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Because ribosome biogenesis plays an essential role in cell proliferation, control mechanisms may have evolved to recognize lesions in this critical anabolic process. To test this possibility, we conditionally deleted the gene encoding 40S ribosomal protein S6 in the liver of adult mice. Unexpectedly, livers from fasted animals deficient in S6 grew in response to nutrients even though biogenesis of 40S ribosomes was abolished. However, liver cells failed to proliferate or induce cyclin E expression after partial hepatectomy, despite formation of active cyclin D-CDK4 complexes. These results imply that abrogation of 40S ribosome biogenesis may induce a checkpoint control that prevents cell cycle progression.

We have identified a novel gene with homologies to the Drosophila Sex comb on midleg (Scm) gene from the short arm of the X chromosome. Scm is a member of the Polycomb group (PcG) genes, which encode transcriptional repressors essential for appropriate development in the fly and in mammals. The newly identified transcript named SCML2 (sex comb on midleg like-2, HGMW-approved symbol) is ubiquitously expressed and encodes a protein of 700 amino acids. SCML2 maps very close to the recently identified SCML1, revealing the presence of a new gene cluster in Xp22. The homology and map location identify SCML2 as a candidate gene for Xp22-linked developmental disorders, including the oral-facial-digital type I (OFDI) syndrome. A study of the SCML1-SCML2 cluster in primates indicates that the two genes are localized to the same region in Old World monkeys, New World monkeys, and prosimians, suggesting that the duplication event leading to the formation of the SCML cluster on Xp22 occurred before primate divergence., (Copyright 1999 Academic Press.)

Eukaryotic protein kinases are part of a large and expanding family of proteins. Through our transcriptional mapping effort in the Xp22 region, we have isolated and sequenced the full-length transcript of STK9, a novel cDNA highly homologous to serine-threonine kinases. A number of human genetic disorders have been mapped to the region where STK9 has been localized including Nance-Horan (NH) syndrome, oral-facial-digital syndrome type 1 (OFD1), and a novel locus for nonsyndromic sensorineural deafness (DFN6). To evaluate the possible involvement of STK9 in any of the above-mentioned disorders, a 2416-bp full-length cDNA was assembled. The entire genomic structure of the gene, which is composed of 20 coding exons, was determined. Northern analysis revealed a transcript larger than 9.5 kb in several tissues including brain, lung, and kidney. The mouse homologue (Stk9) was identified and mapped in the mouse in the region syntenic to human Xp. This location is compatible with the location of the Xcat mutant, which shows congenital cataracts very similar to those observed in NH patients. Sequence homologies, expression pattern, and mapping information in both human and mouse make STK9 a candidate gene for the above-mentioned disorders., (Copyright 1998 Academic Press.)

We have recently reported isolation of the gene responsible for X-linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X-specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.

Aims and Background: Recent preclinical data have suggested that lonidamine may potentiate the acitivity of mitomycin C in human colon cancer cell lines LoVo and HT29., Study Design: A phase II study was carried out in 14 patients with advanced colorectal cancer pretreated with fluorouracil and folinic acid. Treatment consisted of lonidamine, 600 mg po, followed after 2 h by mitomycin, 20 mg/m2 by iv bolus, followed by lonidamine, 150 mg tio for 5 days; the cycle was repeated every 6 weeks., Results: No objective response was seen. Three patients had stable disease; the median survival for the whole group was 4 months. Although hematologic toxicity was negligible, lonidamine-related side effects were moderate to severe in most patients and mainly represented by myalgia and gastric pain., Discussion: Despite a sound preclinical rationale, this schedule of lonidamine and mitomycin C was ineffective and toxic in patients with advanced colorectal cancer. More experimental data about lonidamine are needed in order to design more effective regimens based on the combination of this interesting drug with other anticancer agents.

Twenty-six patients with advanced colorectal cancer were treated with a combination based on multimodal biochemical modulation of 5-fluorouracil by means of high dose folinic acid, low-dose alpha-2b interferon and dipyridamole. The overall response rate was 42% (95% confidence intervals = 23%. 61%) with four complete remissions (15%). The median duration of response was 9 months and the median survival for responders was 15 months (all patients = 12 months). Toxic side effects included oral mucositis (grade III-IV = 38%) and a generally mild flu-like syndrome. This regimen seems active and safe enough to be compared with the combination of fluorouracil and high-dose folinic acid.

Thirty-two patients with advanced breast cancer were treated with mitomycin-C 10 mg/m2 IV and vinblastine 6 mg/m2 IV every 21 days in combination with lonidamine 450 mg/day P.O. and prednisone 15 mg/day P.O. given continuously. Among the 29 evaluable patients (all but three pretreated with an anthracycline-based regimen), one complete remission (CR) and six partial remissions (PR) (response rate, 24%) were seen. The median duration of response was 14 months (range, 4-30 months). Median survival for responders was 18 months (range, 4-30 months). Hematological toxicity was uncommon; the main lonidamine-related side effects were myalgia, abdominal cramps, and reversible deafness; these side effects were severe in two, one, and one patients, respectively. The regimen seems to have a reasonable degree of activity and toxicity in advanced, refractory breast cancer. The role of lonidamine in the treatment of this disease warrants further evaluation.

Twelve patients with refractory (8 pts) and relapsing (4 pts) myeloma were treated with Peptichemio. Teniposide and high-dose dexamethasone. Eight patients experienced an objective response (5 out 8 with refractory and 3 out 4 with relapsing disease) with a median duration of 10+ months. Overall toxicity was mild to moderate and chiefly haematological. Our preliminary results seem very promising and justify a larger phase II study with this regimen.

This paper reports experience with high-dose folinic acid (HDFA) and 5-fluorouracil (5-FU) in the treatment of 130 patients with various types of tumor. While the objective results obtained from gastrointestinal malignancies (response rate = 15%) are no better than those usually gained by 5-FU alone, impressive results were achieved in patients with advanced and mainly pretreated breast cancer (response rate = 44%). Haematological toxicity was generally mild, while oral mucositis, diarrhoea and conjunctivitis were major side effects. Our data suggest that HDFA and 5-FU seem a very promising combination and warrant further investigation.

Forty patients with metastatic breast cancer were treated with a new combination regimen consisting of cyclophosphamide, epirubicin, high-dose folinic acid and 5-fluorouracil (super-FEC). A major objective response was observed in 32 patients (80%). Among these, 11 patients (27%) experienced a complete remission. The median duration of response was 10+ and 12+ months for CR and PR, respectively. The most common side-effect was oral mucositis (Grade III = nine patients; grade IV = two patients), while haematological toxicity was virtually absent. Considering the high-risk characteristics of the vast majority of the enrolled patients (75% had dominant visceral disease), these preliminary results suggest that super-FEC has a powerful activity in poor-prognosis metastatic breast cancer with an acceptable degree of toxicity.

In male Wistar rats standardized from birth in LD 12:12 conditions (with light from 0700 to 1900 hr), samples of mucosa from the body of the stomach were isolated in vitro and mounted in a Ussing-type chamber. Spontaneous secretion of the hydrogen ion (H+)during 45 min of incubation was measured. Some electric parameters [transmucosal potential difference (PD) and electrical resistance (R)] were detected in the gastric mucosa both during H+ secretion and during inhibition of acid secretion by cimetidine. The variables studied were analyzed with the single cosinor method, and all revealed a circadian rhythm with acrophases during the dark span. The higher values of PD and R found during the dark hours are unrelated to acid secretion and may indicate a greater efficiency of ionic pumps and a limited passive permeability.

We have investigated the activity of tamoxifen in 12 post-menopause patients affected by advanced breast carcinoma and, in this specific case, by metastatic pleural effusion. A receptor assay was carried out on all patients to assess the estrogen and progesterone receptor activity in pleural effusion tumor cells, cytologically confirmed. The assay was performed both at the moment of the diagnostic check and after a week of 30 mg/die of tamoxifen therapy. We obtained a temporary reduction of the pleural effusion in 5 patients out of 12 (42%). Four out of these 5 patients presented estrogen receptors (ER+) at the first assay. In the 4 patients with negative receptors (ER-) neither a decrease of the percentage of tumoral cells, nor a reduction of the effusion was ascertained. This study shows that also for pleural effusions tamoxifen's therapeutic benefit was obtainable only in those patients with estrogen receptors in the tumoral cells.

Thirty patients with advanced and mainly pretreated breast cancer were treated with a combination of premarin, prednimustine, high-dose folinic acid and 5-fluorouracil. Among the 30 evaluable patients, 9 (30%) achieved an objective response (median duration: 9 months). Oral mucositis was the limiting toxicity, while myelosuppression was quite mild. In spite of considerable activity as salvage regimen, these results do not seem better than those achieved in our Institute with high-dose folinic acid and 5-fluorouracil alone.

Intra-arterial 24 hour blood pressure (BP) recording (OXFORD MEDILOG) was carried out in 10 patients with essential hypertension, 6 males and 4 females, aged between 41 and 58 years, 3 at WHO stage 1 and 7 at stage 2, in basal conditions and after 6 weeks of treatment with a fixed combination of 160 mg of slow-release oxprenolol and 20 mg of chlorthalidone per tablet (tb). The fixed combination was given once daily, in the morning, at the dosage of 1 tb, which was increased to 2 tbs o.d. after the first 2 weeks in 6 patients. Computer calculated mean BP and heart rate (HR) values from each consecutive hour of the day were obtained in all patients. Hourly trend of BP and HR were plotted and circadian variations were thus determined. Treatment with fixed combination o.d. significantly reduced systolic and diastolic BP, compared to pretreatment values, throughout of the 24 hours (p less than 0.01; p less than 0.001), without altering the circadian rhythm. Before and after 6 weeks of treatment, a bicycle exercise test was performed in 8 patients, who reached 85% of the maximal predicted HR. Pretreatment resting mean BP (+/- SD) was 190 +/- 31/108 +/- 10 mmHg (HR: 68 +/- 9 b/min) and those during the last minute of exercise 242 +/- 29/125 +/- 5 mmHg (HR: 147 +/- 13 b/min); posttreatment resting BP was 161 +/- 20/88 +/- 7 mmHg (HR: 58 +/- 7 b/min) and at peak exercise, 212 +/- 16/106 +/- 7 mmHg (p less than 0.025 for the systolic pressure; p less than 0.001 for the diastolic pressure).(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic rigidity, plasma noradrenaline and adrenaline, and hemodynamic parameters were measured in 48 essential hypertensive patients, 25 younger than 45 (Group I) and 23 of 45 years and over (Group II). Aortic rigidity was determined by the ratio of pulse pressure over stroke volume. Aortic rigidity and hemodynamic parameters were also determined after combined alpha-beta receptor blockade induced by Labetalol (mg 100 IV) or by Propranolol (mg 10 IV) plus Phentolamine (mg 10 IV). The aortic rigidity index was significantly higher in Group II, systolic arterial pressure being significantly higher. All other data, including plasma noradrenaline and adrenaline, were not significantly different in the two groups. In Group II a significant correlation (r = 0.62) was noted between aortic rigidity indexes and plasma noradrenaline values. The alpha-beta receptor blockade induced a decrease of aortic rigidity particularly in Group II, owing to a more marked decrease of systolic arterial pressure. A highly significant correlation was noted in Group II between the changes in aortic rigidity index and the basal plasma noradrenaline levels (r = 0.81). Therefore, the aortic rigidity in essential hypertensive patients older than 45 is influenced by the sympathetic nervous system activity, as judged by plasma noradrenaline levels. This influence seems related to an increase with age of aortic responsiveness to sympathetic stimulation.

Thirty-two patients with moderate to severe essential hypertension whose supine diastolic blood pressure (SDBP) was greater than or equal to 95 mm Hg following 2 weeks' treatment with the optimal dosage of beta blocker-diuretic combination were randomly assigned to the addition of either captopril 25 mg or 50 mg b.i.d. After 6 weeks' treatment, if patients were not normalized (SDBP less than 95 mm Hg), the dose of captopril was doubled for a further 6 weeks. The addition of captopril led to a significant fall in standing and supine diastolic and systolic blood pressure at the end of the sixth and twelfth week of treatment. There was no difference in the change in blood pressure between the two groups. At the end of the study SDBP was normalized in 66% of patients and a further 12.5% had their SDBP reduced by greater than 10%. Captopril 25 or 50 mg administered twice daily proved to be a very effective antihypertensive agent when added to a beta blocker-diuretic combination in patients resistant to optimal doses of these drugs.

We treated 20 patients with squamous cell carcinoma of the esophagus with the following regimen: cisplatin = 100 mg/m2 i.v. day 1, HDFA = 200 mg/m2 i.v. day 1 to 5, 5-fluorouracil = 370 mg/m2 i.v. day 1 to 5 repeated every 28 days. Among the 17 evaluable patients, 4 (23%) had a partial remission, 6 had stable disease while 7 progressed. The median survival for all patients was 6+ months. Grade III or IV toxicity included 2 patients with grade III leukopenia, 1 with grade III thrombocytopenia, 1 patient with grade IV and 3 patients with grade III oral mucositis, 3 patients with grade III diarrhea. The regimen did not seem particularly active in the treatment of squamous cell carcinoma of the esophagus and had manageable but substantial toxicity.

We treated 21 patients with advanced breast cancer with buserelin, aminoglutethimide and cortisone acetate in an attempt to obtain a complete estrogen blockade both in premenopausal and postmenopausal patients. Ten patients (47%) obtained an objective response without any relevant side-effects. Dealing with hormonal data, it must be outlined that serum testosterone levels decreased significantly in postmenopausal patients, suggesting a possible explanation for the activity of luteinizing hormone-releasing hormone analogue in this group of patients.