RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis.

Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy.

A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy.

Killing cancer cells through the induction of apoptosis is one of the main mechanisms of chemotherapy. However, numerous cancer cells have primary or acquired apoptosis resistance, resulting in chemoresistance. In this study, using a novel chalcone derivative chalcone-24 (Chal-24), we identified a novel anticancer mechanism through autophagy-mediated necroptosis (RIP1- and RIP3-dependent necrosis). Chal-24 potently killed different cancer cells with induction of necrotic cellular morphology while causing no detectable caspase activation. Blocking the necroptosis pathway with either necrostatin-1 or by knockdown of RIP1 and RIP3 effectively blocked the cytotoxicity of Chal-24, suggesting that Chal-24-induced cell death is associated with necroptosis. Chal-24 robustly activated JNK and ERK and blockage of which effectively suppressed Chal-24-induced cytotoxicity. In addition, Chal-24 strongly induced autophagy that is dependent on JNK-mediated phosphorylation of Bcl-2 and Bcl-xL and dissociation of Bcl-2 or Bcl-xL from Beclin-1. Importantly, suppression of autophagy, with either pharmacological inhibitors or small interfering RNAs targeting the essential autophagy components ATG7 and Beclin-1, effectively attenuated Chal-24-induced cell death. Furthermore, we found that autophagy activation resulted in c-IAP1 and c-IAP2 degradation and formation of the Ripoptosome that contributes to necroptosis. These results thus establish a novel mechanism for killing cancer cells that involves autophagy-mediated necroptosis, which may be employed for overcoming chemoresistance.

Biological microdosimetry based on radiation cytotoxicity data.

Researchers in the field of radiation microdosimetry have attempted to explain the relative biological effectiveness (RBE) of different ionising photon radiation sources on the basis of the singly stochastic, microdose metric lineal energy y, which only addresses physical stochasticity related to energy (ε) deposition via single events in the critical targets (cell nuclei assumed here). Biological stochasticity related to variable nuclei geometries and cell orientations (relative to the incoming radiation) is usually not addressed. Here a doubly stochastic microdose metric, the single-event hit size q (=ε/T), is introduced which allows the track length T to be stochastic. The new metric is used in a plausible model of metabolic-activity-based in vitro cytotoxicity of low-dose ionising photon radiation. The cytotoxicity model has parameters E{q} (average single-event hit size with q assumed to be exponentially distributed) and E{α}, which is the average value of the cellular response parameter α. E{α} is referred to as the biological signature and it is independent of q. Only E{q} is needed for determination of RBE. The model is used to obtain biological-microdosimetry-based q spectra for 320-kV X-rays and (137)Cs gamma rays and the related RBE for cytotoxicity. The spectra are similar to published lineal energy y spectra for 200-kV X-rays and (60)Co gamma rays for 1-µm biological targets.

[Psychosocial factors associated with hospital readmission of patients with organic psychoses]. / Factores psicosociales relacionados con la rehospitalización de pacientes con psicosis orgánica.

OBJECTIVE: To assess the relationship between psychosocial factors, frequent relapses and hospital readmissions in patients with organic psychoses. MATERIAL AND METHODS: A cross-sectional descriptive study was conducted among 33 patients diagnosed with organic psychosis, seen at Hospital Psiquiatrico Guillermo Dávila, of Instituto Mexicano del Seguro Social in Mexico City. Patients had been readmitted more than two occasions during 1993-1994. Data collection instruments consisted of recorded interviews, five-minute dialogues of expressed emotions (EE), and combined questionnaires to assess perception of illness and the physician-patient relationship. The Kappa statistic and Cronbach's alpha were used to establish the validity and reliability of the measurements; descriptive and inferential methods were used for statistical data analysis. RESULTS: A high percentage (60.9%) of patient's relatives showed high level of EE, as measured by their expression of criticism, hostility, or emotional over-involvement; 64.3% of study subjects lived for more than 35 hours per week with relatives having high EE levels. CONCLUSIONS: High EE levels were associated with frequent readmissions to the psychiatric ward. Greater perception of illness characteristics was observed among relatives than in patients. Even though a satisfactory physician-patient relationship was found, it was not conducive to improving the perception of illness nor compliance with therapy.

Response to 45 degrees head-down tilt as measured by organ weight/body weight ratios and spiral computed tomography.

BACKGROUND: Exposure to microgravity or simulated microgravity causes significant shifts in body fluids which may initiate physiological adaptations to the microgravity stressor. It is imperative to understand the physiological adaptations to microgravity in order to develop appropriate countermeasures to the deleterious aspects (i.e., muscle and bone wasting) of long-term spaceflights. HYPOTHESIS: The significant shifts in body fluids by 45 degrees head-down tilt can be measured by changes in organ weight/body weight (OW/BW) ratios and non-invasively by spiral computed tomography. METHODS: In a previous study (14), rats were weighed and exposed to either 45 degrees head-down tilt (45HDT) or a prone control position for one of the following experimental times: 0.5 h, 1 h, 2 h, 4 h, 8 h, or 24 h. A radioactive tracer was injected intramuscularly immediately prior to the start of the experimental time periods. At the end of the experiment, the major organs were harvested, weighed, and measured for gamma radiation levels. We used the organ weights from this previous study to calculate OW/BW ratios for the present study. Additionally, in the present study, rats in the 14-d experimental groups were weighed, lightly anesthetized to facilitate placement in the 45HDT position, and placed in a specially designed 45HDT cage (45HDT group) or left unrestrained in the cages (control group). At the end of the 14-d experimental time period, the rats were anesthetized and their lung densities measured with spiral computed tomography. RESULTS: The OW/BW ratios for the liver, kidneys, and spleen of 24 h 45HDT rats were significantly lower (p<0.05) than control values while at 1 h the 45HDT rats had a higher kidney OW/BW ratio. Lung density from the 14-d 45HDT rats was 24.4% greater than control rats' values. CONCLUSIONS: The physiological change due to the 45HDT position to simulate microgravity begins as early as 1 h, and the kidney appears to be the first organ affected. Spiral computed tomography may offer a viable method of non-invasively measuring organ densities in the 45HDT model. The OW/BW data generated in the present study does not correlate with the changes in radioactive tracer distribution data from our previous study.

Changes in radioactive tracer distribution in rats after 24 hours of 45 degrees hind limb unweighting.

INTRODUCTION: Changes in radioactive tracer distribution were examined in rats after exposure to a simulated microgravity model of 45 degrees head down tilt (45HDT) or 45 degrees hind limb unweighting (45HU) for up to 24 h. METHODS: Rats were randomly assigned to either 45HDT (or 45HU) experimental groups or control groups for each time point of 0.5 h, 1 h, 2 h, 4 h, 8 h, or 24 h. The 0.5-h through 8-h experimental rats were anesthetized and placed head-down on a ramp at 45 degrees, while control rats were placed in a prone position. Non-anesthetized rats in the 24-h experimental group were tail-suspended at 45 degrees, while control rats were allowed unrestrained movement. Technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, physical half-life of 6.02 h, MW = 492 amu) and indium-labeled diethylenetriamine pentaacetate (111In DTPA, physical half-life of 3.5 d, MW = 545 amu) were used to measure body organ distributions of the radioactive tracers at the 0.5-h-8-h and 24-h time points, respectively. Major organs were harvested after each time period and measured for radioactive counts. Light and electron micrographs were examined. RESULTS: Mean 111InDTPA counts for the lungs, kidneys, and brains of the 24 h 45HU groups were significantly higher than control counts. Light and electron microscopy demonstrated the development of pulmonary edema in the alveolar septal areas after 2 h of 45HDT, and a shift in edema to the pulmonary airways and pulmonary arteries after 24 h of 45HU. CONCLUSIONS: Pulmonary edema development, accompanied by a significant increase in 111InDTPA lung, kidney, and brain counts in the 24-h 45HU groups, suggests vascular injury in the microcirculation of these organs.

The swing-lock removable partial denture.

The swing-lock removable partial denture is a good treatment alternative for maxillofacial prosthodontics, periodontally compromised dentitions and where some conventional designs for removable partial dentures cannot be applied. This paper presents clinical applications of the SLRPD. Indications, contraindications, advantages and disadvantages are discussed.

Margin configuration, die spacers, fitting of retainers/crowns, and soldering.

This article focuses on different margin configurations and the criteria they must meet to be considered clinically successful. In addition, the use of die spacers to lessen the cement film thickness to achieve a better marginal adaptation of cast restorations is presented. Also, the article presents a step by step method for fitting crowns or retainers in the laboratory and in a clinical setting to make this important procedure less time consuming, more precise, and easy to finalize. Finally, soldering in dentistry and the criteria required for its successful execution are discussed.