Nevin Manimala

JCO Precis Oncol. 2023 Sep;7:e2300088. doi: 10.1200/PO.23.00088.

ABSTRACT

PURPOSE: Recurrent gene mutations in speckle-type POZ protein (SPOP), the substrate-binding component of E3 ubiquitin ligase, are associated with tumor progression in prostate and endometrial cancers. Here, we characterized SPOP mutations in these cancers and explored their association with molecular and immune signatures and patient outcomes.

METHODS: There were 7,398 prostate cancer and 19,188 endometrial cancer samples analyzed for clinical and molecular profiles at Caris Life Sciences. Overall survival (OS) was analyzed using Kaplan-Meier survival curves. Statistical significance was determined using chi-square and Mann-Whitney U tests, with P values adjusted for multiple comparisons.

RESULTS: SPOP mutations were identified in 9.2% of prostate and 4.3% of endometrial cancers. Mutations clustered in the SPOP meprin and TRAF-C homology domain, with no significant overlap between cancer types. SPOP mutation was associated with differential comutation profiles and opposing tumor immune microenvironment signatures for each cancer, with greater immune infiltration in SPOP-mutated endometrial cancer. SPOP-mutated prostate and endometrial cancers displayed altered epigenetic gene expression, including opposite regulation of BRD2 transcripts. In SPOP-mutant prostate cancer, higher expression of androgen receptor-regulated transcripts and improved OS after treatment with hormonal agents were observed. In endometrial cancer, hormone receptor expression was significantly lower in SPOP-mutated tumors and differences in OS were highly dependent on the particular hotspot mutation and histologic subtype.

CONCLUSION: These data indicate that SPOP mutations drive opposing molecular and immune landscapes in prostate and endometrial cancers-suggesting a loss-of-function mechanism in prostate cancer and gain-of-function mechanism in endometrial cancer-and provide a rationale for tailored therapeutic approaches.

PMID:37677121 | DOI:10.1200/PO.23.00088

JCO Clin Cancer Inform. 2023 Sep;7:e2300007. doi: 10.1200/CCI.23.00007.

ABSTRACT

PURPOSE: To describe clinical research professionals (CRPs)’ experiences with electronic patient-reported outcome (ePRO) data collection systems in oncology clinical trials and identify correlates of CRPs’ attitude toward technology.

METHODS: An online survey was conducted among 210 CRPs from 125 National Cancer Institute-funded research sites. Measures included CRPs’ demographic characteristics, working years, employment locations, and previous experiences with various types of ePROs. Their attitude toward technology was measured by the Technology Attitude Scale-Adapted. The Wilcoxon signed-rank test was used to compare two subdomains of attitude (perceived usefulness [PU] and perceived ease of use [PEU]). Multiple linear regression was used to explore correlates of (1) overall attitude, (2) PU, and (3) PEU. The significance level was 5%.

RESULTS: Participants’ median age was 41 years (range, 21-67). Most were female (90%) and White (82%). More than half of the participants had previous experiences with web-based ePROs using patients’ own devices (72%) or site-/sponsor-provided on-site devices (eg, kiosks or tablets; 64%). CRPs who were 60 years or older (β = -0.32, P < .05) or worked for 10-20 years (β = -0.11, P < .05) had relatively negative attitudes, controlling for other factors. Previous experiences with more ePRO types were associated with more positive attitudes (β = 0.08, P = .02). Similar correlates were found with PU but not with PEU.

CONCLUSION: This study revealed that CRPs had various experiences with ePRO systems and attitudes toward technology. Age, working years, and previous experiences with ePROs were correlates of overall attitude toward technology and PU. These findings suggest necessary targeted training to facilitate ePRO use in oncology clinical trials by improving CRPs’ awareness and attitude toward technology.

PMID:37677111 | DOI:10.1200/CCI.23.00007

J Vis Exp. 2023 Sep 1;(199). doi: 10.3791/65712.

ABSTRACT

Lipids are structural building blocks of cell membranes; lipid species vary across cell organelles and across organisms. This variety results in different mechanical and structural properties in the membrane that directly impact the molecules and processes that occur at this interface. Lipid composition is dynamic and can serve to modulate cell signaling processes. Computational approaches are increasingly used to predict interactions between biomolecules and provide molecular insights to experimental observables. Molecular dynamics (MD) is a technique based on statistical mechanics that predicts the movement of atoms based on the forces that act on them. MD simulations can be used to characterize the interaction of biomolecules. Here, we briefly introduce the technique, outline practical steps for beginners who are interested in simulating lipid bilayers, demonstrate the protocol with beginner-friendly software, and discuss alternatives, challenges, and important considerations of the process. Particularly, we emphasize the relevance of using complex lipid mixtures to model a cell membrane of interest to capture the appropriate hydrophobic and mechanical environments in simulation. We also discuss some examples where membrane composition and properties modulate the interactions of bilayers with other biomolecules.

PMID:37677042 | DOI:10.3791/65712

J Vis Exp. 2023 Sep 1;(199). doi: 10.3791/65484.

ABSTRACT

There has been an increase in the use of in vivo and in vitro intestinal models to study the pathophysiology of inflammatory intestinal diseases, for the pharmacological screening of potentially beneficial substances, and for toxicity studies on potentially harmful food components. Of relevance, there is a current demand for the development of cell-based in vitro models to substitute animal models. Here, a protocol for a basic, “healthy tissue” three-dimensional (3D) intestinal equivalent model using cell lines is presented with the dual benefit of providing both experimental simplicity (standardized and easily repeatable system) and physiological complexity (Caco-2 enterocytes with a supporting immune component of U937 monocytes and L929 fibroblasts). The protocol also includes paraffin embedding for light microscopic evaluation of fixed intestinal equivalents, thereby providing the advantage of analyzing multiple visual parameters from a single experiment. Hematoxylin and eosin (H&E) stained sections showing the Caco-2 columnar cells forming a tight and regular monolayer in control treatments are used to verify the efficacy of the model as an experimental system. Using gluten as a pro-inflammatory food component, parameters analyzed from sections include reduced monolayer thickness, as well as disruption and detachment from the underlying matrix (H&E), decreased tight junction protein expression as shown from occludin staining (quantifiable statistically), and immune-activation of migrating U937 cells as evidenced from the cluster of differentiation 14 (CD14) staining and CD11b-related differentiation into macrophages. As shown by using lipopolysaccharide to simulate intestinal inflammation, additional parameters that can be measured are increased mucus staining and cytokine expression (such as midkine) that can be extracted from the medium prior to fixation. The basic three-dimensional (3D) intestinal mucosa model and fixed sections can be recommended for inflammatory status and barrier integrity studies with the possibility of analyzing multiple visual quantifiable parameters.

PMID:37677028 | DOI:10.3791/65484

Ann Med. 2023;55(2):2252442. doi: 10.1080/07853890.2023.2252442.

ABSTRACT

OBJECTIVE: To investigate the differences in the viscoelastic properties between normal trapezius muscles and those in patients with trapezius myofascial pain syndrome (MPS) using real-time shear-wave elastography (SWE).

MATERIALS AND METHODS: This study included 31 patients with trapezius MPS and 31 volunteers. Sixty-one trapezius muscles (41 and 20 on the affected and non-affected side, respectively) of patients with MPS and 62 normal trapezius muscles in volunteers were assessed. Conventional ultrasonic parameters, including skeletal muscle thickness, resistance index (RI), and mean shear wave velocity (SWV_mean) of trapezius muscles, were obtained in the seated position with the shoulders and neck relaxed. The daily neck leaning time (unit:hours) of all participants was obtained using a questionnaire.

RESULTS: Ultrasound showed no statistically significant differences in thickness or RI of the trapezius muscles of the affected and non-affected sides in MPS patients versus normal trapezius muscles (p = 0.976 and 0.106, respectively). In contrast, the SWV_mean of trapezius muscles in patients with MPS was significantly higher than that of normal trapezius muscles in both the affected and non-affected sides (4.41 ± 1.02 m/s vs. 3.35 ± 0.79 m/s, p < 0.001; 4.05 ± 0.63 m/s vs. 3.35 ± 0.79 m/s, p = 0.002). There was no significant difference between the SWV_mean of the trapezius muscles on the affected and non-affected sides in patients with MPS (4.41 ± 1.02 m/s vs. 4.05 ± 0.63 m/s, p = 0.225). Correlation analysis showed that daily neck forward time was positively correlated with the SWV_mean of the trapezius muscles on the affected and non-affected sides in patients with MPS (r = 0.635, p < 0.001; r = 0.576, p = 0.008).

CONCLUSION: SWE can quantitatively evaluate stiffness of trapezius muscles in patients with trapezius MPS. The stiffness of both affected and non-affected trapezius muscles increased in patients with trapezius MPS, and the degree of increase positively correlated with the time of cervical forward leaning.

PMID:37676997 | DOI:10.1080/07853890.2023.2252442

Biopreserv Biobank. 2023 Sep 7. doi: 10.1089/bio.2023.0007. Online ahead of print.

NO ABSTRACT

PMID:37676979 | DOI:10.1089/bio.2023.0007

Telemed J E Health. 2023 Sep 7. doi: 10.1089/tmj.2023.0225. Online ahead of print.

ABSTRACT

Background: Telemedicine has expanded rapidly during the COVID-19 pandemic. Data on telemedicine utilization are lacking, and racial/ethnic disparities in utilization and satisfaction are unknown among breast cancer patients. Methods: This was a longitudinal study, with two surveys conducted in 2020 and 2021, among patients enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort. Telemedicine utilization was modeled using mixed-effects logistic regression. Telemedicine satisfaction, assessed using a 5-point Likert scale, was modeled using mixed-effects proportional odds regression. Qualitative data on satisfaction were coded and analyzed using grounded theory. Results: Of 1,721 respondents, most (70.3%) were White, followed by 23.6% Black, 3.1% Asian, and 3.0% Hispanic. The median duration from breast cancer diagnosis to survey was 5.5 years (interquartile range: 2.7-9.4). In 2020, 59.2% reported telemedicine use; in 2021, 64.9% did, with a statistically significant increase (p < 0.001). Black patients had greater odds of telemedicine use than White patients (adjusted odds ratio [AOR] = 1.55, 95% confidence interval [CI]: 1.17-2.05). In 2020, 90.3% reported somewhat-to-extreme satisfaction; in 2021, 91.2% did, with a statistically significant, although clinically small, increase (p = 0.038). There were no racial/ethnic differences in telemedicine satisfaction between Black (AOR = 1.05, 95% CI: 0.81-1.35), Asian (AOR = 0.63, 95% CI: 0.34-1.16), or Hispanic (AOR = 0.63, 95% CI: 0.33-1.21) and White patients. Major themes emerged from the respondents that explained their levels of satisfaction were convenience, safety, specialty dependence, and technical issues. Conclusions: Telemedicine utilization and satisfaction were high among breast cancer patients over time and across races/ethnicities. Telemedicine could have great potential in reducing barriers to care and promoting health equity for breast cancer patients. However, patients’ perceived challenges in accessing high-quality virtual care should be addressed.

PMID:37676974 | DOI:10.1089/tmj.2023.0225

PLoS One. 2023 Sep 7;18(9):e0287474. doi: 10.1371/journal.pone.0287474. eCollection 2023.

ABSTRACT

Vision has been shown to be an active process that can be shaped by top-down influences. Here, we add to this area of research by showing a surprising example of how visual perception can be affected by cognition (i.e., cognitive penetration). Observers were presented, on each trial, with a picture of a computer-generated football player and asked to rate the slenderness of the player on an analog scale. The results of two experiments showed that observers perceived athletes wearing small jersey numbers as more slender than those with high numbers. This finding suggests that the cognition of numbers quantitatively alters body size perception. We conjecture that this effect is the result of previously learned associations (i.e., prior expectations) affecting perceptual inference. Such associations are likely the result of implicit learning of the statistical regularities of number and size attributes co-occurrences by the nervous system. We discuss how these results are consistent with previous research on statistical learning and how they fit into the Bayesian framework of perception. The current finding supports the notion of top-down influences of cognition on perception.

PMID:37676917 | DOI:10.1371/journal.pone.0287474

PLoS Genet. 2023 Sep 7;19(9):e1010921. doi: 10.1371/journal.pgen.1010921. Online ahead of print.

ABSTRACT

Transcriptome-wide association studies (TWAS) aim to detect relationships between gene expression and a phenotype, and are commonly used for secondary analysis of genome-wide association study (GWAS) results. Results from TWAS analyses are often interpreted as indicating a genetic relationship between gene expression and a phenotype, but this interpretation is not consistent with the null hypothesis that is evaluated in the traditional TWAS framework. In this study we provide a mathematical outline of this TWAS framework, and elucidate what interpretations are warranted given the null hypothesis it actually tests. We then use both simulations and real data analysis to assess the implications of misinterpreting TWAS results as indicative of a genetic relationship between gene expression and the phenotype. Our simulation results show considerably inflated type 1 error rates for TWAS when interpreted this way, with 41% of significant TWAS associations detected in the real data analysis found to have insufficient statistical evidence to infer such a relationship. This demonstrates that in current implementations, TWAS cannot reliably be used to investigate genetic relationships between gene expression and a phenotype, but that local genetic correlation analysis can serve as a potential alternative.

PMID:37676898 | DOI:10.1371/journal.pgen.1010921

PLoS One. 2023 Sep 7;18(9):e0283308. doi: 10.1371/journal.pone.0283308. eCollection 2023.

ABSTRACT

The Gull Alpha Power Lomax distribution is a new extension of the Lomax distribution that we developed in this paper (GAPL). The proposed distribution’s appropriateness stems from its usefulness to model both monotonic and non-monotonic hazard rate functions, which are widely used in reliability engineering and survival analysis. In addition to their special cases, many statistical features were determined. The maximum likelihood method is used to estimate the model’s unknown parameters. Furthermore, the proposed distribution’s usefulness is demonstrated using two medical data sets dealing with COVID-19 patients’ mortality rates, as well as extensive simulated data applied to assess the performance of the estimators of the proposed distribution.

PMID:37676891 | DOI:10.1371/journal.pone.0283308