Loss of caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis.

Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.

A thematic review of scientific and family interests in Canavan Disease: where are the developmentalists?

BACKGROUND: Canavan Disease is a degenerative neurological condition resulting in a spongy deterioration of the brain. Much research has been conducted by the medical community regarding this condition, but little research can be found in the psychological literature. METHOD: A review of the scientific literature related to Canavan Disease using the Psychinfo and PubMed databases was conducted covering a 5-year span from 2006 through 2011. Concurrently, a review of parent initiated topics found on the most popular Canavan Disease Internet discussion board was conducted for comparison purposes. RESULTS: When comparing the topics discussed and information sought among parents with the themes noted in the extant scientific literature, researchers found an exceedingly small overlap between the two communities of interest. In the scientific literature, published research on Canavan Disease focused on three areas: the biochemistry of Canavan Disease, diagnosis and genetic counselling, and clinical therapeutic approaches in Canavan Disease. Of the 42 unique topics raised on a popular Internet discussion board, however, only three (7%) fell into the category of diagnosis and genetic counselling, none (0%) fell into the category of the biochemistry of Canavan Disease, and four fell into the category of clinical therapeutic approaches in Canavan Disease (10%). Of the four posts addressing clinical therapeutic approaches to Canavan Disease, only one post truly overlapped with the topics addressed by the scientific community. Worded differently, while these three categories comprise 100% of the extant scientific literature regarding Canavan Disease, they comprise only 17% of the parent-raised topics. The remaining 83% of parent-raised topics addressed concerns not currently being focusing upon by the scientific community, namely, non-medical practical issues, information regarding specific characteristics of Canavan Disease, non-medical developmental and quality of life issues, and day-to-day developmental and medical concerns. CONCLUSION: By comparing the extant literature on Canavan Disease with the topics of interest raised by parents and caregivers, it seems clear that there is a significant 'underlap' of topics raised by these two communities of interest, one that may reflect a lack of sensitivity on the part of the scientific community to meet the needs of this population of knowledge seekers. It is the suggestion of these authors that developmental psychology may be the appropriate scientific field within which to address this need and fill this gap in the current literature.

Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis.

Gastrointestinal toxicity is the primary limiting factor in abdominal and pelvic radiotherapy, but has no effective treatment currently. We recently showed a critical role of the BH3-only protein p53 upregulated modulator of apoptosis (PUMA) in acute radiation-induced GI damage and GI syndrome in mice. Growth factors such as insulin-like growth factor 1 (IGF-1) and basic fibroblast growth factor (bFGF) have been shown to protect against radiation-induced intestinal injury, although the underlying mechanisms remain to be identified. We report here the suppression of PUMA through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p53 axis in the intestinal stem cells as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. IGF-1 or bFGF impaired radiation-induced apoptosis and the expression of PUMA and p53 in the crypt cells and intestinal stem cells. Using colonic epithelial cells that undergo PUMA-dependent and radiation-induced apoptosis, we found that a PI3K inhibitor, dominant-negative PI3K or Mdm2 antagonist restored the induction of PUMA, p53 and apoptosis in the presence of growth factors. In contrast, overexpression of AKT suppressed the induction of PUMA and p53 by radiation. Furthermore, inhibiting PI3K or activating p53 abrogated growth factor-mediated suppression of apoptosis and PUMA expression in the intestinal crypts and stem cells after radiation.

The SceneScore for improved pre-hospital triage of motor-vehicle crash victims.

The SceneScore is a simple mechanism of injury scoring system designed to facilitate the appropriate triage of crash victims. It comprises 7 variables including age, collision type, impact location, airbag deployment, steering wheel deformity, intrusion, and restraint use. A cutoff value of 7 or 8 provides the maximum balance between sensitivity and specificity, with sensitivities of 75% to 83% and specificities of 29% to 46%. For cases triaged to the trauma center based only on high suspicion of injury, the SceneScore reduces the overtriage rate by almost half. Proper application of the SceneScore may lead to improved triage and enhanced communication of mechanism of injury criteria.

IGF-I differentially regulates IGF-binding protein expression in primary mammary fibroblasts and epithelial cells.

Elucidating how mitogens facilitate epithelial/stromal interactions is critical given that mitogens regulate mammary gland development and function. IGF-I is a potent mammary cell mitogen that is locally produced in the mammary gland. Since IGF-binding proteins (IGFBPs) regulate IGF-I bioavailability, we characterized the cell-type-specific production of IGFBP in primary bovine mammary epithelial (BME) and fibroblast (BMF) cells. Cells were treated with IGF-I and mRNA levels were analyzed via quantitative real-time (qRT)-PCR and Northern blot analysis. Media conditioned by cells treated with IGF-I for 48 h were analyzed via ligand blotting with 125I-labeled IGF-I and -II and immunoblotting with specific IGFBP antibodies. A reciprocal regulation of IGFBP-3 and -5 by IGF-I was observed between the two cell types. IGF-I induced large dose-dependent increases in IGFBP-3 mRNA and protein levels in BME cells, while IGFBP-5 protein was barely detectable and mRNA levels were detectable only by qRT-PCR. In BMFs, IGF-I induced large increases in IGFBP-5 mRNA and protein while IGFBP-3 mRNA was only slightly increased by IGF-I treatment and the protein was difficult to detect. IGFBP-6 mRNA was detected by Northern blot analysis in both cell types but was not regulated by IGF-I. In BME cells, IGFBP-6 protein levels were readily detectable under basal conditions and were increased by IGF-I. Interestingly, IGFBP-6 protein could not be detected in media conditioned by BMFs. IGFBP-4 mRNA was readily seen by Northern blot analysis in BMFs, however qRT-PCR was required to detect IGFBP-4 mRNA in BME cells. IGF-I increased IGFBP-4 mRNA levels by 2-fold in both cell types. IGFBP-4 protein was only detectable in media conditioned by BME cells when stimulated by IGF-I. In contrast, IGFBP-4 was present in media conditioned by untreated BMFs but was not consistently increased by IGF-I treatment. This was explained by the finding that IGF-I stimulated proteolysis of IGFBP-4, as evidenced by the appearance of two immuno-responsive fragments of 18 and 14 kDa. This proteolysis was specific to IGFBP-4, and was not observed in BME cells. We confirmed the protease to be pregnancy-associated plasma protein A (PAPP-A) by immunoblotting with an antibody against human PAPP-A/proMBP (pro form of eosinophil major basic protein) complex. In vitro immuno-neutralization experiments showed that blocking PAPP-A prevented the ability of IGF-I to stimulate IGFBP-4 proteolysis. IGFBP-2 mRNA and protein levels were observed under basal conditions in both cell types, with no significant regulation by IGF-I. The analysis of cell-type-specific regulation of the IGF system in both primary mammary epithelial cells and stromal cells will assist in the characterization of the mechanisms behind the role of the IGF system in normal mammary physiology and ultimately breast cancer.

The distributional pattern of diverticular disease.

In Western communities diverticular disease occurs mainly in the sigmoid colon. This contrasts with Oriental populations, in which diverticula occur mainly in the right colon. Diverticular disease has recently emerged in black South Africans. This study shows that diverticula in this population occurs predominantly in the descending colon. The variable anatomic distribution of diverticula in different ethnic groups implies that fiber deficiency is not the only factor responsible for this condition. It is suggested that diverticular disease may comprise several entities with different causes.

Blood gas pH and pulmonary response to the inhalation of low osmolar contrast media iopamidol and ioxaglate.

Effects of inhalation of diluted low-osmolar ionic ioxaglate and nonionic iopamidol 200 water-soluble radiographic contrast media on neonatal pig lung were evaluated. Our purpose was to assess the suitability of these substances for the radiologic investigation of upper gastrointestinal problems in human neonates in whom aspiration may occur. We used two-week-old baby piglets weighing 2.5-3.5 kg as the experimental model because they are similar in weight and size to a human neonate. The effects of intratracheal instillation of isosmolar contrast media were evaluated using the parameters of (1) blood gas exchange, (2) clinical status, (3) radiology, and (4) histopathology. The piglets showed no clinical or radiologic abnormality; blood gas exchange, initially impaired, rapidly returned to normal. Long-term (four days) follow up showed mild, self limiting but persistent infiltrates in the lungs at histology. We conclude that these diluted contrast media are suitable for upper gastrointestinal examination in neonates.

Preventing nursing burnout: a challenge for liaison psychiatry.

The authors conducted a study to assess and compare the level of job satisfaction among five groups of registered nurses working at UCLA Hospital. Fifty-seven female nurses completed the MMPI, Locus of Control Test, Work Environment Scale, and a questionnaire designed to assess job satisfaction. Results showed that there were no significant personality differences among the five groups of nurses. Significant differences between some of the groups were found in demographic variables and in work-related variables such as involvement, task orientation, work pressure, sense of authority on the job, and perceived communication with peers or other groups in the work environment. Nurses on the Medicine unit tended to have lower overall job satisfaction than those in the other units. The involvement of the Psychiatric Liaison Service on the five nursing units is described and discussed as a possible method for providing psychosocial support to the nurses and reducing high turnover rates.