A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity

High-grade serous ovarian carcinoma is characterised by TP53 mutation and extensive chromosome instability (CIN). Because our understanding of CIN mechanisms is based largely on analysing established cell lines, we developed a workflow for generating ex vivo cultures from patient biopsies to provide models that support interrogation of CIN mechanisms in cells not extensively cultured in vitro. Here, we describe a “living biobank” of ovarian cancer models with extensive replicative capacity, derived from both ascites and solid biopsies. Fifteen models are characterised by p53 profiling, exome sequencing and transcriptomics, and karyotyped using single-cell whole-genome sequencing. Time-lapse microscopy reveals catastrophic and highly heterogeneous mitoses, suggesting that analysis of established cell lines probably underestimates mitotic dysfunction in advanced human cancers. Drug profiling reveals cisplatin sensitivities consistent with patient responses, demonstrating that this workflow has potential to generate personalized avatars with advantages over current pre-clinical models and the potential to guide clinical decision making

Single-injection thoracic paravertebral block and postoperative analgesia after mastectomy: a retrospective cohort study

BackgroundThe treatment of postoperative pain after mastectomy is an area of increasing interest, as this treatment option is now considered a standard of care for those affected by breast cancer. Thoracic paravertebral nerve block (tPVB) using local anesthetics administered before mastectomy can theoretically provide postoperative analgesia, thereby facilitating a more comfortable and shorter hospitalization.MethodsIn this retrospective cohort study, we aimed to determine the duration and degree to which tPVB provides postoperative analgesia in patients who underwent either unilateral or bilateral mastectomy (n = 182). We retrospectively examined the numeric rating scale (NRS) for pain scores recorded by nursing staff throughout individual patient hospitalizations, looking specifically at the following time points: arrival from the postanesthesia care unit to the surgical wards, noon on postoperative day 1 (POD1), and discharge. We also examined the number of days until patients were discharged from the hospital.ResultsOur results revealed a statistically significant decrease in NRS in pain scores for patients who had received a tPVB (n = 92) on arrival from the postanesthesia care unit to the surgical wards (mean NRS decrease of 1.9 points; 99% confidence interval [CI], -3.0 to -0.8; P < .001) but did not show statistically significant decreases in NRS for pain scores for patients at noon on POD1 (mean NRS decrease of 0.3 points at noon on POD1, P = .43) or at discharge (mean NRS decrease of 0.1 point at discharge, P = .65). Moreover, use of tPVB did not have an impact on time until discharge (average decrease of 0.5 hours; 95% CI, -6 to +5 hours, P = .87).ConclusionsSingle-injection tPVB appears to provide meaningful postoperative analgesia in the immediate postoperative period after mastectomy but not after the first day of surgery

The ‘heritagisation’ of the British seaside resort: The rise of the ‘old penny’ arcade.

Amusement arcades have long been a key component of the British seaside resort. For almost a century, they enjoyed popularity and success and became established as a quintessential feature of the British seaside holiday. However, the advent of home-based video games along with recent gambling legislation has led to a decline of the seaside amusement arcade sector. Arcades gained a reputation as unsavoury places and their appearance and fortunes often mirrored those of the resorts in which they were located. However, over the past decade, a new variant of the seaside amusement arcade has appeared, featuring mechanical machines working on pre-decimal currency. Such ‘old penny arcades’ frequently describe themselves as museums or heritage centres and they offer an experience based on a nostalgic affection for the ‘traditional’ seaside holiday. They have appeared in the context of an increasing interest in the heritage of the British seaside resort and constitute one element of the ‘heritagisation’ of such resorts. This paper argues that such arcades can be important elements of strategies to reposition and rebrand resorts for the heritage tourism market

Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo

Meeting Abstracts: Proceedings of the Thirteenth International Society of Sports Nutrition (ISSN) Conference and Expo Clearwater Beach, FL, USA. 9-11 June 201

Single-injection thoracic paravertebral block and postoperative analgesia after mastectomy: a retrospective cohort study.

BackgroundThe treatment of postoperative pain after mastectomy is an area of increasing interest, as this treatment option is now considered a standard of care for those affected by breast cancer. Thoracic paravertebral nerve block (tPVB) using local anesthetics administered before mastectomy can theoretically provide postoperative analgesia, thereby facilitating a more comfortable and shorter hospitalization.MethodsIn this retrospective cohort study, we aimed to determine the duration and degree to which tPVB provides postoperative analgesia in patients who underwent either unilateral or bilateral mastectomy (n = 182). We retrospectively examined the numeric rating scale (NRS) for pain scores recorded by nursing staff throughout individual patient hospitalizations, looking specifically at the following time points: arrival from the postanesthesia care unit to the surgical wards, noon on postoperative day 1 (POD1), and discharge. We also examined the number of days until patients were discharged from the hospital.ResultsOur results revealed a statistically significant decrease in NRS in pain scores for patients who had received a tPVB (n = 92) on arrival from the postanesthesia care unit to the surgical wards (mean NRS decrease of 1.9 points; 99% confidence interval [CI], -3.0 to -0.8; P < .001) but did not show statistically significant decreases in NRS for pain scores for patients at noon on POD1 (mean NRS decrease of 0.3 points at noon on POD1, P = .43) or at discharge (mean NRS decrease of 0.1 point at discharge, P = .65). Moreover, use of tPVB did not have an impact on time until discharge (average decrease of 0.5 hours; 95% CI, -6 to +5 hours, P = .87).ConclusionsSingle-injection tPVB appears to provide meaningful postoperative analgesia in the immediate postoperative period after mastectomy but not after the first day of surgery

Multiple-low-dose therapy: effective killing of high-grade serous ovarian cancer cells with ATR and CHK1 inhibitors

High-grade serous ovarian cancer (HGSOC) is an aggressive disease that typically develops drug resistance, thus novel biomarker-driven strategies are required. Targeted therapy focuses on synthetic lethality—pioneered by PARP inhibition of BRCA1/2-mutant disease. Subsequently, targeting the DNA replication stress response (RSR) is of clinical interest. However, further mechanistic insight is required for biomarker discovery, requiring sensitive models that closely recapitulate HGSOC. We describe an optimized proliferation assay that we use to screen 16 patient-derived ovarian cancer models (OCMs) for response to RSR inhibitors (CHK1i, WEE1i, ATRi, PARGi). Despite genomic heterogeneity characteristic of HGSOC, measurement of OCM proliferation was reproducible and reflected intrinsic tumour-cell properties. Surprisingly, RSR targeting drugs were not interchangeable, as sensitivity to the four inhibitors was not correlated. Therefore, to overcome RSR redundancy, we screened the OCMs with all two-, three- and four-drug combinations in a multiple-low-dose strategy. We found that low-dose CHK1i-ATRi had a potent anti-proliferative effect on 15 of the 16 OCMs, and was synergistic with potential to minimise treatment resistance and toxicity. Low-dose ATRi-CHK1i induced replication catastrophe followed by mitotic exit and post-mitotic arrest or death. Therefore, this study demonstrates the potential of the living biobank of OCMs as a drug discovery platform for HGSOC

Fall Risk Associated with Continuous Peripheral Nerve Blocks Following Knee and Hip Arthroplasty.

Combined scientific advances in pharmaceutical agents, perineural blocks, and pump delivery capabilities such as those used with continuous peripheral nerve blocks have demonstrated advantages in pain management for patients undergoing joint arthroplasty. This report documents the incidence of falls increased after the implementation of a continuous peripheral nerve block program for patients undergoing knee and hip arthroplasty in an academic medical center

Effects of trauma, economic hardship, and stress on neurocognition and everyday function in HIV.

ObjectiveThe causes of neurocognitive and everyday functioning impairment among aging people living with HIV (PLWH) are multifactorial. Exposure to stress and trauma can result in neurocognitive deficits via activation of neurological and other biological mechanisms.MethodPLWH (n = 122) and persons without HIV (n = 95), 35-65 years of age, completed four questionnaires that were used to generate a trauma, economic hardship (food insecurity and low socioeconomic status), and stress composite variable (TES). Participants also completed a comprehensive neuropsychological battery and standardized self-reports of activities of daily living (ADLs). We examined the independent and interactive effects of TES and HIV status on neurocognitive performance and ADL declines.ResultsPLWH had more traumatic events, more food insecurity, lower socioeconomic status, and higher perceived stress compared with HIV- individuals (all ps < .0001). Among PLWH, a higher composite TES score was associated with worse executive functioning (p = .02), worse learning (p = .02), worse working memory (p = .02), and more ADL declines (p < .0001), even after controlling for relevant demographic, psychiatric, substance use, and HIV disease covariates. On their own, individual TES components did not predict these outcomes. Conversely, no significant relationships were observed between TES and cognitive domains nor ADL declines among HIV- individuals.ConclusionsA composite score of trauma, economic hardship, and stress was significantly associated with worse neurocognitive performance and functional declines among PLWH. These adverse experiences may contribute to neurocognitive and daily functioning difficulties commonly observed among PLWH. Longitudinal studies are needed to elucidate the relationships between economic/psychosocial adversities and cognitive/functional outcomes over time, and examine potential mediators, such as inflammatory biomarkers. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

Effects of trauma, economic hardship, and stress on neurocognition and everyday function in HIV.

ObjectiveThe causes of neurocognitive and everyday functioning impairment among aging people living with HIV (PLWH) are multifactorial. Exposure to stress and trauma can result in neurocognitive deficits via activation of neurological and other biological mechanisms.MethodPLWH (n = 122) and persons without HIV (n = 95), 35-65 years of age, completed four questionnaires that were used to generate a trauma, economic hardship (food insecurity and low socioeconomic status), and stress composite variable (TES). Participants also completed a comprehensive neuropsychological battery and standardized self-reports of activities of daily living (ADLs). We examined the independent and interactive effects of TES and HIV status on neurocognitive performance and ADL declines.ResultsPLWH had more traumatic events, more food insecurity, lower socioeconomic status, and higher perceived stress compared with HIV- individuals (all ps < .0001). Among PLWH, a higher composite TES score was associated with worse executive functioning (p = .02), worse learning (p = .02), worse working memory (p = .02), and more ADL declines (p < .0001), even after controlling for relevant demographic, psychiatric, substance use, and HIV disease covariates. On their own, individual TES components did not predict these outcomes. Conversely, no significant relationships were observed between TES and cognitive domains nor ADL declines among HIV- individuals.ConclusionsA composite score of trauma, economic hardship, and stress was significantly associated with worse neurocognitive performance and functional declines among PLWH. These adverse experiences may contribute to neurocognitive and daily functioning difficulties commonly observed among PLWH. Longitudinal studies are needed to elucidate the relationships between economic/psychosocial adversities and cognitive/functional outcomes over time, and examine potential mediators, such as inflammatory biomarkers. (PsycINFO Database Record (c) 2018 APA, all rights reserved)