Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA-Associated Pancreatic Cancer in the Clinical and Preclinical Setting.

Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions. SIGNIFICANCE: glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.

A Biphasic COVID-19 Clinical Course in Anti-CD20 Treated Patients: Case Series and Review of the Literature.

We describe four cases of COVID-19 infection during the Omicron wave, in patients treated with anti-CD20 monoclonal antibodies. All cases follow a similar biphasic clinical course consisting of respiratory deterioration, which occurred a few weeks after convalescence from initial mild to asymptomatic infection. Possible explanations are discussed. LEARNING POINTS: Four cases of COVID-19 infection in anti-CD20 treated patients are described.These cases display a unique biphasic course that was previously undescribed: respiratory deterioration weeks after convalescence.Awareness of such a course and rapid utilisation of bronchoalveolar lavage will lead to quicker diagnosis and more timely, appropriate treatment.

Erratum to Peer et al. (2021) Data quality of platforms and panels for online behavioral research.

This erratum reports on a technical error that was discovered in Study 2 of Peer et al. (2021). Because of this technical error, some specific findings on participants' proclivity for dishonesty reported in the paper have been found incorrect. We detail the error, which only affected female participants, and its impact on the findings and report on the reanalyzed findings accounting for the error. The new findings do not change the conclusions provided in the paper, and show again that participants from MTurk are more likely to engage in dishonest behavior than participants from Prolific or CloudResearch.

Data quality of platforms and panels for online behavioral research.

We examine key aspects of data quality for online behavioral research between selected platforms (Amazon Mechanical Turk, CloudResearch, and Prolific) and panels (Qualtrics and Dynata). To identify the key aspects of data quality, we first engaged with the behavioral research community to discover which aspects are most critical to researchers and found that these include attention, comprehension, honesty, and reliability. We then explored differences in these data quality aspects in two studies (N ~ 4000), with or without data quality filters (approval ratings). We found considerable differences between the sites, especially in comprehension, attention, and dishonesty. In Study 1 (without filters), we found that only Prolific provided high data quality on all measures. In Study 2 (with filters), we found high data quality among CloudResearch and Prolific. MTurk showed alarmingly low data quality even with data quality filters. We also found that while reputation (approval rating) did not predict data quality, frequency and purpose of usage did, especially on MTurk: the lowest data quality came from MTurk participants who report using the site as their main source of income but spend few hours on it per week. We provide a framework for future investigation into the ever-changing nature of data quality in online research, and how the evolving set of platforms and panels performs on these key aspects.

The Epitranscriptome in Translation Regulation.

The cellular proteome reflects the total outcome of many regulatory mechanisms that affect the metabolism of messenger RNA (mRNA) along its pathway from synthesis to degradation. Accumulating evidence in recent years has uncovered the roles of a growing number of mRNA modifications in every step along this pathway, shaping translational output. mRNA modifications affect the translation machinery directly, by influencing translation initiation, elongation and termination, or by altering mRNA levels and subcellular localization. Features of modification-related translational control are described, charting a new and complex layer of translational regulation.

Epitranscriptomics: regulation of mRNA metabolism through modifications.

Cellular RNAs can be modified post-transcriptionally with dynamic and reversible chemical modifications. These modifications can alter the structure and metabolism of mRNA, but only recent methodological and conceptual advances allowed systematic mapping and functional analysis to unfold the role they play in mRNA biology. Mapping the most common internal mRNA modification, N6-methyladenosine (m6A), paved the way for the deciphering of other types of mRNA modifications, such as N1-methyladenosine (m1A). RNA methylation provides dynamic regulation to the processing, export, translation and stability of mRNA molecules, thereby influencing fundamental biological and pathological processes such as differentiation, cellular response to stress and tumorigenesis. This review summarizes the key methods and the recent discoveries in the field of epitranscriptomics through the prism of post-transcriptional mRNA methylation in eukaryotes.

The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA.

Gene expression can be regulated post-transcriptionally through dynamic and reversible RNA modifications. A recent noteworthy example is N(6)-methyladenosine (m(6)A), which affects messenger RNA (mRNA) localization, stability, translation and splicing. Here we report on a new mRNA modification, N(1)-methyladenosine (m(1)A), that occurs on thousands of different gene transcripts in eukaryotic cells, from yeast to mammals, at an estimated average transcript stoichiometry of 20% in humans. Employing newly developed sequencing approaches, we show that m(1)A is enriched around the start codon upstream of the first splice site: it preferentially decorates more structured regions around canonical and alternative translation initiation sites, is dynamic in response to physiological conditions, and correlates positively with protein production. These unique features are highly conserved in mouse and human cells, strongly indicating a functional role for m(1)A in promoting translation of methylated mRNA.

Using Nonnaive Participants Can Reduce Effect Sizes.

Although researchers often assume their participants are naive to experimental materials, this is not always the case. We investigated how prior exposure to a task affects subsequent experimental results. Participants in this study completed the same set of 12 experimental tasks at two points in time, first as a part of the Many Labs replication project and again a few days, a week, or a month later. Effect sizes were markedly lower in the second wave than in the first. The reduction was most pronounced when participants were assigned to a different condition in the second wave. We discuss the methodological implications of these findings.

Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.

Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.

Wilms' tumor blastemal stem cells dedifferentiate to propagate the tumor bulk.

An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms' tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1(+)) aldehyde dehydrogenase 1-positive (ALDH1(+)) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1(+) WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.

"Heads or tails?"--a reachability bias in binary choice.

When asked to mentally simulate coin tosses, people generate sequences that differ systematically from those generated by fair coins. It has been rarely noted that this divergence is apparent already in the very 1st mental toss. Analysis of several existing data sets reveals that about 80% of respondents start their sequence with Heads. We attributed this to the linguistic convention describing coin toss outcomes as "Heads or Tails," not vice versa. However, our subsequent experiments found the "first-toss" bias reversible under minor changes in the experimental setup, such as mentioning Tails before Heads in the instructions. We offer a comprehensive account in terms of a novel response bias, which we call reachability. It is more general than the 1st-toss bias, and it reflects the relative ease of reaching 1 option compared to its alternative in any binary choice context. When faced with a choice between 2 options (e.g., Heads and Tails, when "tossing" mental coins), whichever of the 2 is presented first by the choice architecture (hence, is more reachable) will be favored. This bias has far-reaching implications extending well beyond the context of randomness cognition; in particular, to binary surveys (e.g., accept vs. reject) and tests (e.g., True-False). In binary choice, there is an advantage to what presents first.

"I cheated, but only a little": partial confessions to unethical behavior.

Confessions are people's way of coming clean, sharing unethical acts with others. Although confessions are traditionally viewed as categorical-one either comes clean or not-people often confess to only part of their transgression. Such partial confessions may seem attractive, because they offer an opportunity to relieve one's guilt without having to own up to the full consequences of the transgression. In this article, we explored the occurrence, antecedents, consequences, and everyday prevalence of partial confessions. Using a novel experimental design, we found a high frequency of partial confessions, especially among people cheating to the full extent possible. People found partial confessions attractive because they (correctly) expected partial confessions to be more believable than not confessing. People failed, however, to anticipate the emotional costs associated with partially confessing. In fact, partial confessions made people feel worse than not confessing or fully confessing, a finding corroborated in a laboratory setting as well as in a study assessing people's everyday confessions. It seems that although partial confessions seem attractive, they come at an emotional cost.

Reputation as a sufficient condition for data quality on Amazon Mechanical Turk.

Data quality is one of the major concerns of using crowdsourcing websites such as Amazon Mechanical Turk (MTurk) to recruit participants for online behavioral studies. We compared two methods for ensuring data quality on MTurk: attention check questions (ACQs) and restricting participation to MTurk workers with high reputation (above 95% approval ratings). In Experiment 1, we found that high-reputation workers rarely failed ACQs and provided higher-quality data than did low-reputation workers; ACQs improved data quality only for low-reputation workers, and only in some cases. Experiment 2 corroborated these findings and also showed that more productive high-reputation workers produce the highest-quality data. We concluded that sampling high-reputation workers can ensure high-quality data without having to resort to using ACQs, which may lead to selection bias if participants who fail ACQs are excluded post-hoc.

When two motivations race: The effects of time-saving bias and sensation-seeking on driving speed choices.

Time-saving bias-people's biased judgments in estimating the time saved when increasing speed-has been found to strongly impact driving speed choices. However, this bias may be relevant only when the driver's motivation for increasing speed is to arrive sooner. If, on the other hand, the driver is motivated by the desire to experience thrill and sensation, a driver's level of sensation-seeking might better explain choices of speed. In this study, participants were asked to estimate the journey time when increasing speed and to estimate the speed required to arrive on time. They also indicated the speed they would personally choose in such a situation. Next, participants filled out Zuckerman's (1994) Sensation Seeking Scale. Results showed that both time-saving estimations and the Disinhibition scale of Sensation Seeking (as well as drivers' gender) contributed independently and additively to drivers' choice of speed and that time-saving bias' role was somewhat stronger than sensation-seeking.

Estimating time savings: the use of the proportion and percentage heuristics and the role of need for cognition.

People generally overestimate the time they can save when increasing from a relatively high driving speed. Previous research suggested that people follow a Proportion Heuristic, calculating the time saved as the proportion of speed increase from the new higher speed. The present study suggests that drivers use another heuristic - the Percentage Heuristic - to calculate how much time they save by increasing speed. In the percentage heuristic, the initial (rather than higher) speed is used as the denominator. Using a discriminating set of questions, we classified participants' responses as normative (correct answer), as following the proportion or percentage heuristic, or some other strategy. We found that participants used the percentage heuristic more often, perhaps because it predicts linearly increasing values of time saved when increasing speed. In addition, we found that participants high in need for cognition (NFC) gave correct answers more often than low NFC participants who relied more on heuristics.

Speeding and the time-saving bias: how drivers' estimations of time saved in higher speed affects their choice of speed.

According to the time-saving bias, drivers overestimate the time saved when increasing from an already relatively high speed and underestimate the time saved when increasing from a relatively low speed. This study examined the effect the time-saving bias may have on drivers' choice of speed using hypothetical situations. Drivers were presented with a situation involving acceleration from a relatively low speed in order to arrive at a destination on time and were asked to estimate the time that could be saved by increasing to higher speeds. Drivers also estimated the speed required for arriving on time, the speed they would personally choose and the speed they believed other drivers would opt for in such a situation. Results showed that drivers indeed underestimated the time that could be saved by increasing from a low speed. In addition, drivers who showed a high time-saving bias (above median) indicated notably higher speeds in all three categories above and their indicated speeds exceeded the speed limit more frequently. These findings suggest that the time-saving bias may help explain why drivers, in some situations, prefer an overly high speed and violate the legal speed limit.