Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased Raf-1 ubiquitin-dependent degradation

The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 microM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex.     

Can an inert sleeping pill affect sleep? Effects on polysomnographic,behavioral and subjective measures

RATIONALE: Since two recent meta-analyses on sleep changes associated with placebo in clinical trials suggested a beneficial effect of placebo treatments, pointing to a dissociation between subjective and objective measures of sleep, the current experiment was directly aimed to assess the effects of an inert compound, administered with the suggestion that it was a hypnotic substance in subjects with mild sleep complaints. OBJECTIVES: The aim of this study was to compare subjective, behavioral, polysomnographic (PSG), and quantitative electroencephalographic (EEG) changes during a night preceded or not by the intake of two 50-mg lactose capsules. METHODS: Ten female students, selected by the Pittsburgh Sleep Quality Index, slept for three consecutive nights in a sleep laboratory, with the experimental (EXP) night defined by the administration of two 50-mg lactose pills. Self-ratings of sleep quality and performance were assessed upon morning awakening of baseline (BSL) and EXP nights. RESULTS: The EXP nights were self-rated as more restful and characterized by a decreased number of nocturnal awakenings than the BSL nights. PSG measures showed that wakefulness after sleep onset significantly decreased during the EXP night as compared to the BSL night. The EXP nights also showed an increase of 0.5-4.0 Hz power during nonrapid eye movement sleep and a decrease of EEG activity in the beta frequency range during rapid eye movement sleep only at central brain sites. A specific improvement of behavioral measures was also found upon morning awakening after the EXP night compared to the BSL night. CONCLUSIONS: The administration of an inert pill improves both the subjective and objective quality of sleep. The reduced sleep fragmentation and the effects on some quantitative EEG markers of sleep homeostasis suggest that the experimental manipulation induced coherent changes in the subsequent sleep, resembling an enhancement of sleep pressure. The regional differences of EEG activity suggest the involvement of a specific physiological mechanism distinct from that of effective treatments.     

Fixed dose-rate gemcitabine infusion as first-line treatment for advanced-stage carcinoma of the pancreas and biliary tree

BACKGROUND: Gemcitabine infusion at the fixed dose rate of 10 mg/m(2) per minute (FDR-gemcitabine) has pharmacokinetic advantages and may result in improved therapeutic efficacy. METHODS: Between April 2002 and September 2003, 40 patients with advanced-stage pancreatic adenocarcinoma (PDAC; n = 27) or biliary tree carcinoma (BTC; n = 13) were treated with weekly FDR-gemcitabine (1000 mg/m(2)). The primary end point was the response rate. The secondary end points were progression-free and overall survival (PFS and OS), tumor marker response, and clinical benefit response (CBR). RESULTS: The overall response rate (ORR) on an intent-to-treat basis was 15% (95% confidence interval [95% CI], 4-26%). A positive CBR was obtained in 14 of 29 (48%) patients. Seventeen of 25 (68%) patients had a reduction in carbohydrate antigen 19-9 (CA 19-9) of > 25%. The median time to treatment failure and the median PFS were 17 weeks (95% CI, 13-22 weeks) and 19 weeks (95% CI, 15-23 weeks), respectively. The median OS was 40 weeks (95% CI, 36-45 weeks) and the 1-year actuarial survival rate was 25.8%. Multivariate analysis showed that a performance status score of 0-1 at study entry and locally advanced disease were the only independent predictors of longer PFS and OS, whereas a reduction in CA 19-9 serum levels > 75% was an independent predictor of longer PFS, but had no impact on OS. Toxicity was mild with Grade 3-4 neutropenia (according to the National Cancer Institute-Common Toxicity Criteria [version 2.0]) in 18 of 427 treatment weeks (4.2%), and Grade 3 anemia and thrombocytopenia in 6 of 427 treatment weeks (1.4%) and 9 of 427 treatment weeks (2.1%), respectively, and asymptomatic Grade 3-4 transaminase elevation in 21 of 427 treatment weeks (4.9%). CONCLUSIONS: FDR-gemcitabine at the weekly dose of 1000 mg/m(2) demonstrated promising activity, despite negligible toxicity, in patients with advanced-stage PDAC and BTC.     

Pap smear rates among Haitian immigrant women in eastern Massachusetts

OBJECTIVE: Given limited prior evidence of high rates of cervical cancer in Haitian immigrant women in the U.S., this study was designed to examine self-reported Pap smear screening rates for Haitian immigrant women and compare them to rates for women of other ethnicities. METHODS: Multi-ethnic women at least 40 years of age living in neighborhoods with large Haitian immigrant populations in eastern Massachusetts were surveyed in 2000-2002. Multivariate logistic regression analyses were used to examine the effect of demographic and health care characteristics on Pap smear rates. RESULTS: Overall, 81% (95% confidence interval 79%, 84%) of women in the study sample reported having had a Pap smear within three years. In unadjusted analyses, Pap smear rates differed by ethnicity (p=0.003), with women identified as Haitian having a lower crude Pap smear rate (78%) than women identified as African American (87%), English-speaking Caribbean (88%), or Latina (92%). Women identified as Haitian had a higher rate than women identified as non-Hispanic white (74%). Adjustment for differences in demographic factors known to predict Pap smear acquisition (age, marital status, education level, and household income) only partially accounted for the observed difference in Pap smear rates. However, adjustment for these variables as well as those related to health care access (single site for primary care, health insurance status, and physician gender) eliminated the ethnic difference in Pap smear rates. CONCLUSIONS: The lower crude Pap smear rate for Haitian immigrants relative to other women of color was in part due to differences in (1) utilization of a single source for primary care, (2) health insurance, and (3) care provided by female physicians. Public health programs, such as the cancer prevention programs currently utilized in eastern Massachusetts, may influence these factors. Thus, the relatively high Pap rate among women in this study may reflect the success of these programs. Public health and elected officials will need to consider closely how implementing or withdrawing these programs may impact immigrant and minority communities.     

Racial and Ethnic Approaches to Community Health (REACH) Detroit partnership: improving diabetes-related outcomes among African American and Latino adults

OBJECTIVES: We sought to determine the effects of a community-based, culturally tailored diabetes lifestyle intervention on risk factors for diabetes complications among African Americans and Latinos with type 2 diabetes. METHODS: One hundred fifty-one African American and Latino adults with diabetes were recruited from 3 health care systems in Detroit, Michigan, to participate in the Racial and Ethnic Approaches to Community Health (REACH) Detroit Partnership diabetes lifestyle intervention. The curriculum, delivered by trained community residents, was aimed at improving dietary, physical activity, and diabetes self-care behaviors. Baseline and postintervention levels of diabetes-specific quality-of-life, diet, physical activity, self-care knowledge and behaviors, and hemoglobin A1C were assessed. RESULTS: There were statistically significant improvements in postintervention dietary knowledge and behaviors and physical activity knowledge. A statistically significant improvement in A1C level was achieved among REACH Detroit program participants (P<.0001) compared with a group of patients with diabetes in the same health care system in which no significant changes were observed (P=.160). CONCLUSIONS: A culturally tailored diabetes lifestyle intervention delivered by trained community residents produced significant improvement in dietary and diabetes self-care related knowledge and behaviors as well as important metabolic improvements.     

Exposure to PCBs and p,p'-DDE and human sperm chromatin integrity

Persistent organochlorine pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (p,p'-DDE), the major metabolite of dichlorodiphenyltrichloroethane (DDT), are stable lipophilic compounds widely found in the environment and in the general population. They can enter the food chain, and their negative impact on male reproduction is currently under active scrutiny. To explore the hypothesis that environmental exposure to these compounds is associated with altered sperm chromatin structure integrity in human sperm, we conducted a study of 176 Swedish fishermen (with low and high consumption of fatty fish, a very important exposure source of POPs). We determined serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and p,p'-DDE, and we used the sperm chromatin structure assay (SCSA) to assess sperm DNA/chromatin integrity. When CB-153 serum levels (individual dose range, 39-1,460 ng/g lipid) were categorized into equally sized quintiles, we found an association with the DNA fragmentation index (%DFI). A significantly lower %DFI was found in the lowest CB-153 quintile (< 113 ng/g lipid) compared with the other quintiles; there was a similar tendency, although not statistically significant, between %DFI and p,p'-DDE. These results suggest that POP exposure may have a slight negative impact on human sperm chromatin integrity.     

Reintervention in abdominal surgery. Personal experience in emergency

The Authors, regarding their emergency surgical experience, examine the need of reintervention in abdominal surgery at a distance (operations carried out not less than 30 days after previous procedure), a controversial situation, usually dealt with empirical approach. Such a feature is not rare in the experience of a surgeon; nevertheless still few are the studies concerning the severity of the disease and related complications requiring surgery. Occasionally it is really difficult--quite impossible- in these often complex clinical conditions, to identify the aetiology and even to perform a pre-operative diagnosis. Sometimes other factors may inhibit an exhaustive evaluation (acute onset of the symptoms, time spent from the former procedure, choice of the patient to refer to another surgeon) thus conditioning an adequate review of the first surgical act. The Authors study the more frequently observed clinical features, post-surgical abdominal adhesive syndrome, cancer recurrence, incisional hernia. Former surgical diseases and the latter one may be the same, but not necessarily. Surgery is only a feature of the treatment (multimodal treatment) in case of neoplastic recurrence. Morbidity and mortality concerning the latter surgical procedure are higher than the mere sum of those related to both the former and last operation performed (pre-operative disease understaging). Finally it must be stressed the need for early and accurate diagnosis to clearly steer the choice and course of surgical action.