leica TPS402. Contours of the beach were generated using data collected in March and November 2005. The survey method provided 2 mm measuring accuracy and 4–10 m horizontal spacing. The net accretion volume of the foreshore was about 11, 215 m3 from March to November. After sand sculpture activity, the axis of the sand trough migrated onshore from about 3.5 m to 17.5 m on the foreshore beach in November. At the same time, the axis of the sandbar crest migrated onshore no more than 42.25 m on the northwest foreshore; and it migrated offshore no more than 23.75 m on the southeast foreshore. On the northwest and southeast foreshore beach, two strips of erosion areas with a thickness of 0–0.2 m appeared on the sandbar crest. Accretion occurred at the bottom of the sand trough with a thickness of ∼0.2–0.6 m. The sandbar height decreased after sand sculpture activity, and it was no more than 0.7 m in March and 0.6 m in November. Human activities, such as sand digging on the sandbar crest during sand sculpture activity, also can disturb the beach morphology of intertidal bar systems. This phenomenon also was validated by comparison of beach morphology, the results of a color artificial tracer experiment and a sediment transportation trend prediction.

The B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor involved in B cell terminal differentiation. Recent studies suggest that it also plays roles in the differentiation of myeloid and T cells. Using reporter gene analysis, we found that the mouse Blimp-1 promoter constructs of 4.4 kb, 2.5 kb and 1.6 kb exerted similar transcription activity in vitro. To study the Blimp-1 promoter function in vivo, we generated a mouse transgenic line in which the expression of EGFP is driven by the 4.4 kb Blimp-1 promoter fragment. EGFP expression was detected in multiple hematopoietic lineages including hematopoietic progenitor cells (c-kit+), B cells at various developmental stages (B220+, IgM+, IgD+ and CD138+), myeloid cells (Gr1+ and CD11b+) and T cells (CD4+ and CD8+). Furthermore, we demonstrated, for the first time, that this Blimp-1 promoter fragment also drives EGFP expression in erythroid lineage (Ter119+) and embryonic livers. Finally, EGFP was expressed in the testes of transgenic mice in a cell-specific manner with expression weakly in primary spermatocytes and strongly in spermatids, but not in spermatogonia or spermatozoa. Our studies collectively suggest that Blimp-1 may play a general role in the development of hematopoietic lineages and a stage-specific role in spermatogenesis.

The frequency and prognostic relevance of translocations t(11;14) and t(4;14), the most common translocations involving the immunoglobulin heavy chain (IgH) gene in multiple myeloma (MM), were investigated in 128 patients treated with intensive chemotherapy and autologous stem cell transplant. Myeloma cells were identified by cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (cIg-FISH) for detection of translocations t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12.8%) and t(4;14) in 15 of 120 (12.5%) patients. Progression-free and overall survivals were similar for patients with or without t(11;14). However, patients with t(4;14) had significantly shorter progression-free (median 9.9 months vs. 25.8 months; P = 0.0003) and overall survivals (median 18.3 months vs. 48.1 months; P < 0.0001) than patients without t(4;14). The t(4;14) was associated with IgA and t(11;14) with light chain MM. There was no association between the t(11;14) or t(4;14) and other biological parameters including age, gender, haemoglobin, beta-2 microglobulin, C-reactive protein, calcium, creatinine, albumin, or the percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14) as the only adverse prognostic factor for both progression-free survival and overall survival. Our results indicate that the t(4;14) detected by cIg-FISH is associated with a poor prognosis in MM patients receiving intensive chemotherapy and autotransplant.

The role of CD4+ vs CD8+ T cells in contact hypersensitivity (CHS) remains controversial. In this study, we used gene knockout (KO) mice deficient in CD4+ or CD8+ T cells to directly address this issue. Mice lacking either CD4+ or CD8+ T cells demonstrated depressed CHS responses to dinitrofluorobenzene and oxazolone compared with wild-type C57BL/6 mice. The depression of CHS was more significant in CD8 KO mice than in CD4 KO mice. Furthermore, in vivo depletion of either CD8+ T cells from CD4 KO mice or CD4+ T cells from CD8 KO mice virtually abolished CHS responses. Lymph node cells (LNCs) from hapten-sensitized CD4 and CD8 KO mice showed a decreased capacity for transferring CHS. In vitro depletion of either CD4+ T cells from CD8 KO LNCs or CD8+ T cells from CD4 KO LNCs resulted in a complete loss of CHS transfer. LNCs from CD4 and CD8 KO mice produced significant amounts of IFN-γ, indicating that both CD4+ and CD8+ T cells are able to secrete IFN-γ. LNCs from CD8, but not CD4, KO mice were able to produce IL-4 and IL-10, suggesting that IL-4 and IL-10 are mainly derived from CD4+ T cells. Intracellular cytokine staining of LNCs confirmed that IFN-γ-positive cells consisted of CD4+ (Th1) and CD8+ (type 1 cytotoxic T) T cells, whereas IL-10-positive cells were exclusively CD4+ (Th2) T cells. Collectively, these results suggest that both CD4+ Th1 and CD8+ type 1 cytotoxic T cells are crucial effector cells in CHS responses to dinitrofluorobenzene and oxazolone in C57BL/6 mice.

The clinical and histopathological findings in a case of inflammatory linear verrucose epidermal nevus coexisting with lichen amyloidosus are presented. A 33-year-old woman had had linear verrucose lesions which were histopathologically compatible with ILVEN, and with which no amyloid deposits were associated, on her left lower leg for 30 years. She had noticed keratotic papules around the verrucose lesions on the left leg for the last 3 years. Histopathology of these papules revealed amyloid deposits in the upper dermis under the hyperkeratotic and acanthotic epidermis. Topical application of DMSO liniment with dexamethasone successfully treated the ILVEN. This remission of both lesions and itching also alleviated the keratotic papules on the left leg.

Kinase hyperactivity often results in deregulation of cellular pathways involved in proliferation and survival. In multiple myeloma (MM), for example, the translocation of FGFR3, a receptor tyrosine kinase (RTK), to the immunoglobulin heavy chain locus is found in 15% of patients. FGFR3 mutations, activating the receptor, are found in both primary patient samples and cell lines, supporting the role of FGFR3 signaling in the pathogenesis of the disease. In recent years, several other kinases have also been reported to be somatically mutated in hematologic and solid organ malignancy. Furthermore, mutated kinases are ideal targets for therapeutics. These observations have led us (and others) to attempt kinome-wide sequencing in the hope of identifying other, as yet unidentified, somatic mutations in MM by focusing on RTKs. Of note, major sequencing efforts are currently being launched that may in part be duplicative. Subsequently, we report here our data to date derived from the sequencing of the kinase domains of 31 candidate genes and one kinase-regulatory gene CKS1B. Although we did not find recurrent mutation in genes other than FGFR3, we have noted non-synonymous sequence differences in ROR2, EGFR, GUCY2F and EPHB4 that are not present in dbSNP or pooled DNA from ethnically diverse populations that may now be further studied in larger cohorts of MM patients for any pharmacogenetic significance.

Clonal plasma cells from patients with multiple myeloma (MM), plasma cell leukemia (PCL) and human myeloma cell lines (HMCLs) were analyzed for deletions/mutations of the tumor suppressor gene PTEN. By interphase-FISH, hemizygous PTEN deletions were detected in 4 (5.6%) of 71 MM patients, 2 (20%) of 10 PCLs, and 2 (20%) of 10 HMCLs. PTEN deletions were detected in 4 MM patients at diagnosis with stage III disease (Durie-Salmon). Of the six cases with PTEN deletions, 1 MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. Sequencing analysis did not detect PTEN mutations in 11 primary MM and 5 PCL cases. Our results indicate that alterations of PTEN are uncommon in MM patients, and PTEN deletions tend to occur in advanced disease suggesting that they are secondary, rather than primary, events in the pathogenesis of MM.

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by frequent 13q deletions and IgH translocations that have clinical prognostic significance. We evaluated clonal plasma cells by interphase fluorescence in situ hybridization (FISH) and combined with immunofluorescence detection of cytoplasmic light chain (cIg-FISH) for the presence of 13q deletions and IgH translocations. The FISH results were compared with conventional cytogenetic analysis. Of the 25 bone marrow specimens from MM patients, 11 (44%) had 13q deletions. IgH translocations involving cyclin D1 (t(11;14)) and FGFR3 (t(4;14)) were found in 32 and 36%, respectively. P53 deletions were detected in 20% of the cases. One patient had coexistence of t(ll;14) and t(4;14), which has not been previously reported. Conventional cytogenetic analysis was performed in 15 cases and revealed complex numerical and structural changes in 7. Karyotype analysis failed to detect 3 of 6 cases with 13q deletions, and also missed most of the IgH translocations and p53 deletions detected by cIg-FISH. On the other hand, the complex numerical and structural changes shown by conventional cytogenetics were not demonstrated by interphase FISH. Since 13q deletions, IgH translocations and a hypodiploid karyotype are significant prognostic factors for MM, our study illustrates the importance of combining conventional cytogenetics with interphase FISH analysis in patients with MM.

The frequency and prognostic relevance of translocations t(11;14) and t(4;14), the most common translocations involving the immunoglobulin heavy chain (IgH) gene in multiple myeloma (MM), were investigated in 128 patients treated with intensive chemotherapy and autologous stem cell transplant. Myeloma cells were identified by cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (cIg-FISH) for detection of translocations t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12.8%) and t(4;14) in 15 of 120 (12.5%) patients. Progression-free and overall survivals were similar for patients with or without t(11;14). However, patients with t(4;14) had significantly shorter progression-free (median 9.9 months vs. 25.8 months; P = 0.0003) and overall survivals (median 18.3 months vs. 48.1 months; P0.0001) than patients without t(4;14). The t(4;14) was associated with IgA and t(11;14) with light chain MM. There was no association between the t(11;14) or t(4;14) and other biological parameters including age, gender, haemoglobin, beta-2 microglobulin, C-reactive protein, calcium, creatinine, albumin, or the percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14) as the only adverse prognostic factor for both progression-free survival and overall survival. Our results indicate that the t(4;14) detected by cIg-FISH is associated with a poor prognosis in MM patients receiving intensive chemotherapy and autotransplant.

The t(4;14) translocation in multiple myeloma (MM) is identified in 15% of patient samples and dysregulates both FGFR3 and multiple myeloma SET domain (MMSET).[1][1] Activating FGFR3 mutations are observed in cell lines and late-stage MM, but the incidence of mutation in newly diagnosed patients

Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (approximately 500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and approximately 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for 'LPDL related lipase'), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.

Correction to: Leukemia (2007) 21, 1124–1127. doi:10.1038/sj.leu.2404612 The authors of the above paper inadvertently submitted the incorrect supplementary information. They have corrected this information in Supplementary Table 1, which shows the complete list of 280 probe IDs representing 185 unique kinases as presented in the heat map of Figure 2 below.

HACS1 is a SH3 (Src homology 3) and SAM (sterile alpha motif) domain containing adaptor protein that is expressed in activated B and dendritic cells, is up-regulated by Interleukin 4 in the process of B cell activation and likely serves to dampen the immune response. To elucidate the function of HACS1, we generated HACS1 gene knockout mice by deletion of the SH3 and SAM domains. HACS1−/− mice were viable and fertile and had normal bone marrow B cell development and normal splenic T and B cell populations. However, adult HACS1−/− mice had increased numbers of peritoneal B1 cells (IgM+CD5+). Upon LPS plus BCR or TCR stimulations, splenic cells from HACS1−/− mice demonstrated an upregulation of activation markers with increased intensity of CD23 expression or increased population of CD69 positive cells. Purified B220+ splenic B cells from HACS1−/− mice showed increased cell proliferation upon BCR stimulation. Both T helper type 1 (Th1) and T helper type 2 (Th2) humoral responses were enhanced in HACS1−/− mice upon immunization with T cell-dependent antigen NP-KLH, which resulted in increased production of interferon-gamma (IFN-γ), anti-NP IgG2a and IL-4, as well as anti-NP IgG1 and IgE. Upon immunization with T cell-independent antigens such as TNP-LPS and TNP-Ficoll, HACS1−/− mice had increased production of anti-TNP IgM and IgG3 as compared to normal controls. The in vitro maturation of bone marrow-derived dentritic cells from HACS1−/− mice was similar to wild-type mice but HACS1−/− dentritic cells showed increased IL-12 production upon stimulation with anti-CD40 or LPS. There was no significant difference in antigen uptake by cultured dentritic cells from non-immunized wild-type or knockout mice. However, in immunized mice, an increase in antigen uptake in HACS1−/− dentritic cells was observed. We further demonstrate that the HACS1−/− B cells had increased tyrosine phosphorylation in the resting state. As deletion of the SH3 & SAM domains of HACS1 appears to generate a hypersensitive immune response, our results collectively support that HACS1 negatively regulates adaptive immunity.

B lymphocyte induced maturation protein-1 (Blimp-1) is a transcriptional repressor involved in B-lymphocyte differentiation and reported to be relatively plasma cell specific. The mechanisms that control its gene expression remain unknown although internal regulatory sequences have been postulated as required for B cell specificity. Aimed at directing therapeutic proteins into myeloma cells, we employed a transgenic strategy in studying the Blimp-1 promoter. We first cloned 5kb, 2.5kb and 1.6kb Blimp-1 promoter fragments from a BAC clone that contains the entire mouse Blimp-1 gene and fused the promoters to the luciferase reporter gene. As compared to a basal promoter PGL3, the Blimp-1 promoter fragments all demonstrated high and similar transcriptional activity (>7 fold over baseline) when transfected into BHK, Raji, OCIMy5 cells and R1 ES cells but weak activity (

In approximately 50% of Multiple Myeloma (MM), translocation of non random genes into the IgH locus is believed to be the seminal event in the pathogenesis of the disease. Another 50% of cases are hyperdiploid and trisomic to certain autosomes, but do not harbor any translocation and thus are believed to have genetic alterations in unidentified loci. These observations, together with the finding of somatic mutations in FGFR3, N- and K-RAS, MYC, TP53 and CDKN2C/p18INK4C during the later stages of MM indicate that defective signaling pathways likely play a role in the progression of this malignancy. Of relevance then, in recent years recurrent mutations in kinases have frequently been implicated in malignancies including notably colon cancer and melanoma. We have therefore begun a comprehensive effort to sequence the tyrosine kinome for mutations and genetic polymorphisms in MM. Of particular interest are 90 receptor tyrosine kinases, 43 receptor tyrosine kinase-like, 5 receptor guanylate cyclase, and a lipid kinase. We report here results from our pilot high throughput exon scanning in 32 human MM cell lines which initially focused on 13 kinases known to be somatically mutated in human cancers. To date we have expanded this effort to assess 30 genes with sequence obtained which currently spans 80% coverage of the kinase domains of these genes. A total of 1.9 million bp have been sequenced across 235 exons. No recurrent mutations have been identified in the kinase domains of the cancer-associated genes: SRC, ILK1, KIT, GUCY2F, PDGFRA; in the genetic disorder-associated kinases: BTK, EPHA4, LAMA2, EPHB6, ACVR2; and in the mutation hot spots of frequently mutated cancer gene PIK3CA. A novel missense mutation is however identified upstream of the kinase domain of FGFR3 changing a Ser residue to Arg at codon 433. This residue, which is conserved across species and in FGFR1 and FGFR2, has not been reported in myeloma and in thanatophoric dysplasia, but the biological significance of this mutation is unknown. Several single nucleotide polymorphisms were identified in the coding regions of some of these kinases. Notably, synonymous polymorphisms in the kinase domains of EPHA4, PDGFRA3, KIT, MLK1, ILK1, NTRK3, FLT3, ABL1, FES, MLK4, and EGFR1 were identified that changed a codon but not the amino acid. More importantly, we identified non-synonymous amino acid variations in the kinase domains of EPHA4, GUCY2F, PTK2, and PIK3CA genes that are more likely to effect variability in the activity of these kinases. In summary, no recurrent kinase mutations of significance in Myeloma development or progression have yet been identified. Sequencing of the known cancer associated kinases in MGUS and hyperdiploid MM patients is now underway and our data set is being expanded to include all 139 kinases.