Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.     

Argyrophilic cells in 202 human mucinous breast carcinomas. Relation to histopathologic and clinical factors

Two hundred two human, mucinous breast carcinomas were investigated for the presence of argyrophilic granules, and these granules were found in 25% of the cases. The granules were located in the cytoplasm and were heterogeneously distributed within the tumors. Tumors with granules were otherwise morphologically indistinguishable from those tumors without granules. The recurrence-free survival was independent of the presence of granules, and no relation was found to other clinical or histopathologic factors. Tumors with granules were found to be estrogen-receptor positive, and they appear to have a slightly less aggressive growth pattern than tumors without granules, but the difference is far from being statistically significant. It is concluded that there is no convincing evidence that this group of primary breast carcinomas with argyrophilia originates from APUD cells.     

Factors altering the sleep of burned children

Although few studies have been conducted on burn patients, they indicate that sleep of burned children is altered. We suggest in this review, on the basis of the limited data available that factors contributing to sleep disruption in burned individuals may be broadly categorized as pathophysiological responses to the injury, the pain and discomfort experienced by the patient and medications used to treat these symptoms, and the physical environment in the Burns Intensive Care Unit. The responses to thermal injury include alterations in circulating neuropeptides, hormones, and immune-active substances, many of which are known to regulate/modulate sleep. Medications for the management of pain and for treating symptoms of various injury-induced stress and anxiety disorders may also alter sleep. Finally, frequent disruptions of the patient by medical staff is but one of the many environmental factors that may contribute to disrupted sleep. Severe burns induce a hypermetabolic response that may result in peripheral wasting, that depletes substrates necessary for tissue repair, and is associated with reduced growth hormone. Burn-induced growth hormone insufficiency is aggressively treated to counteract peripheral wasting and to aid in wound healing of skin graft donor sites. We speculate that improvement of sleep quality would result in a less severe reduction in growth hormone due to the well documented relationship between slow-wave sleep onset and growth hormone secretion. Such improvement in spontaneous growth hormone secretion patterns may aid in recovery by supporting tissue repair and by minimizing the hypermetabolic response to thermal injury. The experiments to test such hypotheses remain to be conducted, yet the results of such experiments may provide the basis for beginning to answer the question of whether or not sleep aids in recovery from injury.     

Monoclonal anti-human prostatic acid phosphatase antibodies

Hybrid cell lines producing monoclonal antibodies against human prostatic acid phosphatase (E. C. 3.1.3.2) were prepared by the fusion of mouse myeloma cells with the spleen cells of BALB/c mice and Lewis rats immunized with prostatic acid phosphatase (PAP). Approximately 14% of the hybrid cell microcultures which produced specific antibodies were cloned, and 6 eventually yielded stable cell lines. The monoclonal antibodies produced by these 6 hybridomas were characterized for their isotypes, isoelectric points, concentrations and affinities. The specificity of these monoclonal antibodies was further investigated by radioimmunoassay and immunohistochemical methods. All of the 6 monoclonal antibodies exhibited strict specificity for prostatic acid phosphatase.     

Assessment of the role of "enkephalinase" in cholecystokinin inactivation

Cholecystokinin octapeptide and the C-terminal tetrapeptide are hydrolysed by a highly purified preparation of "enkephalinase" (EC 3.4.24.11). In both cases the Asp-PheNH2 bond is hydrolysed and the Gly4-Trp5 bond of the octapeptide is also cleaved, though more slowly. Evaluated from the appearance of Phe-NH2, the Km for the hydrolysis of the octapeptide by the purified peptidase is 57 microM and that for the tetrapeptide 65 microM. The apparent affinities of these peptides for the enzyme in striatal membranes are similar. The importance of this hydrolysis in the inactivation of endogenous cholecystokinin was assessed by studying the fate of cholecystokinin immunoreactivity released from slices of rat cerebral cortex and striatum by depolarization with potassium. In the absence of any peptidase inhibitor only 16% of the peptide released from the tissue was recovered in immunoreactive form in the medium, indicating that endogenous cholecystokinin octapeptide is, like other neuropeptides, rapidly and extensively hydrolysed following release. Selective inhibition of "enkephalinase" by Thiorphan (DL-3-mercapto-2-benzylpropanoyl glycine) did not significantly alter the recovery from slices of cerebral cortex and had only a very slight effect in the case of striatal slices. This suggests that, while cholecystokinin octapeptide is a substrate for "enkephalinase", this enzyme plays a less important (if any) role in the inactivation of endogenous cholecystokinin than for the opioid peptides.     

Species-specific tissue antigens. II. A human species-specific antigen possessing esterase activity

An esterase that is limited in species distribution to human and monkey tissues was demonstrated by enzymoimmunoelectrophoresis and enzymoimmunodiffusion. The monkey esterase exhibited a slightly faster electrophoretic mobility than the human tissue esterase. An antigenically identical esterase found in concentrated human urine had a mobility slightly more anodal than the human tissue esterase. Despite the differences in electrophoretic mobility among the human tissue esterase, urinary esterase and monkey tissue esterase, they all reacted in enzymoimmunodiffusion with antiserum to cellular or urinary esterase to produce lines of immunologic identity. Tissues of the other species tested did not exhibit the human cathodal esterase.     

Seroresponses to human papillomavirus types 16, 18, 31, 33, and 45 virus-like particles in South African women with cervical cancer and cervical intraepithelial neoplasia

The aim of the study was to determine the prevalence of antibodies to human papillomavirus (HPV) types 16, 18, 31, 33, and 45 in woman in Cape Town with cervical intraepithelial neoplasia (CIN) (n = 95), cervical cancer (n = 40), female blood donors (n = 95) and children (n = 110). The enzyme-linked immunosorbent assay (ELISA) made use of baculovirus synthesised HPV virus like particles (VLPs) as antigen. Antibodies to at least one HPV type were detected in sera from 75% of cancer patients, 71.6% of CIN patients, 44.2% of blood donors and 27.3% of children. Sera from 95 women with CIN were compared with age-matched female blood donors. There was a significant association of seropositivity to VLP-16 (P = 0.006) and VLP-45 (P = 0.008) with CIN compared with the blood donors. There was also a significant difference in the seropositivity of women with CIN to any of the five virus-like particle (VLP) types compared to the blood donors (P = 0.0002: OR = 3.2). Thirty-nine of sixty-nine (56.5%) women with CIN were found to be HPV-16 DNA positive. The average age of women in this group that were VLP-16 seropositive was 34 years and those found to be VLP-16 seronegative was 52 years of age. Antibodies to all five VLP types were detected in these populations, thus an ideal vaccine should induce protection from infection by a wide range of HPV types.