Treatment intervals and survival for women diagnosed with early breast cancer in Queensland: the Breast Cancer Outcomes Study, a population-based cohort study.

OBJECTIVES: To assess associations between breast cancer-specific survival and timeliness of treatment, based on 2020 Australian guidelines for the treatment of early breast cancer. DESIGN: Population-based cohort study; analysis of linked Queensland Cancer Register, patient medical record, and National Death Index data, supplemented by telephone interviews. SETTING, PARTICIPANTS: Women aged 20-79 years diagnosed with invasive breast cancer during 1 March 2010 - 30 June 2013, followed to 31 December 2020. MAIN OUTCOME MEASURES: Breast cancer-specific survival for women who received or did not receive treatment within the recommended timeframe, overall and for six treatment intervals; optimal cut-points for each treatment interval; characteristics of women for whom treatment was not provided within the recommended timeframe. RESULTS: Of 5426 eligible women, 4762 could be invited for interviews; complete data were available for 3044 women (56% of eligible women, 65% of invited women). Incomplete compliance with guideline interval recommendations was identified for 1375 women (45%); their risk of death from breast cancer during the follow-up period was greater than for those for whom guideline compliance was complete (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.04-1.96). Risk of death was greater for women for whom the diagnosis to surgery interval exceeded 29 days (aHR, 1.76; 95% CI, 1.19-2.59), the surgery to chemotherapy interval exceeded 36 days (aHR, 1.63; 95% CI, 1.13-2.36), or the chemotherapy to radiotherapy interval exceeded 31 days (aHR, 1.83; 95% CI, 1.19-2.80). Treatment intervals longer than recommended were more frequent for women for whom breast cancer was detected by public facility screening (adjusted odds ratio [aOR], 1.58; 95% CI, 1.22-2.04) or by symptoms (aOR, 1.39; 95% CI, 1.09-1.79) than when cancer had been detected in private facilities, and for women without private health insurance (aOR, 1.96; 95% CI, 1.66-2.32) or living outside major cities (aOR, 1.38; 95% CI, 1.18-1.62). CONCLUSIONS: Breast cancer-specific survival was poorer for women for whom the diagnosis to surgery, surgery to chemotherapy, or chemotherapy to radiotherapy intervals exceeded guideline-recommended limits. Our findings support 2020 Australian guideline recommendations regarding timely care.

A prognostic survival model for women diagnosed with invasive breast cancer in Queensland, Australia.

PURPOSE: Prognostic models can help inform patients on the future course of their cancer and assist the decision making of clinicians and patients in respect to management and treatment of the cancer. In contrast to previous studies considering survival following treatment, this study aimed to develop a prognostic model to quantify breast cancer-specific survival at the time of diagnosis. METHODS: A large (n = 3323), population-based prospective cohort of women were diagnosed with invasive breast cancer in Queensland, Australia between 2010 and 2013, and followed up to December 2018. Data were collected through a validated semi-structured telephone interview and a self-administered questionnaire, along with data linkage to the Queensland Cancer Register and additional extraction from medical records. Flexible parametric survival models, with multiple imputation to deal with missing data, were used. RESULTS: Key factors identified as being predictive of poorer survival included more advanced stage at diagnosis, higher tumour grade, "triple negative" breast cancers, and being symptom-detected rather than screen detected. The Harrell's C-statistic for the final predictive model was 0.84 (95% CI 0.82, 0.87), while the area under the ROC curve for 5-year mortality was 0.87. The final model explained about 36% of the variation in survival, with stage at diagnosis alone explaining 26% of the variation. CONCLUSIONS: In addition to confirming the prognostic importance of stage, grade and clinical subtype, these results highlighted the independent survival benefit of breast cancers diagnosed through screening, although lead and length time bias should be considered. Understanding what additional factors contribute to the substantial unexplained variation in survival outcomes remains an important objective.

Factors associated with being diagnosed with high severity of breast cancer: a population-based study in Queensland, Australia.

PURPOSE: This study explores factors that are associated with the severity of breast cancer (BC) at diagnosis. METHODS: Interviews were conducted among women (n = 3326) aged 20-79 diagnosed with BC between 2011 and 2013 in Queensland, Australia. High-severity cancers were defined as either Stage II-IV, Grade 3, or having negative hormone receptors at diagnosis. Logistic regression models were used to estimate odds ratios (ORs) of high severity BC for variables relating to screening, lifestyle, reproductive habits, family history, socioeconomic status, and area disadvantage. RESULTS: Symptom-detected women had greater odds (OR 3.38, 2.86-4.00) of being diagnosed with high-severity cancer than screen-detected women. Women who did not have regular mammograms had greater odds (OR 1.78, 1.40-2.28) of being diagnosed with high-severity cancer than those who had mammograms biennially. This trend was significant in both screen-detected and symptom-detected women. Screen-detected women who were non-smokers (OR 1.77, 1.16-2.71), postmenopausal (OR 2.01, 1.42-2.84), or employed (OR 1.46, 1.15-1.85) had greater odds of being diagnosed with high-severity cancer than those who were current smokers, premenopausal, or unemployed. Symptom-detected women being overweight (OR 1.67, 1.31-2.14), postmenopausal (OR 2.01, 1.43-2.82), had hormone replacement therapy (HRT) < 2 years (OR 1.60, 1.02-2.51) had greater odds of being diagnosed with high-severity cancer than those of healthy weight, premenopausal, had HRT > 10 years. CONCLUSION: Screen-detected women and women who had mammograms biennially had lower odds of being diagnosed with high-severity breast cancer, which highlighted the benefit of regular breast cancer screening. Women in subgroups who are more likely to have more severe cancers should be particularly encouraged to participate in regular mammography screening.

Trehalose suppresses cadmium-activated Nrf2 signaling pathway to protect against spleen injury.

Cadmium (Cd), as a kind of ubiquitous and highly toxic heavy metal pollutants, has been known to result in immunotoxicity in animals. As a multifunctional bioactivity disaccharide, trehalose (Tre) is characterized by antioxidative, antiapoptotic, and accelerating autophagy. In this study, Sprague-Dawley (SD) rats were fed with cadmium chloride (CdCl2) and/or Tre to explore the molecular mechanisms of Tre-protected against spleen injury caused by Cd exposure. Firstly, the results showed that Tre partially recovered splenic pathological changes induced by Cd exposure. Secondly, Tre dramatically declined the level of methane dicarboxylic aldehyde (MDA) and elevated the level of total antioxidant capacity (T-AOC) to weaken oxidative stress caused by Cd exposure in spleen tissue. Moreover, the results showed that Tre significantly suppressed Cd-induced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and up-regulated the protein expression of nuclear Nrf2. Thirdly, Tre remarkably reduced the protein expression of sequestosome 1 (p62/SQSTM1) and microtubule-associated protein light chain 3II (LC-3II) to restore autophagy inhibition induced by Cd exposure. Finally, the results of TUNEL and the expression of apoptosis marker proteins showed that Tre significantly inhibited Cd-induced apoptosis in spleen tissue to exert its protective effects. In summary, the results indicated that Tre modulated Nrf2 signaling pathway, which interacted with apoptosis and autophagy to against Cd-induced spleen injury, providing potential therapeutic strategies for the prevention and treatment of Cd-related immune system diseases.

The Effect of Choice on Motor Learning for Learners With Different Levels of Intrinsic Motivation.

This study examines whether the positive effect of choice on motor learning in a dart-throwing task varies by intrinsic motivation. Participants were allocated to a highly motivated or less-motivated group based on measured task motivation and randomly to a Choice or No Choice group. In Experiment 1, participants in the Choice group chose their dart color. In Experiment 2, they chose when to observe a model demonstration. Results showed that the effect of choice on motor learning differed between highly and less-motivated participants in Experiment 1 (i.e., interaction between motivation and choice) but not Experiment 2 (i.e., main effects of motivation and choice). Specifically, motor learning was enhanced in less-motivated but not highly motivated participants when choosing dart color, while it was enhanced regardless of initial intrinsic motivation when choosing model-demonstration time. Therefore, external provision of choice in a motor-learning situation may not be equally effective across learners.

Characterization of a Novel Intestinal Glycerol-3-phosphate Acyltransferase Pathway and Its Role in Lipid Homeostasis.

Dietary triglycerides (TG) are absorbed by the enterocytes of the small intestine after luminal hydrolysis into monacylglycerol and fatty acids. Before secretion on chylomicrons, these lipids are reesterified into TG, primarily through the monoacylglycerol pathway. However, targeted deletion of the primary murine monoacylglycerol acyltransferase does not quantitatively affect lipid absorption, suggesting the existence of alternative pathways. Therefore, we investigated the role of the glycerol 3-phosphate pathway in dietary lipid absorption. The expression of glycerol-3-phosphate acyltransferase (GPAT3) was examined throughout the small intestine. To evaluate the role for GPAT3 in lipid absorption, mice harboring a disrupted GPAT3 gene (Gpat3(-/-)) were subjected to an oral lipid challenge and fed a Western-type diet to characterize the role in lipid and cholesterol homeostasis. Additional mechanistic studies were performed in primary enterocytes. GPAT3 was abundantly expressed in the apical surface of enterocytes in the small intestine. After an oral lipid bolus, Gpat3(-/-) mice exhibited attenuated plasma TG excursion and accumulated lipid in the enterocytes. Electron microscopy studies revealed a lack of lipids in the lamina propria and intercellular space in Gpat3(-/-) mice. Gpat3(-/-) enterocytes displayed a compensatory increase in the synthesis of phospholipid and cholesteryl ester. When fed a Western-type diet, hepatic TG and cholesteryl ester accumulation was significantly higher in Gpat3(-/-) mice compared with the wild-type mice accompanied by elevated levels of alanine aminotransferase, a marker of liver injury. Dysregulation of bile acid metabolism was also evident in Gpat3-null mice. These studies identify GPAT3 as a novel enzyme involved in intestinal lipid metabolism.

Severity and risk factors of interval breast cancer in Queensland, Australia: a population-based study.

BACKGROUND: Interval breast cancers (BC) are those diagnosed within 24 months of a negative mammogram. This study estimates the odds of being diagnosed with high-severity BC among screen-detected, interval, and other symptom-detected BC (no screening history within 2 years); and explores factors associated with being diagnosed with interval BC. METHODS: Telephone interviews and self-administered questionnaires were conducted among women (n = 3,326) diagnosed with BC in 2010-2013 in Queensland. Respondents were categorised into screen-detected, interval, and other symptom-detected BCs. Data were analysed using logistic regressions with multiple imputation. RESULTS: Compared with screen-detected BC, interval BC had higher odds of late-stage (OR = 3.50, 2.9-4.3), high-grade (OR = 2.36, 1.9-2.9) and triple-negative cancers (OR = 2.55, 1.9-3.5). Compared with other symptom-detected BC, interval BC had lower odds of late stage (OR = 0.75, 0.6-0.9), but higher odds of triple-negative cancers (OR = 1.68, 1.2-2.3). Among women who had a negative mammogram (n = 2,145), 69.8% were diagnosed at their next mammogram, while 30.2% were diagnosed with an interval cancer. Those with an interval cancer were more likely to have healthy weight (OR = 1.37, 1.1-1.7), received hormone replacement therapy (2-10 years: OR = 1.33, 1.0-1.7; > 10 years: OR = 1.55, 1.1-2.2), conducted monthly breast self-examinations (BSE) (OR = 1.66, 1.2-2.3) and had previous mammogram in a public facility (OR = 1.52, 1.2-2.0). CONCLUSION: These results highlight the benefits of screening even among those with an interval cancer. Women-conducted BSE were more likely to have interval BC which may reflect their increased ability to notice symptoms between screening intervals.

Evidence for regulated monoacylglycerol acyltransferase expression and activity in human liver.

Intrahepatic lipid accumulation is extremely common in obese subjects and is associated with the development of insulin resistance and diabetes. Hepatic diacylglycerol and triacylglycerol synthesis predominantly occurs through acylation of glycerol-3-phosphate. However, an alternative pathway for synthesizing diacylglycerol from monoacylglycerol acyltransferases (MGAT) could also contribute to hepatic glyceride pools. MGAT activity and the expression of the three genes encoding MGAT enzymes (MOGAT1, MOGAT2, and MOGAT3) were determined in liver biopsies from obese human subjects before and after gastric bypass surgery. MOGAT expression was also assessed in liver of subjects with nonalcoholic fatty liver disease (NAFLD) or control livers. All MOGAT genes were expressed in liver, and hepatic MGAT activity was readily detectable in liver lysates. The hepatic expression of MOGAT3 was highly correlated with MGAT activity, whereas MOGAT1 and MOGAT2 expression was not, and knockdown of MOGAT3 expression attenuated MGAT activity in a liver-derived cell line. Marked weight loss following gastric bypass surgery was associated with a significant reduction in MOGAT2 and MOGAT3 expression, which were also overexpressed in NAFLD subjects. These data suggest that the MGAT pathway is active and dynamically regulated in human liver and could be an important target for pharmacologic intervention for the treatment of obesity-related insulin resistance and NAFLD.

Factors influencing participants' engagement with an interactive text-message intervention to improve sun protection behaviors: "SunText" randomized controlled trial.

There is growing evidence suggesting that text-message-based interventions are effective to promote sun protection behaviors. However, it is still unclear how engagement and adherence with the intervention messages can be optimized through intervention design. This study evaluated the effect of different combinations of personalized and two-way interactive messages on participant engagement with a theory-based skin cancer prevention intervention. In the SunText study conducted in February-July 2019 in Queensland, Australia participants 18-40 years were randomized to four different text message schedules using a Latin square design. This study analyzed if the order and intensity in which the schedules were received were associated with participants' level of engagement, and if this differed by demographic factors. Out of the 389 participants enrolled in the study, 375 completed the intervention period and remained for analysis. The overall intervention engagement rate was 71% and decreased from the beginning to the end of the study (82.2%-61.4%). The group starting with personalized, but not interactive messaging showed the lowest engagement rate. The intervention involving interactive messages three times a week for 4 weeks achieved the highest engagement rate. The intervention with increasing frequency (personalized and interactive three times a week for 2 weeks; then daily for 2 weeks) had lower engagement than intervention with constant or decreasing frequency. Engagement with two-way interactive messages was high across all intervention groups. Results suggest enhanced engagement with constant or decreasing message frequency compared to increasing frequency.

[Identification of Soil Heavy Metal Sources Around a Copper-silver Mining Area in Ningxia Based on GIS].

This study area was based on the catchment area of the Yaoxianzi ditch located in the arid region of western China. A total of 194 topsoil samples of 0-20 cm depth were collected using the mesh distribution method. The contents of nine heavy metals (Ni, Cu, Zn, As, Ag, Cr, Cd, Hg, and Pb) were determined using ICP-MS. The source and spatial distribution of heavy metals were analyzed using PMF and IDW. Spatial autocorrelation and clustering and outlier analysis were performed using the Spatial Statistical Analysis tool of ArcGIS. The main sources and distribution areas of heavy metals in the soil were obtained through comprehensive analysis. In the study area, the average values of Hg, Ag, Cd, and Pb were 20.48, 3.13, 2.23, and 1.12 times the background values, and the maximum values of Cd, Cu, Pb, and As were 10.92, 5.52, 2.03, and 1.39 times the filter values, respectively. The coefficients of variation of Cu, Cd, Pb, and Hg were ordered as Cu(283.23%)>Cd(224.77%)>Pb(144.40%)>Hg(67.12%) and were closely affected by human activities. The heavy metals in the soil around mining areas came from four main sources:natural parent material (32%), the mixed source of mining activities and transportation (17.1%), the mixed source of industrial activities and atmospheric sedimentation (40.3%), and the mixed source of agricultural activity and putting sandy gravel in farmland (10.6%). Cr and Ni, As and Cu, Hg, and Cd could represent these four sources of heavy metal pollution, respectively. The main sources of soil heavy metal pollution were mining activities and agricultural activities. The heavily contaminated areas were distributed in the mining areas in the south of the study area and in the planting areas in the eastern, central, and northwestern parts of the study area.

Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis.

Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.

Crude probability of death for cancer patients by spread of disease in New South Wales, Australia 1985 to 2014.

BACKGROUND: To estimate trends in the crude probability of death for cancer patients by sex, age and spread of disease over the past 30 years in New South Wales, Australia. METHODS: Population-based cohort of 716,501 people aged 15-89 years diagnosed with a first primary cancer during 1985-2014 were followed up to 31 December 2015. Flexible parametric relative survival models were used to estimate the age-specific crude probability of dying from cancer and other causes by calendar year, sex and spread of disease for all solid tumours combined and cancers of the colorectum, lung, female breast, prostate and melanoma. RESULTS: Estimated 10-year sex, age and spread-specific crude probabilities of cancer death generally decreased over time for most cancer types, although the magnitude of the decrease varied. For example, out of 100 fifty-year old men with localized prostate cancer, 12 would have died from their cancer if diagnosed in 1985 and 3 in 2014. Greater degree of spread was consistently associated with higher probability of dying from cancer, although outcomes for lung cancer were consistently poor. For both males and females, the probability of non-cancer deaths was higher among older patients, those diagnosed with localized cancers and where cancer survival was higher. CONCLUSION: Crude probabilities presented here may be useful in helping clinicians and their patients better understand prognoses and make informed decisions about treatment. They also provide novel insights into the relative contributions that early detection and improved treatments have on the observed temporal patterns in cancer survival.

Optimizing Texting Interventions for Melanoma Prevention and Early Detection: A Latin Square Crossover RCT.

INTRODUCTION: Text messaging is an effective way to reach large populations with health promotion support. This study aims to establish the optimal text messaging intervention to achieve behavior change in young adults at risk of skin cancer. STUDY DESIGN: Latin square crossover RCT. SETTING/PARTICIPANTS: Participants were women and men aged 18-40 years living in Queensland, Australia who owned a smartphone and had ≥2 skin cancer risk factors. INTERVENTION: Participants were enrolled from December 2018 to February 2019 and completed an eligibility survey. Eligible participants were randomized to 4 different text message interventions using a Latin square design with varying personalization, interactivity, and message frequency (February 2019‒July 2019). Each intervention lasted for 1 month; between interventions, participants had a 1-week washout period in which they completed an online questionnaire. Participants completed a 6-month follow-up online survey in January 2020. MAIN OUTCOME MEASURES: Measures included self-reported sun protection habits and sunburns. RESULTS: A total of 277 (71.2% response rate) participants completed the 6-month follow-up. The sun protection habits index was significantly higher in all the 4 text messaging interventions (p<0.01 for each intervention) than at baseline, with similar sun protection habits improvements among all interventions (p=0.27). Sunburn rates decreased significantly over time (p<0.01 each intervention), with all the 4 interventions achieving reductions in sunburn rates during the intervention periods (p=0.78). Overall, the sunburn rates decreased from 40.3% at baseline to 7.0% at the end of the intervention, and at 6-month follow-up, it remained significantly below baseline levels at 23.5% (p<0.01). CONCLUSIONS: Regular text messaging interventions result in significantly increased sun protection and decreased sunburn in young adults. TRIAL REGISTRATION: This study is registered at the Australian and New Zealand Clinical Trials Registry ACTRN12618001299291.

Persistent activation of Nrf2 promotes a vicious cycle of oxidative stress and autophagy inhibition in cadmium-induced kidney injury.

Nuclear factor erythroid 2-related factor 2 (Nrf2) serves as the master regulator of antioxidant signaling and inhibition or hyperactivation of Nrf2 pathway will result in the redox imbalance to induce tissue injury. Herein, we established cadmium (Cd)-exposed rat kidney injury model by intraperitoneal injection with CdCl2 (1.5 mg/kg body weight) and cytotoxicity model of NRK-52E cells by CdCl2 (5 µM) exposure to reveal the role of Nrf2 hyperactivation in Cd-induced nephrotoxicity. Data from the in vitro and in vivo study showed that Cd caused Nrf2 nuclear retention due to nuclear-cytoplasmic depletion of Kelch-like ECH-associated protein 1 (Keap1) and Sequestosome-1(SQSTM1/p62) accumulation, leading to the persistent activation of Nrf2. Moreover, we established inhibited models of Cd-induced prolonged Nrf2 activation using siRNA-mediated gene silencing in vitro and pharmacological inhibition in vivo for subsequent assays. First, Cd-induced cytotoxicity, renal injury and concomitant oxidative stress were markedly alleviated by Nrf2 inhibition. Second, Cd-induced autophagy inhibition was notably alleviated by Nrf2 inhibition. Further, we revealed underlying molecular mechanisms of the crosstalk between persistent activation of Nrf2 and autophagy inhibition in Cd-induced nephrotoxicity. Data showed that Cd-induced lysosomal dysfunction evidenced by impaired lysosomal biogenesis and degradation capacity was markedly recovered by Nrf2 inhibition. Meanwhile, Cd-impaired autophagosome-lysosome fusion was obviously restored by Nrf2 inhibition. In conclusion, our findings revealed that persistent activation of Nrf2 promoted a vicious cycle of oxidative stress and autophagy inhibition in Cd-induced nephrotoxicity.

ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study ( NCT03248882 ) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study ( NCT03776175 ) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging-proton density fat fraction. Dose-dependent reductions in liver fat reached 50-65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was -7.2 (-13.9, 0.0), -17.1 (-22.7, -11.1), -49.9 (-53.3, -46.2), -55.9 (-59.0, -52.4) and -64.8 (-67.5, -62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) -44.6% (-54.8, -32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was -44.5% (-55.0, -31.7) and -35.4% (-47.4, -20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone.

Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction.

OBJECTIVE: Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), and related comorbidities. Whether this metabolic dysfunction is driven by the excess dietary calories contained in fructose or whether fructose catabolism itself is uniquely pathogenic remains controversial. We sought to test whether a small molecule inhibitor of the primary fructose metabolizing enzyme ketohexokinase (KHK) can ameliorate the metabolic effects of fructose. METHODS: The KHK inhibitor PF-06835919 was used to block fructose metabolism in primary hepatocytes and Sprague Dawley rats fed either a high-fructose diet (30% fructose kcal/g) or a diet reflecting the average macronutrient dietary content of an American diet (AD) (7.5% fructose kcal/g). The effects of fructose consumption and KHK inhibition on hepatic steatosis, insulin resistance, and hyperlipidemia were evaluated, along with the activation of DNL and the enzymes that regulate lipid synthesis. A metabolomic analysis was performed to confirm KHK inhibition and understand metabolite changes in response to fructose metabolism in vitro and in vivo. Additionally, the effects of administering a single ascending dose of PF-06835919 on fructose metabolism markers in healthy human study participants were assessed in a randomized placebo-controlled phase 1 study. RESULTS: Inhibition of KHK in rats prevented hyperinsulinemia and hypertriglyceridemia from fructose feeding. Supraphysiologic levels of dietary fructose were not necessary to cause metabolic dysfunction as rats fed the American diet developed hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, which were all reversed by KHK inhibition. Reversal of the metabolic effects of fructose coincided with reductions in DNL and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP). We report that administering single oral doses of PF-06835919 was safe and well tolerated in healthy study participants and dose-dependently increased plasma fructose indicative of KHK inhibition. CONCLUSIONS: Fructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia, and hepatic steatosis, which were reversed by KHK inhibition.

Impact of area-level socioeconomic status and accessibility to treatment on life expectancy after a cancer diagnosis in Queensland, Australia.

AIMS: This study quantifies geographic inequities in loss of life expectancy (LOLE) by area-level socioeconomic status (SES) and accessibility to treatment. METHODS: Analysis was conducted using a population-based cancer-registry cohort (n = 371,570) of Queensland (Australia) residents aged 50-89 years, diagnosed between 1997-2016. Flexible parametric survival models were used to estimate LOLE by area-level SES and accessibility for all invasive cancers and the five leading cancers. The gain in life years that could be achieved if all cancer patients experienced the same relative survival as those in the least disadvantaged-high accessibility category was estimated for the 2016 cohort. RESULTS: For all invasive cancers, men living in the most disadvantaged areas lost 34 % of life expectancy due to their cancer diagnosis, while those from the least disadvantaged areas lost 25 %. The corresponding percentages for women were 33 % and 23 %. Accessibility had a lower impact on LOLE than SES, with patients from low accessibility areas losing 0-4 % more life expectancy than those from high accessibility areas. For cancer patients diagnosed in 2016 (n = 24,423), an estimated 101,387 life years will be lost. This would be reduced by 19 % if all patients experienced the same relative survival as those from the least disadvantaged-high accessibility areas. CONCLUSION: The impact of a cancer diagnosis on remaining life expectancy varies by geographical area. Establishing reasons why area disadvantage impacts on life expectancy is crucial to inform subsequent interventions that could increase the life expectancy of cancer patients from more disadvantaged areas.

Quantifying the Number of Cancer Deaths Avoided Due to Improvements in Cancer Survival since the 1980s in the Australian Population, 1985-2014.

BACKGROUND: This study quantifies the number of potentially "avoided"cancer deaths due to differences in 10-year relative survival between three time periods, reflecting temporal improvements in cancer diagnostic and/or treatment practices in Australia. METHODS: National population-based cohort of 2,307,565 Australians ages 15 to 89 years, diagnosed with a primary invasive cancer from 1985 to 2014 with mortality follow-up to December 31, 2015. Excess mortality rates and crude probabilities of cancer deaths were estimated using flexible parametric relative survival models. Crude probabilities were then used to calculate "avoided cancer deaths" (reduced number of cancer deaths within 10 years of diagnosis due to survival changes since 1985-1994) for all cancers and 13 leading cancer types. RESULTS: For each cancer type, excess mortality (in the cancer cohort vs. the expected population mortality) was significantly lower for more recently diagnosed persons. For all cancers combined, the number of "avoided cancer deaths" (vs. 1985-1994) was 4,877 (1995-2004) and 11,385 (2005-2014) among males. Prostate (1995-2004: 2,144; 2005-2014: 5,099) and female breast cancer (1,127 and 2,048) had the highest number of such deaths, whereas <400 were avoided for pancreatic or lung cancers across each period. CONCLUSIONS: Screening and early detection likely contributed to the high number of "avoided cancer deaths" for prostate and female breast cancer, whereas early detection remains difficult for lung and pancreatic cancers, highlighting the need for improved preventive and screening measures. IMPACT: Absolute measures such as "avoided cancer deaths" can provide a more tangible estimate of the improvements in cancer survival than standard net survival measures.

Temporal Trends in Population-Level Cure of Cancer: The Australian Context.

BACKGROUND: With the improvements in cancer diagnosis and treatment, more patients with cancer are surviving for longer periods than before. This study aims to quantify the proportion cured and median survival time for those who are not cured for major cancers in Australia. METHODS: Australian population-based cohort of 2,164,172 cases, ages 15 to 89 years, whose first cancer diagnosis between 1982 and 2014 was one of 22 leading cancers, were followed up to December 2014. Flexible parametric cure models were used to estimate the proportion cured and median survival time for those uncured by age, sex, and spread of disease, and temporal trends in these measures. RESULTS: Cure estimates could be generated for 19 of the 22 cancer types. The unadjusted proportion cured ranged from 5.0% for pancreatic cancer to 90.0% for melanoma. Median survival time for those uncured ranged from 0.35 years for pancreatic cancer to 6.05 years for prostate cancer. Cancers were divided into four groups according to their proportion cured in the 1980s and the degree of improvement over 28 years. Esophageal, stomach, pancreatic, liver, gallbladder, lung, and brain cancer had lower proportion cured and smaller improvements over time. CONCLUSIONS: For cancers with poor survival in which little has changed over time either in prolonging life or achieving statistical cure, efforts should be focused on reducing the prevalence of known risk factors and earlier detection, thereby enabling more effective treatment. IMPACT: Cure models provide unique insights into whether survival improvements are due to prolonging life or through curing the disease.

Temporal trends in loss of life expectancy after a cancer diagnosis among the Australian population.

BACKGROUND: Loss of life expectancy (LOLE) provides valuable insights into the impact of cancer. We evaluated the temporal trends in LOLE for Australian cancer patients and the gain in life years for recently diagnosed patients due to survival improvements. METHODS: Analysis was conducted using an Australian population-based cohort (n = 1,865,154) aged 50-89 years, who were primarily diagnosed with one of 19 leading cancers between 1982-2015. Flexible parametric survival models were used to estimate LOLE and the proportion of life lost (POLL) by year, age group, sex, and, for New South Wales only, spread of disease. The total years of LOLE and gain in life years due to survival improvements were estimated for those diagnosed in 2014. RESULTS: For 19 cancers combined, LOLE and POLL were significantly lower for more recent diagnoses. Cancer-specific temporal trends were consistent by age, sex, and spread of disease (where relevant) although the magnitude varied. Prostate, kidney, or non-Hodgkin lymphoma experienced the largest decreases in POLL over time. For the 2014 diagnoses, an estimation of 403,094 life years lost will be caused by the 19 cancers. With the increase in cancer survival over time, the 2014 cohort will gain an extra 432,588 life years (52 %) compared to that experienced by the 1982 cohort. CONCLUSION: While reduced impact of a cancer diagnosis on LOLE over time is encouraging, the growing number of cancer survivors in Australia is likely to pose complex challenges for cancer patients, their care givers, and health-care systems.