The role of Eag and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line.

The voltage gated potassium (K+) channels Eag and HERG have been implicated in the pathogenesis of various cancers, through association with cell cycle changes and programmed cell death. The role of these channels in the onset and progression of ovarian cancer is unknown. An understanding of mechanism by which Eag and HERG channels affect cell proliferation in ovarian cancer cells is required and therefore we investigated their role in cell proliferation and their effect on the cell cycle and apoptosis of ovarian cancer cells

Preclinical evaluation of a new robot-assisted surgical system for use in gynecology minimal access surgery

Funder: CMR SurgicalAbstractRobot-assisted laparoscopy has been developed to overcome some of the important limitations of conventional laparoscopy. In particular, the provision of stable magnified three-dimensional vision, tremor filtering, motion scaling, and articulated instruments with robot-assisted surgery has the potential to enable more surgeons to perform more complex surgery compared with conventional laparoscopy. The aim of this study was to evaluate the utility of a new robot-assisted surgical system (Versius, CMR Surgical, Cambridge, UK) for gynecologic procedures in a preclinical setting. Cadaveric sessions were conducted to evaluate the ability of the system to complete all surgical steps required for a robot-assisted total laparoscopy hysterectomy. A live animal (porcine) model was used to assess the system in performing oviduct removal as a surrogate for robot-assisted total laparoscopy hysterectomy. Procedures were performed by experienced gynecologic surgeons, supported by a surgical team. The precise surgical steps conducted to conclude that the procedures could be fully completed were systematically recorded, as well as instruments used and endoscope angle. In total, six gynecologic procedures were performed in cadavers by four surgeons; 16/17 procedures were completed successfully. Positioning of the ports and bedside units reflected the surgeons’ preferred laparoscopic setup and enabled good surgical access and reach, as exemplified by the high procedure completion rate. Oviduct removal procedures performed in pigs were all completed successfully by a single surgeon. This preclinical study of a new robot-assisted surgical system for gynecologic procedures demonstrated the safety and effectiveness of the system in cadaver and porcine models. Further studies are required to assess its clinical utility.</jats:p

Gaps and Overlaps in Cancer Multidisciplinary Team Communication: Analysis of Speech

Funder: Health Services and Delivery Research Programme; FundRef: https://doi.org/10.13039/501100002001 Guided by the principles of conversation analysis, we examined the communication practices used to negotiate levels of participation in cancer multidisciplinary team meetings and their implications for patient safety. Three cancer teams participated. Thirty-six weekly meetings were video recorded, encompassing 822 case reviews. A cross-section was transcribed using Jefferson notation. We found a low frequency of gaps between speakers (3%), high frequency of overlaps (24%), and no-gaps-no-overlaps (73%), suggesting fast turn transitions. Securing a turn to speak is challenging due to a systematic reduction in turn-taking opportunities. We contribute to group research with the development of a microlevel methodology for studying multidisciplinary teams. </jats:p

Relationships Between Communication, Time Pressure, Workload, Task Complexity, Logistical Issues and Group Composition in Transdisciplinary Teams: A Prospective Observational Study Across 822 Cancer Cases

Introduction: Functional perspective of team decision-making highlights the importance of understanding the relationship between team interaction/communication during a given task, the internal factors that emanate from within a group (e.g., team composition), and the external circumstances (e.g., workload and time pressures). As an underexplored area, we explored these relationships in the context of multidisciplinary team (MDT) meetings (aka tumor boards). Materials and methods: Three cancer MDTs with 44 team members were recruited from three teaching hospitals in the United Kingdom. Thirty of their weekly meetings encompassing 822 case reviews were filmed. Validated instruments were used to assess each case: Bales' Interaction Process Analysis that captures frequency of task-oriented and socio-emotional interactions/communication; and Measure of case-Discussion Complexity that captures clinical and logistic complexities. We also measured team size, disciplinary diversity, gender, time-workload pressure, and time-on-task. Partial correlation analysis controlling for team/tumor type and case complexity was used for analysis. Results: Clinical complexity positively correlated with task-oriented communication, e.g., gives opinion (r = 0.51, p 0.05), however, case reviews with more males present were associated with more tension (r = 0.09, p < 0.01) and less disagreements (r = −0.11, p < 0.01), while when more females present there were more disagreements (r = 0.10, p < 0.01) and less tension (r = −0.11, p < 0.01). Discussion: To the best of our knowledge, this is the first study to assess the relationship between MDT interaction/communication and the external/internal factors. Smaller size, gender balanced teams with core disciplines present, and streamlining workload to reduce time-workload pressure, time-on-task effects, and logistical issues appear more conducive to building and maintain optimal MDTs. Our methodology could be applied to other MDT-driven areas of healthcare

The Eag potassium channel as a new prognostic marker in ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer is the second most common cancer of the female genital tract in the United Kingdom (UK), accounting for 6% of female deaths due to cancer. This cancer is associated with poor survival and there is a need for new treatments in addition to existing chemotherapy to improve survival. Potassium (K⁺) channels have been shown to be overexpressed in various cancers where they appear to play a role in cell proliferation and progression.</p> <p>Objectives</p> <p>To determine the expression of the potassium channels Eag and HERG in ovarian cancer tissue and to assess their role in cell proliferation.</p> <p>Methods</p> <p>The expression of Eag and HERG potassium channels was examined in an ovarian cancer tissue microarray. Their role in cell proliferation was investigated by blocking voltage-gated potassium channels in an ovarian cancer cell line (SK-OV-3).</p> <p>Results</p> <p>We show for the first time that high expression of Eag channels in ovarian cancer patients is significantly associated with poor survival (P = 0.016) unlike HERG channel expression where there was no correlation with survival. There was also a significant association of Eag staining with high tumour grade (P = 0.014) and presence of residual disease (P = 0.011). Proliferation of SK-OV-3 cells was significantly (P < 0.001) inhibited after treatment with voltage gated K⁺channel blockers.</p> <p>Conclusion</p> <p>This novel finding demonstrates a role for Eag as a prognostic marker for survival in patients with ovarian cancer.</p

Eag and HERG potassium channels as novel therapeutic targets in cancer

Voltage gated potassium channels have been extensively studied in relation to cancer. In this review, we will focus on the role of two potassium channels, Ether à-go-go (Eag), Human ether à-go-go related gene (HERG), in cancer and their potential therapeutic utility in the treatment of cancer. Eag and HERG are expressed in cancers of various organs and have been implicated in cell cycle progression and proliferation of cancer cells. Inhibition of these channels has been shown to reduce proliferation both in vitro and vivo studies identifying potassium channel modulators as putative inhibitors of tumour progression. Eag channels in view of their restricted expression in normal tissue may emerge as novel tumour biomarkers

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Does the Performance of Splenectomy as Part of Cytoreductive Surgery Carry a Worse Prognosis Than in Patients Not Receiving Splenectomy? A Propensity Score Analysis and Review of the Literature

Background & Objectives Ultra-radical (UR) procedures, including splenectomy, are utilized to increase complete cytoreduction rates during Cytoreductive Surgery (CRS) performed with the aim of complete macroscopic clearance of disease. The purpose of this study was to investigate if splenectomy negatively impacts survival when undertaken during CRS for advanced ovarian cancer (AOC) and compare published splenectomy and cytoreduction rates. Methods A retrospective review of all consecutive patients who underwent cytoreductive surgery for AOC between 16/05/2013-28/01/2019. Survival, baseline patient characteristics, complications and surgical parameters were recorded. Propensity scored matching (PSM) was performed to reduce bias. Results 154 patients identified over 71 months. 97 underwent standard, 57 underwent UR surgery, 27 patients received splenectomy (17.5%) No difference was seen in overall survival (OS) between all patients (median OS 34 months (95%CI 25.9–41.1) and patients who underwent splenectomy (median OS not yet reached) (p = >0.05). After PSM for various baseline covariates, no significant difference in splenectomy versus non-splenectomy patients (3-year survival 54% compared to 56%) (P > 0.05). Three splenectomy specific complications occurred; one each of pancreatic tail injury, left pleural effusion and streptococcal pharyngitis during chemotherapy. We found wide variation in utilization of splenectomy in published case series; from 9% to 35%. Conclusions Splenectomy performed as part of CRS is not detrimental to survival in AOC. There is a wide variation in utilization of splenectomy in published case series with little correlation with cytoreduction rates