The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma

Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1–1 μ) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 μ) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL

Visual Properties of Transgenic Rats Harboring the Channelrhodopsin-2 Gene Regulated by the Thy-1.2 Promoter

Channelrhodopsin-2 (ChR2), one of the archea-type rhodopsins from green algae, is a potentially useful optogenetic tool for restoring vision in patients with photoreceptor degeneration, such as retinitis pigmentosa. If the ChR2 gene is transferred to retinal ganglion cells (RGCs), which send visual information to the brain, the RGCs may be repurposed to act as photoreceptors. In this study, by using a transgenic rat expressing ChR2 specifically in the RGCs under the regulation of a Thy-1.2 promoter, we tested the possibility that direct photoactivation of RGCs could restore effective vision. Although the contrast sensitivities of the optomotor responses of transgenic rats were similar to those observed in the wild-type rats, they were enhanced for visual stimuli of low-spatial frequency after the degeneration of native photoreceptors. This result suggests that the visual signals derived from the ChR2-expressing RGCs were reinterpreted by the brain to form behavior-related vision

Extracellular Sulfatases, Elements of the Wnt Signaling Pathway, Positively Regulate Growth and Tumorigenicity of Human Pancreatic Cancer Cells

BACKGROUND: Heparan sulfate proteoglycans (HSPGs) are control elements in Wnt signaling, which bind extracellularly to Wnt ligands and regulate their ability to interact with signal transduction receptors on the cell surface. Sulf-1 and Sulf-2 are novel extracellular sulfatases that act on internal glucosamine-6-sulfate (6S) modifications within HSPGs and thereby modulate HSPG interactions with various signaling molecules, including Wnt ligands. Emerging evidence indicates the importance of reactivated Wnt signaling in a number of cancers, including pancreatic adenocarcinoma. PRINCIPLE FINDINGS: Both Sulf proteins were upregulated in human pancreatic adenocarcinoma tumors and were broadly expressed in human pancreatic adenocarcinoma cell lines. Expression of human extracellular sulfatases Sulf-1 and Sulf-2 enhanced Wnt signaling in a reconstituted system. Three of four pancreatic adenocarcinoma cell lines tested exhibited autocrine Wnt signaling, in that extracellular Wnt ligands were required to initiate downstream Wnt signaling. Exposure of these pancreatic adenocarcinoma cells to a catalytically inactive form of Sulf-2 or siRNA-mediated silencing of endogenous Sulf-2 inhibited both Wnt signaling and cell growth. Sulf-2 silencing in two of these lines resulted in markedly reduced tumorigenesis in immunocompromised mice. CONCLUSIONS/SIGNIFICANCE: We have identified the Sulfs as potentiators of autocrine Wnt signaling in pancreatic cancer cells and have demonstrated their contribution to the growth and tumorigenicity of these cells. Since the Sulfs are extracellular enzymes, they would be attractive targets for therapy of pancreatic cancer. Our results run counter to the prevailing view in the literature that the Sulfs are negative regulators of tumorigenesis

Burkitt lymphoma masquerading as cardiac tamponade

A 61 year old man presented with diffuse large B cell lymphoma of the skin of the back of the shoulder which was excised and treated with chemotherapy (CHOP regime) in 1998. He was in complete remission till he presented in 2002 with extranodal marginal zone lymphoma of the parotid gland for which he underwent superficial parotidectomy and radiotherapy. He continued in remission till 2006 when he presented with recurrent pericardial effusion and tamponade. At median sternotomy, pericardial effusion was drained, an anterior pericardiectomy was done and a left posterior pericardial window made, and an enlarged hard paraaortic lymph node excised. Histology, immunocytochemistry and chromosome analysis revealed Burkitt lymphoma. Patient underwent chemotherapy with CODOX-M regime and continues in remission. This report is unusual on account of the highly atypical presentation of Burkitt lymphoma as cardiac tamponade, only a few cases having been reported previously, the occurrence of three lymphomas of different pathological and genomic profiles in one patient over a period of eight years and the relatively slow rate of growth of an otherwise fulminant tumour with high tumour doubling time. A review of literature with special emphasis on chromosomal diagnosis, transformation of other lymphomas into Burkitt lymphoma and mediastinal and cardiac involvement with Burkitt lymphoma is presented

Purification of chicken carbonic anhydrase isozyme-III (CA-III) and its measurement in White Leghorn chickens

<p>Abstract</p> <p>Background</p> <p>The developmental profile of chicken carbonic anhydrase-III (CA-III) blood levels has not been previously determined or reported. We isolated CA-III from chicken muscle and investigated age-related changes in the levels of CA-III in blood.</p> <p>Methods</p> <p>CA-III was purified from chicken muscle. The levels of CA-III in plasma and erythrocytes from 278 female chickens (aged 1-93 weeks) and 68 male chickens (aged 3-59 weeks) were determined by ELISA.</p> <p>Results</p> <p>The mean level of CA-III in female chicken erythrocytes (1 week old) was 4.6 μg/g of Hb, and the CA-III level did not change until 16 weeks of age. The level then increased until 63 weeks of age (11.8 μg/g of Hb), decreased to 4.7 μg/g of Hb at 73 weeks of age, and increased again until 93 weeks of age (8.6 μg/g of Hb). The mean level of CA-III in erythrocytes from male chickens (3 weeks old) was 2.4 μg/g of Hb, and this level remained steady until 59 weeks of age. The mean plasma level of CA-III in 1-week-old female chickens was 60 ng/mL, and this level was increased at 3 weeks of age (141 ng/mL) and then remained steady until 80 weeks of age (122 ng/mL). The mean plasma level of CA-III in 3-week-old male chickens was 58 ng/mL, and this level remained steady until 59 weeks of age.</p> <p>Conclusion</p> <p>We observed both developmental changes and sex differences in CA-III concentrations in White Leghorn (WL) chicken erythrocytes and plasma. Simple linear regression analysis showed a significant association between the erythrocyte CA-III level and egg-laying rate in WL-chickens 16-63 weeks of age (p < 0.01).</p

Prevalence of self-reported finger deformations and occupational risk factors among professional cooks: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Previous studies have pointed out that the school lunch workers in Japan are suffering from work-related disorders including finger deformations. The purpose of this study was to investigate the prevalence of self-reported finger deformations and the association with job-related risk factors.</p> <p>Methods</p> <p>A cross-sectional questionnaire study of 5,719 subjects (response rate: 81%, 982 men and 4,737 women) was undertaken during September 2003 to February 2004.</p> <p>Results</p> <p>Finger deformations were found among 11.7% of the men and 35.6% of the women studied, with significant differences among sex, age and sex-age groups. For both men and women the pattern of finger deformations across the hand was similar for the right and the left hand. For women, the deformations were found in about 10% of the distal interphalangeal joints of all fingers. Based on multiple logistic regression analyses, the factors female sex, age, the number of cooked lunches per cook and cooking activities were independently associated with the prevalence of finger deformations. High prevalence odds ratios were found for those frequently carrying or using tools by hands such as delivering containers, distributing meals, preparing dishes, washing equipment, cutting and stirring foods.</p> <p>Conclusions</p> <p>Among the school lunch workers studied, women had a higher prevalence of finger deformations on all joints of both hands. Various cooking tasks were associated with the prevalence of finger deformations. The results suggest that improvements in working conditions are important for preventing work-related disorders such as finger deformations.</p

Prefrontal Cortex Lesions Impair Object-Spatial Integration

How and where object and spatial information are perceptually integrated in the brain is a central question in visual cognition. Single-unit physiology, scalp EEG, and fMRI research suggests that the prefrontal cortex (PFC) is a critical locus for object-spatial integration. To test the causal participation of the PFC in an object-spatial integration network, we studied ten patients with unilateral PFC damage performing a lateralized object-spatial integration task. Consistent with single-unit and neuroimaging studies, we found that PFC lesions result in a significant behavioral impairment in object-spatial integration. Furthermore, by manipulating inter-hemispheric transfer of object-spatial information, we found that masking of visual transfer impairs performance in the contralesional visual field in the PFC patients. Our results provide the first evidence that the PFC plays a key, causal role in an object-spatial integration network. Patient performance is also discussed within the context of compensation by the non-lesioned PFC

Mast cells and eosinophils in invasive breast carcinoma

<p>Abstract</p> <p>Background</p> <p>Inflammatory cells in the tumour stroma has gained increasing interest recently. Thus, we aimed to study the frequency and prognostic impact of stromal mast cells and tumour infiltrating eosinophils in invasive breast carcinomas.</p> <p>Methods</p> <p>Tissue microarrays containing 234 cases of invasive breast cancer were prepared and analysed for the presence of stromal mast cells and eosinophils. Tumour infiltrating eosinophils were counted on hematoxylin-eosin slides. Immunostaining for tryptase was done and the total number of mast cells were counted and correlated to the proliferation marker Ki 67, positivity for estrogen and progesterone receptors, clinical parameters and clinical outcome.</p> <p>Results</p> <p>Stromal mast cells were found to correlate to low grade tumours and estrogen receptor positivity. There was a total lack of eosinophils in breast cancer tumours.</p> <p>Conclusion</p> <p>A high number of mast cells in the tumours correlated to low-grade tumours and estrogen receptor positivity. Eosinophils are not tumour infiltrating in breast cancers.</p