Cronobacter sakazakii infection alters serotonin transporter and improved fear memory retention in the rat.

It is well established that Cronobacter sakazakii infection cause septicemia, necrotizing enterocolitis and meningitis. In the present study, we tested whether the C. sakazakii infection alter the learning and memory through serotonin transporter (SERT). To investigate the possible effect on SERT, on postnatal day-15 (PND-15), wistar rat pups were administered with single dose of C. sakazakii culture (infected group; 10(7) CFU) or 100 µL of Luria-Bertani broth (medium control) or without any treatment (naïve control). All the individuals were subjected to passive avoidance test on PND-30 to test their fear memory. We show that single dose of C. sakazakii infection improved fear memory retention. Subsequently, we show that C. sakazakii infection induced the activation of toll-like receptor-3 and heat-shock proteins-90 (Hsp-90). On the other hand, level of serotonin (5-hydroxytryptamine) and SERT protein was down-regulated. Furthermore, we show that C. sakazakii infection up-regulate microRNA-16 (miR-16) expression. The observed results highlight that C. sakazakii infections was responsible for improved fear memory retention and may have reduced the level of SERT protein, which is possibly associated with the interaction of up-regulated Hsp-90 with SERT protein or miR-16 with SERT mRNA. Taken together, observed results suggest that C. sakazakii infection alter the fear memory possibly through SERT. Hence, this model may be effective to test the C. sakazakii infection induced changes in synaptic plasticity through SERT and effect of other pharmacological agents against pathogen induced memory disorder.

ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in "double hit" lymphoma cells.

Double hit lymphoma (DHL) is a recently recognized lymphoma with a survival of less than 2 years. Both ABT-737, a Bcl-2/Bcl-XL inhibitor, and ABT-199, which selectively targets Bcl-2, were potently cytotoxic against DHL cell lines Sc-1 and OcI-LY18, the RL cell line and primary human DHL cells, but not Ramos cells, which lack Bcl-2 expression. ABT-199 was more potent than ABT-737, and is the most promising of the BH3 mimetics to date. The DHL cell lines were also sensitive (< 200 nM) to doxorubicin, methotrexate, cytarabine and the proteosome inhibitor, bortezomib. The combination of chemotherapy with ABT-199 and doxorubicin or cytarabine, bortezomib, YM-155 and JQ1 produced synergistic cell kill against the DHL cell lines. Cells from a patient with DHL were also sensitive to JQ1 and bortezomib, providing a rationale for a clinical trial of these combinations in patients with relapsed DHL.

Clonal X-chromosome inactivation suggests that splenic cord capillary hemangioma is a true neoplasm and not a subtype of splenic hamartoma.

Splenic hamartoma is a rare tumor-like lesion composed of structurally disorganized red pulp elements. It has been hypothesized that two other splenic lesions, cord capillary hemangioma and myoid angioendothelioma, may fall within the spectrum of splenic hamartoma, simply representing morphological variants. In this study, we compared the vascular and stromal composition of cord capillary hemangioma and myoid angioendothelioma with those of classical hamartoma. In addition, we assessed the clonal vs polyclonal nature of the lesions in nine female cases by performing clonality analysis for X-chromosome inactivation at the human androgen receptor locus (HUMARA) on laser-assisted microdissected samples. In 15 of 17 cases, increased reticulin and/or collagen content was observed. The classical hamartoma cases showed a vasculature predominantly composed of CD8+ CD31+ CD34- splenic sinuses, whereas cases of cord capillary hemangioma and myoid angioendothelioma contained many CD8- CD31+ CD34+ cord capillaries, but very little CD8+ vasculature. All cases lacked expression of D2-40 and Epstein Barr virus-encoded RNA. All cases showed a proliferation index of ≤5% by Ki-67. Cases of classical hamartoma lacked significant perisinusoidal expression of collagen IV and low-affinity nerve growth factor receptor. Both markers were variably expressed in the other lesions. Increased CD163-positive histiocytes were found in four cases (three cord capillary hemangiomas and one myoid angioendothelioma). HUMARA analysis was informative in all nine tested cases, of which three cases showed a non-random X-chromosome inactivation pattern, indicating clonality. All three clonal cases were cord capillary hemangiomas. Our study has shown that in spite of considerable morphologic heterogeneity and overlapping features, classical hamartoma and cord capillary hemangioma and myoid angioendothelioma are different in terms of their vascular and stromal composition. Clonality analysis supports a true neoplastic origin for the cord capillary hemangioma. A larger study using additional immunohistochemical and molecular studies is necessary to further evaluate the biological significance of the current findings.

Activated B-cell immunophenotype might be associated with poor prognosis of primary central nervous system lymphomas.

Primary central nervous system (PCNS) diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin's lymphoma whose growth is restricted to the central nervous system and eye. Primary CNS DLBCL has a poor prognosis relative to other extranodal DLBCL. Recently DLBCL has been subclassified as germinal and non-germinal center B-cell types using microarray. Germinal center B-cell DLBCL is associated with better prognosis compared to non-germinal center B-cell group. The objective of the study was to subcategorize the PCNS DLBCL into germinal center and non-germinal center DLBCL using immunohistochemistry and to correlate its prognostic significance. 21 immunocompetent patients were diagnosed with PCNS DLBCL over last 20 years at William Beaumont Hospital. Clinical data on outcome were collected and their specimens were retrieved. Immunohistochemical staining was done using markers, CD20, CD10, Bcl-6, MUM-1, MIB-1, Bcl-2 and by molecular analysis of the immunoglobulin heavy chain gene (IgH) variable region. Immunohistochemistry showed 1/21 (positive cases/examined cases) for CD10, 19/21 for Bcl-6, 19/21 for MUM-1 and 15/21 for Bcl-2. The expression pattern of CD10(-) MUM-1(+) is corresponded to the non-germinal center DLBCL. The MIB-1 index ranged from 40--80% with a mean of 57%, indicating a high proliferation of lymphoma cells. The IgH gene variable region analysis showed monoclonality in 15 of 21 cases (71%). Primary CNS DLBCL has a non-germinal center B-cell phenotype in majority of cases and has a high Bcl-2 positivity and MIB-1 index. These features might be associated with poor prognosis.