Role of ß3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression.

Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset. The unresponsiveness to hormone therapies and immunotherapy and the toxicity of chemotherapeutics account for the limited treatment options for TNBC. Ion channels have emerged as possible therapeutic candidates for cancer therapy, but little is known about how ligand gated ion channels, specifically, GABA type A ligand-gated ion channel receptors (GABAAR), affect cancer pathogenesis. Our results show that the GABAA ß3 subunit is expressed at higher levels in TNBC cell lines than non-tumorigenic cells, therefore contributing to the idea that limiting the GABAAR via knockdown of the GABAA ß3 subunit is a potential strategy for decreasing the proliferation and migration of TNBC cells. We employed pharmacological and genetic approaches to investigate the role of the GABAA ß3 subunit in TNBC proliferation, migration, and cell cycle progression. The results suggest that pharmacological antagonism or genetic knockdown of GABAA ß3 subunit decreases TNBC proliferation and migration. In addition, GABAA ß3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. Our findings suggest that membrane bound GABAA receptors containing the ß3 subunit can be further developed as a potential novel target for the treatment of TNBC.

Equipping for risk: Lessons learnt from the UK shale-gas experience on assessing environmental risks for the future geoenergy use of the deep subsurface.

findings are presented from an investigation to improve understanding of the environmental risks associated with developing an unconventional-hydrocarbons industry in the UK. The EQUIPT4RISK project, funded by UK Research Councils, focused on investigations around Preston New Road (PNR), Fylde, Lancashire, and Kirby Misperton Site A (KMA), North Yorkshire, where operator licences to explore for shale gas by hydraulic fracturing (HF) were issued in 2016, although exploration only took place at PNR. EQUIPT4RISK considered atmospheric (greenhouse gases, air quality), water (groundwater quality) and solid-earth (seismicity) compartments to characterise and model local conditions and environmental responses to HF activities. Risk assessment was based on the source-pathway-receptor approach. Baseline monitoring of air around the two sites characterised the variability with meteorological conditions, and isotopic signatures were able to discriminate biogenic methane (cattle) from thermogenic (natural-gas) sources. Monitoring of a post-HF nitrogen-lift (well-cleaning) operation at PNR detected the release of atmospheric emissions of methane (4.2 ± 1.4 t CH4). Groundwater monitoring around KMA identified high baseline methane concentrations and detected ethane and propane at some locations. Dissolved methane was inferred from stable-isotopic evidence as overwhelmingly of biogenic origin. Groundwater-quality monitoring around PNR found no evidence of HF-induced impacts. Two approaches for modelling induced seismicity and associated seismic risk were developed using observations of seismicity and operational parameters from PNR in 2018 and 2019. Novel methodologies developed for monitoring include use of machine learning to identify fugitive atmospheric methane, Bayesian statistics to assess changes to groundwater quality, a seismicity forecasting model seeded by the HF-fluid injection rate and high-resolution monitoring of soil-gas methane. The project developed a risk-assessment framework, aligned with ISO 31000 risk-management principles, to assess the theoretical combined and cumulative environmental risks from operations over time. This demonstrated the spatial and temporal evolution of risk profiles: seismic and atmospheric impacts from the shale-gas operations are modelled to be localised and short-lived, while risk to groundwater quality is longer-term.

United States Value Set for the Functional Assessment of Cancer Therapy-General Eight Dimensions (FACT-8D), a Cancer-Specific Preference-Based Quality of Life Instrument.

OBJECTIVES: To develop a value set reflecting the United States (US) general population's preferences for health states described by the Functional Assessment of Cancer Therapy (FACT) eight-dimensions preference-based multi-attribute utility instrument (FACT-8D), derived from the FACT-General cancer-specific health-related quality-of-life (HRQL) questionnaire. METHODS: A US online panel was quota-sampled to achieve a general population sample representative by sex, age (≥ 18 years), race and ethnicity. A discrete choice experiment (DCE) was used to value health states. The valuation task involved choosing between pairs of health states (choice-sets) described by varying levels of the FACT-8D HRQL dimensions and survival (life-years). The DCE included 100 choice-sets; each respondent was randomly allocated 16 choice-sets. Data were analysed using conditional logit regression parameterized to fit the quality-adjusted life-year framework, weighted for sociodemographic variables that were non-representative of the US general population. Preference weights were calculated as the ratio of HRQL-level coefficients to the survival coefficient. RESULTS: 2562 panel members opted in, 2462 (96%) completed at least one choice-set and 2357 (92%) completed 16 choice-sets. Pain and nausea were associated with the largest utility weights, work and sleep had more moderate utility weights, and sadness, worry and support had the smallest utility weights. Within dimensions, more severe HRQL levels were generally associated with larger weights. A preference-weighting algorithm to estimate US utilities from responses to the FACT-General questionnaire was generated. The worst health state's value was -0.33. CONCLUSIONS: This value set provides US population utilities for health states defined by the FACT-8D for use in evaluating oncology treatments.

Measuring quality of care in autologous breast reconstruction: a Delphi consensus.

Measuring and benchmarking quality of care in surgical oncology has been gaining popularity. In autologous breast reconstruction (ABR), a standardized set of indicators to assess quality of care is lacking. In this study, we defined a set of evidence-based quality indicators for autologous breast reconstruction. First, we performed a systematic review to identify factors related to quality of care in ABR. Variables were categorized depending on their function: indicators related to outcome, indicators related to process and case-mix variables. The review was followed by a 3-round Delphi Consensus to determine which indicators and case-mix-variables were considered relevant and feasible for inclusion in an ABR standard set of indicators. 932 unique articles were identified, of which 110 papers were included in the study. Indicators were categorized by function: outcome, process and case-mix variables. In total, 8 process indicators and 41 outcome indicators were extracted. 30 case-mix-variables were included. Following 3 rounds of questioning in the Delphi Consensus, all respondents agreed on type of ABR, oncological outcomes and patient satisfaction for the standard set. Indicators related to complications were consistently ranked highly. Most process indicators were not chosen after 3 rounds of questioning. 11 case-mix-variables were included in the final set. Following the Delphi Consensus, it was possible to identify 33 process and outcome indicators and 11 case-mix-variables for inclusion for a standard set of quality indicators. With the inclusion of both objective and patient-reported outcome measures, this set of indicators provides a multidimensional measurement tool for quality assessment for ABR.

Utilization of a Population Pharmacokinetic Model to Improve a Busulfan Test-Dose Strategy in Allogeneic Hematopoietic Cell Transplant Recipients.

Busulfan is an alkylating agent used as part of conditioning chemotherapy regimens prior to allogeneic hematopoietic cell transplant (allo-HCT). Pharmacokinetic (PK)-guided test-dose strategies have been shown to improve the number of patients achieving busulfan exposure goals and improve clinical outcomes. However, current practices require extensive PK sampling. In this study, PK data were retrospectively collected from busulfan drug monitoring records from adult allo-HCT recipients who received once-daily intravenous busulfan at the University of North Carolina Medical Center (UNCMC). A population pharmacokinetic (popPK) model was developed to identify sources of interindividual variability and evaluate alternative PK sampling strategies. A 2-compartment model, with covariate effects of actual body weight and sex, best described the data. The typical value of clearance for an 83 kg male was estimated to be 11.21 L/h. Fifty-nine percent of allo-HCT recipients were estimated to have met the UNCMC institutional myeloablative conditioning (MAC) exposure goal based on model post hoc estimates of clearance using all PK samples obtained following MAC dosing. Fifty-seven percent of patients were estimated to have met this goal based on post hoc estimates using a single PK sample. Our results indicate once-daily, intravenous busulfan PK in adult allo-HCT recipients receiving MAC dosing can be reasonably described by a popPK model, and the use of a sparse PK sampling strategy may be feasible for determining target exposure attainment following MAC dosing. Use of a popPK model and sparse PK sampling strategy to carry out busulfan test-dose procedures could reduce health care costs and inconvenience to patients.

Vaccine hesitancy in cancer patients: A rapid review.

INTRODUCTION: Vaccination is a key strategy to limit the impact of the COVID-19 pandemic, among vulnerable groups such as cancer patients. However, COVID-19 vaccine hesitancy is limiting vaccination uptake in this population as in others. This study aimed to synthesise the emerging literature on vaccine hesitancy in this population and in Oncology health professionals, reasons for and factors associated with hesitancy, and interventions that address hesitancy. METHODS: A rapid review was undertaken PubMed, Ovid and Google across all years up to October 2021 for articles in English, from any country or region, addressing the above issues. Individual case studies, opinion pieces, commentary articles and conference abstracts were excluded. Article screening, data extraction and bias assessment were conducted by two authors. A narrative synthesis of the data was undertaken. RESULTS: Eighteen eligible articles were identified. Reported COVID-19 vaccine hesitancy rates varied from 76.7 % to 3.9 %, with a mean of 38.4 %. A large international study (n > 20,000) reported a more conservative hesitancy rate of 19 %. Six broad, common reasons for hesitancy were identified. Oncologist advice was valued by patients. DISCUSSION: Vaccine hesitancy remains a significant concern in the oncology context. Oncologists are key to addressing hesitancy and providing tailored advice to cancer patients. PRACTICE IMPLICATIONS: Where possible, patients appreciate personalised, tailored information about vaccination which addresses its interaction with cancer and its treatment. Education programmes for oncologists to support effective communication in this context are needed. Webinars and peer-to-peer counselling may be useful but remain to be proven.

Fear of progression in chronic illnesses other than cancer: a systematic review and meta-analysis of a transdiagnostic construct.

Fear of cancer recurrence (FCR) is the most common psychosocial issue amongst cancer survivors. However, fear of progression (FoP) has rarely been studied outside of the cancer context. This review aimed to: (1) meta-synthesise qualitative studies of FoP in illnesses other than cancer; and (2) quantify the relationship between FoP and anxiety, depression, and quality of life (QoL) in non-cancer chronic illnesses. We identified 25 qualitative and 11 quantitative studies in a range of chronic illnesses. Participants described fears of progression and recurrence of their illness, including fears of dying, and fears of becoming a burden to family. Fears were often triggered by downward comparison (i.e., seeing people worse off than themselves). Participants coped in different ways, including by accepting the illness or seeking knowledge. Those for whom these fears caused distress reported hypervigilance to physical symptoms and avoidance. Distress, and seeking information, were associated with adherence. In quantitative analyses, FoP was moderately associated with QoL, and strongly associated with anxiety and depression. These results suggest that FoP in illnesses other than cancer is similar to FCR. FoP appears to be an important transdiagnostic construct associated with distress. Evidence-based FCR interventions could be adapted to better manage FoP in other illnesses.

Correlation of Engraftment and Time from Melphalan Administration to Stem Cell Infusion.

Single-agent, high-dose melphalan continues to be the most commonly used conditioning regimen for transplantation-eligible patients with multiple myeloma undergoing autologous stem cell transplantation. The timing of melphalan administration with respect to stem cell infusion has not been clearly defined. Many institutions require a minimum of 24 hours between melphalan administration and stem cell infusion; however, some institutions have adopted shorter intervals based on melphalan's short half-life. Some studies have suggested that shortening the interval between melphalan administration and stem cell infusion may contribute to delays in engraftment, but this correlation has not been clearly evaluated or defined. This multicenter retrospective cohort study evaluated the times to neutrophil and platelet engraftment in patients who received stem cells at least 24 hours after melphalan (≥24 hours cohort) compared with those who received stem cells within 24 hours of melphalan (<24 hours cohort. The study included a total of 723 adult patients, 502 patients in the ≥24 hours cohort and 221 in the <24 hours cohort, treated at 3 transplantation centers between January 1, 2016, and September 30, 2019. Patient characteristics were summarized using descriptive statistics. The Fisher exact test was used to compare nominal categorical variables between the 2 cohorts, and the nonparametric van der Waerden test or Mood median test was used to compare ordinal or continuous variables. The median time to neutrophil engraftment was 12 days for both the ≥24 hours cohort (interquartile range [IQR], 11 to 12 days) and the <24 hours cohort (IQR, 11 to 13 days) (P = .07). The median time to platelet engraftment was 19 days for both the ≥24 hours cohort (IQR, 17 to 22 days) and <24 hours cohort (IQR, 17 to 20 days) (P = .25). The median time between melphalan administration and stem cell infusion in the <24 hours cohort was 18 hours, with a minimum time of 12 hours. The existing literature has not clearly defined the impact of the timing between melphalan administration and stem cell infusion on engraftment in autologous transplantation. The ability to safely shorten the interval between chemotherapy and transplantation could increase logistical flexibility and/or decrease the length of hospital stay. This large multicenter retrospective study did not identify a statistical or clinical impact on engraftment when melphalan was infused <24 hours or ≥24 hours before autologous stem cell infusion.

Sub-second periodicity in a fast radio burst.

Fast radio bursts (FRBs) are millisecond-duration flashes of radio waves that are visible at distances of billions of light years1. The nature of their progenitors and their emission mechanism remain open astrophysical questions2. Here we report the detection of the multicomponent FRB 20191221A and the identification of a periodic separation of 216.8(1) ms between its components, with a significance of 6.5σ. The long (roughly 3 s) duration and nine or more components forming the pulse profile make this source an outlier in the FRB population. Such short periodicity provides strong evidence for a neutron-star origin of the event. Moreover, our detection favours emission arising from the neutron-star magnetosphere3,4, as opposed to emission regions located further away from the star, as predicted by some models5.

The impact of COVID-19 on cancer patients, their carers and oncology health professionals: A qualitative study.

OBJECTIVE: Cancer patients, carers and oncology health professionals have been impacted by the COVID-19 pandemic in many ways, but their experiences and psychosocial responses to the pandemic are still being explored. This study aimed to document the experience of Australians living with cancer, family carers, and Oncology health professionals (HPs) when COVID-19 first emerged. METHODS: In this qualitative study, participants (cancer patients currently receiving treatment, family carers and HPs) completed a semi-structured interview exploring their experiences of COVID-19 and the impact it had on cancer care. Participants also completed the Hospital Anxiety and Depression Scale (patients) and the Depression, Anxiety and Stress Scale (carers and HPs) to assess emotional morbidity. Thematic analysis was undertaken on qualitative data. RESULTS: 32 patients, 16 carers and 29 HPs participated. Qualitative analysis yielded three shared themes: fear and death anxiety, isolation, and uncertainty. For HPs, uncertainty incorporated the potential for moral distress and work-stress. Patients and carers scoring high on anxiety/depression measures were more likely to have advanced disease, expressed greater death anxiety, talked about taking more extreme precautionary measures, and felt more impacted by isolation. CONCLUSION: Cancer and COVID-19 can have compounding psychological impacts on all those receiving or giving care. PRACTICE IMPLICATIONS: Screening for distress in patients, and burnout in HPs, is recommended. Increased compassionate access and provision of creative alternatives to face-to-face support are warrented.

Cell-free DNA analysis in current cancer clinical trials: a review.

Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms 'cfDNA', 'ctDNA', 'liquid biopsy' AND 'cancer OR neoplasm' in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.

Plerixafor strategies for autologous hematopoietic cell transplant mobilization: A comparison of efficacy and cost.

Addition of plerixafor (P) to granulocyte colony stimulating factor (G-CSF) during peripheral blood mobilization of hematopoietic stem cells (HSC) increases the number of patients meeting collection goals prior to autologous stem cell transplant (aSCT). However, use of P is not universal among transplant centers due to cost. This study aims to compare clinical and financial impacts of using an algorithm-based P mobilization strategy versus use in all patients. This was a single center, retrospective analysis of adult patients with myeloma or amyloidosis receiving aSCT who received apheresis of their HSC between 3/1/2017 and 3/1/2019. Patients prior to 3/1/2018 were classified as receiving P "per algorithm" and those after this date were classified as "up-front" P. For the per-algorithm group, P was given for a pre-apheresis CD34+ cell count of <20 cells/µL on mobilization day 5 and patients returned on day 6 for apheresis. Of the 129 patients included, 55 received P per-algorithm and 74 received up-front P. There was a reduction in median number of apheresis days (1.5 vs 1 day, p < 0.001) and an increase in median number of CD34+ cells collected (6.6 vs 8.5 × 106 cells/kg, p < 0.001) with up-front P. Up-front P increased drug cost but reduced apheresis costs, which resulted in a net savings of $121 per patient in total mobilization costs. These findings suggest that use of up-front P for mobilization significantly reduces apheresis days and increases HSC collection yield without increasing overall cost per patient.

Stable 2 W continuous-wave 261.5 nm laser for cooling and trapping aluminum monochloride.

We present a high-power tunable deep-ultraviolet (DUV) laser that uses two consecutive cavity enhanced doubling stages with LBO and CLBO crystals to produce the fourth harmonic of an amplified homebuilt external cavity diode laser. The system generates up to 2.75 W of 261.5 nm laser light with a ∼2 W stable steady-state output power and performs second harmonic generation in a largely unexplored high intensity regime in CLBO for continuous wave DUV light. We use this laser to perform fluorescence spectroscopy on the A1Π â† X1Σ+ transition in a cold, slow beam of AlCl molecules and probe the A1Π|v' = 0, J' = 1〉 state hyperfine structure for future laser cooling and trapping experiments. This work demonstrates that the production of tunable, watt-level DUV lasers is becoming routine for a variety of wavelength-specific applications in atomic, molecular and optical physics.

A mixed methods pilot and feasibility open trial of internet-delivered cognitive behaviour therapy (iCanADAPT Advanced) for people with advanced cancer with depression and/or anxiety.

PURPOSE: Evaluate the feasibility, acceptability and potential efficacy of a form of online therapy for clinical depression and/or anxiety in people living with advanced cancer. METHODS: A single-arm open trial of a six-lesson clinician-supervised, internet-delivered cognitive behavioural therapy (iCBT) transdiagnostic intervention (iCanADAPT Advanced) was undertaken. Qualitative (semi-structured telephone interview conducted at 3-months) and quantitative data (questionnaires collected at pre-, post-, and 3-month follow-up) were analysed. RESULTS: 27 participants partook (26 women, 56% breast cancer, mean age 56yo; average number of mental health diagnoses 1.8, with majority (81%) meeting criteria for generalised anxiety disorder). Feasibility - Unanticipated numbers (48%) of participants had physical health deterioration (cancer progression or death). iCBT had high adherence overall (completion rates: 37% did 6 lessons; 70% did 4 lessons) but adherence was higher for those whose cancer remained stable (completion rates: 43% did 6 lessons; 85% did 4 lessons). Acceptability - the intervention was acceptable to the majority of participants, with high treatment satisfaction. Advisory data was achieved regarding future versions. Potential efficacy - regardless of physical health status, participants who completed the iCBT showed a significant decrease over time in anxiety and depression symptoms. CONCLUSIONS: Online therapies may be useful in assisting those living with advanced cancer dealing with clinical depression and anxiety disorders. The specific modality of clinician supervised iCBT has significant potential to be a suitable modality of online therapy.

Chimeric Antigen Receptor T Cell Therapy: A Comprehensive Review of Clinical Efficacy, Toxicity, and Best Practices for Outpatient Administration.

Chimeric antigen receptor T cell (CAR T) therapy has been integrated into treatment algorithms for acute leukemia, lymphoma, and, most recently, multiple myeloma. The number of clinical trials in both hematologic and solid tumor malignancies for new products and potential indications continues to grow. The clinical toxicities of CAR T therapy include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which often warrant inpatient admission for close monitoring and treatment. Consequently, many centers have built processes around the administration of these cells in the inpatient setting. As new products gain Food and Drug Administration approval with more manageable toxicity profiles, and as institutions gain experience with the management of these toxicities, outpatient administration and monitoring should be expected. In addition, payor reimbursements for inpatient treatment have put the sustainability of inpatient CAR T therapy in jeopardy, especially for centers with a payor mix that includes a high proportion of Medicare patients. This has the serious potential to limit access to care. As the use of CAR T therapy continues to expand, changes in payment models, care settings, or both are needed to ensure the sustainability of safe, efficient, and cost-effective treatment. This review outlines the efficacy and toxicity of currently approved products, as well as best practices to optimize the management of CAR T cell therapy in the outpatient setting.