An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

Life in heaps: a review of microbial responses to variable acidity in sulfide mineral bioleaching heaps for metal extraction.

Industrial heap leaching of low grade mineral sulfide ores is catalysed by the use of acidophilic microorganisms. These microorganisms obtain energy for growth from the oxidation of reduced inorganic or organic compounds, including soluble ferrous ion, reduced inorganic sulfur compounds (RISC) and acid-stable organic compounds. By-products of these oxidative processes, such as soluble ferric ion and sulfuric acid create favourable chemical conditions for leaching. This review is focused on the behaviour of common bioleaching microorganisms, their responses to changing pH in an industrial setting, and how both changes and microbial responses can impact the micro and macro environment.

Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation?

The physiological processes of angiogenesis, vasculogenesis and arteriogenesis contribute to the growth of collateral vessels in response to obstructive arterial disease causing lower limb or myocardial ischaemia, but in clinical practice the endogenous angiogenic response is often suboptimal or impaired, e.g. by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis is an application of biotechnology to stimulate new vessel formation via local administration of pro-angiogenic growth factors in the form of recombinant protein or gene therapy, or by implantation of endothelial progenitor cells that will synthesize multiple angiogenic cytokines. Numerous experimental and clinical studies have sought to establish 'proof of concept' for therapeutic angiogenesis in PAD and myocardial ischaemia using different treatment modalities, but the results have been inconsistent. This review summarises the mechanisms of angiogenesis and the results of recent trials evaluating the efficacy and safety of different gene therapy, recombinant protein and cellular-based treatment approaches to enhance collateral vessel formation.

Gastrointestinal blood loss in triathletes: it's etiology and relationship to sports anaemia.

Twenty male triathletes (R 18-39 mean = 27.5 yrs) provided blood and faecal samples during intense training, pre-race taper and post-competition. All answered a closed-end questionnaire on intake of aspirin, NSAIDS, Vitamin C, iron and red meat. History of GIT blood loss and training distances were also obtained. Blood samples were taken on three occasions and analysed for Haemoglobin(Hb) and Serum Ferritin concentrations. Faecal specimens were collected on five occasions and assessed for blood loss using Haemoccult II and Monohaem (a monoclonal antibody test specific for human haemoglobin). Mean Hb and 95% confidence intervals at the three stages were 14.53gm/l (13.95-15.10), 14.9gm/l (14.46-15.34), 14.57gm/l (14.18-14.97) respectively. There was a small, but statistically significant, increase in Hb during the pre-race taper period (paired t = 2.65, p < 0.05), and a non-significant drop in Hb post-event (paired t = 1.89, p = 0.075). Mean ferritin, MCV and haematocrit values did not significantly change. Eighty percent of the group exhibited faecal blood loss on one or more of the tests used. There were significant increases in both Haemoccult (chi 2 = 5.44, p < 0.04) and Monohaem (chi 2 = 7.36 p < 0.02). Regression analysis demonstrated a significant relationship between training Hb and total training intensity (R = -0.61, F1,l5 = 8.98, p < 0.009) and training run intensity (R = -0.55, F1,l5 = 6.17, p < 0.026), as estimated using Coopers aerobic points system. These results confirm that GIT blood loss is common in endurance athletes, and appears to be related to exercise intensity. The possible mechanisms of blood loss are discussed.

Football injuries in Australia at the élite level.

OBJECTIVE: To determine injury profiles for the élite level competitions of football played in Australia. DESIGN: Over the 1992 seasons, all injuries were prospectively recorded from 26 clubs in football competitions which included the Australian Football League (AFL), New South Wales Rugby League (NSWRL) and New South Wales Rugby Union (NSWRU). RESULTS: Some 2398 injuries were reported. In Australian Rules football, the most common injury was the hamstring tear (13%); this also accounted for the most time missed due to injury (16%). In rugby league and union, the most common injuries were head and facial lacerations (11% and 20%) followed by concussion (8% and 5%). The injuries accounting for most time missed were fractures and knee ligament injuries in the rugby codes. In Australian Rules football there were more lower limb muscle strain injuries, a high proportion of which were recurrences, with a significant incidence during training sessions. In the rugby codes, minor injuries to the head and neck were more common, particularly in forwards. While rugby league players suffered the most injuries, AFL injuries were on average more severe and consequently the total time missed through injury by players in these two codes was very similar. Rugby union had a significantly lower injury prevalence at the élite club competition level than rugby league or Australian Rules football. CONCLUSION: Injury rates in the élite football competitions are high, warranting ongoing analysis and further study in particular areas.

Efficient and effective root canal retreatment without chloroform.

A root canal retreatment technique is described which eliminates the need for chloroform as a gutta percha solvent. This technique utilizes the gutta percha softening actions of both a self-heating instrument and the heat-potentiated solvent action of eucalyptol. In addition, sonics/ultrasonics and/or Gates-Glidden drills are suggested as useful adjuncts to canal debridement during re-preparation of the canal system. Given the controversy regarding the toxicity of chloroform, both for dental patients and dental personnel, practitioners may wish to consider using this retreatment technique to eliminate chloroform from endodontic retreatment procedures, while still achieving effective, efficient root canal retreatment.

Viking magnetic properties investigation: further results.

The amounts of magnetic particles held on the reference test chart and backhoe magnets on lander 2 and lander 1 are comparable, indicating the presence of an estimated 3 to 7 percent by weight of relatively pure, strongly magnetic particles in the soil at the lander 2 sampling site. Preliminary spectrophotometric analysis of the material held on the backhoe magnets on lander 1 indicates that its reflectance characteristics are indistinguishable from material within a sampling trench with which it has been compared. The material on the RTC magnet shows a different spectrum, but it is suspected that the difference is the result of a reflectance contribution from the magnesium metal covering on the magnet. It is argued that the results indicate the presence, now or originally, of magnetite, which may be titaniferous.

Viking magnetic properties investigation: preliminary results.

Three permanent magnet arrays are aboard the Viking lander. By sol 35, one array, fixed on a photometric reference test chart on top of the lander, has clearly attracted magnetic particles from airborne dust; two other magnet arrays, one strong and one weak, incorporated in the backhoe of the surface sampler, have both extracted considerable magnetic mineral from the surface as a result of nine insertions associated with sample acquisition. The loose martian surface material around the landing site is judged to contain 3 to 7 percent highly magnetic mineral which, pending spectrophotometric study, is thought to be mainly magnetite.

Magnetic properties of lunar samples.

The magnetic properties of samples of rock, fines, and magnetic separate from the fines from Apollo 11 have been measured. Native iron, or possibly nickel-iron, of submicroscopic particle size is the most important constituent, with minor contributions from ilmenite, paramagnetic iron minerals, and other iron-titanium oxides. The remanent magnetization of a sample of the micro-breccia rapidly acquires a viscous magnetization and does not appear to have a significant stable remanence. The crystalline sample has a weak natural remanence showing some stability.