Recent methodological developments allow expression measurement of many genes simultaneously, thereby revealing patterns of gene expression that can be related to phenotype. We hypothesized that through the use of such methods we could identify patterns of gene expression associated with the malignant phenotype in human bronchial epithelial cells (BEC). To test this hypothesis, a recently developed quantitative reverse transcriptase polymerase chain reaction method was used to assess simultaneously expression of 15 genes mechanistically associated with cell-cycle control (c-myc, E2F-1, p21, rb, PCNA, cyclin D2, cyclin D3, cyclin E, cdc2, CDK2, CDK4, mad, max p21, max p22, and p53) in normal cell cultures from five individuals and in nine different malignant BEC lines. Relative to the mean expression levels in cultured normal cell populations, expression of c-myc, E2F-1, PCNA, cyclin E, and CDK4 messenger RNA (mRNA) were significantly increased and expression of p21 and p53 mRNA were significantly decreased in one or two, but not all three subtypes (squamous, adenocarcinoma and small cell) of carcinoma cell lines evaluated. No single cell-cycle control gene discriminated all three subtypes from normal cell populations. In contrast, the gene expression index c-myc x E2F-1/p21 separated all carcinoma cell lines from all normal cell populations initially evaluated. This malignancy index was validated in an additional three cultured normal BEC and three carcinoma cell lines, as well as three pairs of matched primary normal bronchial epithelial and primary bronchogenic carcinoma samples, and three pairs of matched primary normal lung parenchyma and primary bronchogenic carcinoma tissue. Again, the c-myc x E2F-1/ p21 index successfully discriminated all cultured and primary normal from malignant samples and thereby had a predictive value of 1 (no false positives and no false negatives). We hypothesize that because of functional mutations in cell-cycle regulatory genes (e.g., p53 and/or rb), cells lose the ability to maintain a pattern of gene expression mechanistically associated with normal, division-limited homeostatic equilibrium. Because the c-myc x E2F-1/p21 gene expression index has high specificity for malignant tissue, it will allow confirmation that there is a significant amount of tumor tissue present in small (e.g., fine-needle) biopsy specimens prior to evaluating them for expression of other genes, such as those involved in chemoresistance or radioresistance. In addition, the goal of most gene therapy efforts is to alter levels of gene expression quantitatively. This index and others derived in a similar manner may better define potential gene therapy targets as well as response of targeted genes to therapy.
To determine the effect of induced polymorphic VT/VF on the cerebral circulation, transcranial Doppler (TCD) ultrasonography was used to prospectively assess changes in cerebral blood flow velocity during ICD implantation. Fourteen patients (13 men, 1 woman, mean age 58 +/- 20 years, range 34-74 years) who were survivors of an out of hospital cardiac arrest, were evaluated during routine ICD implantation. TCD ultrasonography was used to assess middle cerebral artery systolic velocity (Vs), diastolic velocity (Vd), pulsatility index (PI = Vs-Vd/Vmean) and resistance index (RI = Vs-Vd/Vs) before, during, and after DFT testing with alternating current induction of polymorphic VT/VF. In each of the 14 patients studied, concomitant with the abrupt onset of hypotension, TCD sonography demonstrated a 33% +/- 28% decrease in diastolic velocity, a 42% +/- 28% increase in systolic velocity, a 190% +/- 141% increase in PI, and a 44% +/- 19% increase in RI. These findings reflect an increase in cerebrovascular resistance secondary to arteriolar vasoconstriction distal to the point of insonation of the middle cerebral artery. This response is paradoxic, as the expected response of the cerebral circulation to hypotension is vasodilation, but it is consistent with observations made in other acute hypotensive settings, such as tilt induced neurocardiogenic syncope.
In the clinical staging of malignancy, radionuclide bone scanning has played an increasingly important role. An area of increased radionuclide uptake on technetium 99 ( V c ) bone scan which is not visualized on skeletal radiographs can present a significant diagnostic dilemma. This can be further compounded by nonrevealing percutaneous or open surgical biopsies. The authors present a method of definitively localizing the appropriate site for bone biopsy in such circumstances. Use of this technique has allowed us to ascertain that isolated rib lesions in two patients with extra-osseous malignancies were not due to metastatic disease.Cancer 59 zontal planes (Figs. 1 and 2). A slun mark is placed directly over the rib lesion. Alternatively, a small quantity of sterile methylene blue dye may be injected directly onto the periosteal surface of the underlying rib. The patient is then transported to the surgical unit, anesthetized, and positioned on the operating table. Due to the degree of skin mobility over the thoracic cage, the accuracy of the skin mark should at this point be reconfirmed with a portable gamma camera. Open biopsy is then performed with a 3-cm segment of rib resected on either side of the skin mark. Anatomic orientation is maintained and the specimen is scanned using a pinhole collimator (Fig. 3) to confirm that the suspicious lesion has been entirely removed. Needles are placed into the resected rib to outline the area of increased radionuclide uptake and the specimen is submitted for decalcification and histologic examination.
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