Familial Mediterranean fever (FMF) is caused by mutations in MEFV, which encodes pyrin. The nature of substitutions P369S and R408Q in exon 3 remains unclear. Exon 3 encoding pyrin's B-box domain is ...necessary for interactions with proline serine threonine phosphatase interacting protein 1 (PSTPIP1). The aim was to characterise the phenotype of patients with these substitutions and to determine their functional significance.
A database of genetic tests undertaken at the US National Institutes of Health was interrogated. Symptoms and signs were classified according to Tel-Hashomer criteria. Coimmunoprecipitation techniques were employed to determine the variants' effects on pyrin/PSTPIP1 interactions.
A total of 40 symptomatic and 4 asymptomatic family members with these substitutions were identified. P369S and R408Q were found in cis, and cosegregated in all patients sequenced. Clinical details were available on 22 patients. In all, 5 patients had symptoms and signs fulfilling a clinical diagnosis of FMF, and 15 received colchicine. In patients not achieving the criteria, trials of anti-tumour necrosis factor (TNF) agents resulted in partial or no benefit; resolution of symptoms was noted in those receiving anakinra. The carrier frequency was higher in the patient cohort than in controls but was not statistically significant. Coimmunoprecipitation studies demonstrated that these pyrin variants did not affect binding to PSTPIP1.
P369S/R408Q substitutions are associated with a highly variable phenotype, and are infrequently associated with typical FMF symptoms, however a trial of colchicine is warranted in all. Functional and modelling studies suggest that these substitutions do not significantly affect pyrin's interaction with PSTPIP1. This study highlights the need for caution in interpreting genetic tests in patients with atypical symptoms.
Several investigators have proposed that carcinoembryonic antigen (CEA), an immunogenic antigen expressed by colon carcinoma, may also be expressed by human melanoma. Because sialyl Lewisx (sLex), ...the carbohydrate moiety of CEA, has been identified in melanoma, we compared CEA and sLex levels in colon carcinoma cells and melanoma cells.
CEA levels were assessed for expression on the cell surface and in cell lysates of cutaneous melanoma cell lines by two different kinds of ELISA, and by Western blot analysis of immunoprecipitated CEA using monoclonal antibodies (Mabs) T84-66 and COL-1, which have defined specificities for CEA. Colon carcinoma cells and purified CEA were positive controls.
Both Mabs reacted strongly with cell surface and cell lysates of colon cancer. Mab T84-66 reacted well with cell surface but not cell lysates of melanoma. COL-1 reacted poorly with cell surface but its binding increased with the density of melanoma cell lysates. Both Mabs intensely stained the blots of purified CEA and colon carcinoma lysates immunoprecipitated with the respective Mabs, but failed to stain the immunoprecipitates of melanoma cell lysates. Both Mabs bound to lysates immunoprecipitated with anti-sLex Mab in colon carcinoma, but not in melanoma. Cell-surface expression of CEA and sLex was significantly correlated (r2: 0.88) in colon cancer cells but not in melanoma.
Our results confirm the presence of CEA in colon carcinoma but not in human cutaneous melanoma cell lines.
Quantisation on a manifold with singular edge Chang, Der-Chen; Habal, N.; Schulze, B.-W.
Journal of pseudo-differential operators and applications,
09/2013, Letnik:
4, Številka:
3
Journal Article
Boundary value problems and mixed problems play a role in many applications of physics, cf. (Harutyunyan et al., Elliptic mixed, transmission and singular crack problems,
2008
), and parametrices and ...asymptotics of solutions may be expressed within suitable pseudo-differential algebras. The boundary-wedge approach of Schulze (Pseudo-differential operators on manifolds with edges,
1989
), Schulze (Ann Glob Anal Geom 8(3):261–297,
1990
) belongs to the calculus on singular manifolds. The present article continues this concept and develops new quantisations in the framework of operators on manifolds with singular edges.
Holomorphic corner symbols Habal, N.; Schulze, B.-W.
Journal of pseudo-differential operators and applications,
12/2011, Letnik:
2, Številka:
4
Journal Article
We consider pseudo-differential operators on a manifold
M
with corners of second order. Locally near a corner point
c
the space
M
is modelled on a cone
for a compact manifold
B
with smooth edge. We ...establish some essential elements of the corner pseudo-differential calculus locally near
c
represented as Mellin operators with holomorphic symbols, with values in the ideal of Mellin and Green operators of the edge algebra over
B
.
The immunogenicity of the polyvalent tumor cell vaccine CancerVax has been correlated with the survival of patients receiving active immunotherapy for melanoma. Because the various antigens expressed ...on the vaccine are common to colon adenocarcinoma cells, we examined the survival impact of immune responses elicited by CancerVax in patients with advanced colon cancer refractory to standard therapy.
Twenty-seven patients with American Joint Committee on Cancer (AJCC) stage IV colorectal adenocarcinoma were entered prospectively into the study. CancerVax was coadministered with bacille Calmette-Guerin (BCG) for the first 2 weeks of vaccine treatment. Blood was drawn at the start of therapy and every 2 weeks thereafter to measure serum titers of immunoglobulin (Ig)G and IgM against TA90 (a 90-kD immunogen common to colon cancer and CancerVax cells) and against purified protein derivative (PPD), a nontumor control antigen. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) reaction to vaccine cells and to PPD. Mean follow-up time was 17.5 months.
There was a significant (P = .0001) increase in anti-TA90 IgG and IgM titers and in DTH response to vaccine cells. Humoral and skin responses to TA90 did not correlate with responses to PPD (P = .199 for IgM, P = .958 for IgG, and P = .149 for DTH). This suggests that these responses are not a manifestation of general immune competence. The median overall survival (OS) was 21.9 months for the entire group. Overall survival was higher among patients whose IgMTA90 titer was >800 (P = .003) or whose disease-free interval exceeded 12 months (P = .031). Multivariate Cox regression analysis-using age, sex, disease-free interval, disease status, extent of metastasis, humoral responses, and DTH responses-found only peak IgMTA90 titer to be a significant predictor of overall survival (P = .0365).
CancerVax can induce measurable humoral and cellular immune responses to tumor-associated antigens in patients with advanced-stage colon cancer. These responses correlate with overall survival. This novel therapeutic regimen for patients with advanced colon cancer merits further investigation.
Sentinel lymphadenectomy (SLND) is fast becoming the procedure of choice for staging primary breast carcinoma and melanoma. This simpler and less morbid alternative to standard lymph node dissection ...can increase the rate of detecting nodal disease. Because the tumor status of the regional lymph nodes remains a significant prognostic tool in both diseases, clinicians may use SLND to facilitate selection of patients for adjuvant chemotherapy. Although SLND has been validated by institutions worldwide, it continues to evolve. The following review will examine current data and controversies surrounding this emerging technology.
The development of second primary malignancies (SPM) in patients with gastrointestinal carcinoid tumors is a well-described phenomenon, with reported rates as high as 55%. There is a predilection for ...gastrointestinal and genitourinary adenocarcinomas, but a variety of other malignancies have been reported as well. The etiology of this malignant predisposition may be rooted in the tumorigenic properties of the various neuroendocrine peptides elaborated and secreted by neuroendocrine cells. Peptides such as secretin, gastrin, bombesin, cholecystokinin (CCK), and vasoactive intestinal peptide (VIP) are believed to promote the growth of tumor cells. As many as 30 peptides and amines identified in neuroendocrine cells may have similar properties. This review of the literature on carcinoid-associated second primary malignancies is accompanied by a case report of metastatic carcinoid identified during surgical exploration for a perforating colon adenocarcinoma.
Although carcinoembryonic antigen (CEA) is the most frequently used marker for colon cancer, it is elevated in only 70% of patients with advanced disease and in even fewer patients with earlier ...stages of disease. We previously identified a 90-kDa glycoprotein, TA90, which is present in serum in the form of circulating immune complexes. TA90 is found in a variety of solid neoplasms but rarely in healthy controls (3.2%). We hypothesized that this new tumor-associated antigen may be a useful marker for colon cancer.
Serum samples from 59 patients with known colon adenocarcinoma were analyzed for the presence of CEA and TA90. Fifty-one (86%) patients had distant metastases; the remaining patients had clinically localized primary colon cancer. A murine monoclonal antibody-based enzyme-linked immunosorbent assay was used to measure concentrations of TA90-specific circulating immune complexes (TA90-IC). A positive value was defined as an optical density of more than 0.410 at 405 nm. Forty-seven (80%) of the 59 patients had serum samples for TA90 and CEA drawn at the same time.
TA90-IC concentrations were elevated more frequently than CEA concentrations (82.9% vs. 70.2%; P = .134). The combination of both markers identified more patients with colon carcinoma than did either marker alone (93.6%; P < .001).
Concomitant use of TA90-IC and CEA identified 93.6% of patients with advanced colon cancer. The role of TA90-IC in screening and monitoring progression of earlier disease deserves further investigation.
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