The interferon-inducible, double-stranded RNA (dsRNA)-activated protein kinase, PKR, plays key roles in regulation of cell growth and differentiation, and has been postulated as a tumor suppressor. Downstream effectors of PKR include the translation initiation factor, eIF2a, and the transcription factor, NF-kB. We found elevated levels of PKR protein, dsRNA-dependent PKR autophosphorylation activity, and phosphorylated eIF2a in melanoma cells compared to nontransformed melanocytes in culture. Treatment with interferon-a2b further induced PKR expression and activity. Immunohistochemical analysis of primary melanomas demonstrated minimal PKR immunoreactivity, but melanoma lymph node metastases expressed a high level of PKR protein. Furthermore, analysis of colon cancer specimens revealed that transformation from normal mucosa to adenomas and carcinomas was coincident with an increase in PKR expression. These data do not support the concept of PKR as a classic tumor suppressor but instead suggest that PKR upregulation occurs at defined steps in cancer progression, probably as a cellular response to neoplasia.

We report a case of a 52-year-old man with multiple myeloma and rapidly progressive heart failure who died unexpectedly from a probable arrhythmia. Postmortem examination revealed infiltrative amyloid cardiomyopathy, a rare cause of predominantly diastolic myocardial disease. Cardiac amyloidosis should be considered in any patient presenting with congestive heart failure, preserved systolic function, and a discrepancy between a low QRS voltage on electrocardiography and an apparent left ventricular hypertrophy on sonogram. The pattern of left ventricular diastolic dysfunction changes during the course of amyloidosis and the classically described restrictive physiology occurs only in advanced stages of the disease.

We have shown that administration of the antifibrotic agent cis-4-hydroxy-L-proline (cHyp) to rats at the onset of exposure to hypoxia prevents collagen accumulation in pulmonary arteries and the rise in pulmonary blood pressure. In this experiment, we tested whether cHyp is effective when administered after hypertension was already established. Rats were exposed to hypoxia (10% O2) for 21 days. Groups were hypoxic animals treated with cHyp (200 mg/kg sc twice daily) on days 10-21 (hypoxic cHyp) and saline-injected hypoxic animals (hypoxic). On day 21, we measured mean right ventricular pressure, hematocrit, collagen content of main and intrapulmonary arteries, and wall thickness of arterioles. Treatment reduced right ventricular pressure from 21 +/- 1 to 17 +/- 1 mmHg (P less than 0.05), hematocrit from 66 +/- 1 to 56 +/- 1% (P less than 0.05), hydroxyproline content of intrapulmonary arteries from 30 +/- 3 to 11 +/- 2 micrograms/vessel (P less than 0.05), and wall thickness from 27 +/- 3 to 16 +/- 2 microns (P less than 0.05). These results show that vascular collagen content is increased in established pulmonary hypertension and that cHyp treatment is effective in partially preventing the hemodynamic, structural, and biochemical changes if started after pulmonary hypertension is established. cHyp may also affect the rheological properties of blood.

Tumor-induced osteomalacia (TIO) is typically caused by phosphaturic mesenchymal tumor (PMT) that secretes the phosphaturic hormone, fibroblast growth factor-23 (FGF23), resulting in decreased phosphate reabsorption in kidneys, hypophosphatemia, and finally osteomalacia. Rare cases of malignant tumor manifesting with TIO other than PMT had been reported, although in most of these reports, except one, circulating FGF23 levels were not evaluated and tissue expressing of FGF23 was not confirmed. In this article, we report a case of TIO in a patient with pulmonary small cell carcinoma with liver metastasis. The patient manifested with hypophosphatemia. His circulating level of FGF23 was markedly increased. The expression of FGF23 in tumor cells was confirmed. Furthermore, the regulatory mechanism of FGF23 in this patient was also investigated.

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