MRJF4, a novel histone deacetylase inhibitor, induces p21 mediated autophagy in PC3 prostate cancer cells.

Autophagy is a cellular defense mechanism which occurs through degradation and recycling of cytoplasmic constituents and represents a caspase—independent alternative to cell death by apoptosis. It is generally accepted that the suppression of autophagy in many cancer cells is directly correlated to malignancy; hence, the control of autophagy genes could represent a target for cancer therapy. The inhibition of cell proliferation through autophagy activation could be an important mechanism for many anti—tumor drugs. Here we report the effects of a novel histone deacetylase inhibitor MRJF4 (racemic mixture) and of its two enantiomers [(+)—MRJF4 and (—)—MRJF4] on the morphological and molecular mechanisms causing death and migration of PC3 prostatic cancer cells. In particular, we investigated the occurrence of the autophagic process, both at morphological and molecular levels (LC3 expression), and its relationship with p21, a key molecule which regulates cell cycle and autophagy cell death. Moreover, pERK/Nf—kB driven intracellular signaling, the expression of MMP9 protein — a key component of cell migration — invasion, and metastasis were assayed. Our results showed that the anti—proliferative effects of MRJF4 due to autophagy occurrence, documented by LC3 increase and ultrastructural modifications, and the reduction of invasiveness seem to be mediated by the down—regulation of pERK/NF—kB signaling pathway, along with p21 up—regulation.

Pseudo-obstruction associated with colonic ischemia: successful management with colonoscopic decompression.

Colonic pseudo-obstruction has been associated with colonic ischemia in only 7-10% of cases. When both conditions are present, most authors recommend immediate laparotomy because of the additional weakening of the bowel wall induced by the presence of ischemia and the resultant increased risk of perforation. We report on three patients with pseudo-obstruction and right-sided colonic ischemia who were successfully managed with colonoscopic decompression with tube placement. Surgery may not be required in patients with pseudo-obstruction and associated colonic ischemia.

The diagnostic yield of superior mesenteric angiography: correlation with the pattern of gastrointestinal bleeding.

In an attempt to evaluate the usefulness of mesenteric angiography in relation to the nature and rate of gastrointestinal bleeding, we reviewed the records of all patients hospitalized at Montefiore Medical Center between 1983 and 1986 who had mesenteric angiography as part of their diagnostic evaluation for gastrointestinal bleeding. Fifty-eight patients were classified according to the pattern of blood loss: 14 patients with chronic occult, 28 patients with recurrent acute, and 16 patients with acute bleeding. The sensitivity and specificity of mesenteric angiography for each group was: chronic occult, 40% sensitivity and 100% specificity; recurrent acute, 30% sensitivity and 100% specificity; acute, 47% sensitivity and 100% specificity. Vascular lesions accounted for most of the diagnosed abnormalities, including four of five lesions in patients with chronic blood loss and four of six lesions in each of the groups with recurrent acute and acute bleeding. A positive angiogram was correlated with a high likelihood of surgery in patients with recurrent acute as well as acute hemorrhage. Five of six in the former group and six of seven in the latter group required an operative procedure. Mesenteric angiography is an integral part of the diagnostic evaluation of patients with gastrointestinal bleeding, although the frequency of positivity varies with the pattern of bleeding.

Identical genetic profiles in primary and metastatic bladder tumors.

Transitional cell carcinoma of the bladder has been shown repeatedly to possess abnormal genetic profiles. During long periods recurrent tumors in the bladder consistently show the same type of genetic profile with each recurrence. We report on a patient with metastatic bladder cancer who had similar genetic profiles of the primary lesion and thoracocentesis fluid from the metastatic site. The significance of these findings is discussed.

Colonic ischemia complicating immunotherapy with interleukin-2 and interferon-alpha.

Colonic ischemia (CI) is a rare complication of high-dose interleukin-2 (IL-2) immunotherapy. This complication occurred in three of 141 patients (2.1%) with metastatic cancer treated with high-dose IL-2 therapy; CI only developed in patients receiving interferon-alpha (IFN) with IL-2 (three of 21, 14%) compared with none of 120 in those patients receiving IL-2 alone (P equals 0.0009). Severe diarrhea (greater than or equal to 7 bowel movements/day) also was significantly more common in patients receiving IFN with IL-2 (six of 21, 29%) than in those receiving IL-2 alone (three of 120, 2.5%, P equals 0.001) and preceded the clinical diagnosis of CI in all three patients. Three of nine patients with severe diarrhea had CI. Hematochezia occurred in four patients, all of whom received IFN with IL-2; three had CI, and the other patient had nonspecific colitis. Differences in vasopressor use did not explain the increased risk of CI in patients receiving IFN; those receiving IFN with IL-2 required phenylephrine less often than patients receiving IL-2 alone (P equals 0.01). The administration of lymphokine-activated killer (LAK) cells had no significant effect on the incidence of CI, severe diarrhea, peritonitis, or vasopressor use; two of three patients with CI, however, had their ischemic episode within 24 hours after the last of three LAK cell infusions. In conclusion, CI is an unusual complication of high-dose IL-2 and IFN immunotherapy. In patients receiving such combination therapy, severe diarrhea is a risk factor for the subsequent occurrence of CI.