Drug-induced liver injury remains a major cause of drug attrition. Furthermore, novel drugs are being developed for treating liver diseases. However, differences between animals and humans in liver ...pathways necessitate the use of human-relevant liver models to complement live animal testing during preclinical drug development. Microfabrication tools and synthetic biomaterials now allow for the creation of tissue subunits that display more physiologically relevant and long-term liver functions than possible with declining monolayers.
The authors discuss acellular enzyme platforms, two-dimensional micropatterned co-cultures, three-dimensional spheroidal cultures, microfluidic perfusion, liver slices and humanized rodent models. They also present the use of cell lines, primary liver cells and induced pluripotent stem cell-derived human hepatocyte-like cells in the creation of cell-based models and discuss in silico approaches that allow integration and modeling of the datasets from these models. Finally, the authors describe the application of liver models for the discovery of novel therapeutics for liver diseases.
Engineered liver models with varying levels of in vivo-like complexities provide investigators with the opportunity to develop assays with sufficient complexity and required throughput. Control over cell-cell interactions and co-culture with stromal cells in both two dimension and three dimension are critical for enabling stable liver models. The validation of liver models with diverse sets of compounds for different applications, coupled with an analysis of cost:benefit ratio, is important for model adoption for routine screening. Ultimately, engineered liver models could significantly reduce drug development costs and enable the development of more efficacious and safer therapeutics for liver diseases.
This study assessed the psychological predictors of preferences for return of comprehensive tumor genomic profiling (CTGP) results in patients with advanced cancers, enrolled in the Molecular ...Screening and Therapeutics Program. Patients completed a questionnaire prior to undergoing CTGP. Of the 1434 who completed a questionnaire, 96% would like to receive results that can guide treatment for their cancer, and preference for receiving this type of result was associated with lower tolerance of uncertainty. Sixty‐four percent would like to receive results that cannot guide treatment, and lower tolerance of uncertainty, self‐efficacy, and perceived importance were associated with this preference. Fifty‐nine percent would like to receive variants of unknown significance, which was associated with lower tolerance of uncertainty, higher self‐efficacy, and perceived importance. Eighty‐six percent wanted to receive germline results that could inform family risk. This was associated with higher self‐efficacy, perceived importance, and perceived susceptibility. Although most patients wanted to receive all types of results, given the differing patient preferences regarding the return of results depending on the utility of the different types of results, it appears critical to safeguard patient understanding of result utility to achieve informed patient choices. This should be accompanied by appropriate consent processes.
Objective
This study aimed to discern preferences for receiving somatic molecular profiling (MP) results in cancer patients who have given consent to undergo testing.
Methods
We conducted a ...mixed‐methods study to explore patients' views on which MP results they would like to receive and why. Advanced cancer patients (n = 1299) completed questionnaires after giving consent to participate in a parent genomics study and undergoing MP. A subset of patients (n = 20) participated in qualitative interviews.
Results
Almost all (96%) participants were interested in receiving results which would direct cancer treatment (ie, were actionable). A smaller majority wanted to access results which were not actionable (64%) or were variants of unknown significance (60%). Most (86%) were interested in finding out about germline findings, though not as a priority. Themes identified in interview data were: (a) Cancer is the focus; (b) Trust in clinicians; and (c) Respect for a right not to know.
Conclusions
The majority of advanced cancer patients undergoing MP prioritised results which would lead to treatment options. They trusted their oncologists to help them navigate the results return process. While there was interest in knowing about other results, this was a lesser priority. Nevertheless, given high levels of interest in receiving all results, ethical aspects of not providing uninformative results requires further research, including a consideration of patient rationales for desiring this information and what health professionals can and should do to support patients in the absence of meaningful information being available.
Genomic Sequencing (GS) to identify high cancer risk will soon enter clinical practice at significant cost to the health system. This study aimed to quantify perceived value of GS to Australian ...cancer patients and their first‐degree relatives participating in a genomic sequencing study, and factors associated with value. Participants were recruited upon consent to the genomics study. Eligible participants (with cancer of likely genetic etiology, or a first‐degree relative) completed a questionnaire prior to GS. Willingness to pay was assessed via hypothetical trade‐off scenarios of actionable result return rates of 1%, 10%, 20%, 30%, 40% or 50%. Of 348 probands and 213 relatives (92% and 93% response rate), 81% would consistently have GS for as little as a 1% actionable return rate. Participants would pay a median of $1,000 for return rates of at least 20% (probands) or 30% (relatives), and $300 for lower return rates. Probands with common cancers and negative attitudes to uncertainty were more likely to have GS; those with higher education were more willing to pay $1,000 and $3,000 for lower return rates. This study found high interest in, but lower willingness to pay for GS in cancer patients and their first‐degree relatives, possibly due to inability to pay. Further research is needed to improve our understanding of how individuals in different risk circumstances, trade‐off the risks, harms, and benefits of GS.
A dataset to describe exposed bedrock and surficial geology of Antarctica has been constructed by the GeoMAP Action Group of the Scientific Committee on Antarctic Research (SCAR) and GNS Science. Our ...group captured existing geological map data into a geographic information system (GIS), refined its spatial reliability, harmonised classification, and improved representation of glacial sequences and geomorphology, thereby creating a comprehensive and coherent representation of Antarctic geology. A total of 99,080 polygons were unified for depicting geology at 1:250,000 scale, but locally there are some areas with higher spatial resolution. Geological unit definition is based on a mixed chronostratigraphic- and lithostratigraphic-based classification. Description of rock and moraine polygons employs the international Geoscience Markup Language (GeoSciML) data protocols to provide attribute-rich and queryable information, including bibliographic links to 589 source maps and scientific literature. GeoMAP is the first detailed geological map dataset covering all of Antarctica. It depicts 'known geology' of rock exposures rather than 'interpreted' sub-ice features and is suitable for continent-wide perspectives and cross-discipline interrogation.
Abstract Some of the largest climatic changes in the Arctic have been observed in Alaska and the surrounding marginal seas. Near-surface air temperature (T2m), precipitation ( P ), snowfall, and sea ...ice changes have been previously documented, often in disparate studies. Here, we provide an updated, long-term trend analysis (1957–2021; n = 65 years) of such parameters in ERA5, NOAA U.S. Climate Gridded Dataset (NClimGrid), NOAA National Centers for Environmental Information (NCEI) Alaska climate division, and composite sea ice products preceding the upcoming Fifth National Climate Assessment (NCA5) and other near-future climate reports. In the past half century, annual T2m has broadly increased across Alaska, and during winter, spring, and autumn on the North Slope and North Panhandle (T2m > 0.50°C decade −1 ). Precipitation has also increased across climate divisions and appears strongly interrelated with temperature–sea ice feedbacks on the North Slope, specifically with increased (decreased) open water (sea ice extent). Snowfall equivalent (SFE) has decreased in autumn and spring, perhaps aligned with a regime transition of snow to rain, while winter SFE has broadly increased across the state. Sea ice decline and melt-season lengthening also have a pronounced signal around Alaska, with the largest trends in these parameters found in the Beaufort Sea. Alaska’s climatic changes are also placed in context against regional and contiguous U.S. air temperature trends and show ∼50% greater warming in Alaska relative to the lower-48 states. Alaska T2m increases also exceed those of any contiguous U.S. subregion, positioning Alaska at the forefront of U.S. climate warming. Significance Statement This study produces an updated, long-term trend analysis (1957–2021) of key Alaska climate parameters, including air temperature, precipitation (including snowfall equivalent), and sea ice, to inform upcoming climate assessment reports, including the Fifth National Climate Assessment (NCA5) scheduled for publication in 2023. Key findings include widespread annual and seasonal warming with increased precipitation across much of the state. Winter snowfall has broadly increased, but spring and autumn snowfalls have decreased as rainfall increased. Autumn warming and precipitation increases over the North Slope, in particular, appear related to decreased sea ice coverage in the Beaufort Sea and Chukchi Seas. These trends may result from interrelated processes that accelerate Alaska climate changes relative to those of the contiguous United States.
Implementation of any new medical test, including germline genome sequencing (GS) to inform cancer risk, should take place only when a test is effective, ethically justifiable and acceptable to a ...population. Little empirical evidence exists on patient views regarding GS for cancer risk. The aim of this study was to elicit opinions on who should be offered GS and who should pay for it. Participants with a probable genetic basis for their cancer (n = 335) and blood relatives (n = 199) were recruited to undergo GS and invited to complete questionnaires at baseline. A subset (n = 40) also participated in qualitative interviews about their views regarding access to GS to detect cancer risk. Our response rate was 92% for questionnaires and 100% for interviews. Participants expressed high enthusiasm overall for access to GS for those with a family history of cancer and anyone who requested testing, but enthusiasm was lower for universal access, if opting out was possible and finances not an issue. Rationales for these views reflected maximising the sound use of resources. Challenges to introducing community screening via GS to limit cancer burden were raised, including the current limits of science and individual ability to cope with uncertain results. Participants undergoing GS supported cancer risk testing for those with a family history of cancer but were concerned about the challenges of designing and implementing a population‐based GS cancer‐screening program.
Comprehensive genomic profiling (CGP) is increasingly used to guide cancer therapy. This study aimed to characterise oncologists' experiences and needs when utilising genomic results.
An electronic ...survey distributed nation-wide to practising medical oncologists in Australia explored oncologists' experiences with consenting, interpreting and communicating CGP results to patients.
The survey was completed by 108 of 333 oncologists (32%) and most respondents (
= 97, 90%) had referred patients for CGP. Using a 100-point visual analogue scale score VAS, where higher values indicate greater confidence, most oncologists were confident consenting patients for referral median 75 (Interquartile range, IQR: 53-85), discussing CGP results (median VAS: 70, IQR: 51-80), but significantly less confident discussing secondary germline findings (median VAS: 56, IQR 30-70,
< 0.001). Confidence with pursuing therapies based on CGP results increased with clinical experience (mean VAS increases by 4.8 per 5 years of experience,
< 0.001). Most oncologists (
= 68, 63%) reported wanting assistance with interpretation of CGP and patient-centric resources to aid communication with patients.
Oncologists are integrating genomics into clinical care, but only display moderate confidence in communication and changing management accordingly. The development of patient- and clinician- targeted resources may assist with routine utilisation of CGP results in cancer care.
(Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb's cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers ...4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.
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