Impact of the COVID-19 Pandemic on Outcomes for Patients with Lung Cancer Receiving Curative-intent Radiotherapy in the UK.

AIMS: Previous work found that during the first wave of the COVID-19 pandemic, 34% of patients with lung cancer treated with curative-intent radiotherapy in the UK had a change to their centre's usual standard of care treatment (Banfill et al. Clin Oncol 2022;34:19-27). We present the impact of these changes on patient outcomes. MATERIALS AND METHODS: The COVID-RT Lung database was a prospective multicentre UK cohort study including patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between April and October 2020. Data were collected on patient demographics, radiotherapy and systemic treatments, toxicity, relapse and death. Multivariable Cox and logistic regression were used to assess the impact of having a change to radiotherapy on survival, distant relapse and grade ≥3 acute toxicity. The impact of omitting chemotherapy on survival and relapse was assessed using multivariable Cox regression. RESULTS: Patient and follow-up forms were available for 1280 patients. Seven hundred and sixty-five (59.8%) patients were aged over 70 years and 603 (47.1%) were female. The median follow-up was 213 days (119, 376). Patients with stage I-II non-small cell lung cancer (NSCLC) who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.859) or death (P = 0.884); however, they did have increased odds of grade ≥3 acute toxicity (P = 0.0348). Patients with stage III NSCLC who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.216) or death (P = 0.789); however, they did have increased odds of grade ≥3 acute toxicity (P < 0.001). Patients with stage III NSCLC who had their chemotherapy omitted had no significant increase in distant relapse (P = 0.0827) or death (P = 0.0661). CONCLUSION: This study suggests that changes to radiotherapy and chemotherapy made in response to the COVID-19 pandemic did not significantly affect distant relapse or survival. Changes to radiotherapy, namely increased hypofractionation, led to increased odds of grade ≥3 acute toxicity. These results are important, as hypofractionated treatments can help to reduce hospital attendances in the context of potential future emergency situations.

Changes in the Management of Patients having Radical Radiotherapy for Lung Cancer during the First Wave of the COVID-19 Pandemic in the UK.

AIMS: In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I-III lung cancer from April to October 2020. MATERIALS AND METHODS: Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression. RESULTS: In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease. CONCLUSIONS: The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes.

Seismic velocities of CaSiO3 perovskite can explain LLSVPs in Earth's lower mantle.

Seismology records the presence of various heterogeneities throughout the lower mantle1,2, but the origins of these signals-whether thermal or chemical-remain uncertain, and therefore much of the information that they hold about the nature of the deep Earth is obscured. Accurate interpretation of observed seismic velocities requires knowledge of the seismic properties of all of Earth's possible mineral components. Calcium silicate (CaSiO3) perovskite is believed to be the third most abundant mineral throughout the lower mantle. Here we simultaneously measure the crystal structure and the shear-wave and compressional-wave velocities of samples of CaSiO3 perovskite, and provide direct constraints on the adiabatic bulk and shear moduli of this material. We observe that incorporation of titanium into CaSiO3 perovskite stabilizes the tetragonal structure at higher temperatures, and that the material's shear modulus is substantially lower than is predicted by computations3-5 or thermodynamic datasets6. When combined with literature data and extrapolated, our results suggest that subducted oceanic crust will be visible as low-seismic-velocity anomalies throughout the lower mantle. In particular, we show that large low-shear-velocity provinces (LLSVPs) are consistent with moderate enrichment of recycled oceanic crust, and mid-mantle discontinuities can be explained by a tetragonal-cubic phase transition in Ti-bearing CaSiO3 perovskite.

Detection and clinical impact of human leukocyte antigen antibodies in lung transplantation: A systematic review and meta-analysis.

There is significant variability in lung transplant centers' approach to HLA antibodies, creating heterogeneity regarding their clinical significance. Some institutions use beads coated with multiple HLA to screen candidate sera and then use single antigen bead (SAB) to determine antibody identity if the pre-screen is positive. Other centers do not pre-screen, using SAB alone, which may detect low-level antibodies of unknown significance. The primary objective of this study was to review the current literature to identify sources of heterogeneity in the identification of pre- and post-lung transplant HLA antibodies, particularly regarding antibody-detection methods. A random effects model meta-analysis was used to evaluate the relationship between pre-transplant HLA antibodies and the development of de novo donor-specific antibodies (dnDSA) and dnDSA and chronic lung allograft dysfunction (CLAD). Each outcome was stratified by the method of antibody detection (pre-screen followed by SAB vs SAB alone). We identified 13 cohort studies with a total of 3039 patients. The use of pre-screening followed by SAB testing and the use of induction immunosuppression were associated with lower prevalence of dnDSA. Patients with pre-transplant HLA antibodies were more likely to develop dnDSA (hazard ratio [HR] = 1.49, 95% confidence interval [CI]: 1.19-1.86, P < .001). dnDSA was associated with CLAD (HR = 2.02, 95% CI = 1.37-2.97, P < .001). When considering studies using SAB alone, however, pre-transplant antibody status was no longer associated with dnDSA and dnDSA was no longer associated with CLAD. Based on the current literature, SAB-alone testing may detect less clinically relevant antibodies than pre-screening followed by SAB.

High-temperature ab initio calculations on FeSi and NiSi at conditions relevant to small planetary cores.

The Fe-Ni-Si system is potentially a very important component of terrestrial planetary cores. However, at present, even the behaviour of the FeSi and NiSi end members is poorly understood, especially at low to moderate pressures-the data for FeSi are contradictory and NiSi has been little studied. For FeSi, there is general agreement that there is a phase transition from the ε-FeSi to the CsCl structure with increasing pressure, but, in experiments, there is disagreement as to the position and slope of the phase boundary and the range of coexistence of the two phases. In this paper we have used ab initio lattice dynamics calculations to determine the phase boundary between the ε-FeSi and CsCl structures as a function of pressure and temperature in both FeSi and NiSi. For FeSi, we find that the transition pressure at zero Kelvin is ~11 GPa and that the boundary between the ε-FeSi and CsCl phases varies little with temperature, having a slight negative Clapeyron slope, going from ~11 GPa at 300 K to ~3 GPa at 2000 K. For NiSi, there is much greater variation of the transition pressure with temperature, with a much shallower negative Clapeyron slope, going from ~156 GPa at 300 K to ~94 GPa at 2000 K.

Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis.

AIMS: Indirect evidence from randomized controlled trials (RCTs) was used to estimate the effect of dapagliflozin, a new agent with a novel mechanism of action (SGLT-2 inhibition), relative to other anti-diabetes therapies after 1 year of treatment. METHODS: A systematic literature review and Bayesian network meta-analysis (NMA) of RCTs involving anti-diabetes treatments added to metformin were conducted. RCTs enrolling subjects with type 2 diabetes inadequately controlled on metformin monotherapy were included. Comparators included dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), sulphonylureas, glucagon-like peptide-1 (GLP-1) analogues and dapagliflozin. Outcomes of interest were mean change from baseline HbA1c, weight and systolic blood pressure, and incidence of hypoglycaemia. RESULTS: From 4270 abstracts, six RCTs were included in the primary analysis; no RCTs involving GLP-1 analogues met primary inclusion criteria. All RCTs were actively controlled with sulphonylureas. The mean change in HbA1c from baseline was similar across comparators. The treatment effect (95% credible interval) of dapagliflozin on HbA1c was -0.08% (-0.25, 0.10) relative to DPP-4 inhibitors, -0.02% (-0.24, 0.21) relative to TZDs and 0.00% (-0.16, 0.16) relative to sulphonylureas. Non-sulphonylureas showed significantly lower risk of hypoglycaemia relative to sulphonylureas. Dapagliflozin had a significant effect on weight change: the relative difference was -2.74 kg (-5.35, -0.10) compared with DPP-4 inhibitors, and -4.67 kg (-7.03, -2.35) compared with sulphonylureas. Systolic blood pressure was not meta-analysed due to infrequent reporting. CONCLUSION: Compared with DPP-4 inhibitors, TZDs and sulphonylureas, dapagliflozin offers similar HbA1c control after 1 year, with similar or reduced risk of hypoglycaemia and the additional benefit of weight loss, when added to metformin.

A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes.

The effect of hypoxia on global gene expression in human adipocytes has been examined using DNA microarrays. Adipocytes (Zen-Bio, day 12 post-differentiation) were exposed to hypoxia (1% O(2)) or 'normoxia' (21% O(2)) for 24 h and extracted RNA probed with Agilent arrays containing 41,152 probes. A total of 1346 probes were differentially expressed (>2.0-fold change, P < 0.01) in response to hypoxia; 650 genes were up-regulated (including LEP, IL6, VEGF, ANGPTL4) and 650 down-regulated (including ADIPOQ, UCP2). Major genes not previously identified as hypoxia-sensitive in adipocytes include AQP3, FABP3, FABP5 and PPARGC1A. Ingenuity analysis indicated that several pathways and functions were modulated by hypoxia, including glucose utilization, lipid oxidation and cell death. Network analysis indicated a down-regulation of p38/MAPK and PGC-1α signalling in the adipocytes. It is concluded that hypoxia has extensive effects on human adipocyte gene expression, consistent with low O(2) tension underlying adipose tissue dysfunction in obesity.

Modulation of adipokine production, glucose uptake and lactate release in human adipocytes by small changes in oxygen tension.

Adipose tissue becomes hypoxic in obesity, and cell culture studies have demonstrated that hypoxia leads to major changes in adipocyte function. Studies on the response of adipocytes to low O2 tension have employed marked hypoxia (1% O2). Here, we have examined the effects of modest hypoxia, utilising differing concentrations of O2 (1-21%), on adipokine production and glucose uptake by human adipocytes. Incubation with 10% O2 (24 h) increased expression of the leptin, vascular endothelial growth factor (VEGF) and Angptl4 genes, while leptin expression was elevated even at 15% O2 (compared to 'normoxia'-21% O2). Overall, there was a concentration-dependent increase in the expression of these genes as O2 fell, with the highest mRNA level evident at 1% O2. Parallel changes were observed in the secretion of leptin, VEGF and IL-6 into the medium, an increased release being evident at 10% O2 (15% O(2) for leptin). Adiponectin gene expression was reduced at 15% O2 and below, while adiponectin release was significantly reduced at 5% O2. Both 2-deoxy-D: -glucose uptake and lactate release showed progressive increases as O2 concentration fell, being significantly raised at 10% and 5% O2, respectively. The alterations in substrate transport were accompanied by parallel changes in transporter gene expression, GLUT1 and MCT1 mRNA level increasing from 15% and 10% O2, respectively. These results indicate that marked responses to reduced O2 concentration are exhibited by human adipocytes at O2 levels well above those associated with hypoxia and employed in cell culture studies. Adipocytes are sensitive to small changes in O2 tension.

KvSNP: accurately predicting the effect of genetic variants in voltage-gated potassium channels.

MOTIVATION: Non-synonymous single nucleotide polymorphisms (nsSNPs) in voltage-gated potassium (Kv) channels cause diseases with potentially fatal consequences in seemingly healthy individuals. Identifying disease-causing genetic variation will aid presymptomatic diagnosis and treatment of such disorders. NsSNP-effect predictors are hypothesized to perform best when developed for specific gene families. We, thus, created KvSNP: a method that assigns a disease-causing probability to Kv-channel nsSNPs. RESULTS: KvSNP outperforms popular non gene-family-specific methods (SNPs&GO, SIFT and Polyphen) in predicting the disease potential of Kv-channel variants, according to all tested metrics (accuracy, Matthews correlation coefficient and area under receiver operator characteristic curve). Most significantly, it increases the separation of the median predicted disease probabilities between benign and disease-causing SNPs by 26% on the next-best competitor. KvSNP has ranked 172 uncharacterized Kv-channel nsSNPs by disease-causing probability. AVAILABILITY AND IMPLEMENTATION: KvSNP, a WEKA implementation is available at www.bioinformatics.leeds.ac.uk/KvDB/KvSNP.html. CONTACT: d.r.westhead@leeds.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Obesity, its associated disorders and the role of inflammatory adipokines in companion animals.

Obesity is characterised by an expansion of white adipose tissue mass that can lead to adverse health effects, such as decreased longevity, diabetes mellitus, orthopaedic and respiratory disease and neoplasia. Once thought a passive fuel depot, adipose tissue is now recognised as an active endocrine organ that communicates with the brain and peripheral tissues by secreting a wide range of hormones and protein factors, collectively termed adipokines. Examples include leptin, adiponectin, cytokines (tumour necrosis factor-alpha, interleukin-6), chemokines, acute phase proteins, haemostatic and haemodynamic factors and neurotrophins. Adipokines can influence various body systems, and perturbation of normal endocrine function is thought central to the development of many associated conditions. This review focuses on the medical consequences of obesity in companion animals, assesses the endocrine function of adipose tissue in disease pathogenesis, and highlights the potential role of adipokines as biomarkers of obesity-associated disease.

Adipokine expression and secretion by canine adipocytes: stimulation of inflammatory adipokine production by LPS and TNFalpha.

Adiposity and obesity are increasing in dogs. We have examined here the endocrine function of canine adipose tissue and the regulation of production of inflammation-related adipokines by dog adipocytes. Adiponectin, leptin, IL-6, MCP-1 and TNFalpha genes were expressed in the main adipose depots of dogs, but there were no major depot differences in mRNA levels. Each adipokine was expressed in canine adipocytes differentiated in culture and secreted into the medium (leptin undetected). IL-6, MCP-1 and TNFalpha were also expressed and secreted by preadipocytes; adiponectin and leptin were only expressed after adipocyte differentiation. The inflammatory mediators LPS and TNFalpha had major stimulatory effects on the expression and secretion of IL-6, MCP-1 and TNFalpha; there was a >5,000-fold increase in IL-6 mRNA level with LPS. IL-6 release into the medium was increased >50-fold over 24 h with LPS and TNFalpha, while MCP-1 release was increased 23- and 40-fold by TNFalpha and LPS, respectively. However, there was no effect, or small reductions, in adiponectin and leptin mRNA levels with the inflammatory mediators. Dexamethasone-stimulated leptin gene expression, had no effect on adiponectin expression, but decreased the expression and secretion of IL-6 and MCP-1. The PPARgamma agonist rosiglitazone stimulated both adiponectin and leptin expression and inhibited the expression of IL-6, MCP-1 and TNFalpha; MCP-1 secretion was reduced. These results demonstrate that canine adipocytes express and secrete key adipokines and show that adipocytes of this species are highly responsive to inflammatory mediators with the induction of major increases in the production of inflammation-related adipokines.

Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes.

Hypoxia modulates white adipose tissue function, and this includes stimulating glucose uptake and the expression of facilitative glucose transporters (particularly GLUT1) in adipocytes. This study has examined the effect of hypoxia on lactate release from adipocytes and whether the monocarboxylate transporters that mediate lactate transport (MCTs1-4) are expressed in human adipocytes and are induced by low O(2) tension. Exposure of human Simpson-Golabi-Behmel syndrome adipocytes to 1% O(2) for 24 h resulted in increased lactate release (2.3-fold) compared with cells in normoxia (21% O(2)). Screening by reverse transcription polymerase chain reaction indicated that the genes encoding MCT1, MCT2, and MCT4 are expressed in human adipose tissue, and in adipocytes and preadipocytes in culture. Hypoxia (48 h) increased MCT1 (8.5-fold) and MCT4 (14.3-fold) messenger RNA (mRNA) levels in human adipocytes, but decreased MCT2 mRNA (fourfold). MCT1 protein level was also increased (2.7-fold at 48 h) by hypoxia, but there was no change in MCT4 protein. The changes in MCT gene expression induced by hypoxia were reversed on return to normoxia. Treatment with the hypoxia mimetic CoCl(2) resulted in up-regulation of MCT1 (up to twofold) and MCT4 (fivefold) mRNA level, but there was no significant effect on MCT2 expression. It is concluded that hypoxia increases lactate release from adipocytes and modulates MCT expression in a type-specific manner, with MCT1 and MCT4 expression being hypoxia-inducible transcription factor-1 (HIF-1) dependent. Increased lactate production and monocarboxylate transporter expression are likely to be key components of the adaptive response of adipocytes to low O(2) tension as adipose tissue mass expands in obesity.

Cellular hypoxia and adipose tissue dysfunction in obesity.

Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFalpha, IL-1beta, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammation-related adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity.

IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes.

Inflammation occurs in adipose tissue in obesity. We have examined whether IL-33, a recently identified IL-1 gene family member, and its associated receptors are expressed in human adipocytes. IL-33, IL-1RL1 and IL-1RAP gene expression was observed in human visceral white fat, in preadipocytes and in adipocytes (SGBS cells). Treatment with TNFalpha for 24h induced a 6-fold increase in IL-33 mRNA level in preadipocytes and adipocytes. Time-course studies with adipocytes showed that the increase in IL-33 mRNA with TNFalpha was maximal (>55-fold) at 12h. This response was markedly different to IL-1beta (peak mRNA increase at 2h; 5.4-fold) and 1L-18 (peak mRNA increase at 6h; >1500-fold). Exposure of adipocytes to hypoxia (1% O(2), 24h) did not alter IL-33 mRNA level; in preadipocytes, however, there was a 3-fold increase. Human adipocytes and preadipocytes express IL-33, but the various IL-1 family members exhibit major differences in responsiveness to TNFalpha.

Hypoxia and the endocrine and signalling role of white adipose tissue.

White adipose tissue is a major endocrine and signalling organ. It secretes multiple protein hormones and factors, termed adipokines (such as adiponectin, leptin, IL-6, MCP-1, TNFalpha) which engage in extensive cross-talk within adipose tissue and with other tissues. Many adipokines are linked to inflammation and immunity and these include cytokines, chemokines and acute phase proteins. In obesity, adipose tissue exhibits a major inflammatory response with increased production of inflammation-related adipokines. It has been proposed that hypoxia may underlie the inflammatory response in adipose tissue and evidence that the tissue is hypoxic in obesity has been obtained in animal models. Cell culture studies have demonstrated that the expression and secretion of key adipokines, including leptin, IL-6 and VEGF, are stimulated by hypoxia, while adiponectin (with an anti-inflammatory action) production falls. Hypoxia also stimulates glucose transport by adipocytes and may have a pervasive effect on cell function within adipose tissue.

NGF gene expression and secretion by canine adipocytes in primary culture: upregulation by the inflammatory mediators LPS and TNFalpha.

Obesity is the commonest nutritional disorder of companion animals. In rodents and humans, white adipose tissue is a major endocrine and secretory organ, releasing adipokines linked to inflammation. In this study, we examined whether nerve growth factor (NGF), a target-derived neurotrophin central to the development/maintenance of sympathetic innervation and an inflammatory response protein, is synthesized and secreted by canine adipocytes. NGF mRNA was detected in each of the major fat depots (the subcutaneous, inguinal, gonadal, perirenal, and falciform ligaments) of dogs at similar levels. Canine adipocytes, differentiated from preadipocytes (inguinal depot) in primary culture, expressed the NGF gene and secreted NGF both pre- and post-differentiation. Treatment of the differentiated adipocytes with LPS resulted in a dramatic increase in NGF mRNA levels (20-fold at 24 h) and in NGF protein in the medium (60-fold at 24 h). The proinflammatory cytokine TNFalpha also led to a substantial increase in NGF mRNA levels (11-fold) and protein secretion (16-fold), while IL-6 had little effect. In contrast, dexamethasone decreased both NGF mRNA levels (80%) and protein release (60%). The PPARgamma agonist rosiglitazone also reduced NGF secretion. These results demonstrate that canine white adipocytes synthesize and secrete NGF, the powerful upregulation by LPS and TNFalpha indicating that the neurotrophin is strongly linked to the inflammatory response in canine WAT. Canine adipocytes appear highly sensitive to inflammatory stimuli.