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Diameters for drainage stacks and vent lines within high-rise building drainage systems are determined by consulting building standard agencies’ design codes. While these are critical design decisions, codes are based upon dated research (1940s to 1970s), which has numerous inherent limitations, and the methodologies employed within the codes are unclear. Thus, a new methodology is presented which is based upon an analogy with other forms of multiphase flow transport systems. This methodology assumes, as a pre-condition, that flows of air and the flow of water within the stack are reasonably steady over time. Component diameters must then be chosen which ensure an acceptably large air supply or air–water flow ratio, and an acceptably small pressure excursion within the stack. Two ways to implement this methodology are presented: an ‘explicit approach’, in which component diameters are directly calculated using empirical correlations, and an ‘implicit approach’, in which component diameters are determined by iteration, using a hydraulic model. The methodology pre-conditions of the approach are then discussed. The physical geometry of the stack and branches tends to promote steady water flow but to render air flow very susceptible to temporary interruptions. A need to maintain the air pathway within high-rise drainage systems using components to supplement the air feed drawn in through the roof vent as required is highlighted.

Supplementary Data from Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment

Supplementary Figure from Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4–4.5) or long-term (median 29 months; range 23.5–41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders.Implications:Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

Purpose:In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation.Patients and Methods:In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis.Results:In 247 patients, the overall prevalence of ctDNA, AR aberrations, and TP53 inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS (HR, 2.01 or 2.17, respectively; P < 0.0001 for both), any AR aberration with PFS2 (1.74; P = 0.024), and TP53 or BRCA2 inactivation with OS (2.06; P = 0.003; or 3.1; P < 0.0001).Conclusions:Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and TP53/BRCA2 inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.

Purpose: Abiraterone may suppress androgens that stimulate breast cancer growth. We conducted a biomarker analysis of circulating tumor cells (CTCs), formalin-fixed paraffin-embedded tissues (FFPETs), and serum samples from postmenopausal estrogen receptor (ER)+ breast cancer patients to identify subgroups with differential abiraterone sensitivity.Methods: Patients (randomized 1:1:1) were treated with 1,000 mg/d abiraterone acetate + 5 mg/d prednisone (AA), AA + 25 mg/d exemestane (AAE), or exemestane. The biomarker population included treated patients (n = 293). The CTC population included patients with ≥3 baseline CTCs (n = 104). Biomarker [e.g., androgen receptor (AR), ER, Ki-67, CYP17] expression was evaluated. Cox regression stratified by prior therapies in the metastatic setting (0/1 vs. 2) and setting of letrozole/anastrozole (adjuvant vs. metastatic) was used to assess biomarker associations with progression-free survival (PFS).Results: Serum testosterone and estrogen levels were lowered and progesterone increased with AA. Baseline AR or ER expression was not associated with PFS in CTCs or FFPETs for AAE versus exemestane, but dual positivity of AR and ER expression was associated with improved PFS [HR, 0.41; 95% confidence interval (CI), 0.16–1.07; P = 0.070]. For AR expression in FFPETs obtained n = 67), a trend for improved PFS was noted for AAE versus exemestane (HR, 0.56; 95% CI, 0.24–1.33; P = 0.19).Conclusions: An AA pharmacodynamic effect was shown by decreased serum androgen and estrogen levels and increased progesterone. AR and ER dual expression in CTCs and newly obtained FFPETs may predict AA sensitivity. Clin Cancer Res; 22(24); 6002–9. ©2016 AACR.

Supplementary Data for Smith et al SPARTAN AR Aberrations

Supplementary Table S1. Biomarkers evaluated Supplementary Table S2. Additional biomarker associations with PFS by treatment

Supplementary Data Supplementary Table S1 Characteristics of the patient-derived xenograft models and protein expression by immunohistochemistry Supplementary Table S2. Primer sequences used in real-time PCR analysis Supplementary Table S3. Microarray gene expression analysis of steroidogenic genes in AA- versus vehicle-treated tumors upon AAresistance (end of study, EOS) Supplementary Table S4. Castration effects (vs. intact) on LuCaP PDX AR gene expression Supplementary Table S5. Upregulated genes in both ultraresponsive LuCaP 136CR and minimal responder LuCaP 35CR: lack of involvement in AR/GR signaling Supplementary Fig. S1. Treatment scheme and survival curves for AA on CRPC PDXs. Castration-resistant tumors were developed by either A, implanting castration-resistant tumors into castrated SCID mice (LuCaP 70CR), or B, implanting androgen-sensitive tumors into intact SCID mice and castrating mice when the tumor reached 100 mm3 (LuCaP 86.2CR). Castrated mice with castration-resistant tumors were treated orally with either vehicle or AA (0.5 mmol/kg/day) on a weekly schedule of 5 days on, 2 days off. Tumors were measured twice weekly. Mice were sacrificed and tumors were harvested on D7 or when tumors reached 1,000 mm3 (EOS). Supplementary Fig. S2. Differential gene expression associated with secreted proteins in the AA ultraresponder LuCaP 136CR. A, Chart showing 44% (68 genes) of 156 genes that were differentially expressed in the ultraresponder LuCaP 136CR (vs. intermediate responder LuCaP 96CR and minimal responder LuCaP 35CR) and were mapped into gene family coding for secreted proteins. Supervised clustering analyses showing 68 genes coding for secreted proteins at B, D7 and C, EOS. Red: high gene expression; green: low gene expression. Supplementary Fig. S3. Heat map showing the top 10 upregulated and top 10 downregulated genes representing secreted proteins in the LuCaP models at D7 and EOS. Yellow: high gene expression; blue: low gene expression. The heat map showed a homogeneous upregulation of the top 10 upregulated genes in LuCaP 136CR and a heterogeneous downregulation of the top 10 downregulated genes in LuCaP 136CR. Supplementary Fig. S4. qPCR confirmation on the top 10 downregulated genes of secreted proteins identified in the AA ultraresponder LuCaP 136CR versus intermediate responder LuCaP 77CR and LuCaP 96CR, and minimal responder LuCaP 35CR. Each data point represented one animal. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Supplementary Fig. S5. GSEA showing the association between differentially expressed genes upon AA treatment (D7) and resistance (EOS) in the LuCaP models with biological functions. False discovery rate

Supplementary Figure S1. Comparison of associations of the negative expression of androgen receptor (AR) (< 10%) with progression-free survival (PFS).

Purpose: To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).Experimental Design: SCID mice bearing LuCaP 136CR, 77CR, 96CR, and 35CR PDXs were treated with AA. Tumor volume and prostate-specific antigen were monitored, and tumors were harvested 7 days after treatment or at end of study for gene expression and immunohistochemical studies.Results: Three phenotypic groups were observed based on AA response. An ultraresponsive phenotype was identified in LuCaP 136CR with significant inhibition of tumor progression and increased survival, intermediate responders LuCaP 77CR and LuCaP 96CR with a modest tumor inhibition and survival benefit, and LuCaP 35CR with minimal tumor inhibition and no survival benefit upon AA treatment. We identified a molecular signature of secreted proteins associated with the AA ultraresponsive phenotype. Upon resistance, AA ultraresponder LuCaP 136CR displayed reduced androgen receptor (AR) signaling and sustainably low nuclear glucocorticoid receptor (nGR) localization, accompanied by steroid metabolism alteration and epithelial–mesenchymal transition phenotype enrichment with increased expression of NF-κB–regulated genes; intermediate and minimal responders maintained sustained AR signaling and increased tumoral nGR localization.Conclusions: We identified a molecular signature of secreted proteins associated with AA ultraresponsiveness and sustained AR/GR signaling upon AA resistance in intermediate or minimal responders. These data will inform development of noninvasive biomarkers predicting AA response and suggest that further inhibition along the AR/GR signaling axis may be effective only in AA-resistant patients who are intermediate or minimal responders. These findings require verification in prospective clinical trials. Clin Cancer Res; 23(9); 2301–12. ©2016 AACR.

PDF file - 111K, Cyclin D1 dependent DHT regulated gene expression.

PDF file - 131K, Endogenous cyclin D1 maintains prostate cancer stem cell population.

Endogenous cyclin D1 promotes LNCaP cell proliferation and DNA synthesis (S1); The epithelial population in Cyclin D1+/+ PECs is predominantly composed of luminal CK8+ cells (S2).

PDF file - 293K, Supplemental Figure 1. Reduced DACH1 mRNA in NSCLC. Supplemental Figure 2. DACH1 and p53 co-localized in a nuclear extranucleolar location.Supplemental Figure 3. Western blot analysis of H1299 cells treated with 5-Aza-2'- deoxycytidine (5MM) for 5 days and Trichostatin A (1MM, 8hrs).Supplemental Figure 4. EGFR and DACH1 expression in NSCLC vs. SCLC.

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PDF file - 38K, Supplemental Table 1. Genes binding both P53 and DACH1 in ChIP Seq.

PDF file - 208K, DHT regulated gene pathways in cyclin D1+/+ and cyclin D1-/- mouse prostates.

XLSX file - 118K, Functional annotation clustering of cyclin D1 induced genes.

XLSX file - 398K, Lists of genes differentially regulated by DHT in cyclin D1+/+ mice, DHT regulated genes in cyclin D1-/- mice and genes differentially regulated by cyclin D1.

PDF file - 83K, Cyclin D1 is required for prostate development in vivo.

PDF file - 107K, Cyclin D1 expression signature is induced in prostatospheres and induction of Wnt.

Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promote DNA double-strand break repair to reduce DNA damage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of γH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgen-enhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormone-mediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance. Cancer Res; 76(2); 329–38. ©2015 AACR.

Improved clinical management of prostate cancer has been impeded by an inadequate understanding of molecular genetic elements governing tumor progression. Gene signatures have provided improved prognostic indicators of human prostate cancer. The TGF-β/BMP-SMAD4 signaling pathway, which induces epithelial–mesenchymal transition (EMT), is known to constrain prostate cancer progression induced by Pten deletion. Herein, cyclin D1 inactivation reduced cellular proliferation in the murine prostate in vivo and in isogenic oncogene–transformed prostate cancer cell lines. The in vivo cyclin D1–mediated molecular signature predicted poor outcome of recurrence-free survival for patients with prostate cancer (K-means HR, 3.75, P = 0.02) and demonstrated that endogenous cyclin D1 restrains TGF-β, Snail, Twist, and Goosecoid signaling. Endogenous cyclin D1 enhanced Wnt and ES cell gene expression and expanded a prostate stem cell population. In chromatin immunoprecipitation sequencing, cyclin D1 occupied genes governing stem cell expansion and induced their transcription. The coordination of EMT restraining and stem cell expanding gene expression by cyclin D1 in the prostate may contribute to its strong prognostic value for poor outcome in biochemical-free recurrence in human prostate cancer. Cancer Res; 74(2); 508–19. ©2013 AACR.

BACKGROUND: Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment. PATIENTS AND METHODS: Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS). RESULTS: Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients. CONCLUSIONS: Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.

This paper evaluates the technical aspects of grid-connected photovoltaic (PV) systems and distributed energy resources (DERs) interconnection grid codes. The advanced functions of smart PV inverters and smart grid solutions are discussed as well as the gaps of the existing grid codes that hinder DER ancillary services. An online survey targeted the key stakeholders and industry experts have been conducted to investigate advanced inverters potential of providing DER ancillary services to distribution grids. The survey results are discussed in details and recommendations for the reactive power support of DER inverters and DER interconnection codes enhancements are presented.Keywords: Distributed Energy Sources, Distributed Energy Resource Interconnection Grid Codes, Distributed Energy Resource Ancillary Services, Distributed Energy Resource Integration, Advanced Inverters Capabilities, Volt/Var ControlJEL Classifications: P48, Q42, Q48DOI: https://doi.org/10.32479/ijeep.8758

A model is presented which allows steady-state pressure profiles in high-rise wastewater drainage networks to be related to intake air flowrates and discharge water flowrates. This model is developed using data taken from academic literature, and is based on experimental observations which suggest that a vertical annular downflow develops over distance such that the pressure gradient in the wet stack may be expressed as the sum of junction components and developed flow components. The model is used to analyse a simplified ‘medium rise’ primary vented system of height 40 m, hosting two inflow junctions, crossvents and Air Admittance Valves (AAVs). The model illustrates how the air supply configuration affects the airflow rates within the stack and the vents, and how the configuration affects the steady-state hydraulic pressure profile. The model offers the possibility of an alternative approach to the design of high-rise wastewater drainage networks, compared to existing design codes. These codes generally do not explain the role that the air admitted into the network has upon its performance.

Optimal therapeutic strategy remains an unmet need in localised high-risk prostate cancer (LHRPC). Androgen biosynthesis inhibition in the preoperative setting may improve outcomes. In this single-centre randomised trial, we looked at therapy outcomes of preoperative treatment with abiraterone acetate+prednisone (AAP)+luteinising hormone-releasing hormone agonist (LHRHa) or LHRHa alone followed by radical prostatectomy in 65 men. We did not see a significant difference of organ-confined carcinoma (p=0.27). However, tumour volume measures were significantly lower for AAP+LHRHa treatment (p≤0.001). Of note, lower tumour epithelium volume correlated with improved biochemical recurrence-free survival at ≥4-yr follow-up (p=0.0014). Tumours pretreated with AAP+LHRHa had lower proliferation and androgen signalling expression than LHRHa. On multivariate analysis, glucocorticoid receptor (GR) overexpression correlated with persistent tumours in AAP+LHRHa (p=0.018). The presence of nuclear androgen receptor splice variant (nARV7) correlated with persistent tumours in both arms. No new safety signals were observed. This is the first study investigating the role of preoperative AAP+LHRHa versus LHRHa alone in LHRPC. We report significant cytoreduction by tumour volume measures inversely correlating with biochemical relapse. Validation of these proposed tumour volume measures is planned. A potential role of GR in resistance to androgen biosynthesis inhibition warrants further study. PATIENT SUMMARY: This is the first study of abiraterone acetate plus leuprolide versus leuprolide alone in high-risk localised prostate cancer followed by prostatectomy. Patients in the combination arm had a significantly smaller tumour size.

Tumor cells of metastatic castration-resistant prostate cancer (mCRPC) patients with homologous recombination deficiency (HRD) are highly sensitive to the blockade of DNA single-strand break repair via the inhibition of the poly(adenosine diphosphate-ribose) polymerase (PARP) family of nuclear proteins. Niraparib is a highly selective PARP inhibitor, with activity against PARP-1/2 DNA-repair polymerases, and the Resolution HRD assay is being developed as a companion diagnostic for niraparib. Detection of HRD in cell free DNA (cfDNA) isolated from blood is minimally invasive and is of special benefit to mCRPC patients, many without accessible lesions. The Resolution HRD assay identifies patients with substitutions, insertions, deletions, and homozygous deletions of the ATM, BRCA1, BRCA2, BRIP1, CDK12 (except homozygous deletions), CHEK2, FANCA, HDAC2, and PALB2 genes by targeted NGS sequencing of cfDNA isolated from plasma. Analytical performance of the Resolution HRD assay was validated using cfDNA from mCRPC patient plasma, cfDNA from healthy donor plasma, and contrived samples with a wide spectrum of technically challenging genetic aberrations along with CRISPR-engineered human cell lines with ATM and BRCA2 gene deletions. The LOD95 was established for substitutions, insertions, deletions, and homozygous deletions for genes represented in the HRD panel with variant types including complex indels, long indels, and challenging genomic settings including homopolymeric and GC-rich regions. mCRPC specimens were used to confirm an acceptable level of precision near 1X LOD and 2-3X LOD concentrations for all 4 variant types. No false-positives were detected in any samples from healthy donors. Resolution HRD has been validated to give consistent results across the 15-30 ng input range. Studies to confirm accuracy of the Resolution HRD test results using a validated orthogonal method will be presented. The Resolution HRD assay offers highly sensitive, specific, and robust test results, and meets analytical requirements for clinical applications. It is intended as a companion diagnostic to niraparib in combination with abiraterone acetate plus prednisone (AAP) for the treatment of mCRPC patients. Citation Format: Julia Pollak, Kristy Potts, PuiYee Chan, Chen-Hsun Tsai, Angela Liao, Carly Garrison, Taylor Brown, Paul Stull, Zhen Li, Christine Baker, Kavita Garg, Ira Pekker, Michael Farabaugh, Michael Gormley, Lesley Farrington, Katherine Bell, Usha Singh. Analytical validation of the Resolution HRD plasma assay used to identify mCRPC patients with mutations, including homozygous deletions, in DNA repair genes as a companion diagnostic for niraparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 52.

5066 Background: TITAN, a phase 3 PBO-controlled study in patients (pts) with mCSPC, showed APA + ADT improved radiographic progression-free survival and OS vs PBO + ADT. In this exploratory analysis, we report the relationships between biomarkers and OS in TITAN. Methods: Circulating tumor (ct)DNA and genomic aberrations in 17 PC-related genes, including androgen receptor (AR), were assessed at baseline (BL; 114 pts) and end of study treatment (EOST; 129 pts) using next-generation sequencing. ctDNA was assessed qualitatively; genomic aberrations were assessed within ctDNA-positive samples as inactivation (heterozygous/homozygous deletion or single nucleotide variant [SNV]) or activation (amplification or SNV). Associations of detected ctDNA/aberrations at BL or EOST with OS, and biomarkers at EOST with OS on subsequent therapies, were evaluated using univariate or multivariate analyses and Cox proportional hazards model; results were stratified by treatment arm. Results: Among pts from both treatment groups, 36% had detectable ctDNA, of which 27% had any genomic AR aberration and 24% had AR gene amplification at BL; prevalence of these biomarkers increased significantly from BL to EOST (Table). The most prevalent non-AR aberrations at BL ( TP53, homologous recombination repair [HRR] pathway, PTEN, RB1, and PIK3CA genes) increased at EOST but not significantly (Table). Among assessed aberrations, presence of ctDNA or any AR genomic aberrations at BL (HR, 1.9 or 6.7; all p < 0.05) and any AR genomic aberrations or PI3K pathway activation at EOST (1.7, p < 0.05 or 2.2, p < 0.001) was significantly associated with poor OS in multivariate analyses from both treatment groups. In univariate analyses of pts who received subsequent therapy (chemotherapy: 106; hormonal therapy: 161), worse OS was associated only with PIK3CA activation, PI3K pathway activation, or TP53 inactivation at EOST (3.7, p < 0.05; 2.4, p < 0.05; 3.0, p < 0.01, respectively) in chemo-treated pts. A small sample size in some biomarker subgroups limits interpretation. Conclusions: These hypothesis-generating data from TITAN show that presence of ctDNA or select AR and non-AR biomarkers at BL or EOST were associated with poor OS. The predictive value of these biomarkers for survival in mCSPC needs further confirmation. Clinical trial information: NCT02489318. [Table: see text]

5020 Background: NIRA + AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. There is a paucity of data supporting use of PARP inhibitors in pts with HRR gene alterations other than BRCA1/2. We report on the efficacy of NIRA + AAP in pts with mCRPC and a qualifying single gene HRR alteration other than BRCA1/2. Methods: A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) across 186 pts (91 randomized to NIRA + AAP, 95 to PBO + AAP) with an alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene (excluding cooccurring alterations) . This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity are also presented. Results: (Table). Pts with PALB2 or CHEK2 alterations had consistent improvement across all endpoints. In pts with ATM alterations benefit was observed in TCC, TSP, TPSA and ORR. There was benefit only in TPSA and ORR for pts with CDK12 alterations. When combined into functional groups, pts with an alteration in the HRR-Fanconi pathway ( BRIP1, FANCA, and PALB2) as well as pts with a HRR associated alteration ( CHEK2 or HDAC2) showed improvement in all endpoints. Conclusions: These data support the overall conclusions of the MAGNITUDE primary analysis and support benefit of NIRA + AAP in pts with HRR mutations beyond BRCA1/2. Clinical trial information: NCT03748641. [Table: see text]

National design guides provide essential guidance for the design of building drainage systems, which primarily ensure the basic objectives of preventing odor ingress and cross-transmission of disease through water-trap seal retention. Current building drainage system design guides only extend to buildings of 30 floors, while modern tall buildings frequently extend to over 100 floors, exceeding the predictive capability of current design guides in terms of operating system conditions. However, the same design guides are being used for tall buildings as would be used for low-rise buildings. A complicating factor is the historic roots of current design guides and standards (including the interpretation of the governing fluid mechanics principles and margins of safety), causing many design differences to exist for the same conditions internationally, such as minimum trap seal retention requirements, stack-to-vent cross-vent spacing, and even stack diameter. The design guides also differ in the size and scale of the systems they cover, and most make no allowance for the specific building drainage system requirements of tall buildings. This paper assesses the limitations of applying current building drainage system design guides when applied to the case of tall buildings. Primarily, the assessments used in this research are based on codes from Europe, the USA and Australia/New Zealand as representative of the most common approaches and from which many other codes and standards are derived. The numerical simulation model, AIRNET, was used as the analysis tool. Our findings confirm that current design guides, which have been out of date for a number of decades, are now in urgent need of updating as code-compliant systems have been shown to be susceptible to water-trap seal depletion, a risk to cross-transmission of disease, which is a major public health concern, particularly in view of the current COVID-19 pandemic.