Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study.

In this multicenter study, we investigated the kinetics of neutrophil recovery in relation to acuity and survival among 125 children undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who required invasive mechanical ventilation (IMV). Recovery of neutrophils, whether prior to or after initiation of IMV, was associated with a significantly decreased risk of death relative to never achieving neutrophil recovery. A transient increase in acuity (by oxygenation index and vasopressor requirements) occurred among a subset of the patients who achieved neutrophil recovery after initiation of IMV; 61.5% of these patients survived to discharge from the intensive care unit (ICU). Improved survival among patients who subsequently achieved neutrophil recovery on IMV was not limited to those with peri-engraftment respiratory distress syndrome. The presence of a respiratory pathogen did not affect the risk of death while on IMV but was associated with an increased length of IMV (p < 0.01). Among patients undergoing HCT who develop respiratory failure and require advanced therapeutic support, neutrophil recovery at time of IMV and/or presence of a respiratory pathogen should not be used as determining factors when counseling families about survival.

Correction to: Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Formation of occlusive platelet aggregates in whole blood caused by low concentrations of ADP.

Minute concentrations of ADP are released when platelets are exposed to shear stress during extracorporeal flow. However, based on current methods, these low concentrations have not been shown to have a significant impact on platelet function. We report here the formation of rigid microaggregates (MA) in response to low concentrations of ADP. A newly developed light scattering whole blood aggregometer (LSWBA) was used to detect an aggregation dose response to ADP (0-2 microM) in heparinized (1.5 U/ml) human blood. Although the LSWBA showed that ADP induced MA were reversible, evidence provided by constant pressure filtration (50 mm Hg) suggested that aggregates existed as rigid particles in the blood for up to 6 minutes. The possible implications of these findings to extracorporeal circulation are discussed.

In vitro model for studying the effects of hemodynamics on device induced thromboembolism in human blood.

Biomateria related thromboembolism is a complex phenomenon, affected by such variables as biomaterial surface chemistry, hemodynamics, and individual donor variations. Thus, isolation of the individual variables would greatly facilitate the understanding and inhibition of this phenomenon. A low volume in vitro model with this potential has been developed, with the initial focus on studying the influence of hemodynamics on thromboembolism (TE) in human blood. Patterned after a larger in vitro model for bovine blood used successfully in our laboratory, the smaller model directed fresh human blood in a single pass through 1/32 inch ID PVC tubing and a flow cell at 3 ml/min. The flow cell consisted of alternating abrupt expansions and contractions of cylindrical tubing that could be modified to study the effects of hemodynamic parameters on TE. Thrombus growth in the flow cell was monitored visually by transillumination microscopy. Emboli from the flow cell were detected continuously by a light-scattering microemboli detector (LSMD), and their strength was assessed by using the constant-pressure filtration (CPF) method. Preliminary studies confirmed the potential of this model. Thrombi were observed visually in the flow cell at sites of high vorticity and at flow separation and reattachment points and were also observed to embolize. Emboli were detected by the LSMD downstream of the flow cell in significantly greater numbers than upstream and were coincident with the embolization of thrombi observed visually. Emboli collected downstream of the flow cell occluded the CPF filters at 50 mm Hg, suggesting that they possessed sufficient strength to occlude microvessels. This model may be used to aid in developing a computer model of thromboembolism, which could subsequently be refined with clinical data.

Transcutaneous oxygen monitoring: economic impact on neonatal care.

Five years (1978 to 1982) of respiratory care data were reviewed to determine the changes in patient charges, hospital costs, and frequency of neonatal blood gas analysis created by the introduction of transcutaneous oxygen monitoring. During the 4 years of transcutaneous oxygen monitoring (1979 to 1982), an estimated $196,000 reduction in patient charges was accomplished. When reduced patient charges were balanced with the increased cost to the hospital for equipment, supplies, and personnel time, a net reduction of more than $100,000 for health care delivery was achieved. Transcutaneous oxygen monitoring is an example of technologic achievement in which society receives both economic and medical benefits.

Effect of selected dietary buffers upon utilization of concentrate- or roughage-based cattle diets: laboratory studies.

Four chemical buffers were evaluated with in vitro rumen fermentation studies using both an 80% concentrate and a 50% roughage diet. Treatments included a positive control (PC), negative control (NC) and four buffered diets in which 500 mg of either CaHPO4, CaCO3, NaHCO3 or Na4P2O7 were added. The PC consisted of unbuffered diet with one part rumen fluid and four parts McDougall's artificial saliva. In the unbuffered NC and buffered treatments, three-fourths of the artificial saliva was replaced by iso-osmotic saline. In the concentrate-based diet, NaHCO3 and Na4P2O7 elevated (P less than .05) pH above the NC. Starch digestion and total VFA were increased (P less than .05) by NaHCO3 compared with the NC while the molar proportion of individual VFA was not altered. Tetrasodium pyrophosphate had no effect on starch digestion or total VFA, but did increase (P less than .05) the molar proportion of acetic acid. Regarding the 50% roughage diet, both NaHCO3 and Na4P2O7 elevated (P less than .05) starch and cellulose digestion and total VFA compared with the NC. Both NaHCO3 and Na4P2O7 increased (P less than .05) the molar proportion of acetate to equal that of the PC. Tetrasodium pyrophosphate decreased (P less than .05) apparent starch digestion compared with the NC, but increased (P less than .05) the molar proportion of acetate. Compared with the NC, CaHPO4 and Na4P2O7 increased the quantity of microbial alpha-amino N in both diets. Soluble P was highly correlated with microbial protein synthesis in both the concentrate- and roughage-based diets (.92 and .90, respectively).

Infant ventilator design: performance during expiratory limb occlusion.

We examined the specifications and design of the inspiratory pressure regulating valve of 8 continuous flow, pressure-limited infant ventilators. Two pressure regulating designs are currently available; one placing the primary pressure regulating valve on the inspiratory limb, the other placing it on the expiratory limb. Seven ventilators incorporate the latter design to limit inspiratory pressure and must have a safety pressure-relief valve located on the inspiratory limb to vent pressure in case of circuit occlusion. These pressure-relief valves are generally set by the manufacturer far in excess of pressures normally used for infant ventilation. Alarm systems are often absent or inadequate to warn of high pressure conditions during circuit obstruction. A case report detailing the fatal complication of prolonged excessive airway pressure during circuit occlusion is presented. Improvements in the pressure-relief valve designs currently available are possible, and may be necessary to provide adequate protection from barotrauma. The majority of infant ventilators currently available expose the patient to unnecessary excessive airway pressures in the case of expiratory limb occlusion, and the lack of alarm systems may leave the operator unaware of malfunction.