Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer.

Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.

EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer.

BACKGROUND: Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and plays an oncogenic role in various cancers through catalysis-dependent or catalysis-independent pathways. However, the related mechanisms contributing to ovarian cancer (OC) are not well understood. METHODS: The levels of EZH2 and H3K27me3 were evaluated in 105 OC patients by immunohistochemistry (IHC) staining, and these patients were stratified based on these levels. Canonical and noncanonical binding sites of EZH2 were defined by chromatin immunoprecipitation sequencing (ChIP-Seq). The EZH2 solo targets were obtained by integrative analysis of ChIP-Seq and RNA sequencing data. In vitro and in vivo experiments were performed to determine the role of EZH2 in OC growth. RESULTS: We showed that a subgroup of OC patients with high EZH2 expression but low H3K27me3 exhibited the worst prognosis, with limited therapeutic options. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked OC cell proliferation and tumorigenicity in vitro and in vivo. Integrative analysis of genome-wide chromatin and transcriptome profiles revealed extensive EZH2 occupancy not only at genomic loci marked by H3K27me3 but also at promoters independent of PRC2, indicating a noncanonical role of EZH2 in OC. Mechanistically, EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing tricarboxylic acid cycle (TCA cycle) activity, which contributed to the growth of OC. CONCLUSIONS: These data reveal a novel oncogenic role of EZH2 in OC and identify potential therapeutic strategies for OC by targeting the noncatalytic activity of EZH2.

Learning emotional dialects: A British population study of cross-cultural communication.

The aim of the current research was to explore whether we can improve the recognition of cross-cultural freely-expressed emotional faces in British participants. We tested several methods for improving the recognition of freely-expressed emotional faces, such as different methods for presenting other-culture expressions of emotion from individuals from Chile, New Zealand and Singapore in two experimental stages. In the first experimental stage, in phase one, participants were asked to identify the emotion of cross-cultural freely-expressed faces. In the second phase, different cohorts were presented with interactive side-by-side, back-to-back and dynamic morphing of cross-cultural freely-expressed emotional faces, and control conditions. In the final phase, we repeated phase one using novel stimuli. We found that all non-control conditions led to recognition improvements. Morphing was the most effective condition for improving the recognition of cross-cultural emotional faces. In the second experimental stage, we presented morphing to different cohorts including own-to-other and other-to-own freely-expressed cross-cultural emotional faces and neutral-to-emotional and emotional-to-neutral other-culture freely-expressed emotional faces. All conditions led to recognition improvements and the presentation of freely-expressed own-to-other cultural-emotional faces provided the most effective learning. These findings suggest that training can improve the recognition of cross-cultural freely-expressed emotional expressions.

"The many faces of sorrow": An empirical exploration of the psychological plurality of sadness.

Sadness has typically been associated with failure, defeat and loss, but it has also been suggested that sadness facilitates positive and restructuring emotional changes. This suggests that sadness is a multi-faceted emotion. This supports the idea that there might in fact be different facets of sadness that can be distinguished psychologically and physiologically. In the current set of studies, we explored this hypothesis. In a first stage, participants were asked to select sad emotional faces and scene stimuli either characterized or not by a key suggested sadness-related characteristic: loneliness or melancholy or misery or bereavement or despair. In a second stage, another set of participants was presented with the selected emotional faces and scene stimuli. They were assessed for differences in emotional, physiological and facial-expressive responses. The results showed that sad faces involving melancholy, misery, bereavement and despair were experienced as conferring dissociable physiological characteristics. Critical findings, in a final exploratory design, in a third stage, showed that a new set of participants could match emotional scenes to emotional faces with the same sadness-related characteristic with close to perfect precision performance. These findings suggest that melancholy, misery, bereavement and despair can be distinguishable emotional states associated with sadness.

"Speak of the Devil and he Shall Appear": Religiosity, Unconsciousness, and the Effects of Explicit Priming in the Misperception of Immorality.

Psychological theory and research suggest that religious individuals could have differences in the appraisal of immoral behaviours and cognitions compared to non-religious individuals. This effect could occur due to adherence to prescriptive and inviolate deontic religious-moral rules and socio-evolutionary factors, such as increased autonomic nervous system responsivity to indirect threat. The latter thesis has been used to suggest that immoral elicitors could be processed subliminally by religious individuals. In this manuscript, we employed masking to test this hypothesis. We rated and pre-selected IAPS images for moral impropriety. We presented these images masked with and without negatively manipulating a pre-image moral label. We measured detection, moral appraisal and discrimination, and physiological responses. We found that religious individuals experienced higher responsivity to masked immoral images. Bayesian and hit-versus-miss response analyses revealed that the differences in appraisal and physiological responses were reported only for consciously perceived immoral images. Our analysis showed that when a negative moral label was presented, religious individuals experienced the interval following the label as more physiologically arousing and responded with lower specificity for moral discrimination. We propose that religiosity involves higher conscious perceptual and physiological responsivity for discerning moral impropriety but also higher susceptibility for the misperception of immorality.

Cancer-associated fibroblasts impact the clinical outcome and treatment response in colorectal cancer via immune system modulation: a comprehensive genome-wide analysis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment are associated with poor prognosis and chemoresistance in multiple solid tumours. However, there is a lack of universal measures of CAFs in colorectal cancer (CRC). The aim of this study was to assess the utility of a fibroblast-related gene signature (FRGS) for predicting patient outcomes and reveal its relevant mechanism. METHODS: The GSE39582 dataset, which includes 316 CRC patients who did not receive adjuvant chemotherapy was used as a discovery cohort to identify the prognostic fibroblast-related genes (FRGs). A total of 1352 CRC patients were divided into one training cohort (GSE39582, n = 461) and two validation cohorts (TCGA, n = 338; meta-validation, n = 553) for the construction of the FRGS and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to explore the underlying mechanism. The ability of the FRGS to predict immunotherapy response was further tested in a clear cell renal cell carcinoma (ccRCC) cohort. RESULTS: An 11-gene signature that had prognostic value for stage II/III CRC patients in both validation cohorts was developed (TCGA cohort: HR = 1.90, 95% CI 1.16-3.12, P < 0.01; meta-validation cohort: HR = 1.95, 95% CI 1.39-2.73, P < 0.001). A high level of CAFs was correlated with worse prognosis in CRC patients who did not receive adjuvant chemotherapy (HR = 3.63, 95% CI 2.24-5.88, P < 0.001). Importantly, patients in the low-risk group were found to be benefit from chemotherapy (P < 0.01), but not in the high CAF group (P > 0.05). Similar results were found in the TCGA cohort. Integrated with clinical characteristics, the FRGS was confirmed to be an independent prognostic factor in the multivariate analysis after adjustment for tumour TNM stage (GSE39582 cohort: HR = 3.19, 95% CI 1.88-5.41, P < 0.001; TCGA cohort: HR = 5.00, 95% CI 1.58-15.85, P = 0.007; meta-validation cohort: HR = 2.99, 95% CI 1.44-6.21, P = 0.003). Furthermore, the enrichment analysis found that the antitumour immune response was suppressed and the infiltration of CD4 T cells and M1 macrophages was depressed in the high CAF group. The FRGS was also found to have value in predicting for immunotherapy response in the ccRCC cohort. CONCLUSIONS: The 11-gene FRGS had independent prognostic value for CRC patients, as well as utility in the prediction of benefit from chemotherapy. CAFs in the tumour microenvironment might have an impact on the prognosis of CRC patients via inhibiting immune response.

Protein-protein interaction analysis reveals a novel cancer stem cell related target TMEM17 in colorectal cancer.

BACKGROUND: Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking. METHODS: Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC. RESULTS: By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/ß-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients. CONCLUSION: Collectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).

Individual conscious and unconscious perception of emotion: Theory, methodology and applications.

In this manuscript we review a seminal debate related to subliminality and concerning the relationship of consciousness, unconsciousness, and perception. We present the methodological implementations that contemporary psychology introduced to explore this relationship, such as the application of unbiased self-report metrics and Bayesian analyses for assessing detection and discrimination. We present evidence concerning an unaddressed issue, namely, that different participants and stimulus types require different thresholds for subliminal presentation. We proceed to a step-by-step experimental illustration of a method involving individual thresholds for the presentation of masked emotional faces. We show that individual thresholds provide Bayesian evidence for null responses to the presented faces. Conversely, we show in the same database that when applying established but biased non-individual criteria for subliminality physiological changes occur and relate - correctly, and most importantly incorrectly - to perception concerning the emotional type, and the valence and intensity of a presented masked emotional face.

Impact of pelvic dimensions on anastomotic leak after anterior resection for patients with rectal cancer.

AIM: The impact of pelvis on the development of anastomotic leak (AL) in rectal cancer (RC) patients who underwent anterior resection (AR) remains unclear. The aim of this study was to evaluate the impact of pelvic dimensions on the risk of AL. METHODS: A total of 1058 RC patients undergoing AR from January 2013 to January 2016 were enrolled. Pelvimetric parameters were obtained using abdominopelvic computed tomography scans. RESULTS: Univariate analyses showed that pelvic inlet, pelvic outlet, interspinous distance, and intertuberous distance were significantly associated with the risk for AL (P < 0.05). Multivariate analysis confirmed that pelvic inlet and intertuberous distance were independent risk factors for AL (P < 0.05). Significant factors from multivariate analysis were assembled into the nomogram A (without pelvic dimensions) and nomogram B (with pelvic dimensions). The area under curve (AUC) of nomogram B was 0.72 (95% CI 0.67-0.77), which was better than the AUC of nomogram A (0.69, [95% CI 0.65-0.74]), but didn't reach a statistical significance (P = 0.199). Decision curve supported that nomogram B was better than nomogram A. CONCLUSION: Pelvic dimensions, specifically pelvic inlet and intertuberous distance, seemed to be independent predictors for postoperative AL in RC patients. Pelvic inlet and intertuberous distance incorporated with preoperative radiotherapy, preoperative albumin, conversion, and tumor diameter in the nomogram might provide a clinical tool for predicting AL.

"There Is No (Where a) Face Like Home": Recognition and Appraisal Responses to Masked Facial Dialects of Emotion in Four Different National Cultures.

The theory of universal emotions suggests that certain emotions such as fear, anger, disgust, sadness, surprise and happiness can be encountered cross-culturally. These emotions are expressed using specific facial movements that enable human communication. More recently, theoretical and empirical models have been used to propose that universal emotions could be expressed via discretely different facial movements in different cultures due to the non-convergent social evolution that takes place in different geographical areas. This has prompted the consideration that own-culture emotional faces have distinct evolutionary important sociobiological value and can be processed automatically, and without conscious awareness. In this paper, we tested this hypothesis using backward masking. We showed, in two different experiments per country of origin, to participants in Britain, Chile, New Zealand and Singapore, backward masked own and other-culture emotional faces. We assessed detection and recognition performance, and self-reports for emotionality and familiarity. We presented thorough cross-cultural experimental evidence that when using Bayesian assessment of non-parametric receiver operating characteristics and hit-versus-miss detection and recognition response analyses, masked faces showing own cultural dialects of emotion were rated higher for emotionality and familiarity compared to other-culture emotional faces and that this effect involved conscious awareness.

Laparoscopic versus open pancreatoduodenectomy: a meta-analysis of randomized controlled trials.

INTRODUCTION: the evidence with regard to the benefit of laparoscopic surgery for pancreatoduodenectomy is conflicting. The aim of this meta-analysis was to compare the short-term outcomes in patients undergoing laparoscopic or open pancreatoduodenectomy via randomized controlled trial studies. METHODS: PubMed, Embase and Cochrane Library databases were searched for studies addressing laparoscopic versus open pancreatoduodenectomy up to February 2019. Only randomized controlled trial studies were included. RESULTS: three randomized controlled trial studies were identified, which included a total of 224 patients. Statistically significant differences were found with regard to estimated blood loss in favor of laparoscopic pancreatoduodenectomy (WMD, -150.9 ml; 95% CI, -167.61 to -134.18; p < 0.001) but with longer operative time (WMD, 97.66 min; 95% CI, 21.28 to 174.05; p = 0.01). No significant differences were found for severe postoperative complications (defined as Clavien-Dindo grade ≥ III complications), complication-related mortality within 90 days, blood transfusion requirements, length of hospital stay, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, surgical site infection, readmission rate, reoperation rate, harvested lymph nodes and R0 resection rate. CONCLUSIONS: the perioperative safety of laparoscopic pancreatoduodenectomy, which may have an advantage of lower estimated blood loss, is comparable to that of open pancreatoduodenectomy. Currently, a small volume of cases may be an important reason that affects the evaluation between laparoscopic and open pancreatoduodenectomy. Further evaluation of laparoscopic pancreatoduodenectomy will require large randomized control trials.

A signature of hypoxia-related factors reveals functional dysregulation and robustly predicts clinical outcomes in stage I/II colorectal cancer patients.

BACKGROUND: The hypoxic tumor microenvironment accelerates the invasion and migration of colorectal cancer (CRC) cells. The aim of this study was to develop and validate a hypoxia gene signature for predicting the outcome in stage I/II CRC patients that have limited therapeutic options. METHODS: The hypoxic gene signature (HGS) was constructed using transcriptomic data of 309 CRC patients with complete clinical information from the CIT microarray dataset. A total of 1877 CRC patients with complete prognostic information in six independent datasets were divided into a training cohort and two validation cohorts. Univariate and multivariate analyses were conducted to evaluate the prognostic value of HGS. RESULTS: The HGS consisted of 14 genes, and demarcated the CRC patients into the high- and low-risk groups. In all three cohorts, patients in the high-risk group had significantly worse disease free survival (DFS) compared with those in the low risk group (training cohort-HR = 4.35, 95% CI 2.30-8.23, P < 0.001; TCGA cohort-HR = 2.14, 95% CI 1.09-4.21, P = 0.024; meta-validation cohort-HR = 1.91, 95% CI 1.08-3.39, P = 0.024). Compared to Oncotype DX, HGS showed superior predictive outcome in the training cohort (C-index, 0.80 vs 0.65) and the validation cohort (C-index, 0.70 vs 0.61). Pathway analysis of the high- and low-HGS groups showed significant differences in the expression of genes involved in mTROC1, G2-M, mitosis, oxidative phosphorylation, MYC and PI3K-AKT-mTOR pathways (P < 0.005). CONCLUSION: Hypoxic gene signature is a satisfactory prognostic model for early stage CRC patients, and the exact biological mechanism needs to be validated further.

Lantern-shaped screw loaded with autologous bone for treating osteonecrosis of the femoral head.

BACKGROUND: Treatment for osteonecrosis of the femoral head (ONFH) in young individuals remains controversial. We developed a lantern-shaped screw, which was designed to provide mechanical support for the femoral head to prevent its collapse, for the treatment of ONFH. The purpose of this study was to investigate the efficacy and safety of the lantern-shaped screw loaded with autologous bone for the treatment of pre-collapse stages of ONFH. METHODS: Thirty-two patients were randomly divided into two groups: the lantern-shaped screw group (core decompression and lantern-shaped screw loaded with autogenous bone) and the control group (core decompression and autogenous bone graft). During 36 months follow-up after surgery, treatment results in patients were assessed by X-ray and computed tomography (CT) scanning as well as functional recovery Harris hip score (HHS). RESULTS: Successful clinical results were achieved in 15 of 16 hips (94%) in the lantern-shaped screw group compared with 10 of 16 hips (63%) in the control group (p = 0.0325). Successful radiological results were achieved in 14 of 16 hips (88%) in the lantern-shaped screw group compared with 8 of 16 hips (50%) in the control group (P = 0.0221). CONCLUSION: The lantern-shaped screw loaded with autologous bone for the treatment of pre-collapse stages of ONFH is effective and results in preventing progression of ONFH and reducing the risk of femoral head collapse. TRIAL REGISTRATION: The trial registration number: ChiCTR-TRC-13004078 (retrospectively registered at 2013-11-28).

Differentiating the relationships between traditional and new media use and sleep quality during the COVID-19 pandemic: roles of psychological distress and age.

Background: Numerous studies have consistently demonstrated a decline in sleep quality during the COVID-19 pandemic. The primary objective of this study is to explore the impact of engaging with pertinent epidemic information through the media amid the COVID-19 crisis on individuals' sleep quality and the underlying mechanisms through which this influence operates. Methods: An online cross-sectional study design was employed. A total of 1,063 British adults (36.2% males; M age = 38.85, SD age = 13.36, ranging from 18 to 77 years old) participated in the study and completed our questionnaires, which included media usage frequency during the pandemic, the 10-item Kessler Psychological Distress Scale (K10), the Insomnia Severity Index (ISI), and the Ten-item Personality Inventory (TIPI). Results: Pearson's correlation analyses indicated that there was no significant correlation between COVID-19-related traditional media use (television, radio, newspaper) and psychological distress or sleep quality. However, exposure to information related to COVID-19 through new media use (Facebook, Tik Tok, Twitter) was correlated with greater psychological distress and poorer sleep quality. A moderated mediation analysis showed that psychological distress fully mediated the relationship between new media use and poor sleep, which was moderated by age, with the association between psychological distress and poor sleep quality being stronger among older adults. Conclusion: Exposure to information of COVID-19 via new (but not traditional) media use deteriorated sleep quality through greater psychological distress, and this relationship was stronger among older adults.

Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression.

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

CDK4/6 inhibition augments anti-tumor efficacy of XPO1 inhibitor selinexor in natural killer/T-cell lymphoma.

XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.

Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTL) is an uncommon malignancy with poor prognosis and limited therapeutic options. Activating mutations of signal transducer and activator of transcription 3 (STAT3) are frequently found in patients with NKTL, suggesting that targeted inhibition of STAT3 is a potential therapeutic option for this disease. Here, we have developed a small molecule drug WB737 as a novel and potent STAT3 inhibitor that directly binds to the STAT3-Src homology 2 domain with high affinity. In addition, the binding affinity of WB737 to STAT3 is 250-fold higher than STAT1 and STAT2. Interestingly, WB737 is more selective for NKTL with STAT3-activating mutations in terms of growth inhibition and apoptotic induction when compared with Stattic. Mechanistically, WB737 inhibits both canonical and noncanonical STAT3 signaling via suppression of STAT3 phosphorylation at Tyr705 and Ser727, respectively, thereby inhibiting the expression of c-Myc and mitochondria-related genes. Moreover, WB737 inhibited STAT3 more potently than Stattic, resulting in a significant antitumor effect with undetectable toxicity, followed by almost complete tumor regression in an NKTL xenograft model harboring a STAT3-activating mutation. Taken together, these findings provide preclinical proof-of-concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3-activating mutations.