Inhibition of growth of MDA-MB-231 human breast cancer xenografts in nude mice by bombesin/gastrin-releasing peptide (GRP) antagonists RC-3940-II and RC-3095

We have previously demonstrated that diphtheria toxin (DT) fused to human GM-CSF effectively eliminates human long-term leukemia initiating cells in SCID mice. However, because huGM-CSF does not react with the murine GM-CSF receptor possible side-effects to nonleukemic tissues could not be analyzed in the AML/SCID model. To overcome this problem, we used murine GM-CSF fused to DT and studied the therapeutic index in the rat leukemia model BNML/LT12. In DT-mGM-CSF dose escalation experiments, severe dose-dependent toxicity to organs such as liver, kidney and lung was observed. Therefore, the antileukemic effects were evaluated with the lower doses. Daily intraperitoneal bolus injections of 75 microg/kg/day for 7 days induced a 3 log leukemic cell kill. The dose of 75 microg/kg/day had no effect on the hemopoietic progenitor cell subsets. These in vivo studies show that the DT-GM-CSF fusion protein can be used for specifically targeting leukemic cells and thus has potential as a therapeutic agent in the treatment of AML.     

Effect of dexamethasone and corticosterone on activity levels of ATPase, phosphomonoesterases and phosphodiesterase in liver, muscle and testis of post-hatched White Leghorn chicks

We have investigated the feasibility of using high-titer murine leukemia virus-based retroviral vectors to deliver exogenous genes to naive and chronically inflamed knee joints of rabbits in vivo. Intraarticular injection of retrovirus encoding beta-galactosidase (beta-gal or lacZ) was found to transduce synoviocytes in both naive and inflamed joints, but a significantly higher number of lacZ+ cells were found in inflamed knees. Using a retrovirus encoding a secretable marker, human growth hormone (hGH), quantitative comparison of ex vivo and in vivo gene delivery methods demonstrated that transgene expression following in vivo gene transfer was at least equivalent to that of the ex vivo method in inflamed knees. In addition, hGH transgene expression was maintained for at least 4 weeks. These experiments suggest that high-titer retroviral vector could be used for efficient in vivo gene transfer to inflamed joints in patients with rheumatoid arthritis (RA).     

Homeostatic changes in monkeys in a model of glanders

Some aspects of homeostasis impairment in monkeys infected with Pseudomonas mallei were investigated. The levels of the hormonal shifts, complement components, beta 2-microglobulin and prostaglandins evident of the infection severity were estimated. The pathomorphological profiles of various forms of malleus in the primates were studied.     

Preoperative and intraoperative topographic diagnosis of insulinomas

Altogether 120 patients with organic hyperinsulinism underwent clinical examination and treatment (38 male, 82 female, mean age 44.2 +/- 4.6 years). The cause of hyperinsulinism was benign insulinomas in 96 (80.0%), malignant tumors in 9 (7.5%), and hyperplasia of beta cells in 6 (5.0%). In 9 (7.5%) patients the origin of hyperinsulinism was not diagnosed. The tumor was localized in the head, body, and tail of the pancreas in 31.8%, 36.4%, and 31.8% of cases, respectively. Intraoperative ultrasonography (IOUS) was undertaken in 37 patients, and in 83 cases only intraoperative palpation was done. Arterial stimulated venous sampling (ASVS) was performed in 17 patients (blood was sampled from the right hepatic vein for determination of the insulin level after arterial stimulation by calcium gluconate in different parts of the pancreas). The sensitivity of ultrasonography (US) was 29.5%, computed tomography (CT) 24.2%, angiography 55.9%, superselective angiography (branches of the celiac trunk) 72.2%, and intraoperative palpation 90.0%. ASVS showed an accuracy of 90.0%. Combining angiography with ASVS gave an exact diagnosis of hyperinsulinism in 100% of cases, and IOUS revealed tumors in 100% of cases. Hyperplasia of beta-cells was diagnosed only by means of ASVS. A total of 117 patients underwent surgery, including distal resection of pancreas (n = 39), enucleation of tumor (n = 70), and laparotomy (n = 8). The postoperative mortality associated with insulinomas was 7.7%. The frequency of postoperative complications was 43.6%. Benign insulinomas recurred at a rate of 5.4%. Patients with malignant insulinomas had a 5-year survival of 66.0%. The diagnosis of insulinomas was achieved by a combination of selective angiography, ASVS, and IOUS.     

An analysis of preliminary results in screening for prostatic cancer]

450 males aged over 50 years free of urological symptoms were screened for prostatic cancer using three techniques; finger rectal examination (FRE), transrectal ultrasound investigation (TUI), assay for prostatic specific antigen in the serum (SPSA). SPSA quantities under 4 ng/ml, 4-10 ng/ml, 10-20 ng/ml, over 20 ng/ml were registered in 206(45.8%), 135(30%), 69(15.4%) and 40(8.8%) patients, respectively. Detectability of prostatic cancer increases by 33,37.9, 45.5, 69.2% due to TUI, FRE, TUI + FRE, all the three methods, respectively. Prostatic biopsy was needed in 102 (22.7%) cases. From the 450 examinees, prostatic cancer was diagnosed in 25 (5.6%). SPSA was high in all of them, higher than 10 ng/ml in 92%. 20 (80%) of 25 patients with cancer had early stages of the disease (TI-2). The study is going on.     

Increased cancer mortality following a history of nonmelanoma skin cancer

CONTEXT: Cancer registries have reported an increased incidence of melanoma and certain noncutaneous cancers following nonmelanoma skin cancer (NMSC). Whether these findings were attributable to intensified surveillance, shared risk factors, or increased cancer susceptibility remains unclear. OBJECTIVE: To determine whether a history of NMSC predicts cancer mortality. DESIGN: Prospective cohort with 12-year mortality follow-up adjusted for multiple risk factors. SETTING: Cancer Prevention Study II, United States and Puerto Rico. PARTICIPANTS: Nearly 1.1 million adult volunteers who completed a baseline questionnaire in 1982. MAIN OUTCOME MEASURE: Deaths due to all cancers and common cancers. RESULTS: After adjusting for age, race, education, smoking, obesity, alcohol use, and other conventional risk factors, a baseline history of NMSC was associated with increased total cancer mortality (men's relative risk [RR], 1.30; 95% confidence interval [CI], 1.23-1.36; women's RR, 1.26; 95% CI, 1.17-1.35). Exclusion of deaths due to melanoma reduced these RRs only slightly. Mortality was increased for the following cancers: melanoma (RR, 3.36 in men, 3.52 in women); pharynx (RR, 2.77 in men, 2.81 in women); lung (RR, 1.37 in men, 1.46 in women); non-Hodgkin lymphoma (RR, 1.32 in men, 1.50 in women); in men only, salivary glands (RR, 2.96), prostate (RR, 1.28), testis (RR, 12.7), urinary bladder (RR, 1.41), and leukemia (RR, 1.37); and in women only, breast (RR, 1.34). All-cause mortality was slightly increased (adjusted men's RR, 1.03 [95% CI, 1.00-1.06]; women's RR, 1.04 [95% CI, 1.00-1.09]). CONCLUSIONS: Persons with a history of NMSC are at increased risk of cancer mortality. Although the biological mechanisms are unknown, a history of NMSC should increase the clinician's alertness for certain noncutaneous cancers as well as melanoma.     

Functional region IV of glycoprotein D from herpes simplex virus modulates glycoprotein binding to the herpesvirus entry mediator

Glycoprotein D (gD) of herpes simplex virus (HSV) is essential for virus entry and has four functional regions (I to IV) important for this process. We previously showed that a truncated form of a functional region IV variant, gD1(Delta290-299t), had an enhanced ability to block virus entry and to bind to the herpesvirus entry mediator (HveAt; formerly HVEMt), a cellular receptor for HSV. To explore this phenotype further, we examined other forms of gD, especially ones with mutations in region IV. Variant proteins with deletions of amino acids between 277 and 300 (region IV), as well as truncated forms lacking C-terminal residues up to amino acid 275 of gD, were able to block HSV entry into Vero cells 1 to 2 logs better than wild-type gD1(306t). In contrast, gD truncated at residue 234 did not block virus entry into Vero cells. Using optical biosensor technology, we recently showed that gD1(Delta290-299t) had a 100-fold-higher affinity for HveAt than gD1(306t) (3.3 x 10(-8) M versus 3.2 x 10(-6) M). Here we found that the affinities of other region IV variants for HveAt were similar to that of gD1(Delta290-299t). Thus, the affinity data follow the same hierarchy as the blocking data. In each case, the higher affinity was due primarily to a faster kon rather than to a slower koff. Therefore, once the gDt-HveAt complex formed, its stability was unaffected by mutations in or near region IV. gD truncated at residue 234 bound to HveAt with a lower affinity (2.0 x 10(-5) M) than did gD1(306t) due to a more rapid koff. These data suggest that residues between 234 and 275 are important for maintaining stability of the gDt-HveAt complex and that functional region IV is important for modulating the binding of gD to HveA. The binding properties of any gD1(234t)-receptor complex could account for the inability of this form of gDt to block HSV infection.