Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Preoperative low-dose weekly cisplatin and continuous infusion fluorouracil plus hyperfractionated radiotherapy in stage II-III esophageal carcinoma

BACKGROUND: The optimal regimen of preoperative chemoradiotherapy for resectable esophageal cancer has not been established. We evaluated accelerated hyperfractionated radiotherapy (RT) concurrent to low-dose weekly cisplatin and continuous infusion fluorouracil (LDCI-FU) followed by esophagectomy in patients with locally advanced squamous cell carcinoma (SCC) of the esophagus. METHODS: Patients with clinical stage II or III SCC of the esophagus received cisplatin 30 mg/m2/week (days 1, 8, 15), LDCI-FU 300 mg/m2/day (days 1-21), and concomitant RT to a dose of 45 Gy (150 cGy/fraction, 2 fractions/day) on tumor and affected lymph nodes, followed by radical esophagectomy. RESULTS: From 1997 to 2012, 64 patients were treated with this regimen. Twenty-four patients (37 %) had grade 3 esophagitis, 18 (28 %) of whom required hospitalization. The risk of hospitalization was reduced by placement of a jejunostomy tube before starting induction chemoradiotherapy. Six patients (9 %) had grade 3-4 neutropenia. Fifty-three patients (83 %) underwent esophageal resection and complete resection was achieved in 45 (70 %). The overall median survival was 28 months (95 % CI: 20.4-35.6) and 5-year survival was 38 %. In the 18 patients attaining a pathological complete response, median survival was 132 months and 5-year survival was 72 %. Positron emission tomography standardized uptake values (PET SUVmax) post-chemoradiotherapy were associated with pathological response (p = 0.03) and survival (p = 0.04). CONCLUSIONS: Intensive preoperative hyperfractionated RT concomitant to low-dose cisplatin and LDCI-FU is effective in patients with locally advanced SCC of the esophagus, with good pathological response and survival and manageable toxicities. Post-chemoradiotherapy PET SUV max shows promise as a potential prognostic factor

No disponible

Preoperative low-dose weekly cisplatin and continuous infusion fluorouracil plus hyperfractionated radiotherapy in stage II-III esophageal carcinoma.

BACKGROUND: The optimal regimen of preoperative chemoradiotherapy for resectable esophageal cancer has not been established. We evaluated accelerated hyperfractionated radiotherapy (RT) concurrent to low-dose weekly cisplatin and continuous infusion fluorouracil (LDCI-FU) followed by esophagectomy in patients with locally advanced squamous cell carcinoma (SCC) of the esophagus. METHODS: Patients with clinical stage II or III SCC of the esophagus received cisplatin 30 mg/m2/week (days 1, 8, 15), LDCI-FU 300 mg/m2/day (days 1-21), and concomitant RT to a dose of 45 Gy (150 cGy/fraction, 2 fractions/day) on tumor and affected lymph nodes, followed by radical esophagectomy. RESULTS: From 1997 to 2012, 64 patients were treated with this regimen. Twenty-four patients (37 %) had grade 3 esophagitis, 18 (28 %) of whom required hospitalization. The risk of hospitalization was reduced by placement of a jejunostomy tube before starting induction chemoradiotherapy. Six patients (9 %) had grade 3-4 neutropenia. Fifty-three patients (83 %) underwent esophageal resection and complete resection was achieved in 45 (70 %). The overall median survival was 28 months (95 % CI: 20.4-35.6) and 5-year survival was 38 %. In the 18 patients attaining a pathological complete response, median survival was 132 months and 5-year survival was 72 %. Positron emission tomography standardized uptake values (PET SUVmax) post-chemoradiotherapy were associated with pathological response (p = 0.03) and survival (p = 0.04). CONCLUSIONS: Intensive preoperative hyperfractionated RT concomitant to low-dose cisplatin and LDCI-FU is effective in patients with locally advanced SCC of the esophagus, with good pathological response and survival and manageable toxicities. Post-chemoradiotherapy PET SUVmax shows promise as a potential prognostic factor.

Changing trends in polypoid colorectal cancer diagnosed by colonoscopy.

AIM: This study analysed trends in polypoid colorectal cancer (PCRC) diagnosed by colonoscopy during the period 1995-2008 and compared the patterns observed in the years 2005-2008 with 1995-1998. METHOD: In the period 1995-2008, 24,245 colonoscopies were performed and 1041 patients with PCRC were diagnosed: pediculated (n = 220) or sessile (n = 821). RESULTS: The mean age at diagnosis was 68.3 ± 11.6 years. Males were more likely to have PCRC (males 62.6%vs females 37.4%; P < 0.0001). Significantly more pediculated PCRCs were located in the distal colon (P < 0.001). In the 2005-2008 period the prevalence of PCRC among patients undergoing colonoscopy decreased, the number of polypectomies increased significantly (P < 0.0001) and the pediculated PCRC location changed, with a significant increase in right-sided lesions. CONCLUSION: The prevalence of PCRC in patients undergoing colonoscopy decreased, with a significant increase in the number of polypectomies in the last decade. Pediculated PCRCs were more often located in the left colon and sessile PCRCs in the right colon. From the period 1995-1998 to 2005-2008 the location of pediculated PCRCs changed, with an increase in right-sided lesions.

Developmental exposure to polychlorinated biphenyls 52, 138 or 180 affects differentially learning or motor coordination in adult rats. Mechanisms involved.

Exposure to polychlorinated biphenyls (PCBs) during pregnancy and lactation leads to cognitive impairment and motor disorders in children by mechanisms which remain unknown. It also remains unclear whether different non-dioxin-like PCBs have similar or different mechanisms of neurotoxicity. The main aims of this work were: (1) to assess whether developmental exposure to non-dioxin-like-PCBs 52, 138 or 180 affect cognitive function or motor coordination in 3-4 months-old rats; (2) to shed light on the underlying mechanisms. Female rats were treated with PCBs (1 mg/kg day) in food from gestational-day 7 to postnatal-day 21. The ability to learn a Y maze conditional discrimination task was reduced in rats exposed to PCBs 138 or 180, but not in rats exposed to PCB52. The function of the glutamate-nitric oxide-cGMP pathway (NMDA-induced increase in extracellular cGMP) in cerebellum in vivo was reduced by 33-59% in rats exposed to PCBs 138 or 180, but not by PCB52. The amount of NR1 subunit of NMDA receptors was reduced by 41-49% in rats exposed to PCBs 138 or 180, but not by PCB 52. PCB52 but not 138 or 180 increases extracellular GABA in cerebellum and impairs motor coordination. The effects were similar in males and females. Developmental exposure to different non-dioxin-like PCBs induces different behavioural alterations by different mechanisms. PCB52 impairs motor coordination but not learning while PCB138 or 180 impair learning but not motor coordination. These data are consistent with the following possible mechanisms: (1) developmental exposure to PCBs 138 or 180 reduces the amount of NMDA receptors in cerebellum, which would contribute to reduced function of the glutamate-NO-cGMP pathway, which, in turn, would be a main contributor to the impairment of the ability to learn the Y maze task. (2) Developmental exposure to PCB52 increases extracellular GABA in cerebellum, which would contribute to motor coordination impairment.

Endoscopist experience as a risk factor for colonoscopic complications.

AIM: We aimed to determine the incidence of colonic perforation (CP) following colonoscopy and postpolypectomy bleeding (PPB) in a teaching hospital, assessing the influence of endoscopist experience as a risk factor. METHOD: All colonoscopies performed between 1995 and 2008 were reviewed. Demographic data, endoscopic procedure information, incidence of CP and PPB, and endoscopist experience were recorded. RESULTS: In the 14-year period, 25,214 endoscopic colonic procedures were performed, and 3991 patients underwent polypectomy. The overall CP risk was 0.51/1000 procedures; and PPB 14.7/1000. The relative risk (RR) ratio of complications was 2.8/1000 procedures. The RR rate was highest for endoscopists performing less than 591 procedures per year (4.0/1000 [95% CI, 3.7-4.3] vs 2.9/1000 [95% CI, 2.6-3.2]), P < 0.001). CONCLUSION: The complication rate after colonoscopy was comparable to that previously reported. Colonoscopy carried out by a low-volume endoscopist was independently associated with bleeding and perforation.

Weekly docetaxel with concomitant radiotherapy in patients with inoperable oesophageal cancer.

INTRODUCTION: To evaluate the efficacy and tolerability of weekly docetaxel concurrent with radiotherapy in inoperable oesophageal cancer patients. MATERIAL AND METHODS: Thirty-four oesophageal cancer patients with co-morbid medical conditions, locally advanced tumours (T4) or advanced age (older than 75 years) received docetaxel (20 mg/m2 weekly) plus concurrent radiotherapy (2 Gy daily, to a total dose of 66 Gy). Twenty-two patients (64%) were stage III, 19 of whom had T4 tumours. RESULTS: Twenty-seven patients (79%) completed the planned chemoradiotherapy treatment. Nine patients (26%) achieved a complete response and 8 (24%) achieved a partial response, for an overall response rate of 50%. Median survival was 6 months, and 1-year survival was 35%. Patients with T4 tumours had significantly shorter survival than other patients: 5 months for T4 tumours vs. 11 months for T1-3 (p=0.04). Grade 3-4 oesophagitis occurred in 6 patients (17%). There were two treatment-related deaths due to radiation pneumonitis. CONCLUSIONS: Docetaxel plus concurrent radiotherapy is active in poor-prognosis oesophageal cancer patients, with a lower incidence of severe oesophagitis than with cisplatin-based chemoradiotherapy regimens. This schedule can be considered, especially in patients with non-T4 tumours who are not candidates for oesophageal resection.

Weekly docetaxel with concomitant radiotherapy in patients with inoperable oesophageal cancer

INTRODUCTION: To evaluate the efficacy and tolerability of weekly docetaxel concurrent with radiotherapy in inoperable oesophageal cancer patients. MATERIAL AND METHODS: Thirty-four oesophageal cancer patients with co-morbid medical conditions, locally advanced tumours (T4) or advanced age (older than 75 years) received docetaxel (20 mg/m2 weekly) plus concurrent radiotherapy (2 Gy daily, to a total dose of 66 Gy). Twenty-two patients (64%) were stage III, 19 of whom had T4 tumours. RESULTS: Twenty-seven patients (79%) completed the planned chemoradiotherapy treatment. Nine patients (26%) achieved a complete response and 8 (24%) achieved a partial response, for an overall response rate of 50%. Median survival was 6 months, and 1-year survival was 35%. Patients with T4 tumours had significantly shorter survival than other patients: 5 months for T4 tumours vs. 11 months for T1-3 (p=0.04). Grade 3-4 oesophagitis occurred in 6 patients (17%). There were two treatment-related deaths due to radiation pneumonitis. CONCLUSIONS: Docetaxel plus concurrent radiotherapy is active in poor-prognosis oesophageal cancer patients, with a lower incidence of severe oesophagitis than with cisplatin-based chemoradiotherapy regimens. This schedule can be considered, especially in patients with non-T4 tumours who are not candidates for oesophageal resection (AU)

7-Bromoindirubin-3'-oxime induces caspase-independent cell death.

Indirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.

[Azathioprine and mesalazine in the prevention of postsurgical recurrence of Crohn's disease: a retrospective study]. / Azatioprina y mesalazina en la prevención de la recurrencia posquirúrgica en la enfermedad de Crohn: estudio retrospectivo.

OBJECTIVES: Surgical resection is still a mainstay of the treatment of Crohn's disease (CD). However, recurrence is the rule. The aim of the present study was to evaluate CD recurrence in a series of patients who underwent surgical resection with subsequent treatment with azathioprine (AZA) or mesalazine (5-ASA) and to identify the factors associated with recurrence. METHODS: The medical records of patients with CD who underwent bowel resection during a 4-year period were reviewed. Only patients who received AZA or 5-ASA as prophylaxis for recurrence were included. RESULTS: Thirty-three patients treated with AZA and 16 treated with 5-ASA were included. Endoscopic recurrence was found in 8.6% of the AZA group and in 87.5% of the 5-ASA group (p <0.001). Clinical recurrence occurred in 31.2% of patients in the 5-ASA group and in none in the AZA group (p=0.004). The accumulated probability of both clinical and endoscopic recurrence was significantly lower in the AZA group (p=0.0025 and p=0.005, respectively). Factors associated with a greater risk of endoscopic recurrence were termino-terminal anastomosis and 5-ASA treatment. The only factor associated with clinical recurrence was 5-ASA treatment. CONCLUSION: AZA seems to be more effective than 5-ASA in the prevention of postsurgical endoscopic recurrence of CD. Prospective studies with long-term follow-up are required to establish the true utility of AZA in the prophylaxis of CD recurrence.

Azathioprine without oral ciclosporin in the long-term maintenance of remission induced by intravenous ciclosporin in severe, steroid-refractory ulcerative colitis.

BACKGROUND: Intravenous ciclosporin is considered to be the only alternative to avoid surgery in severe, steroid-refractory ulcerative colitis. In responders, some authors recommend a switch to oral ciclosporin to act as a 'bridge' until the therapeutic action of azathioprine is achieved for maintenance treatment. AIM: To report the short- and long-term outcome of intravenous ciclosporin-responsive ulcerative colitis patients treated with oral azathioprine without oral ciclosporin. METHODS: The records of all patients treated with intravenous ciclosporin for severe, steroid-refractory ulcerative colitis were reviewed. Responders following treatment with azathioprine but without oral ciclosporin as maintenance therapy were included. Patients with colonic cytomegalovirus infection and/or follow-up of less than 1 year were excluded. RESULTS: Twenty-seven patients were included. Steroids were discontinued in 24 (89%). The median follow-up was 36 months. Eighteen (75%) patients presented mild or moderate relapses, which were easily managed with salicylates or steroids. Cumulative probabilities of relapse were 42%, 72% and 77% at 1, 3 and 5 years, respectively. Eleven (40.7%) patients underwent elective colectomy. Cumulative probabilities of colectomy were 29%, 35% and 42% at 1, 3 and 5 years, respectively. No opportunistic infections were observed. CONCLUSIONS: Oral azathioprine seems to be enough to maintain long-term remission induced by intravenous ciclosporin in patients with steroid-refractory ulcerative colitis. The 'bridging step' with oral ciclosporin may not be necessary in this subset of patients, although a randomized controlled trial is warranted to confirm this hypothesis.

The absence of oligonucleosomal DNA fragmentation during apoptosis of IMR-5 neuroblastoma cells: disappearance of the caspase-activated DNase.

Caspase-activated DNase is responsible for the oligonucleosomal DNA degradation during apoptosis. DNA degradation is thought to be important for multicellular organisms to prevent oncogenic transformation or as a mechanism of viral defense. It has been reported that certain cells, including some neuroblastoma cell lines such as IMR-5, enter apoptosis without digesting DNA in such a way. We have analyzed the causes for the absence of DNA laddering in staurosporine-treated IMR-5 cells, and we have found that most of the molecular mechanisms controlling apoptosis are well preserved in this cell line. These include degradation of substrates for caspases, blockade of cell death by antiapoptotic genes such as Bcl-2 or Bcl-X(L), or normal levels and adequate activation of caspase-3. Moreover, these cells display normal levels of caspase-activated DNase and its inhibitory protein, inhibitor of caspase-activated DNase, and their cDNA sequences are identical to those reported previously. Nevertheless, IMR-5 cells lose caspase-activated DNase during apoptosis and recover their ability to degrade DNA when human recombinant caspase-activated DNase is overexpressed. Our results lead to the conclusion that caspase-activated DNase is processed during apoptosis of IMR-5 cells, making these cells a good model to study the relevance of this endonuclease in physiological or pathological conditions.

An abstinence-oriented program for substance use disorders: poorer outcome associated with opiate dependence.

OBJECTIVES: To evaluate the characteristics of patients with various substance-related disorders, and to examine rates of retention in treatment. METHODS: We assessed the demographic characteristics, substance abuse, and psychological distress of 239 men and women at admission. Six-month performance was evaluated, using as criteria length of stay in treatment, abstinence, attendance in therapy sessions, and completion status at discharge. RESULTS: Moderate to severe psychological distress was observed among these individuals. Higher levels of depression were found among women and in individuals with alcohol and sedative use disorders. The primary drug of abuse, frequency of use, and reason for entering treatment were the most significant predictors of retention. CONCLUSIONS: Opiate-addicted clients had the worst prognosis and treatment profiles. Further research is needed to identify factors that would optimize treatment for opiate dependence.

[Effect of prophylactic treatment with intravesical epirubicin in recurrence of superficial bladder tumor]. / Efectos del tratamiento profiláctico con epirrubicina intravesical en la recidiva del tumor vesical superficial.

OBJECTIVES: To determine the efficacy in the prevention of tumor recurrence, disease free interval and side effects of intravesical epirrubicin post-TUR of superficial bladder tumor. METHODS: From February 1993 to November 1997, 57 patients with stage Ta, T1, grade I, II and III tumor of the bladder were studied. These patients were treated with 50 mg epirrubicin in 50 ml saline solution administered intravesically on 15 occasions for one year after surgery. The mean follow-up was 18 months. The follow-up protocol included clinical, analytical, cytological, US and cystoscopic control evaluations every 3 months for the first year, every 6 months for the second and third year, and yearly thereafter. RESULTS: At a mean follow-up of 30.2 months, 31.5% (18/55) of the patients showed tumor recurrence; the disease free interval was 17 months for the remaining 18 patients and 43 months for the overall group. Cystitis was observed as an adverse effect in 5 of 57 patients (8.8%). CONCLUSIONS: The study shows that prophylactic treatment with intravesical epirrubicin for the prevention of recurrence in superficial bladder tumor has few side effects and its efficacy is similar to that reported in other studies.

Oxidative damage to mitochondrial DNA and glutathione oxidation in apoptosis: studies in vivo and in vitro.

Free radicals may be involved in apoptosis although this is the subject of some controversy. Furthermore, the source of free radicals in apoptotic cells is not certain. The aim of this study was to elucidate the role of oxidative stress in the induction of apoptosis in serum-deprived fibroblast cultures and in weaned lactating mammary glands as in vitro and in vivo experimental models, respectively. Oxidative damage to mtDNA is higher in apoptotic cells than in controls. Oxidized glutathione (GSSG) levels in mitochondria from lactating mammary gland are also higher in apoptosis. There is a direct relationship between mtDNA damage and the GSSG/reduced glutathione (GSH) ratio. Furthermore, whole cell GSH is decreased and GSSG is increased in both models of apoptosis. Glutathione oxidation precedes nuclear DNA fragmentation. These signs of oxidative stress are caused, at least in part, by an increase in peroxide production by mitochondria from apoptotic cells. We report a direct relationship between glutathione oxidation and mtDNA damage in apoptosis. Our results support the role of mitochondrial oxidative stress in the induction of apoptosis.