Although the short-term efficacy of internet-delivered cognitive-behavioral therapy (i-CBT) is well-established, its long-term efficacy remains understudied. Robust variance estimation meta-analysis was thus conducted across guided and self-guided i-CBT, synthesizing data from 154 randomized controlled trials (N = 45,335) with ≥ 12-month follow-ups. For binary outcomes, guided (52.3% vs. 38.6%; log-risk ratio [LOG-RR] = 1.15 95% confidence interval [1.04, 1.26]) yielded higher remission, reliable improvement, and response rates, and lower suboptimal treatment outcome rates (9.3% vs. 10.8%; LOG-RR = 0.63 [0.45, 0.80]) than treatment-as-usual, active controls, and waitlists at ≥12 months. Insufficient studies precluded testing the efficacy between self-guided i-CBT and controls for binary outcomes. For baseline-to-12-month dimensional outcomes, guided i-CBT produced greater reductions in anxiety, depressive, post-traumatic stress disorder (PTSD) symptoms, and repetitive negative thinking (Hedges g = -1.86 to -0.31), and self-guided i-CBT yielded stronger reductions in depressive symptoms (g = -0.51) than all controls. For outcome scores aggregated at ≥ 12-month follow-ups, guided i-CBT alleviated anxiety, depression, distress, insomnia, PTSD symptoms, role impairment, emotion regulation, and quality of life (g = -0.31 to 0.26), and self-guided i-CBT yielded lower anxiety and depressive symptoms (g = -0.16 to -0.09) than all controls. No significant differences in efficacy emerged between guided and self-guided i-CBT when sufficient studies existed for a meta-analysis. There was no evidence for publication bias. Long-term efficacy was similar to short-term efficacy for most outcomes. Implementing scalable i-CBTs should entail transparency about their long-term benefits and drawbacks.

Background: Constructs of common mental disorder (CMD) symptoms, including anxiety, depression, obsessions, compulsions, and worry, are observed in a wide range of psychiatric conditions. Reliable and valid measurements of these CMD symptoms are essential for building a generalizable science of psychopathology and ensuring valid comparisons of scores across distinct groups. Accordingly, the current study determined the psychometric properties of four widely used CMD symptom measures in the United States (U.S.) and Singapore. Method: Participants comprised college students (U.S.: n = 292; SG: n = 144) who completed the Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), Obsessive-Compulsive Inventory-Revised (OCI-R), and Penn State Worry Questionnaire-Abbreviated (PSWQ-A). Results: Strict measurement invariance (equal factor loadings, item thresholds, residual variances) was observed for all measures across cultures. Singapore had higher latent mean scores of worry than the U.S. sample. Conclusions: Overall, findings suggest a strong degree of cross-cultural construct compatibility. Given this finding, higher latent factor means for worry, perfectionism, and uncertainty scores likely reflect true group differences, suggesting that these symptom measures can be used to aid further study and assessment of cross-cultural differences in symptom prevalence and presentation in CMDs.

OBJECTIVE: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma (OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC. METHODS: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response. RESULTS: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations. Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin E1 protein levels. We further demonstrated that the combination of a PI3K/mTOR inhibitor (PF-04691502) and palbociclib completely controlled tumor growth in mice. CONCLUSIONS: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.

Two APOBEC DNA cytosine deaminase enzymes, APOBEC3A and APOBEC3B, generate somatic mutations in cancer, thereby driving tumour development and drug resistance. Here, we used single-cell RNA sequencing to study APOBEC3A and APOBEC3B expression in healthy and malignant mucosal epithelia, validating key observations with immunohistochemistry, spatial transcriptomics and functional experiments. Whereas APOBEC3B is expressed in keratinocytes entering mitosis, we show that APOBEC3A expression is confined largely to terminally differentiating cells and requires grainyhead-like transcription factor 3 (GRHL3). Thus, in normal tissue, neither deaminase appears to be expressed at high levels during DNA replication, the cell-cycle stage associated with APOBEC-mediated mutagenesis. In contrast, in squamous cell carcinoma we find that, there is expansion of GRHL3expression and activity to a subset of cells undergoing DNA replication and concomitant extension of APOBEC3A expression to proliferating cells. These findings suggest that APOBEC3A may play a functional role during keratinocyte differentiation, and offer a mechanism for acquisition of APOBEC3A mutagenic activity in tumours.