TNIK Inhibition Sensitizes TNIK-Overexpressing Lung Squamous Cell Carcinoma to Radiotherapy.

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited because of dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for patients with LSCC. Moreover, other options for chemotherapy-ineligible patients are limited. As such, there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. In this study, we investigated inhibiting TRAF2- and NCK-interacting protein kinase (TNIK), which is amplified in 40% of patients with LSCC, as a strategy to sensitize LSCC tumors to chemotherapy and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in patients with LSCC with high TNIK expression.

Culturally adapted cognitive behavioral therapy for psychosis (CaCBTp): A review of key features of cultural adaptation and considerations for psychologists.

Cognitive behavioral therapy for psychosis is an effective treatment for psychosis. However, psychosis presents differentially according to an individual's cultural context, and it is currently unclear which methods have been used to formulate culturally adapted cognitive behavioral therapy for psychosis (CaCBTp). The current systematic review examines the approaches to CaCBTp that have been evaluated to date and comments on preliminary evidence for the efficacy of CaCBTp. Key features of CaCBTp interventions are discussed in reference to broader cultural adaptations of psychosocial interventions for psychosis and culturally adapted cognitive behavioral therapy for other disorders. Overall, our results identified 12 studies and highlighted five overarching themes of cultural adaptation that clinicians should integrate into the design of future CaCBTp interventions, including family members in treatment, targeting stigma, relying on spiritual leaders, using multifaceted models of mental health, and ensuring adequate language match. The results of this review also highlight the paucity of literature in global CaCBTp interventions, as only 10 studies examining CaCBTp interventions were found. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

TNIK inhibition sensitizes TNIK-overexpressing lung squamous cell carcinoma to radiotherapy.

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited due to dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for LSCC patients. Moreover, other options for chemotherapy-ineligible patients are also limited. As such there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. Here, we investigated inhibiting TRAF2 and NCK-interacting protein kinase (TNIK), which is amplified in 40% of LSCC patients, as a strategy to sensitize LSCC tumors to chemo- and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in LSCC patients with high TNIK expression.

Examining the influence of self-referential thinking on aberrant salience and jumping to conclusions bias in individuals with schizophrenia-spectrum disorders.

BACKGROUND AND OBJECTIVES: Cognitive processes such as aberrant salience and the jumping to conclusions (JTC) bias are implicated in the development of delusions. Self-referential thinking is implicated in this process; however, it is unknown how it may interact with aberrant salience and JTC bias in individuals with schizophrenia-spectrum disorders (SSDs). This study examined associations of self-referential thinking with aberrant salience, JTC bias, and delusion severity, and whether self-referential stimuli led to an increase in aberrant salience and JTC bias in SSDs (n = 20) relative to psychiatrically healthy controls (n = 20). METHODS: To assess aberrant salience and JTC bias, participants were asked to complete both self-referential and neutral versions of the Salience Attribution Test (SAT) and the Beads Task, as well as self-report measures of aberrant salience and JTC bias. RESULTS: Self-referential task condition interacted with clinical group to predict JTC beads task scores, such that participants with SSDs exhibited greater levels of JTC bias than psychiatrically healthy controls during the neutral task condition, when controlling for levels of motivation, cognitive insight, and functioning. Self-referential thinking was significantly associated with aberrant salience, JTC bias, and delusion severity. LIMITATIONS: This experiment examined trait-level relationships between variables, so does not provide information about state-level interrelationships and would benefit from replication using more dynamic methods such as ecological momentary assessment. CONCLUSIONS: These findings highlight the interrelationships between self-referential thinking, JTC bias, aberrant salience, and delusion severity, in individuals with SSDs, and support the interactive role of self-referential thinking in predicting JTC bias.

TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.

PURPOSE: Despite well-informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure-function and clinical impact of TP53 mutations in mCSPC. PATIENTS AND METHODS: We performed an international retrospective review of men with mCSPC who underwent next-generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression-free survival (rPFS) and overall survival (OS) evaluated with Kaplan-Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR-246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t-tests and ANOVA. RESULTS: Dominant-negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI]: 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI: 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner. CONCLUSIONS: DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.

Efficacy of Remotely Delivered Evidence-Based Psychosocial Treatments for Schizophrenia-Spectrum Disorders: A Series of Systematic Reviews and Meta-Analyses.

BACKGROUND: Schizophrenia is among the most persistent and debilitating mental health conditions worldwide. The American Psychological Association (APA) has identified 10 psychosocial treatments with evidence for treating schizophrenia and these treatments are typically provided in person. However, in-person services can be challenging to access for people living in remote geographic locations. Remote treatment delivery is an important option to increase access to services; however, it is unclear whether evidence-based treatments for schizophrenia are similarly effective when delivered remotely. STUDY DESIGN: The current study consists of a series of systematic reviews and meta-analyses examining the evidence-base for remote-delivery of each of the 10 APA evidence-based treatments for schizophrenia. RESULTS: Of the 10 treatments examined, only cognitive remediation (CR), cognitive-behavioral therapy (CBT), and family psychoeducation had more than 2 studies examining their efficacy for remote delivery. Remote delivery of CBT produced moderate effects on symptoms (g = 0.43) and small effects on functioning (g = 0.26). Remote delivery of CR produced small-moderate effects on neurocognition (g = 0.35) and small effects on functioning (g = 0.21). There were insufficient studies of family psychoeducation with equivalent outcome measures to assess quantitatively, however, studies of remotely delivered family psychoeducation suggested that it is feasible, acceptable, and potentially effective. CONCLUSIONS: Overall, the evidence-base for remotely delivered treatment for schizophrenia is limited. Studies to date suggest that remote adaptations may be effective; however, more rigorous trials are needed to assess efficacy and methods of remote delivery that are most effective.

Griseofulvin Radiosensitizes Non-Small Cell Lung Cancer Cells and Activates cGAS.

Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non-small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC.

Can cognitive remediation therapy be delivered remotely? A review examining feasibility and acceptability of remote interventions.

Cognitive remediation (CR) is an effective treatment for schizophrenia. However, issues such as motivational impairments, geographic limitations, and limited availability of specialized clinicians to deliver CR, can impede dissemination. Remote delivery of CR provides an opportunity to implement CR on a broader scale. While empirical support for the efficacy of in-person CR is robust, the evidence-base for virtual delivery of CR is limited. Thus, in this review we aimed to evaluate the feasibility and acceptability of remote CR interventions. Nine (n = 847) fully remote and one hybrid CR intervention were included in this review. Attrition rates for remote CR were generally high compared to control groups. Acceptability rates for remote CR interventions were high and responses from caregivers were positive. Further research using more methodologically rigorous designs is required to evaluate appropriate adaptations for remote treatment and determine which populations may benefit more from remote CR.

Information seeking and health anxiety during the COVID-19 pandemic: The mediating role of catastrophic cognitions.

Cognitive-behavioural models of health anxiety propose a positive association between information seeking and health anxiety; however, it is unclear the extent to which cognitive mechanisms may mediate this relationship. Catastrophic cognitions are one type of cognition that may mediate this relationship, and the COVID-19 pandemic has presented an opportunity to examine these relationships within the context of a global health catastrophe. The current study investigated both cross-sectional (N = 797) and longitudinal (n = 395) relationships between information seeking, health anxiety and catastrophizing during the pandemic. Data were collected using Amazon Mechanical Turk during April and May 2020. Information seeking and health anxiety were positively associated both cross-sectionally and longitudinally (rs = .25-.29). Catastrophic cognitions significantly mediated the relationship between information seeking and health anxiety both cross-sectionally and longitudinally. Developing effective methods of reducing information seeking and catastrophizing may serve to reduce health anxiety during global health crises such as the current pandemic.

Predictors and consequences of loneliness during the COVID-19 Pandemic.

The COVID-19 pandemic has created a global context in which social isolation has become normative in order to reduce the risk of COVID-19 transmission. As a result of social distancing policies, the risk for loneliness and associated decline in quality of life has increased. The current study examined factors associated with loneliness and quality of life during the COVID-19 pandemic cross-sectionally (n = 797) and longitudinally (n = 395). Older age and larger social network size were associated with less loneliness, whereas having multiple physical or mental health diagnoses was associated with greater loneliness. Greater virtual social contact was also associated with increased loneliness. Greater loneliness was associated with all domains of quality of life both cross-sectionally and longitudinally. Understanding factors associated with loneliness is critical to developing effective strategies at reducing loneliness and improving quality of life during the pandemic. Contrary to popular perceptions, older age was associated with less loneliness and more virtual social contact was associated with more loneliness. Thus, it may be prudent to deemphasize virtual social contact in public campaigns and to emphasize safe methods of interacting in person.

Known-Groups and Convergent Validity of the Telephone Rey Auditory Verbal Learning Test total Learning Scores for Distinguishing Between Older Adults With Amnestic Cognitive Impairment and Subjective Cognitive Decline.

OBJECTIVE: To examine known-groups validity of a telephone administration of the total learning scores of the Rey Auditory Verbal Learning Test (RAVLT) in discriminating between people with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) and convergent validity of the telephone-RAVLT. METHOD: In total, 83 older adults (age = 71.4 ± 7.0) with SCD or aMCI completed the RAVLT learning trials over the telephone and the Hopkins Verbal Learning Test (HVLT) in-person. RESULTS: Telephone-RAVLT total recall significantly correlated with HVLT total recall (r = .49, p < .001). Significant between group differences were found (effect size = 0.94). CONCLUSIONS: This study provides support for known-groups and convergent validity of the telephone-RAVLT.