Antigen activation of the B-cell receptor (BCR) may play a role in the
pathogenesis of human follicular lymphoma (FL) and other B-cell malignancies.
However, the nature of the antigen(s) recognized by tumor BCRs has not been well
studied. Here, we used unbiased approaches to demonstrate that 42 (19.35%) of
217 tested FL immunoglobulins (Igs) recognized vimentin as a shared autoantigen.
The epitope was localized to the N-terminal region of vimentin for all
vimentin-reactive tumor Igs. We confirmed specific binding to vimentin by using
recombinant vimentin and by performing competitive inhibition studies.
Furthermore, using indirect immunofluorescence staining, we showed that the
vimentin-reactive tumor Igs colocalized with an anti-vimentin monoclonal
antibody in HEp-2 cells. The reactivity to N-terminal vimentin of IgG FL Igs was
significantly higher than that of IgM FL Igs (30.4% vs. 10%; P=0.0022). However,
vimentin-reactive FL Igs did not share complimentarity determining region 3
motifs and were not homologous. Vimentin was expressed in the T-cell rich
regions of FL, suggesting that vimentin is available for binding with tumor BCRs
within the tumor microenvironment. Vimentin was also frequently recognized by
mantle cell lymphoma and multiple myeloma Igs. Our results demonstrate that
vimentin is a shared autoantigen recognized by nonstereotyped FL BCRs and by the
Igs of mantle cell lymphoma and multiple myeloma and suggest that vimentin may
play a role in the pathogenesis of multiple B-cell malignancies. These findings
may lead to better understanding of the biology and natural history of FL and
other B cell malignancies.
There is substantial heterogeneity in the clinical behavior of pancreatic
cancer and in its response to therapy. Some of this variation may be due to
differences in delivery of cytotoxic therapies between patients and within
individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we
previously demonstrated wide inter-patient variability in the delivery of
gemcitabine as well as in the mass transport properties of tumors as measured by
computed tomography (CT) scans. However, the variability of drug delivery and
transport properties within pancreatic tumors is currently unknown. Here, we
analyzed regional measurements of gemcitabine DNA incorporation in the tumors of
the same 12 patients to understand the degree of intra-tumoral heterogeneity of
drug delivery. We also developed a volumetric segmentation approach to measure
mass transport properties from the CT scans of these patients and tested
inter-observer agreement with this new methodology. Our results demonstrate
significant heterogeneity of gemcitabine delivery within individual pancreatic
tumors and across the patient cohort, with gemcitabine DNA incorporation in the
inner portion of the tumors ranging from 38 to 74% of the total.
Similarly, the CT-derived mass transport properties of the tumors had a high
degree of heterogeneity, ranging from minimal difference to almost 200%
difference between inner and outer portions of the tumor. Our quantitative
method to derive transport properties from CT scans demonstrated less than
5% difference in gemcitabine prediction at the average CT-derived
transport value across observers. These data illustrate significant
inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine,
and highlight how this variability can be reproducibly accounted for using
principles of mass transport. With further validation as a biophysical marker,
transport properties of tumors may be useful in patient selection for therapy
and prediction of therapeutic outcome.
Optimal expansion protocols for adoptive human T-cell therapy often include interleukin (IL)-15; however, the mechanism by which IL-15 improves the in vivo antitumor effect of T cells remains to be elucidated. Using human T cells generated from HLA-A2+ donors against novel T-cell epitopes derived from the human U266 myeloma cell line Ig light chain V-region (idiotype) as a model, we found that T cells cultured with IL-15 provided superior resistance to tumor growth in vivo, compared with IL-2, after adoptive transfer into immunodeficient hosts. This effect of IL-15 was associated with delayed/reversed senescence in tumor antigen-specific memory CD8 C T cells mediated through downregulation of P21 WAF1 , P16 INK4a , and P53 expression. Compared to IL-2, IL-15 stimulation dramatically activated JAK3-STAT5 signaling and inhibited the expression of DNA damage genes. Thus, our study elucidates a new mechanism for IL-15 in the regulation of STAT signaling pathways and CD8 C T-cell senescence.
HighlightsA de Garengeot hernia is a femoral hernia containing the appendix.Diagnosis of a de Garengeot hernia is difficult and often made intra-operatively.Incarceration or strangulation tends to be the clinical presentation of a de Garengeot hernia.It is important to have a high clinical suspicion for a de Garengeot hernia in patients with incarcerated or strangulated right femoral hernias.
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