The CEACAM1 tumor suppressor is an ATM and p53-regulated gene required for the induction of cellular senescence by DNA damage.

The p53 tumor-suppressor protein has a key role in the induction of cellular senescence, an important barrier to cancer development. However, very little is known about the physiological mediators of cellular senescence induced by p53. CEACAM1 is an immunoglobulin superfamily member whose expression is frequently lost in human tumors and exhibits tumor-suppressor features in several experimental systems, including Ceacam1 knockout mice. There is currently little understanding of the pathways and mechanisms by which CEACAM1 exerts its tumor-suppressor function. Here we report that CEACAM1 is strongly upregulated during the cellular response to DNA double-strand breaks (DSBs) starting from the lowest doses of DSB inducers used, and that upregulation is mediated by the ataxia telangiectasia mutated (ATM)/p53 pathway. Stable silencing of CEACAM1 showed that CEACAM1 is required for p53-mediated cellular senescence, but not initial cell growth arrest, in response to DNA damage. These findings identify CEACAM1 as a key component of the ATM/p53-mediated cellular response to DNA damage, and as a tumor suppressor mediating cellular senescence downstream of p53.

[New perspectives for radiosensitization in pancreatic carcinoma: a review of mechanisms involved in pancreatic tumorigenesis]. / Mécanismes de carcinogenèse des cancers du pancréas : quelles pistes pour la radiosensibilisation ?

Pancreatic carcinoma is the fifth leading cause of cancer-related mortality. The 5-year overall survival is less than 5 %. This very poor prognosis can be explained both by late diagnosis and by treatment resistance, including resistance to radiation therapy. A better understanding of the pancreatic tumorigenesis and knowledge of the most frequent mutations in pancreatic adenocarcinoma (KRAS, p16, TP53, Smad4) open new perspectives for the development of more effective treatments. This review presents the major genetic and molecular alterations in pancreatic cancer that could be targeted to improve radiosensitization.

Predictive markers for normal tissue reactions: fantasy or reality?

Interpatient heterogeneity in normal tissue reactions varies considerably, yet the genetic determinants and the molecular mechanisms of therapeutic radiation sensitivity remain poorly understood. Predictive assays and markers for normal tissue reactions are still in their infancy, although some progress has been made, particularly, for predicting late toxicity. For instance the T-lymphocyte radiation-induced apoptosis assay was shown to significantly predict differences in late toxicity between individuals and an 18 gene classifier based on radiation-induced expression in subcutaneous fibroblasts has also been identified that differentiated between patients with a high and low risk of radiation-induced fibrosis. However, the technical set-up for gene expression measurements means that this latter assay is unlikely to be introduced soon into a routine clinical setting but has importantly allowed the identification of genes that are involved in the fibrotic process. Serum markers have also been identified that show potential for the prediction of patients who will develop acute and late pulmonary toxicity. Few genetic predictive markers for normal tissue reaction have been identified and validated. Many of the single nucleotide polymorphism association studies have been limited by size and the inclusion of subjects with different kinds of radiation morbidity. International collaboration to assemble well-defined cohorts and technological progress should mean that the identification and validation of such markers using candidate gene approaches and whole genome association studies, which have been successful in other research areas, will make rapid progress.

Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers.

It has been estimated that approximately 1% of the general population are ataxia telangiectasia (AT) mutated (ATM) heterozygotes. The ATM protein plays a central role in DNA-damage response pathways; however, the functional consequences of the presence of either heterozygous truncating or missense mutations on ATM expression and the ionising radiation (IR)-induced cellular phenotype remain to be fully determined. To investigate this relationship, the ATM mRNA and protein levels and several cellular end points were characterised in 14 AT heterozygote (AT het) lymphoblastoid cell lines, compared to normal and AT homozygote lines. The AT het cell lines displayed a wide range of IR-induced responses: despite lower average levels of ATM mRNA and protein expression compared to normal cells, 13 out of 14 were capable of phosphorylating the ATM substrates p53-ser15 and Chk2, leading to a normal cell cycle progression after irradiation. However, cell survival was lower than in the normal cell lines. The presence of a missense compared to a truncating mutation was associated with lower cell survival after exposure to 2 Gy irradiation (P=0.005), and a higher level of ATM mRNA expression (P=0.047). Our results underline the difficulty in establishing a reliable test for determining ATM heterozygosity.

Variation in radiation-induced apoptosis in ataxia telangiectasia lymphoblastoid cell lines.

PURPOSE: To investigate and compare the ability of Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL) from healthy individuals (normals) and ataxia telangiectasia (A-T) patients to undergo apoptosis after exposure to ionizing radiation. MATERIALS AND METHODS: Four normal and eight A-T LCL were exposed to doses of up to 20 Gy ionizing radiation. Apoptosis induction was studied 24 h after irradiation using three different methods: measurement of caspase-3 activity, PARP-1 cleavage and estimation of the sub-G(1) cell fraction. RESULTS: Of the eight A-T LCL tested, all harbouring truncating ATM mutations, five had a higher level of spontaneous apoptosis than the normal LCL as assessed by the sub-G(1) cell fraction. Four of the eight A-T LCLs showed a similar level of radiation-induced apoptosis after exposure to 5 Gy as the normal LCL. The other four A-T LCL showed a greater radiation-induced apoptotic response, as assessed by at least one of the three techniques. CONCLUSIONS: LCL from A-T patients can undergo ionizing radiation-induced apoptosis in spite of a defect in ATM-p53-dependent signalling pathways. However, the apoptotic response is characterized by a large degree of variability between the A-T cell lines, the causes of which remain to be established.

Hyperfast, early cell response to ionizing radiation.

PURPOSE: To determine whether the oscillatory changes of radio-sensitivity which occur within fractions of a second to a few minutes following flash irradiation correlate with an altered incidence of apoptosis, DNA strand breaks or lipid-coupled signalling. MATERIALS AND METHODS: Human tumor cells (SQ-20B, LoVo) or Chinese hamster V79 fibroblasts were exposed to split-dose, pulse irradiation with 3.5 MeV electrons at high dose-rate (12 or 120 Gy x s(-1)) and the effects assessed by clonogenic assays, analysis of DNA cleavage and microscopic observation. RESULTS: The processes underlying oscillatory radiation response were saturable, but did not correlate with an increased incidence of DNA single- or double-strand breaks or apoptosis. N-acetylcysteine and inhibitors of lipid-derived signalling also failed to alter oscillatory response. However, this response did correlate with phenotypic alterations evoking mitotic or delayed cell death. Furthermore, high dose-rate irradiation provided a lower level of instability than protracted gamma-ray irradiation. CONCLUSIONS: It is proposed that the early steps of DNA damage recognition and repair following priming radiation exposure bring about rapid, synchronous remodeling of chromatin, evoking enhanced chromosome damage upon re-irradiation.

Protection of endogenous vitamin E and beta-carotene by aminoguanidine upon oxidation of human low-density lipoproteins by *OH/O(2)*-.

This study was designed to evaluate the antioxidant effect of aminoguanidine toward human low-density lipoproteins (LDLs) initiated by oxygenated free radicals (*OH/O(2)*-) generated by gamma radiolysis. Initial radiolytic yields related to the markers of lipid peroxidation [i.e. decrease in endogenous alpha-tocopherol and beta-carotene, formation of thiobarbituric acid-reactive substances (TBARS) and conjugated dienes] were determined in 3 g liter(-1) LDLs (expressed as total LDL concentration) in the absence and presence of 10 different concentrations of aminoguanidine (from 0.04 to 5 mmol liter(-1)). Fluorescence and relative electrophoretic mobility of oxidized LDLs were also studied as markers that indirectly reflect the attack of the protein moiety of LDLs (namely apolipoprotein B). Our data clearly showed the inhibitory effect of aminoguanidine on lipid peroxidation induced in LDLs by *OH/O(2)*- in a concentration-dependent manner. This effect probably resulted from a scavenging activity of aminoguanidine toward *OH. In contrast, aminoguanidine did not appear to react significantly with O(2)*-, which resulted in a poor residual lipid peroxidation. Our data led us to determine an optimum [aminoguanidine]/[LDL] ratio ranging from 250 to 500 to obtain the best in vitro protection of LDLs under our experimental conditions. It is also of great interest that aminoguanidine was able to protect endogenous alpha-tocopherol and beta-carotene of LDLs upon *OH/O(2)*(-)-induced oxidation.

Poly(ADP-ribose) polymerase, a major determinant of early cell response to ionizing radiation.

PURPOSE: To determine whether DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase (PARP-1) are involved in eliciting the rapid fluctuations of radiosensitivity that have been observed when cells are exposed to short pulses of ionizing radiation. MATERIALS AND METHODS: The effect of DNA-PK and PARP-1 inhibitors on the survival of cells to split-dose irradiation was investigated using Chinese hamster V79 fibroblasts and human carcinoma SQ-20B cells. The responses of PARP-1 proficient and PARP-1 knockout mouse 3T3 fibroblasts were compared in a similar split-dose assay. RESULTS: Inactivation of DNA-PK by wortmannin potentiated radiation-induced cell kill but it did not alter the oscillatory, W-shaped pattern of early radiation response. In contrast, oscillatory radiation response was abolished by 3-aminobenzamide, a reversible inhibitor of enzymes containing a PARP catalytic domain. The oscillatory response was also lacking in PARP-1 knockout mouse 3T3 fibroblasts. CONCLUSION: The results show that PARP-1 plays a key role in the earliest steps of cell response to ionizing radiation with clonogenic ability or growth as endpoint. It is hypothesized that rapid poly(ADP-ribosylation) of target proteins, or recruitment of repair proteins by activated PARP-1 at the sites of DNA damage, bring about rapid chromatin remodelling that may affect the incidence of chromosomal damage upon re-irradiation.

Evaluation of a pharmaceutical care model on diabetes management.

OBJECTIVE: To assess the effectiveness of a pharmaceutical care model on the management of non-insulin-dependent diabetes mellitus (NIDDM) in urban African-American patients. DESIGN: Eligible patients were randomized to either a pharmacist intervention or control group and followed over a 4-month period. Patients in the intervention group received diabetes education, medication counseling, instructions on dietary regulation, exercise, and home blood glucose monitoring, and evaluation and adjustment of their hypoglycemic regimen. Patients in the control group continued to receive standard medical care provided by their physicians. SETTING: A university-affiliated internal medicine outpatient clinic. PARTICIPANTS: The study population consisted of urban African American patients with NIDDM currently attending the clinic. MAIN OUTCOME MEASURES: Primary outcome measures included fasting plasma glucose and glycated hemoglobin concentrations. Secondary outcome endpoints included blood pressure, serum creatinine, creatinine clearance, microalbumin to creatinine ratio, total cholesterol, triglycerides, high-density lipoprotein, and low density lipoprotein concentrations. Quality-of-life assessments were performed in both groups at baseline and at the end of the study. RESULTS: Thirty-nine patients (17 intervention, 22 control) completed the study. The intervention group consisted of 12 women and 5 men with a mean +/- SD age of 59 +/- 12 years, total body weight (TBW) of 93 +/- 22 kg, body mass index (BMI) of 34 +/- 7 kg/m2, and duration of NIDDM 6.8 +/- 6.5 years. The control group consisted of 15 women and 7 men with a mean age of 65 +/- 12 years, TBW of 88 +/- 19 kg, BMI of 33 + 7 kg/m2, and a duration of NIDDM of 6.2 +/- 4.8 y. Significant improvement in glycated hemoglobin (p = 0.003) and fasting plasma glucose (p =0.015) was achieved in the intervention group. No change in glycemia was observed in the control subjects. Statistically significant differences in the final glycated hemoglobin (p = 0.003) and fasting plasma glucose (p = 0.022) concentrations were noted between groups. No significant changes in blood pressure control, lipid profile, renal function parameters, weight, or quality-of-life measures were noted within or between groups. CONCLUSIONS: Our data demonstrate the effectiveness of pharmaceutical care in the reduction of hyperglycemia associated with NIDDM in a group of urban African-American patients.

Frequency of development of early cortical scarring in acute primary pyelonephritis.

Fifty-five cases of primary (that is, without urinary tract abnormalities), acute pyelonephritis (PN) were studied by computed tomodensitometry (CT). There were 48 women and 7 men. All were febrile and 16 had positive blood cultures. In 7 cases, (4 diabetics and 3 malnourished alcoholics) PN was painless, diagnosis was delayed and lesions were severe. Two diabetics underwent emergency nephrectomy for sepsis. Conventional radiological techniques (IVP and ultrasonography) were poorly informative. In contrast, initial CT abnormalities were visible in 44 patients. They consisted of triangular or round hypodense images, diffuse hypodensity in a grossly swollen kidney, and/or abscesses. Hypodense images were presumably due to acute focal ischemia. Renal histology was available in five patients. It showed acute interstitial nephritis with leukocyte infiltrates, edema and hemorrhagic streaks. Pyelonephritis was due to E. coli in 48 cases (87.5%). In 27 cases E. coli isolates were studied by genotypic assays which detect the three most frequent (pap, afa and sfa) of the four operons known to encode adhesin. In all cases, at least one of these genotypic markers of uropathogenicity was found. In 27 cases, repeat CT was done shortly after treatment. It showed healing in only 12. Early cortical scar formation was visible in 2. Final evaluation in 27 cases with adequate follow-up showed that (in addition to the 2 patients who had been nephrectomized), in only 17 of 27 (63%) had the kidneys recovered a normal appearance. In two cases one kidney had undergone atrophy; renal biopsy showed subacute-chronic interstitial nephritis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Renal tolerability of iopromide 370 in patients with chronic renal insufficiency]. / Etude de la tolérance rénale de l'iopromide 370 chez l'insuffisant rénal chronique.

Intravenous injection of iodinated contrast media usually induces modifications of renal function. Adverse effects of contrast media on renal function may affect diuresis, blood flow or glomerular filtration rate. These modifications are mainly related to osmolality but also chemotoxicity. This open study showed that after i.v. injection of a bolus of iopromide 370, a new nonionic contrast medium, there was no untoward effect on renal function in patients with renal insufficiency. This justifies comparative studies in patients with renal impairment including elderly subjects, to confirm the tolerance of this product in high risk groups.

[Information provided by X-ray computed tomography in adrenal pathology]. / Renseignements fournis par la tomodensitométrie dans la pathologie surrénalienne.

After a brief review of the circumstances in which CT scan of the adrenal glands may be carried out, the following are discussed: the role of CT scan in the diagnosis of pheochromocytoma, in functional pathology of the cortex (hyperplasia or tumor) and the problem of incidentalomas. CT scan, a simple examination with immediate and reliable results, enables percutaneous biopsy to be carried out with complete safety.

Atheromatous renal disease.

PURPOSE: Atheroma as a cause of renal failure has been largely overlooked. We wanted to report our experience with atheromatous renal disease over a 12-year period. PATIENTS AND METHODS: Observations on 32 cases of various forms of renal failure in patients with atheromatous renal disease are presented. These patients had been hypertensive for an average of 10.2 +/- 9.2 years. The length of deterioration was an average of 17 months, and at presentation renal insufficiency was severe, with serum creatinine levels of (mean +/- SD) 616 +/- 358 mumol/liter (6.8 +/- 4.0 mg/dl). At this stage, the clinical picture was indistinguishable from other common causes of chronic renal failure in the elderly. Thus, the precise diagnosis would have been overlooked without an aggressive diagnostic workup. All patients underwent angiography and six patients underwent renal biopsy. RESULTS: In 22 cases, renal insufficiency was mainly due to atheromatous stenosis of renal arteries. In six of six patients, the results of renal biopsy showed cholesterol crystal embolism. In four additional cases, there was clinical or histologic evidence of extrarenal cholesterol embolism. In eight, renal artery plaques coexisted with cholesterol embolism. In two patients, renal failure was due only to cholesterol embolism. Renal atheromatous stenoses were developing, as shown on serial angiographies performed in five cases. In seven cases, stenoses involved both the main trunks of renal arteries and several intrarenal branches of too small a diameter to allow reconstructive surgery or percutaneous transluminal angioplasty. In addition, the general condition of most patients was so poor as to preclude surgery. Dialysis was begun in 11 patients, four other patients died, and renal failure was managed conservatively in 11. When undertaken, reconstructive surgery was successful in five of six patients. CONCLUSIONS: Atheromatous renal disease is a frequent and easily overlooked cause of chronic renal insufficiency. It is not only due to renal artery stenosis but also to complex intrarenal lesions, with multiple stenoses of intrarenal vasculature and cholesterol embolism. It should be diagnosed by early angiography and renal biopsy, before the stage of multivisceral complications and at a time when surgery can still be undertaken.

A case of ectopic right renal artery: a radiologic-anatomic variant.

The authors report the anatomic and radiologic findings in a case of ectopic origin of the right renal artery in front of the T11-12 intervertebral disc. This seems to be an extremely rare variant, and the rarity of the reported cases is such as not to allow definition of a percentage incidence. An explanation of this variant may be found in modern concepts of the organogenesis of the renal artery.

[Lymphography in tuberculosis in black African immigrants]. / La lymphographie dans la tuberculose du noir africain transplanté.

Lymphographic data in 23 negro immigrants with lymph nodes tuberculosis almost always mediastinal and/or superficial are reported. In six cases, including two cases with abdominal latero-aortic lymph nodes clinically obvious, lymphography showed abnormalities without doubt. These aspects are compared with data of literature and discussed according to interpretation and significance in tuberculosis very peculiar in negro immigrants.20