Implication of alternative splice transcripts of caspase-3 and survivin in chemoresistance

Recent studies have shown that resistance to apoptosis may contribute to chemoresistance. Alteration of caspases, such as caspase-3, results on decreased apoptosis. Genes of IAP (inhibitor of apoptosis proteins) family, such as survivin, were also implicated in tumor development where they are mutated or have deregulated expression. Initial studies revealed strong survivin expression in several fetal tissues and some proliferating adult tissues, whereas no survivin expression was detected in a range of adult tissues. Although the factors at the origins on survivin re-expression in tumors are still unknown, the anti-apoptotic function of survivin is mediated in part by inhibiting caspase-3 activity. Recently, functionally divergent splice variants resulting from alternative splicing, with apoptotic (for caspase-3) or anti-apoptotic (for survivin) opposite activities have been described. The alternative splice variant, caspase-3s results from exon 6 deletion and shows antagonist of apoptotic property of caspase-3. Three alternative splice variants of survivin (survivin-DeltaEx3, survivin-2B and survivin-3B) differing in their anti-apoptotic properties were reported. While the anti-apoptotic effect of survivin-DeltaEx3 is preserved, survivin-2B has lost its anti-apoptotic potential and may act as a naturally occurring antagonist of survivin and survivin-DeltaEx3. At present, little is known about properties of survivin-3B. Several evidences indicate that in several cancers, the ratio of splice variants is significantly altered, and modifications of splicing pathways have been developed for cancer treatment. Recent investigations have shown that expression of alternative splice variants of caspase-3 and of survivin were also altered in many human cancers, and that variations in their expression were associated with tumor progression and chemoresistance. In this article, we describe recent data concerning alternative splice variants of these two proteins.     

Acute leukemia during pregnancy: a report on 37 patients and a review of the literature

BACKGROUND: Acute leukemia (AL) requiring cytotoxic treatment occurring during pregnancy poses a very difficult therapeutic dilemma. METHODS: By means of a mail questionnaire, information on a series of 37 patients with a diagnosis of AL during pregnancy was collected from 13 French centers between December, 1988 and November, 2003. RESULTS: Thirty-one patients had acute myeloid leukemia (AML), and 6 patients had acute lymphoblastic leukemia (ALL). Nine patients were diagnosed during the first trimester, 10 patients were diagnosed during the second trimester, and 18 patients were diagnosed during the third trimester. Fifteen pregnancies ended with therapeutic or spontaneous abortion. There were 13 normal deliveries, including 1 gemellary pregnancy, and 9 Cesarean sections. Twenty-three healthy babies survived from the 37 pregnancies, of whom 15 babies had been exposed to chemotherapeutic agents. A complete remission was achieved in 34 patients. Eleven women had severe extrahematologic complications during the induction remission course. The median disease-free survival (DFS) was not reached, with a 5-year DFS of 54%. Ten patients developed recurrent disease. Overall, 12 of 37 pregnant women died from leukemia. CONCLUSIONS: Pregnancy does not affect the course of AL. In the first trimester, termination of pregnancy should be discussed because of the potential fetal consequences of chemotherapy. Chemotherapy treatment during the second or third trimester may not require termination of pregnancy, because as remission of AL and delivery of a normal infant are likely to be obtained.     

Social disparities in maternal morbidity during labor and delivery between Mexican-born and US-born White Californians, 1996-1998

OBJECTIVES: To assess maternal health disparities, we compared maternal morbidities during labor and delivery among Mexican-born and US-born White, non-Latina women residing in California. METHODS: This population-based study used linked hospital discharge and birth certificate data for 1996-1998 (862,723 deliveries). We calculated the frequency, and observed and adjusted odds ratios for obstetric complications. Covariates included maternal age, parity, education, prenatal care initiation and payment source, and hospital quality of care. RESULTS: Approximately 1 in 5 deliveries resulted in a obstetric complication. After control for covariates, Mexican-born women were significantly less likely to have 1 or more maternal morbidities than White, non-Latina women but more likely to have complications that reflect the quality of intrapartum care. CONCLUSIONS: Maternal morbidities during labor and delivery are a substantial burden for women in California. The favorable overall outcome of Mexican-born women over US-born White, non-Latinas is surprising given their lower educational attainment, relative poverty, and greater barriers to health care access. The favorable outcomes obscure vulnerabilities in those complications that are sensitive to the quality of intrapartum care.     

Increased toxicity to Ceriodaphnia dubia in mixtures of atrazine and diazinon at environmentally realistic concentrations

The acute toxicity of diazinon in combination with atrazine concentrations of 5, 10, 20, and 40 microg/L was evaluated using Ceriodaphnia dubia. Atrazine concentrations as low as 5 microg/L in combination with diazinon significantly increased toxicity to C. dubia compared to diazinon alone. Atrazine and diazinon residues within water samples collected from 65 subbasins throughout Denton, Texas, USA were used to assess the environmental relevance of pesticide concentrations. A geographical information system was used to examine the relationship between subbasin land uses and pesticide concentrations. Significant correlations were observed between in situ atrazine and diazinon concentrations and some subbasin land uses. Atrazine was significantly (P < 0.05) correlated to diazinon during some months. Of the 276 samples collected, 39% exceeded our experimentally derived diazinon LC(50) value, and 39% exceeded our minimum atrazine concentration of 5.0 microg/L. Results indicate the potential for increased toxicity from mixtures of compounds at environmentally realistic concentrations.     

Sphincter-saving resection for all rectal carcinomas: the end of the 2-cm distal rule

OBJECTIVE: To assess oncologic outcome of patients treated by conservative radical surgery for tumors below 5 cm from the anal verge. SUMMARY BACKGROUND DATA: Standard surgical treatment of low rectal cancer below 5 cm from the anal verge is abdominoperineal resection. METHODS: From 1990 to 2003, patients with a nonfixed rectal carcinoma at 4.5 cm or less from the anal verge and without external sphincter infiltration underwent conservative surgery. Surgery included total mesorectal excision with intersphincteric resection, that is, removal of the internal sphincter, to achieve adequate distal margin. Patients with T3 disease or internal sphincter infiltration received preoperative radiotherapy. RESULTS: Ninety-two patients with a tumor at 3 (range 1.5-4.5) cm from the anal verge underwent conservative surgery. There was no mortality and morbidity was 27%. The rate of complete microscopic resection (R0) was 89%, with 98% negative distal margin and 89% negative circumferential margin. In 58 patients with a follow-up of more than 24 months, the rate of local recurrence was 2% and the 5-year overall and disease-free survival were 81% and 70%, respectively. CONCLUSIONS: The technique of intersphincteric resection permits us to achieve conservative surgery in patients with a tumor close to or in the anal canal without compromising local control and survival. Tumor distance from the anal verge is no longer a limit for sphincter-saving resection.     

The role of recombinant factor VIIa in the treatment of life-threatening haemorrhage in blunt trauma

BACKGROUND: Recombinant factor VIIa (rFVIIa) is a novel haemostatic agent originally developed to treat bleeding in haemophiliacs. Several case reports suggest effectiveness of rFVIIa in the treatment of patients without pre-existing bleeding disorders. The aim of this study is to evaluate treatment with recombinant (rFVIIa) in blunt trauma patients with uncontrolled bleeding. PATIENTS AND METHODS: This study was designed as a retrospective case review. Consecutive patients with life-threatening uncontrolled bleeding due to blunt trauma who were treated with rFVIIa were selected. Data were obtained from medical records. RESULTS: A total of eight blunt trauma patients were treated with rFVIIa for uncontrolled bleeding. After treatment the need for transfusion of red blood cells (RBC) decreased significantly from 31.3 +/- 15.8 to 6.1 +/- 6.8 units (P = 0.003), fresh frozen plasma (FFP) from 13.3 +/- 6.6 to 5 +/- 6.3 units (P = 0.02), and platelets from 3.6 +/- 1.8 to 1.5 +/- 2.3 units (P = 0.01). Three patients died of non-bleeding complications. The other five fully recovered. CONCLUSION: Treatment with rFVIIa reduced or stopped bleeding in all patients. No adverse events were registered. Prospective studies are mandatory to elucidate the role of rFVIIa in blunt trauma.     

Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers

BACKGROUND: The renin-angiotensin system plays a critical role in cardiovascular function, but little is known about the effects of specific cyclooxygenase 2 (COX-2) inhibition on this system in healthy humans under physiologic conditions. METHODS: Twenty-one healthy female volunteers received, in a randomized, double-blind, crossover study, celecoxib 200 mg twice a day, indomethacin 50 mg three times a day, or placebo for 4 days and a single dose, each, on day 5. On day 5 of each treatment, the following parameters were assessed with subjects in an upright position before and after administration of 20 mg furosemide intravenously: plasma renin activity (PRA), plasma aldosterone, serum and urine electrolytes, and creatinine. Index metabolites of prostanoids were analyzed by gas chromatography-tandem mass spectrometry in 24-hour urine on day 4 and in 2-hour urines before and after furosemide administration. RESULTS: Baseline and furosemide-stimulated PRA were reduced to a similar degree by celecoxib and indomethacin. Plasma aldosterone and urinary excretion of potassium showed changes consistent with the alteration of PRA. Urinary excretion rates of prostaglandin E(2), (PGE(2)), 7alpha-hydroxy-5, 11-diketotetranor-prosta-1,16-dioic acid (PGE-M), and 2,3-dinor-thromboxane B(2) (TxB(2)) were not reduced by celecoxib, whereas indomethacin led to a decrease of 40%, 45%, and 80%, respectively. Both active treatments inhibited urinary excretion of 2,3-dinor-6-keto-PGF(1alpha) and 6-keto-PGF(1alpha) by 60% and 40%, respectively. CONCLUSION: Renin-release in healthy humans with normal salt intake is COX-2 dependent. While COX-1 is critical for renal and systemic PGE(2) production, renal prostacyclin synthesis is apparently COX-2 dependent. Finally, the previously demonstrated shift of the thromboxane-prostacyclin balance toward prothrombotic thromboxane by specific COX-2 inhibition is confirmed.     

Impact of polymorphisms in the genes encoding xylosyltransferase I and a homologue in type 1 diabetic patients with and without nephropathy

BACKGROUND: Xylosyltransferase I (XT-I) is the chain-initiating enzyme in the biosynthesis of heparan sulfate proteoglycans (HSPGs). It catalyses the transfer of xylose to specific serine residues in the core protein. The XYLT-II gene codes for a protein highly homologous to the XT-I but its biologic function is not yet known. HSPGs are thought to play an important role in the permeability properties of the glomerular basement membrane (GBM) and thus the xylotransferase genes might be potential candidate genes predisposing to diabetic nephropathy in type 1 diabetic patients. METHODS: We screened all XYLT-I and XYLT-II exons and flanking intron regions in 96 Caucasians with type 1 diabetes (48 with and 48 without diabetic nephropathy) using denaturing high-performance liquid chromatography (DHPLC). We also studied a nondiabetic control group. RESULTS: Applying this technique we identified 13 variations in XYLT-I and 20 in XYLT-II. The variations IVS6-9T>C and IVS6-14_IVS6-13insG in XYLT-II were found with a frequency of 5.2% (5/96) in nondiabetic nephropathy patients, while all nephropathy patients were negative (P= 0.06). Nondiabetic controls also showed the single nucleotide polymorphisms (SNP) at a frequency of 1.1% (5/440). The investigation of the SNPs' influence on clinical characteristics revealed significant associations for c.1989T>C (XYLT-I) and c.2402C>G (XYLT-II) with patients' blood pressure. CONCLUSION: We detected in our cohort associations between DNA sequence variations of genes encoding xylosyltransferases and the occurrence of altered clinical characteristics.