Development of a Multivariable Prediction Model for Risk of Hospitalization With Pressure Injury After Entering Residential Aged Care.

OBJECTIVES: Although largely preventable, pressure injury is a major concern in individuals in permanent residential aged care (PRAC). Our study aimed to identify predictors and develop a prognostic model for risk of hospitalization with pressure injury (PI) using integrated Australian aged and health care data. DESIGN: National retrospective cohort study. SETTING AND PARTICIPANTS: Individuals ≥65 years old (N = 206,540) who entered 1797 PRAC facilities between January 1, 2009, and December 31, 2016. METHODS: PI, ascertained from hospitalization records, within 365 days of PRAC entry was the outcome of interest. Individual, medication, facility, system, and health care-related factors were examined as predictors. Prognostic models were developed using elastic nets penalized regression and Fine and Gray models. Area under the receiver operating characteristics curve (AUC) assessed model discrimination out-of-sample. RESULTS: Within 365 days of PRAC entry, 4.3% (n = 8802) of individuals had a hospitalization with PI. The strongest predictors for PI risk include history of PIs [sub-distribution hazard ratio (sHR) 2.41; 95% CI 1.77-3.29]; numbers of prior hospitalizations (having ≥5 hospitalizations, sHR 1.95; 95% CI 1.74-2.19); history of traumatic amputation of toe, ankle, foot and leg (sHR 1.72; 95% CI 1.44-2.05); and history of skin disease (sHR 1.54; 95% CI 1.45-1.65). Lower care needs at PRAC entry with respect to mobility, complex health care, and medication assistance were associated with lower risk of PI. The risk prediction model had an AUC of 0.74 (95% CI 0.72-0.75). CONCLUSIONS AND IMPLICATIONS: Our prognostic model for risk of hospitalization with PI performed moderately well and can be used by health and aged care providers to implement risk-based prevention plans at PRAC entry.

Provision of a comprehensive medicines review is associated with lower mortality risk for residents of aged care facilities: a retrospective cohort study.

BACKGROUND: no studies have examined the impact of residential medication management review (RMMR, a 24-year government subsidised comprehensive medicines review program) in Australian residential aged care facilities (RACFs) on hospitalisation or mortality. OBJECTIVE: to examine associations between RMMR provision in the 6-12 months after RACF entry and the 12-month risk of hospitalisation and mortality among older Australians in RACFs. DESIGN: retrospective cohort study. SUBJECTS: individuals aged 65-105 years taking at least one medicine, who entered an RACF in three Australian states between 1 January 2012 and 31 December 2015 and spent at least 6 months in the RACF (n = 57,719). METHODS: Cox regression models estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for associations between RMMR provision and mortality. Adjusted subdistribution hazard ratios were estimated for associations between RMMR provision and next (i) emergency department (ED) presentation or unplanned hospitalisation or (ii) fall-related ED presentation or hospitalisation. RESULTS: there were 12,603 (21.8%) individuals who received an RMMR within 6-12 months of RACF entry, of whom 22.2% (95%CI 21.4-22.9) died during follow-up, compared with 23.3% (95%CI 22.9-23.7) of unexposed individuals. RMMR provision was associated with a lower risk of death due to any cause over 12-months (aHR 0.96, 95%CI 0.91-0.99), but was not associated with ED presentations or hospitalisations for unplanned events or falls. CONCLUSIONS: provision of an RMMR in the 6-12 months after RACF entry is associated with a 4.4% lower mortality risk over 12-months but was not associated with changes in hospitalisations for unplanned events or falls.

Medicines use before and after comprehensive medicines review among residents of long-term care facilities: a retrospective cohort study.

BACKGROUND: Residential Medication Management Review (RMMR) is a subsidized comprehensive medicines review program for individuals in Australian residential aged care facilities (RACFs). This study examined weekly trends in medicines use in the four months before and after an RMMR and among a comparison group of residents who did not receive an RMMR. METHODS: This retrospective cohort study included individuals aged 65 to 105 years who first entered permanent care between 1/1/2012 and 31/12/2016 in South Australia, Victoria, or New South Wales, and were taking at least one medicine. Individuals with an RMMR within 12 months of RACF entry were classified into one of three groups: (i) RMMR within 0 to 3 months, (ii) 3 to 6 months, or (iii) within 6 to 12 months of RACF entry. Individuals without RMMRs were included in the comparison group. Weekly trends in the number of defined daily doses per 1000 days were determined in the four months before and after the RMMR (or assigned index date in the comparison group) for 14 medicine classes. RESULTS: 113909 individuals from 1979 RACFs were included, of whom 55021 received an RMMR. Across all three periods examined, decreased use of statins and proton pump inhibitors was observed post-RMMR in comparison to those without RMMRs. Decreases in calcium channel blockers, benzodiazepines/zopiclone, and antidepressants were observed following RMMR provision in the 3-6 and 6-12 months after RACF entry. Negligible changes in antipsychotic use were also observed following an RMMR in the 6-12 months after RACF entry by comparison to those without RMMRs. No changes in use of opioids, ACE inhibitors/sartans, beta blockers, loop diuretics, oral anticoagulants, or medicines for osteoporosis, diabetes or the cognitive symptoms of dementia were observed post-RMMR. CONCLUSIONS: For six of the 14 medicine classes investigated, modest changes in weekly trends in use were observed after the provision of an RMMR in the 6-12 months after RACF entry compared to those without RMMRs. Findings suggest that activities such as medicines reconciliation may be prioritized when an RMMR is provided on RACF entry, with deprescribing more likely after an RMMR the longer a resident has been in the RACF.

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants.

Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery.

The risk of fall-related hospitalisations at entry into permanent residential aged care.

BACKGROUND: Entering permanent residential aged care (PRAC) is a vulnerable time for individuals. While falls risk assessment tools exist, these have not leveraged routinely collected and integrated information from the Australian aged and health care sectors. Our study examined individual, system, medication, and health care related factors at PRAC entry that are predictors of fall-related hospitalisations and developed a risk assessment tool using integrated aged and health care data. METHODS: A retrospective cohort study was conducted on N = 32,316 individuals ≥65 years old who entered a PRAC facility (01/01/2009-31/12/2016). Fall-related hospitalisations within 90 or 365 days were the outcomes of interest. Individual, system, medication, and health care-related factors were examined as predictors. Risk prediction models were developed using elastic nets penalised regression and Fine and Gray models. Area under the receiver operating characteristics curve (AUC) assessed model discrimination. RESULTS: 64.2% (N = 20,757) of the cohort were women and the median age was 85 years old (interquartile range 80-89). After PRAC entry, 3.7% (N = 1209) had a fall-related hospitalisation within 90 days and 9.8% (N = 3156) within 365 days. Twenty variables contributed to fall-related hospitalisation prediction within 90 days and the strongest predictors included fracture history (sub-distribution hazard ratio (sHR) = 1.87, 95% confidence interval (CI) 1.63-2.15), falls history (sHR = 1.41, 95%CI 1.21-2.15), and dementia (sHR = 1.39, 95%CI 1.22-1.57). Twenty-seven predictors of fall-related hospitalisation within 365 days were identified, the strongest predictors included dementia (sHR = 1.36, 95%CI 1.24-1.50), history of falls (sHR = 1.30, 95%CI 1.20-1.42) and fractures (sHR = 1.28, 95%CI 1.15-1.41). The risk prediction models had an AUC of 0.71 (95%CI 0.68-0.74) for fall-related hospitalisations within 90 days and 0.64 (95%CI 0.62-0.67) for within 365 days. CONCLUSION: Routinely collected aged and health care data, when integrated at a clear point of action such as entry into PRAC, can identify residents at risk of fall-related hospitalisations, providing an opportunity for better targeting risk mitigation strategies.

Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition.

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth.

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

Contribution of facility level factors to variation in antibiotic use in long-term care facilities: a national cohort study.

OBJECTIVES: To examine national variation in systemic antibiotic use in long-term care facilities (LTCFs) and identify facility characteristics associated with antibiotic utilization. METHODS: This retrospective cohort study included 312 375 residents of 2536 Australian LTCFs between 2011 and 2016. LTCFs were categorized as low, medium or high antibiotic use facilities according to tertiles of DDDs of systemic antibiotics dispensed per 1000 resident-days. Multivariable logistic regression estimated the associations between facility characteristics (ownership, size, location, medication quality indicator performance, prevalence of after-hours medical practitioner services) and antibiotic use (low versus high). RESULTS: LTCFs in the lowest and highest antibiotic use categories received a median of 54.3 (IQR 46.5-60.5) and 106.1 (IQR 95.9-122.3) DDDs/1000 resident-days, respectively. Compared with not-for-profit LTCFs in major cities, government-owned non-metropolitan LTCFs were less likely to experience high antibiotic use [adjusted OR (aOR) 0.47, 95% CI 0.24-0.91]. LTCFs with 69-99 residents were less likely to experience high antibiotic use (aOR 0.69, 95% CI 0.49-0.97) than those with 25-47 residents annually. Greater prevalence of medical practitioner services accessed after-hours was associated with high antibiotic use [aOR 1.10 (per 10% increase in after-hours services), 95% CI 1.01-1.21]. South Australian LTCFs (aOR 2.17, 95% CI 1.38-3.39) were more likely, while Queensland (0.43, 95% CI 0.30-0.62) and Western Australian (aOR 0.34, 95% CI 0.21-0.57) LTCFs were less likely to experience high antibiotic use than New South Wales LTCFs. CONCLUSIONS: Considerable facility level variation in systemic antibiotic use was observed across Australian LTCFs. Identification of facility characteristics associated with antibiotic use provides a basis for targeted stewardship initiatives.

Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease.

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/- mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.

National Trends in Antibiotic Use in Australian Residential Aged Care Facilities, 2005-2016.

BACKGROUND: Understanding current patterns of antibiotic use in residential aged care facilities (RACFs) is essential to inform stewardship activities, but limited utilization data exist. This study examined changes in prevalence and consumption of antibiotics in Australian RACFs between 2005-2006 and 2015-2016. METHODS: This population-based, repeated cross-sectional analysis included all long-term permanent residents of Australian RACFs between July 2005 and June 2016 who were aged ≥ 65 years. The yearly prevalence rate of antibiotic use and number of defined daily doses (DDDs) of systemic antibiotics per 1000 resident-days were determined annually from linked pharmaceutical claims data. Trends were assessed using ordinary least squares regression. RESULTS: This study included 502 752 residents from 3218 RACFs, with 424.9 million resident-days analyzed. Antibiotics were dispensed on 5 608 126 occasions during the study period, of which 88% were for oral use. Cefalexin, amoxicillin-clavulanic acid, and trimethoprim were the most commonly dispensed antibiotics. The annual prevalence of antibiotic use increased from 63.8% (95% confidence interval [CI], 63.3%-64.4%) to 70.3% (95% CI, 69.9%-70.7%) between 2005-2006 and 2015-2016 (0.8% average annual increase, P < .001). There was a 39% relative increase in total consumption of systemic antibiotics, with utilization increasing from 67.6 to 93.8 DDDs/1000 resident-days during the study period (average annual increase of 2.8 DDDs/1000 resident-days, P < .001). CONCLUSIONS: This nationwide study showed substantial increases in both prevalence of use and total consumption of antibiotics in Australian RACFs between 2005 and 2016. The increasingly widespread use of antibiotics in Australian RACFs is concerning and points to a need for enhanced efforts to optimize antibiotic use in this setting.

Salvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma.

BACKGROUND: Salvage systemic therapy has become the new standard of care in patients with advanced gastric and oesophago-gastric junction (OGJ) adenocarcinoma, following disease progression on first-line fluoropyrimidine and platinum-containing chemotherapy. Pharmacological agents proven to be effective in this setting include both chemotherapy and biological therapy, however, the consensus on the best salvage systemic therapy has not been reached. OBJECTIVES: To assess the effects of systemic chemotherapy and biological therapy, either alone or in combination, on overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric and OGJ adenocarcinoma, whose disease has progressed on, or relapsed after first-line fluoropyrimidine and platinum-containing chemotherapy. Adverse events (AEs), tumour response rate (TRR) and quality of life (QoL) associated with systemic chemotherapy and/or biological therapy were additionally assessed. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, trial registries and proceedings of the major oncology conferences up to October 2020. We additionally handsearched the reference lists of studies. No language restriction was applied. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing salvage systemic therapy (chemotherapy and/or biological therapy) and either another type of salvage systemic therapy, placebo, best supportive care (BSC) or no treatment in patients with gastric and OGJ adenocarcinoma refractory to first-line fluoropyrimidine and platinum-containing chemotherapy. DATA COLLECTION AND ANALYSIS: Two review authors independently performed selection of eligible studies and the primary author extracted study characteristics and outcome data from included studies. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We expressed pooled estimates of effect using hazard ratio (HR) calculated using an inverse variance random-effects model for time-to-event data, and risk ratio (RR) calculated using Mantel-Haenszel random-effects model for binary data. The certainty of evidence was graded using GRADEpro. MAIN RESULTS: We identified 17 RCTs with 5110 participants for inclusion in this review. Tweenty-nine studies are ongoing and twenty studies are awaiting classification. No studies examined the following comparisons: chemotherapy combined with biological therapy versus placebo, BSC or no treatment, chemotherapy combined with biological therapy versus biological therapy, biological therapy versus biological therapy and chemotherapy combined with biological therapy versus chemotherapy combined with biological therapy. Chemotherapy versus placebo, best supportive care or no treatment Chemotherapy probably improves OS (HR = 0.66, 95% CI 0.52 to 0.83, moderate-certainty evidence) based on two studies involving 547 participants and improves PFS (HR = 0.57, 95% CI 0.47 to 0.69, high-certainty evidence) based on one study involving 507 participants over placebo and BSC. Chemotherapy probably increases serious AEs (SAEs) (RR = 1.38, 95% CI 1.20 to 1.59, moderate-certainty evidence) based on one study involving 503 participants. Biological therapy versus placebo, best supportive care or no treatment Biological therapy improves OS (HR = 0.55, 95% CI 0.41 to 0.73, high-certainty evidence) and probably improves PFS (HR = 0.33, 95% CI 0.19 to 0.57, moderate-certainty evidence) over placebo based on three studies involving 781 participants. There is currently insufficient evidence for increased SAEs from biological therapy (RR = 1.14, 95% CI 0.95 to 1.37, low-certainty evidence) based on two studies involving 638 participants. Chemotherapy versus biological therapy This comparison only considered immunotherapy. There is probably no evidence of a difference for OS (HR = 0.82, 95% CI 0.66 to 1.02, moderate-certainty evidence) between chemotherapy and immunotherapy, and immunotherapy probably reduces PFS (HR = 1.27, 95% CI 1.03 to 1.57, moderate-certainty evidence) based on one study involving 395 participants. SAEs may be less frequent with immunotherapy compared to chemotherapy (RR = 0.41, 95% CI 0.30 to 0.57, low-certainty evidence). Chemotherapy combined with biological therapy versus chemotherapy Addition of biological therapy to chemotherapy probably does not improve OS (HR = 0.93, 95% CI 0.83 to 1.04, moderate-certainty evidence) and we are uncertain whether it improves PFS (HR = 0.87, 95% CI 0.74 to 1.02, very low-certainty evidence) based on seven studies involving 2743 participants. We are similarly uncertain whether combined chemotherapy and biological therapy increases SAEs (RR = 1.17, 95% CI 0.95 to 1.44, very low-certainty evidence) based on four studies involving 1618 participants. Chemotherapy versus chemotherapy There is no evidence of a difference for OS and PFS between irinotecan and paclitaxel (HR = 1.13, 95% CI 0.86 to 1.48, low-certainty evidence for OS; HR = 1.14, 95% CI 0.88 to 1.48, low-certainty evidence for PFS) based on one study involving 219 participants. Similarly, there is no evidence to indicate improved OS and PFS from addition of another chemotherapy to docetaxel (HR = 1.05, 95% CI 0.72 to 1.54, low-certainty evidence for OS; HR = 0.75, 95% CI 0.52 to 1.09, low-certainty evidence for PFS) based on two studies involving 121 participants. Grade ≥ 3 neutropenia occurred commonly with both mono- and poly-chemotherapy except for docetaxel-S1 and EOX chemotherapy. AUTHORS' CONCLUSIONS: Survival outcome of patients with advanced gastric and OGJ adenocarcinoma whose disease progressed on first-line fluoropyrimidine and platinum-containing chemotherapy can be improved by chemotherapy and biological therapy. Biological therapy, in particular, achieves this without clear increase in SAEs or QoL impairment. Whether biological therapy is preferred over chemotherapy is still unclear and there is no evidence of a difference for OS outcome, although immunotherapy may be associated with less SAEs. Addition of biological therapy to chemotherapy and poly-chemotherapy are associated with frequent treatment-related toxicity without clear survival benefit.

Development and validation of a frailty index based on Australian Aged Care Assessment Program data.

OBJECTIVES: To develop and validate a frailty index, derived from aged care eligibility assessment data. DESIGN: Retrospective cohort study; analysis of the historical national cohort of the Registry of Senior Australians (ROSA). PARTICIPANTS: 903 996 non-Indigenous Australians aged 65 years or more, living in the community and assessed for subsidised aged care eligibility during 2003-2013. MAIN OUTCOME MEASURES: 44-item frailty index; summary statistics for frailty index score distribution; predictive validity with respect to mortality and entry into permanent residential aged care during the five years after assessment. RESULTS: The mean frailty index score during 2003-2013 was 0.20 (SD, 0.07; range, 0-0.41); the proportion of assessed older people with scores exceeding 0.20 increased from 32.1% in 2003-2005 to 75.0% in 2012-2013. The risks of death and entry into permanent residential aged care at one, three and five years increased with frailty index score level (at one year, high [over 0.35] v low scores [under 0.05]: hazard ratio for death, 5.99; 95% CI, 5.69-6.31; for entry into permanent residential aged care, 8.70; 95% CI, 8.32-9.11). The predictive validity (area under the receiver operating characteristic curve) of Cox proportional hazard models including age, sex, and frailty index score was 0.64 (95% CI, 0.63-0.64) for death and 0.63 (95% CI, 0.62-0.63) for entry into permanent residential aged care within one year of assessment. CONCLUSIONS: We used Australian aged care eligibility assessment program data to construct and validate a frailty index. It can be employed in aged care research in Australia, but its application to aged care planning requires further investigation.

Fatty Acid Oxidation Is an Adaptive Survival Pathway Induced in Prostate Tumors by HSP90 Inhibition.

HSP90 is a molecular chaperone required for stabilization and activation of hundreds of client proteins, including many known oncoproteins. AUY922 (luminespib), a new-generation HSP90 inhibitor, exhibits potent preclinical efficacy against several cancer types including prostate cancer. However, clinical use of HSP90 inhibitors for prostate cancer has been limited by toxicity and treatment resistance. Here, we aimed to design an effective combinatorial therapeutic regimen that utilizes subtoxic doses of AUY922, by identifying potential survival pathways induced by AUY922 in clinical prostate tumors. We conducted a proteomic analysis of 30 patient-derived explants (PDE) cultured in the absence and presence of AUY922, using quantitative mass spectrometry. AUY922 significantly increased the abundance of proteins involved in oxidative phosphorylation and fatty acid metabolism in the PDEs. Consistent with these findings, AUY922-treated prostate cancer cell lines exhibited increased mitochondrial mass and activated fatty acid metabolism processes. We hypothesized that activation of fatty acid oxidation is a potential adaptive response to AUY922 treatment and that cotargeting this process will sensitize prostate cancer cells to HSP90 inhibition. Combination treatment of AUY922 with a clinical inhibitor of fatty acid oxidation, perhexiline, synergistically decreased viability of several prostate cancer cell lines, and had significant efficacy in PDEs. The novel drug combination treatment induced cell-cycle arrest and apoptosis, and attenuated the heat shock response, a known mediator of HSP90 treatment resistance. This combination warrants further preclinical and clinical investigation as a novel strategy to overcome resistance to HSP90 inhibition. IMPLICATIONS: Metabolic pathways induced in tumor cells by therapeutic agents may be critical, but targetable, mediators of treatment resistance.

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.

Fatty acid ß-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited ß-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.

Using elastic nets to estimate frailty burden from routinely collected national aged care data.

OBJECTIVES: To (1) use an elastic net (EN) algorithm to derive a frailty measure from a national aged care eligibility assessment program; (2) compare the ability of EN-based and a traditional cumulative deficit (CD) based frailty measures to predict mortality and entry into permanent residential care; (3) assess if the predictive ability can be improved by using weighted frailty measures. MATERIALS AND METHODS: A Cox proportional hazard model based EN algorithm was applied to the 2003-2013 cohort of 903 996 participants for selecting items to enter an EN based frailty measure. The out-of-sample predictive accuracy was measured by the area under the curve (AUC) from Cox models fitted to 80% training and validated on 20% testing samples. RESULTS: The EN approach resulted in a 178-item frailty measure including items excluded from the 44-item CD-based measure. The EN based measure was not statistically significantly different from the CD-based approach in terms of predicting mortality (AUC 0.641, 95% CI: 0.637-0.644 vs AUC 0.637, 95% CI: 0.634-0.641) and permanent care entry (AUC 0.626, 95% CI: 0.624-0.629 vs AUC 0.627, 95% CI: 0.625-0.63). However, the weighted EN based measure statistically outperforms the weighted CD measure for predicting mortality (AUC 0.774, 95% CI: 0.771-0.777 vs AUC 0.757, 95% CI: 0.754-0.760) and permanent care entry (AUC 0.676, 95% CI: 0.673-0.678 vs AUC 0.671, 95% CI: 0.668-0.674). CONCLUSIONS: The weighted EN and CD-based measures demonstrated similar prediction performance. The CD-based measure items are relevant to frailty measurement and easier to interpret. We recommend using the weighted and unweighted CD-based frailty measures.

Does long-term use of antidiabetic drugs changes cancer risk?

Antidiabetic medications are commonly used around the world, but their safety is still unclear. The aim of this study was to investigate whether long-term use of insulin and oral antidiabetic medications is associated with cancer risk.We conducted a well-designed case-control study using 12 years of data from Taiwan's National Health Insurance Research Database and investigated the association between antidiabetic medication use and cancer risk over 20 years. We identified 42,500 patients diagnosed with cancer and calculated each patient's exposure to antidiabetic drugs during the study period. We matched cancer and noncancer subjects matched 1:6 by age, gender, and index date, and used Cox proportional hazard regression and conditional logistic regression, adjusted for potential confounding factors, that is, medications and comorbid diseases that could influence cancer risk during study period.Pioglitazone (adjusted odds ratio [AOR], 1.20; 95% confidence interval [CI], 1.05-1.38); and insulin and its analogs for injection, intermediate or long acting combined with fast acting (AOR, 1.22; 95% CI, 1.05-1.43) were significantly associated with a higher cancer risk. However, metformin (AOR, 1.00; 95% CI, 0.93-1.07), glibenclamide (AOR, 0.98; 95% CI, 0.92-1.05), acarbose (AOR, 1.06; 95% CI, 0.96-1.16), and others do not show evidence of association with cancer risk. Moreover, the risk for specific cancers among antidiabetic users as compared with nonantidiabetic medication users was significantly increased for pancreas cancer (by 45%), liver cancer (by 32%), and lung cancer (by 18%).Antidiabetic drugs do not seem to be associated with an increased cancer risk incidence except for pioglitazone, insulin and its analogs for injection, intermediate or long acting combined with fast acting.

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Changes in the Composition of the Gut Microbiota and the Blood Transcriptome in Preterm Infants at Less than 29 Weeks Gestation Diagnosed with Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a common chronic lung condition in preterm infants that results in abnormal lung development and leads to considerable morbidity and mortality, making BPD one of the most common complications of preterm birth. We employed RNA sequencing and 16S rRNA gene sequencing to profile gene expression in blood and the composition of the fecal microbiota in infants born at <29 weeks gestational age and diagnosed with BPD in comparison to those of preterm infants that were not diagnosed with BPD. 16S rRNA gene sequencing, performed longitudinally on 255 fecal samples collected from 50 infants in the first months of life, identified significant differences in the relative levels of abundance of Klebsiella, Salmonella, Escherichia/Shigella, and Bifidobacterium in the BPD infants in a manner that was birth mode dependent. Transcriptome sequencing (RNA-Seq) analysis revealed that more than 400 genes were upregulated in infants with BPD. Genes upregulated in BPD infants were significantly enriched for functions related to red blood cell development and oxygen transport, while several immune-related pathways were downregulated. We also identified a gene expression signature consistent with an enrichment of immunosuppressive CD71+ early erythroid cells in infants with BPD. Intriguingly, genes that were correlated in their expression with the relative abundances of specific taxa in the microbiota were significantly enriched for roles in the immune system, suggesting that changes in the microbiota might influence immune gene expression systemically.IMPORTANCE Bronchopulmonary dysplasia (BPD) is a serious inflammatory condition of the lung and is the most common complication associated with preterm birth. A large body of evidence now suggests that the gut microbiota can influence immunity and inflammation systemically; however, the role of the gut microbiota in BPD has not been evaluated to date. Here, we report that there are significant differences in the gut microbiota of infants born at <29 weeks gestation and subsequently diagnosed with BPD, which are particularly pronounced when infants are stratified by birth mode. We also show that erythroid and immune gene expression levels are significantly altered in BPD infants. Interestingly, we identified an association between the composition of the microbiota and immune gene expression in blood in early life. Together, these findings suggest that the composition of the microbiota may influence the risk of developing BPD and, more generally, may shape systemic immune gene expression.

Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRASG13D mutation.

BACKGROUND: Activating mutations in KRAS frequently occur in colorectal cancer (CRC) patients, leading to resistance to EGFR-targeted therapies. METHODS: To better understand the cellular reprogramming which occurs in mutant KRAS cells, we have undertaken a systems-level analysis of four CRC cell lines which express either wild type (wt) KRAS or the oncogenic KRASG13D allele (mtKRAS). RESULTS: RNAseq revealed that genes involved in ribosome biogenesis, mRNA translation and metabolism were significantly upregulated in mtKRAS cells. Consistent with the transcriptional data, protein synthesis and cell proliferation were significantly higher in the mtKRAS cells. Targeted metabolomics analysis also confirmed the metabolic reprogramming in mtKRAS cells. Interestingly, mtKRAS cells were highly transcriptionally responsive to EGFR activation by TGFα stimulation, which was associated with an unexpected downregulation of genes involved in a range of anabolic processes. While TGFα treatment strongly activated protein synthesis in wtKRAS cells, protein synthesis was not activated above basal levels in the TGFα-treated mtKRAS cells. This was likely due to the defective activation of the mTORC1 and other pathways by TGFα in mtKRAS cells, which was associated with impaired activation of PKB signalling and a transient induction of AMPK signalling. CONCLUSIONS: We have found that mtKRAS cells are substantially rewired at the transcriptional, translational and metabolic levels and that this rewiring may reveal new vulnerabilities in oncogenic KRAS CRC cells that could be exploited in future.

Identification of Novel Response and Predictive Biomarkers to Hsp90 Inhibitors Through Proteomic Profiling of Patient-derived Prostate Tumor Explants.

Inhibition of the heat shock protein 90 (Hsp90) chaperone is a promising therapeutic strategy to target expression of the androgen receptor (AR) and other oncogenic drivers in prostate cancer cells. However, identification of clinically-relevant responses and predictive biomarkers is essential to maximize efficacy and treatment personalization. Here, we combined mass spectrometry (MS)-based proteomic analyses with a unique patient-derived explant (PDE) model that retains the complex microenvironment of primary prostate tumors. Independent discovery and validation cohorts of PDEs (n = 16 and 30, respectively) were cultured in the absence or presence of Hsp90 inhibitors AUY922 or 17-AAG. PDEs were analyzed by LC-MS/MS with a hyper-reaction monitoring data independent acquisition (HRM-DIA) workflow, and differentially expressed proteins identified using repeated measure analysis of variance (ANOVA; raw p value <0.01). Using gene set enrichment, we found striking conservation of the most significantly AUY922-altered gene pathways between the discovery and validation cohorts, indicating that our experimental and analysis workflows were robust. Eight proteins were selectively altered across both cohorts by the most potent inhibitor, AUY922, including TIMP1, SERPINA3 and CYP51A (adjusted p < 0.01). The AUY922-mediated decrease in secretory TIMP1 was validated by ELISA of the PDE culture medium. We next exploited the heterogeneous response of PDEs to 17-AAG in order to detect predictive biomarkers of response and identified PCBP3 as a marker with increased expression in PDEs that had no response or increased in proliferation. Also, 17-AAG treatment led to increased expression of DNAJA1 in PDEs that exhibited a cytostatic response, revealing potential drug resistance mechanisms. This selective regulation of DNAJA1 was validated by Western blot analysis. Our study establishes "proof-of-principle" that proteomic profiling of drug-treated PDEs represents an effective and clinically-relevant strategy for identification of biomarkers that associate with certain tumor-specific responses.