The borderline effect for diabetes: when no difference makes a difference.

We hypothesized that people at the borderline of being labeled as "prediabetic" based on A1c blood test results, who initially face equivalent risks of developing diabetes but who are labeled differently, would be more likely to develop diabetes when labeled as "prediabetic" as a result of the label. Study 1 served to establish the psychological effect of the prediabetes label: we surveyed 260 participants on Amazon Mechanical Turk to test whether risk perception significantly increased when comparing A1c test results that differed by 0.1% and led to different diagnostic labels (5.6 and 5.7%) but did not significantly increase when comparing those that differed by 0.1% but received the same label (5.5%/5.6 and 5.7%/5.8%). Study 2 explored whether labels are associated with different rates of developing diabetes when the initial difference in A1c results suggests equivalent risk. Using data from 8,096 patients, we compared patients whose initial A1c results differed by 0.1% and found those who received results labeled as prediabetic (A1c of 5.7%) were significantly more likely to develop diabetes than patients whose initial results were labeled as normal (5.6%). In contrast, patients whose initial results differed by 0.1% but who received the same "normal" label (5.5 and 5.6%) were equally likely to develop diabetes. These preliminary results suggest that diagnostic labels may become self-fulfilling, especially when the underlying pathology of patients receiving different labels does not meaningfully differ.

Mindfulness, curiosity, and creativity.

Curiosity and creativity are manifestations of novelty-seeking mechanisms, closely intertwined and interdependent. This principle aligns seamlessly with the foundational tenets of Langerian mindfulness, which places novelty seeking as a cornerstone. Creativity, curiosity, openness, and flexibility all harmoniously converge in this framework. Spanning over four decades, research in the realm of mindfulness has diligently delved into the intricate interplay among these constructs.

Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations.

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.

Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment.

Pancreatic cancer remains a formidable challenge due to limited treatment options and its aggressive nature. In recent years, the naturally occurring anticancer compound juglone has emerged as a potential therapeutic candidate, showing promising results in inhibiting tumor growth and inducing cancer cell apoptosis. However, concerns over its toxicity have hampered juglone's clinical application. To address this issue, we have explored the use of polymeric micelles as a delivery system for juglone in pancreatic cancer treatment. These micelles, formulated using Poloxamer 407 and D-α-Tocopherol polyethylene glycol 1000 succinate, offer an innovative solution to enhance juglone's therapeutic potential while minimizing toxicity. In-vitro studies have demonstrated that micelle-formulated juglone (JM) effectively decreases proliferation and migration and increases apoptosis in pancreatic cancer cell lines. Importantly, in-vivo, JM exhibited no toxicity, allowing for increased dosing frequency compared to free drug administration. In mice, JM significantly reduced tumor growth in subcutaneous xenograft and orthotopic pancreatic cancer models. Beyond its direct antitumor effects, JM treatment also influenced the tumor microenvironment. In immunocompetent mice, JM increased immune cell infiltration and decreased stromal deposition and activation markers, suggesting an immunomodulatory role. To understand JM's mechanism of action, we conducted RNA sequencing and subsequent differential expression analysis on tumors that were treated with JM. The administration of JM treatment reduced the expression levels of the oncogenic protein MYC, thereby emphasizing its potential as a focused, therapeutic intervention. In conclusion, the polymeric micelles-mediated delivery of juglone holds excellent promise in pancreatic cancer therapy. This approach offers improved drug delivery, reduced toxicity, and enhanced therapeutic efficacy.

Physical healing as a function of perceived time.

In this study we wounded study participants following a standardized procedure and manipulated perceived time to test whether perceived time affected the rate of healing. We measured the amount of healing that occurred across three conditions using a within-subjects design: Slow Time (half as fast as clock time), Normal Time (clock time), and Fast Time (twice as fast as clock time). Based on the theory of mind-body unity-which posits simultaneous and bidirectional influences of mind on body and body on mind-we hypothesized that wounds would heal faster or slower when perceived time was manipulated to be experienced as longer or shorter respectively. Although the actual elapsed time was 28 min in all three conditions, significantly more healing was observed in the Normal Time condition compared to the Slow Time condition, in the Fast Time condition compared to the Normal Time condition, and in the Fast Time condition compared to the Slow Time condition. These results support the hypothesis that the effect of time on physical healing is directly affected by one's psychological experience of time, independent of the actual elapsed time.

MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.

Presenting a sham treatment as personalised increases the placebo effect in a randomised controlled trial.

Background: Tailoring interventions to patient subgroups can improve intervention outcomes for various conditions. However, it is unclear how much of this improvement is due to the pharmacological personalisation versus the non-specific effects of the contextual factors involved in the tailoring process, such as the therapeutic interaction. Here, we tested whether presenting a (placebo) analgesia machine as personalised would improve its effectiveness. Methods: We recruited 102 adults in two samples (N1=17, N2=85) to receive painful heat stimulations on their forearm. During half of the stimulations, a machine purportedly delivered an electric current to reduce their pain. The participants were either told that the machine was personalised to their genetics and physiology, or that it was effective in reducing pain generally. Results: Participants told that the machine was personalised reported more relief in pain intensity than the control group in both the feasibility study (standardised ß=-0.50 [-1.08, 0.08]) and the pre-registered double-blind confirmatory study (ß=-0.20 [-0.36, -0.04]). We found similar effects on pain unpleasantness, and several personality traits moderated the results. Conclusions: We present some of the first evidence that framing a sham treatment as personalised increases its effectiveness. Our findings could potentially improve the methodology of precision medicine research and inform practice. Funding: This study was funded by the Social Science and Humanities Research Council (93188) and Genome Québec (95747).

Precision treatments are therapies that are tailored to a patient's individual biology with the aim of making them more effective. Some cancer drugs, for example, work better for people with specific genes, leading to improved outcomes when compared to their 'generic' versions. However, it is unclear how much of this increased effectiveness is due to tailoring the drug's chemical components versus the contextual factors involved in the personalisation process. Contextual factors like patient beliefs can boost a treatment's outcomes via the 'placebo effect' ­ making the intervention work better simply because the patient believes it to. Personalised treatments typically combine more of these factors by being more expensive, elaborate, and invasive ­ potentially boosting the placebo effect. Sandra et al. tested whether simply describing a placebo machine ­ which has no therapeutic value ­ as personalised would increase its effectiveness at reducing pain for healthy volunteers. Study participants completed several sham physiological and genetic tests. Those in the experimental group were told that their test results helped tailor the machine to increase its effectiveness at reducing pain whereas those in the control group were told that the tests screened for study eligibility. All volunteers were then exposed to a series of painful stimuli and used the machine to reduce the pain for half of the exposures. Participants that believed the machine was personalised reported greater pain relief. Those with a stronger desire to be seen as different from others ­ based on the results of a personality questionnaire ­ experienced the largest benefits, but only when told that the machine was personalised. This is the first study to show that simply believing a sham treatment is personalised can increase its effectiveness in healthy volunteers. If these results are also seen in clinical settings, it would suggest that at least some of the benefit of personalised medicine could be due to the contextual factors surrounding the tailoring process. Future work could inform doctors of how to harness the placebo effect to benefit patients undergoing precision treatments.

Feasibility of an Online Langerian Mindfulness Program for Stroke Survivors and Caregivers.

Mindfulness is promising for individuals with neurological disorders and their caregivers to improve psychological well-being. The potential application of a Langerian mindfulness intervention, focused on attention to variability, however, is still unknown. The objective of the study was to determine the feasibility (usability, satisfaction, and potential effectiveness on psychological well-being) of an online mindfulness intervention for stroke survivors and caregivers. Using mixed methods, 11 stroke survivors and three caregivers participated in a 3-week, online, Langerian mindfulness intervention. A semi-structured interview assessed the intervention's usability and gathered feedback. Self-reported measures about psychological well-being were documented remotely 3 times (preintervention, postintervention, and 1-month follow-up). Qualitatively, participants were highly satisfied with the intervention and reported subjective benefits, but the usability of the online platform was poor. None of the self-reported measures changed over time. This study provided evidence of feasibility of an online Langerian mindfulness intervention in a new population: stroke survivors and caregivers.

An online non-meditative mindfulness intervention for people with ALS and their caregivers: a randomized controlled trial.

Objectives: Mindfulness-based interventions seem to be effective in promoting QOL of ALS patients and caregivers, but most require substantial time. In the Langerian approach, mindfulness can be easily promoted with mental tasks and short lectures. This study aims to explore the impact of an ALS-specific online Langerian mindfulness training program on QOL of ALS patients. Methods: We developed and tested with an Randomized Controlled Trial (RCT) a 5-week active learning mindfulness program. Participants were recruited from the ALS clinic at Penn State Health and online and were randomly assigned to either the mindfulness group or a wait-list control group. The primary outcome was the patient's QOL after the treatment. 3 and 6-month follow-ups, together with anxiety, depression, care burden, and physical function, assessed at all times for both patients and caregivers, were explored as secondary outcomes. Results: 47 ALS patients and 27 caregivers were recruited. Among the ALS patients, the experimental group reported higher levels of QOL at the end of the treatment (d = 0.54). Moreover, they showed lower values of depression, anxiety, and negative emotions, compared to the controls, over time. The caregivers from the mindfulness group reported lower scores of care burden, depression, and anxiety, with higher values of energy and emotional well-being over time. Conclusions: This small RCT provides preliminary evidence that this intervention leads to an increase of QOL and a reduction in psychological comorbidities in ALS patients and caregivers. Given the relatively short time commitment, it may be easily implemented by the ALS community.

Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.

The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

The effect of mindful attention training for pain modulation capacity: Exploring the mindfulness-pain link.

OBJECTIVE: Mindfulness has been shown to be beneficial for chronic pain. The underlying mechanisms of the mindfulness-pain link, however, are yet to be established. Particularly, the effects of mindfulness on pain modulation, which is shown to be dysfunctional among chronic pain patients, barely has been tested. This study investigated whether a short mindful attention training based on Langerian mindfulness mitigates reductions in pain modulation. METHOD: Systemic quantitative-somatosensory testing of conditioned pain modulation (CPM) was conducted in 60 undergraduates, who were randomly assigned to one of three groups: (1) Pain-specific mindful attention training; (2) nonspecific mindful attention training; and (3) no mindful attention training. CPM was tested before and after the intervention. RESULTS: As hypothesized, a reduction in CPM magnitude was observed only in the control group, whereas this reduction was abolished in the two mindfulness groups. CONCLUSIONS: Langerian mindfulness may mitigate pain modulation reduction as observed in chronic pain, thus shedding light on its potential advantages.

Glucose metabolism responds to perceived sugar intake more than actual sugar intake.

The authors examine study participants who have Type 2 diabetes to determine whether cognition affects glucose levels in contrast to widely held suppositions. Thirty participants who have type 2 diabetes consume beverages that have identical ingredients but have deceptive nutrition facts labels. Blood glucose levels measured four times before and after beverage consumption show that blood glucose levels increase when participants believe the beverage has high sugar content as portrayed on the labels. Also, individual eating behaviors and nutritional satisfaction are linked to changes in blood glucose levels. The study results support the concept of anticipatory budgeting on glucose metabolism. The findings provide pressing evidence for the psychobiological model of chronic disease, suggesting that psychological intervention programs may be important for diabetes management, beyond current programs in which type 2 diabetes is managed through diet, exercise, and medications only.

Altering MYC phosphorylation in the epidermis increases the stem cell population and contributes to the development, progression, and metastasis of squamous cell carcinoma.

cMYC (MYC) is a potent oncoprotein that is subject to post-translational modifications that affect its stability and activity. Here, we show that Serine 62 phosphorylation, which increases MYC stability and oncogenic activity, is elevated while Threonine 58 phosphorylation, which targets MYC for degradation, is decreased in squamous cell carcinoma (SCC). The oncogenic role of MYC in the development of SCC is unclear since studies have shown in normal skin that wild-type MYC overexpression can drive loss of stem cells and epidermal differentiation. To investigate whether and how altered MYC phosphorylation might affect SCC development, progression, and metastasis, we generated mice with inducible expression of MYCWT or MYCT58A in the basal layer of the skin epidermis. In the T58A mutant, MYC is stabilized with constitutive S62 phosphorylation. When challenged with DMBA/TPA-mediated carcinogenesis, MYCT58A mice had accelerated development of papillomas, increased conversion to malignant lesions, and increased metastasis as compared to MYCWT mice. In addition, MYCT58A-driven SCC displayed stem cell gene expression not observed with MYCWT, including increased expression of Lgr6, Sox2, and CD34. In support of MYCT58A enhancing stem cell phenotypes, its expression was associated with an increased number of BrdU long-term label-retaining cells, increased CD34 expression in hair follicles, and increased colony formation from neonatal keratinocytes. Together, these results indicate that altering MYC phosphorylation changes its oncogenic activity-instead of diminishing establishment and/or maintenance of epidermal stem cell populations like wild-type MYC, pS62-MYC enhances these populations and, under carcinogenic conditions, pS62-MYC expression results in aggressive tumor phenotypes.

PIN1 Provides Dynamic Control of MYC in Response to Extrinsic Signals.

PIN1 is a phosphorylation-directed member of the peptidyl-prolyl cis/trans isomerase (PPIase) family that facilitates conformational changes in phosphorylated targets such as c-MYC (MYC). Following signaling events that mediate phosphorylation of MYC at Serine 62, PIN1 establishes structurally distinct pools of MYC through its trans-cis and cis-trans isomerization activity at Proline 63. Through these isomerization steps, PIN1 functionally regulates MYC's stability, the molecular timing of its DNA binding and transcriptional activity, and its subnuclear localization. Recently, our group showed that Serine 62 phosphorylated MYC can associate with the inner basket of the nuclear pore (NP) in a PIN1-dependent manner. The poised euchromatin at the NP basket enables rapid cellular response to environmental signals and cell stress, and PIN1-mediated trafficking of MYC calibrates this response. In this perspective, we describe the molecular aspects of PIN1 target recognition and PIN1's function in the context of its temporal and spatial regulation of MYC.

Manipulating sleep duration perception changes cognitive performance - An exploratory analysis.

OBJECTIVES: To test the effect of perceived sleep duration on cognitive performance. METHODS: Sixteen healthy individuals [8F; mean age (± SD): 24.2 ± 3.0 years)] received an 8-h sleep opportunity followed by a 5-h opportunity on two consecutive nights. Upon waking, they were randomized to being informed that they received either an 8-h or 5-h sleep opportunity, via a clock that ran either fast, slow or normally. Cognitive performance was assessed using 10-min auditory psychomotor vigilance tests and subjective sleepiness ratings. Homeostatic and circadian sleep drive was assessed using waking electroencephalography (EEG). RESULTS: Reaction time was significantly quicker when individuals thought that they had slept for 8 h but given a 5-h sleep opportunity. Conversely, reaction times were significantly slower when individuals thought they had 5 h of sleep but given an 8-h sleep opportunity. EEG delta power (1.0-4.5 Hz) during wake increased significantly when sleep was restricted to 5 h, and individuals thought they slept for 5 h, but this increase was attenuated with a perceived sleep duration of 8 h following a 5-h opportunity. EEG delta power did not increase, however, with perceived sleep restriction. EEG high-alpha activity (10.5-11.5 Hz) was consistently higher when participants thought that they had an 8-h sleep opportunity, regardless of the actual duration. CONCLUSIONS: These results suggest that perceived sleep duration may modulate psychosomatic responses. Additional studies with predefined outcomes and analyses are necessary to confirm these findings, which may have important implications for understanding how sleep affects cognition and psychosomatic responses.

Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity.

The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in HER2+ disease, examining the relationship between HER2 expression and MYC phosphorylation in HER2+ patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC;NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC;NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.

Correction: Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer.

[This corrects the article DOI: 10.1371/journal.pcbi.1006840.].

Ageing as a mindset: a study protocol to rejuvenate older adults with a counterclockwise psychological intervention.

INTRODUCTION: Although ageing is generally perceived as a biologically determined process, the literature increasingly points to the importance of psychological factors in the ageing process, specifically age-related stereotypes or cognitive mindsets. Such stereotypes reflect self-perceptions and others' perceptions about the ageing process and can have a strong influence on health and life satisfaction, specifically through self-fulfilling prophecy mechanisms. This study aimed to investigate whether changes in mindsets can change the ageing process. METHODS AND ANALYSIS: This study replicates in large part the original 1979 'Counterclockwise' experiment by Ellen Langer and will involve a group of older adults (aged 75+) taking part of a 1-week retreat outside of Milan, Italy. Participants will be instructed and helped to relive their younger selves, acting as if they are living in the year 1989. The week-long residential programme is designed to prime this perception by incorporating a completely retrofitted physical environment, as well as providing opportunities to engage in social activities that would have been common in the late 1980s. This 'counterclockwise' intervention will be tested as a randomised control trial comprised of the experimental ('counterclockwise') group, an active control group (same activities, no time manipulation) and a no-treatment group. Ninety participants will be randomly allocated to one of these three conditions. Every participant will be assessed for medical, cognitive, psychological and age appearance at four time points: at the time of recruitment, after the intervention (ie, after a week for the no-treatment group) and again after 6 and 12 months. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committees of the Department of Psychology of Università Cattolica del Sacro Cuore and Don Gnocchi Foundation. Results will be disseminated through peer-reviewed journals, scientific meetings and direct presentation to the general population. TRIAL REGISTRATION NUMBER: NCT03552042; Pre-results.

Reducing Delirium and Improving Patient Satisfaction With a Perioperative Mindfulness Intervention: A Mixed-Methods Pilot Study.

Postoperative delirium (incidence estimated up to 82%) can be ameliorated with nonpharmacologic methods. Mindfulness has not yet been incorporated into these methods, although mindfulness has been demonstrated to help patients adapt to illness and hospitalization. To reduce postoperative delirium incidence and increase patient satisfaction, this study employs a program of thought exercises based on Langerian mindfulness. Preoperatively, cardiac surgical patients listened to a mindfulness or informational audio; mindfulness subjects were also guided by the principal investigator through mindfulness exercises. Postoperatively, mindfulness subjects were visited twice daily for mindfulness exercises. For all patients, delirium screening was performed twice daily. Before discharge, affective status and satisfaction with hospital stay were assessed. No patients who completed the study screened positive for delirium. Trends include (1) lower (improved) median anxiety and depression scores postoperatively when considering both study groups together; (2) both groups rated the hospital more favorably on global satisfaction measures; (3) both groups shared generally positive comments regarding the audio files (qualitative data). Audio files and mindfulness exercises are associated with patient satisfaction among cardiothoracic surgery patients. The absence of delirium precludes determination of the effectiveness of the intervention in reducing delirium incidence.