Patterns of Structural Variation Define Prostate Cancer Across Disease States

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation reflects the genomic landscape of this disease. We comprehensively characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes in mCRPC. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.

P070 Oronasal masks are associated with increased airway collapsibility and increased therapeutic CPAP requirements

Introduction Continuous positive airway pressure (CPAP) delivered via oronasal masks are associated with lower adherence, higher residual AHI and CPAP requirement in comparison to nasal masks. Mechanisms contributing to increased CPAP requirement are not well understood. This physiological study aimed to assess the effect of mask type on upper airway anatomy and collapsibility. Methods 13 OSA patients, underwent a sleep study during which they wore both nasal and oronasal mask for half the night each (order randomized). CPAP was manually titrated to determine therapeutic pressure. Passive upper airway collapsibility was assessed using the Pcrit technique. Participants then underwent an MRI wearing both the nasal and oronasal mask. Cine MRI was used to dynamically assess cross-sectional area of the retroglossal airway across the respiratory cycle with each mask interface. Scans were repeated at 4cmH2O, as well as at the nasal and oronasal therapeutic pressures. Results The oronasal mask was associated with both higher therapeutic pressure requirements (∆M±SEM; +2.6±0.5, p<0.001) and higher Pcrit (+2.4±0.5cmH2O, p=0.001) compared to the nasal mask. The change in therapeutic pressure between masks was strongly correlated with the change in Pcrit (r2= 0.73, p=0.003). Preliminary MRI analyses indicate robust increases in cross-sectional area associated with increasing pressure. After controlling for pressure and breath-phase, the retroglossal area was larger when using a nasal compared to an oronasal mask (+12.42±5.87mm2, p=0.03). Conclusions These preliminary findings suggest that oronasal masks worsen the collapsibility of the airway which likely contributes to the need for an elevated therapeutic pressure relative to nasal masks.

Negative pressure wound therapy—two novel approaches to healing dehisced vascular bypass wounds

The use of negative pressure wound therapy (NPWT) in surgical wound healing by secondary intention is well known. Its use in healing dehisced vascular bypass wounds is contraindicated by manufacturers due to exposed vasculature and risk of bleeding. There is an increasing body of knowledge to support the use of NPWT in vascular wounds in order to prevent graft excision and the need for flap closure. This paper reports the use of two different approaches using NPWT to heal dehisced, infected vascular groin bypass wounds in two patients. Both patients had lower limb bypass using Dacron (Vascutek Ltd., UK) grafts and subsequently became infected, dehisced and required debridement. Following debridement, graft was visible in the wound bed and NPWT was applied to facilitate healing. Case one had polyurethane (black) foam and a layer of petroleum-impregnated cellulose acetate mesh to prevent adherence to the graft. Case two had polyvinyl alcohol (white) (PVA) foam applied to the wound. The PVA foam was used in Case two due to pain at dressing changes. Negative pressure was initially –25mmHg but increased gradually to –125mmHg and –150mmHg, respectively, the therapeutic pressure for the respective foams. Dressings were changed every 48–72 hours and infection treated with antibiotics as appropriate. After eight days and 28 days of NPWT, respectively, graft was no longer visible. No significant bleeding was noted. These two case studies would suggest that, with precautions taken to protect the vasculature, the use of NPWT in healing dehisced vascular groin wounds is an appropriate treatment.

Molecular docking-based screening for novel inhibitors of the human immunodeficiency virus type 1 protease that effectively reduce the viral replication in human cells

Therapeutic pressure by protease inhibitors (PIs) contributes to accumulation of mutations in the HIV type 1 (HIV-1) protease (PR) leading to development of drug resistance with subsequent therapy failure. Current PIs target the active site of PR in a competitive manner. Identification of molecules that exploit non-active site mechanisms of inhibition is essential to overcome resistance to current PIs. Potential non-active site HIV-1 protease (PR) inhibitors (PI) were identified by in silico screening of almost 140,000 molecules targeting the hinge region of PR. Inhibitory activity of best docking compounds was tested in an in vitro PR inhibition biochemical assay. Five compounds inhibited PR from multiple HIV-1 subtypes in vitro and reduced replicative capacity by PI-sensitive or multi-PI resistant HIV-1 variants in human cells ex vivo. Antiviral activity was boosted when combined with Ritonavir, potentially diminishing development of drug resistance, while providing effective treatment for drug resistant HIV-1 variants.

Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first map proteasome-associated genetic co-dependencies. We identify cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results lead us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We show these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC proteomics reveal that JGs overcome PI resistance not via the expected mechanism of inhibiting cytosolic HSP70s, but instead through mitochondrial-localized HSP70, HSPA9, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize dynamics of myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

0630 Comparison Between the Use of APAP and Manual Titration During Split Night Polysomnography for Diagnosis and Treatment of OSA

Introduction CPAP remains the gold standard treatment for OSA, CPAP titration can be done using manual titration or using APAP devices, CPAP titration can be done using full night or split night protocol. The aim of the study Is to compare between the use of APAP and manual titration to determine the needed CPAP pressure during split night polysomnography for diagnosis and treatment of OSA. Methods 100 patients with severe OSA were enrolled after exclusion of patients with heart failure or respiratory failure. After diagnostic polysomnography, patients were divided into 2 groups: group1 offered manual CPAP titration and Group2 offered APAP titration, the time for CPAP titration was at least 4 hours in both groups. Results both groups were matched as regard age, gender, BMI, sleep parameters and AHI (44.52 ± 7.81/hour in group1 and 42.66 ± 9.68/hour in group2 with no statistical significance, after CPAP titration AHI was significantly improved in both groups, the time needed to reach the therapeutic pressure was significantly lower in group2 than in group1, attended technician was needed only in group1. Conclusion Use of APAP was equal to manual titration in this group of patients with severe OSA, with decreased cost and lesser time to reach the therapeutic pressure, large multicenter trials are needed to modify the guidelines in view of using APAP in split night protocol for diagnosis and treatment of OSA. Support no conflict of interest