Independent transcriptional patterns reveal biological processes associated with disease-free survival in early colorectal cancer.

BACKGROUND: Bulk transcriptional profiles of early colorectal cancer (CRC) can fail to detect biological processes associated with disease-free survival (DFS) if the transcriptional patterns are subtle and/or obscured by other processes' patterns. Consensus-independent component analysis (c-ICA) can dissect such transcriptomes into statistically independent transcriptional components (TCs), capturing both pronounced and subtle biological processes. METHODS: In this study we (1) integrated transcriptomes (n = 4228) from multiple early CRC studies, (2) performed c-ICA to define the TC landscape within this integrated data set, 3) determined the biological processes captured by these TCs, (4) performed Cox regression to identify DFS-associated TCs, (5) performed random survival forest (RSF) analyses with activity of DFS-associated TCs as classifiers to identify subgroups of patients, and 6) performed a sensitivity analysis to determine the robustness of our results RESULTS: We identify 191 TCs, 43 of which are associated with DFS, revealing transcriptional diversity among DFS-associated biological processes. A prominent example is the epithelial-mesenchymal transition (EMT), for which we identify an association with nine independent DFS-associated TCs, each with coordinated upregulation or downregulation of various sets of genes. CONCLUSIONS: This finding indicates that early CRC may have nine distinct routes to achieve EMT, each requiring a specific peri-operative treatment strategy. Finally, we stratify patients into DFS patient subgroups with distinct transcriptional patterns associated with stage 2 and stage 3 CRC.

While treatments for patients with colorectal cancer have improved, many patients (around 30-50%) have cancers that will eventually relapse and these patients will die due to their disease. Researchers have been studying the genes involved in colorectal cancer to help us understand why some cancers might relapse. However, current methods to do this may miss subtle or hidden patterns in the gene activity related to cancer relapse. To deal with this, we used a special method called consensus-independent component analysis (c-ICA) to dig more deeply into the activity of genes. This helped us to uncover some potential biological processes underpinning colorectal cancer relapse, which ultimately could help researchers to identify better treatments for patients with colorectal cancer.

Everolimus decreases [U-13C]glucose utilization by pyruvate carboxylase in breast cancer cells in vitro and in vivo.

Reprogrammed metabolism is a hallmark of cancer, but notoriously difficult to target due to metabolic plasticity, especially in response to single metabolic interventions. Combining mTOR inhibitor everolimus and mitochondrial complex 1 inhibitor metformin results in metabolic synergy in in vitro models of triple-negative breast cancer. Here, we investigated whether the effect of this drug combination on tumor size is reflected in changes in tumor metabolism using [U-13C]glucose labeling in an MDA-MB-231 triple negative breast cancer xenograft model. The in vitro effects of everolimus and metformin treatment on oxidative phosphorylation and glycolysis reflected changes in 13C-labeling of metabolites in MDA-MB-231 cells. Treatment of MDA-MB-231 xenografts in SCID/Beige mice with everolimus resulted in slower tumor growth and reduced tumor size and tumor viability by 35%. Metformin treatment moderately inhibited tumor growth but did not enhance everolimus-induced effects. High serum levels of everolimus were reached, whereas levels of metformin were relatively low. Everolimus decreased TCA cycle metabolite labeling and inhibited pyruvate carboxylase activity. Metformin only caused a mild reduction in glycolytic metabolite labeling and did not affect pyruvate carboxylase activity or TCA cycle metabolite labeling. In conclusion, treatment with everolimus, but not metformin, decreased tumor size and viability. Furthermore, the efficacy of everolimus was reflected in reduced 13C-labeling of TCA cycle intermediates and reduced pyruvate carboxylase activity. By using in-depth analysis of drug-induced changes in glucose metabolism in combination with measurement of drug levels in tumor and plasma, effects of metabolically targeted drugs can be explained, and novel targets can be identified.

Investigating the relationship between specific negative symptoms and metacognitive functioning in psychosis: A systematic review.

BACKGROUND: Disrupted metacognition is implicated in development and maintenance of negative symptoms, but more fine-grained analyses would inform precise treatment targeting for individual negative symptoms. AIMS: This systematic review identifies and examines datasets that test whether specific metacognitive capacities distinctly influence negative symptoms. MATERIALS & METHODS: PsycINFO, EMBASE, Medline and Cochrane Library databases plus hand searching of relevant articles, journals and grey literature identified quantitative research investigating negative symptoms and metacognition in adults aged 16+ with psychosis. Authors of included articles were contacted to identify unique datasets and missing information. Data were extracted for a risk of bias assessment using the Quality in Prognostic Studies tool. RESULTS: 85 published reports met criteria and are estimated to reflect 32 distinct datasets and 1623 unique participants. The data indicated uncertainty about the relationship between summed scores of negative symptoms and domains of metacognition, with significant findings indicating correlation coefficients from 0.88 to -0.23. Only eight studies investigated the relationship between metacognition and individual negative symptoms, with mixed findings. Studies were mostly moderate-to-low risk of bias. DISCUSSION: The relationship between negative symptoms and metacognition is rarely the focus of studies reviewed here, and negative symptom scores are often summed. This approach may obscure relationships between metacognitive domains and individual negative symptoms which may be important for understanding how negative symptoms are developed and maintained. CONLCLUSION: Methodological challenges around overlapping participants, variation in aggregation of negative symptom items and types of analyses used, make a strong case for use of Individual Participant Data Meta-Analysis to further elucidate these relationships.

Investigating the relationship between negative symptoms and metacognitive functioning in psychosis: An individual participant data meta-analysis.

PURPOSE: Negative symptoms are a persistent, yet under-explored problem in psychosis. Disturbances in metacognition are a potential causal factor in negative symptom development and maintenance. This meta-analysis uses individual participant data (IPD) from existing research to assess the relationship between negative symptoms and metacognition treated as summed scores and domains. METHODS: Data sets containing individuals with negative symptoms and metacognition data, aged 16+ with psychosis, were identified according to pre-specific parameters. IPD integrity and completeness were checked and data were synthesized in two-stage meta-analyses of each negative symptoms cluster compared with metacognition in seemingly unrelated regression using restricted maximum likelihood estimation. Planned and exploratory sensitivity analyses were also conducted. RESULTS: Thirty-three eligible data sets were identified with 21 with sufficient similarity and availability to be included in meta-analyses, corresponding to 1301 participants. The strongest relationships observed were between summed scores of negative symptoms and metacognition. Metacognitive domains of self-reflectivity and understanding others' minds, and expressive negative symptoms emerged as significant in some meta-analyses. The uncertainty of several effect estimates increased significantly when controlling for covariates. CONCLUSIONS: This robust meta-analysis highlights the impact of using summed versus domain-specific scores of metacognition and negative symptoms, and relationships are not as clear-cut as once believed. Findings support arguments for further differentiation of negative symptom profiles and continued granular exploration of the relationship between metacognition and negative symptoms.

Self-stigma and cognitive insight in individuals at ultra-high risk for psychosis.

Background: Impaired cognitive insight and increased self-stigma have been consistently reported in individuals diagnosed with schizophrenia spectrum disorders, but little is known about its presence in individuals at ultra-high risk of developing a psychosis, although self-stigma is associated with transition.to psychosis. The current study examined whether self-stigma is already present in individuals at ultra-high risk of psychosis, and whether this is associated with impaired cognitive insight. Methods: 184 participants were recruited divided over three groups, namely individuals diagnosed with a schizophrenia spectrum disorder (SSD; n = 92, 34% females), individuals at ultra-high risk for psychosis (UHR; n = 43, 59% females) and general population controls (GPC; n = 49, 27% females). All participants completed assessments on demographic information (gender, age, education), and cognitive insight. In addition, participants with SSD and individuals at UHR completed a questionnaire on self-stigma. Results: The level of self-stigma did not differ between individuals at UHR and individuals diagnosed with SSD. Cognitive insight also did not differ significantly between the three groups, but the subscale self-reflection differed between the three groups [F(2,184) = 4.20, p = 0.02], with the UHR and SSD groups showing more self-reflection. Pearson's correlation analyses showed that in individuals at UHR total cognitive insight and its self-reflection subscale were significantly associated with the alienation subscale of self-stigma, and in individuals with SSD self-certainty subscale of cognitive insight was significantly associated with stereotype endorsement. Conclusion: Findings show that self-stigma was already present in the UHR phase, to a similar degree as in individuals with a diagnosis of a SSD, and is thus not dependent of previous experience of having a label of SSD. Cognitive insight in individuals at UHR of psychosis appears to be intact, but individuals at UHR showed more self-reflectiveness, and individuals at risk with high cognitive insight also experience high levels of self-stigma. Overall findings from our study suggest that pre-emptive interventions targeting self-stigma, while considering cognitive insight, are needed early on in manifestation of psychotic illness, preferably already in the UHR phase.

BEATVIC, a body-oriented resilience therapy for individuals with psychosis: Short term results of a multi-center RCT.

BACKGROUND: Individuals with a psychotic disorder are at an increased risk of victimization, but evidenced-based interventions are lacking. AIMS: A body-oriented resilience therapy ('BEATVIC') aimed at preventing victimization was developed and its effectiveness was assessed in a multicenter randomized controlled trial. METHODS: 105 people with a psychotic disorder were recruited from six mental health centers. Participants were randomly allocated to 20 BEATVIC group sessions (n = 53) or befriending group sessions (n = 52). Short term effects on risk factors for victimization (e.g. social cognitive deficits, inadequate interpersonal behavior, low self-esteem, internalized stigma, aggression regulation problems), physical fitness and secondary outcomes were expected. At six-month follow-up, the effect on victimization (either a 50% reduction or an absence of victimization incidents) was examined. RESULTS: Intervention-dropout was 28.30% for BEATVIC and 39.62% for befriending. In both conditions the majority of participants (60.5% BEATVIC vs 62.9% befriending) showed a reduction or absence of victimization incidents at six months follow-up, which was not significantly different according to condition. Multilevel analyses revealed no main effect of time and no significant time x group interaction on other outcome measures. Per protocol analyses (participants attending ≥ 75% of the sessions) did not change these results. CONCLUSIONS: Although a reduction or absence of victimization was found at short term follow-up for the majority of participants, BEATVIC was not more effective than the active control condition. No short-term additional effects on risk factors of victimization were found. Analysis of the data at 2-year follow-up is warranted to investigate possible effects in the long-term. TRIAL REGISTRATION NUMBER: Current Controlled Trials: ISRCTN21423535.

NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition.

Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian cancer with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC is characterized by activation of MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be a good treatment option for a subset of patients. Understanding MEKi-resistance mechanisms and subsequent identification of rational drug combinations to suppress resistance may greatly improve LGSOC treatment strategies. Both gain-of-function and loss-of-function CRISPR-Cas9 genome-wide libraries were used to screen LGSOC cell lines to identify genes that modulate the response to MEKi. Overexpression of MAML2 and loss of MAP3K1 were identified, both leading to overexpression of the NOTCH target HES1, which has a causal role in this process as its knockdown reversed MEKi resistance. Interestingly, increased HES1 expression was also observed in selected spontaneous trametinib-resistant clones, next to activating MAP2K1 (MEK1) mutations. Subsequent trametinib synthetic lethality screens identified SHOC2 downregulation as being synthetic lethal with MEKis. Targeting SHOC2 with pan-RAF inhibitors (pan-RAFis) in combination with MEKi was effective in parental LGSOC cell lines, in MEKi-resistant derivatives, in primary ascites cultures from patients with LGSOC, and in LGSOC (cell line-derived and patient-derived) xenograft mouse models. We found that the combination of pan-RAFi with MEKi downregulated HES1 levels in trametinib-resistant cells, providing an explanation for the synergy that was observed. Combining MEKis with pan-RAFis may provide a promising treatment strategy for patients with LGSOC, which warrants further clinical validation.

Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities.

Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs.

Empathy and Its Relationship With Social Functioning in Individuals at Ultra-High Risk for Psychosis.

Introduction: Social functioning is often impaired in the ultra-high-risk (UHR) phase of psychosis. There is some evidence that empathy is also impaired in this phase and that these impairments may underlie difficulties in social functioning. The main aim of this study was to investigate whether cognitive and affective empathy are lower in people in the UHR phase of psychosis in comparison to healthy controls, and whether possible impairments have the same magnitude as in people with schizophrenia. A second aim was to examine whether there is a relationship between empathy and social functioning in individuals in the UHR phase. Method: Forty-three individuals at UHR for psychosis, 92 people with a schizophrenia spectrum disorder, and 49 persons without a psychiatric disorder completed the Interpersonal Reactivity Index (IRI), Questionnaire of Cognitive and Affective Empathy (QCAE), and Faux Pas as instruments to measure empathy. The Time Use survey was used to measure social functioning. MAN(C)OVA was used to analyse differences between groups on empathy and social functioning, and correlations were calculated between empathy measures and social functioning for each group. Results: The UHR group presented significantly lower levels of self-reported cognitive empathy than the healthy controls, but not compared to patients with SSD, while performance-based cognitive empathy was unimpaired in the UHR group. On the affective measures, we found that people with UHR and patients with SSD had significantly higher levels of self-reported distress in interpersonal settings compared to healthy controls. In the UHR group, perspective-taking was negatively associated with time spent on structured social activities. In the SSD group, we found that structured social activities were positively associated with perspective-taking and negatively associated with personal distress in interactions with others. Lastly, in people without mental illness, social activities were positively associated with performance-based perspective-taking. Conclusion: Impairments in subjective cognitive empathy appear to be present in the UHR phase, suggesting that difficulties in interpreting the thoughts and feelings of others precede the onset of psychotic disorders. This can inform future interventions in the UHR phase.

Satisfaction with social connectedness as a predictor for positive and negative symptoms of psychosis: A PHAMOUS study.

PURPOSE: This study examines satisfaction with social connectedness (SSC) as predictor of positive and negative symptoms in people with a psychotic disorder. METHODS: Data from the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS) was used from patients assessed between 2014 and 2019, diagnosed with a psychotic disorder (N = 2109). Items about social connectedness of the Manchester short assessment of Quality of Life (ManSA) were used to measure SSC. Linear mixed models were used to estimate the association of SSC with the Positive and Negative Syndrome Scale (PANSS) after one and two years against α = 0.01. Analyses were adjusted for symptoms, time since onset, gender and age. Additionally, fluctuation of positive and negative symptom scores over time was estimated. RESULTS: The mean duration of illness of the sample was 18.8 years (SD 10.7) with >65% showing only small variation in positive and negative symptoms over a two to five-year time period. After adjustment for covariates, SSC showed to be negatively associated with positive symptoms after one year (ß = -0.47, p < 0.001, 95% CI = -0.70, -025) and two years (ß = -0.59, p < 0.001, 95% CI = -0.88, -0.30), and for negative symptoms after one year (ß = -0.52, p < 0.001, 95% CI = -0.77, -0.27). The prediction of negative symptoms was not significant at two years. CONCLUSION: This research indicates that interventions on SSC might positively impact mental health for people with psychosis. SSC is a small and robust predictor of future levels of positive symptoms. Negative symptoms could be predicted by SSC at one year.

Longitudinal assessments of therapeutic alliance predict work performance in vocational rehabilitation for persons with schizophrenia.

OBJECTIVES: To promote functional recovery in persons diagnosed with a psychotic disorder, vocational interventions have emerged over the last few decades which range from sheltered employment to supported employment in the community. DESIGN: Using data from a 6-month vocational rehabilitation programme, we examined whether assessments of the therapeutic alliance were related to the quality of work performed in this work placement. Our first hypothesis was that stronger alliances would be related to better work performance. Second, we expected that client assessments of the TA would better predict outcomes than therapist assessments. Third, we expected that the discrepancy between assessment scores from the client and therapist (client rating minus therapist rating) would be a better predictor for outcome than individual assessments by the therapists or clients. RESULTS: Clients systematically rated the alliance higher than therapists. Modelling the data longitudinally, we found both therapist and client ratings predictive of outcome, though client assessments over time were inversely related to work performance. CONCLUSIONS: Discrepancy in scores was also shown to be predictive of work performance during the program. Clinicians are advised to routinely assess the therapeutic alliance from both client and therapist perspectives and calculate the discrepancy between them as they may indicate ruptures are occurring and thus hamper the intervention. PRACTITIONER POINTS: Clinicians are advised to regularly assess the therapeutic alliance from both their own and the client's perspective. Growing discrepancy in scores may impede intervention effectiveness. Therapeutic alliance may help buffer against work stresses experienced by participants in a vocational programme. Be aware that therapists tend to rate the alliance lower than their clients.

Longitudinal changes in therapeutic alliance with people with psychosis: Relationship between client and therapist assessments.

Although the clinical significance of therapeutic alliance with people with psychosis is well established, the agreement between client and therapist assessments of therapeutic alliance and the longitudinal changes of both assessments have been rarely addressed. The current study examined client and therapist assessments of therapeutic alliance longitudinally and sought to determine whether insight and severity of symptoms moderated the degree to which therapist and client assessments were in agreement with one another. Forty-five participants diagnosed with a schizophrenia spectrum disorder and their therapists were administered a therapeutic alliance questionnaire (Working Alliance Inventory-Short Form) monthly for 6 months. Baseline symptoms were assessed using the PANSS. Results did not produce evidence that insight into illness moderated the relationship between agreement on the therapeutic alliance. However, symptoms of emotional discomfort at baseline predicted differences in agreement between clients and therapists on the relationship aspect of therapeutic alliance over the course of therapy. These results suggest that the ability to express symptoms of emotional discomfort may affect whether clients and therapists form similar appraisals of the strength of the therapeutic alliance.

Establishment and characterisation of testicular cancer patient-derived xenograft models for preclinical evaluation of novel therapeutic strategies.

Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients' response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer.

Monitoring Soil Moisture Dynamics Using Electrical Resistivity Tomography under Homogeneous Field Conditions.

There is a gap between lab experiments where resistivity-soil moisture relations are generally very good and field studies in complex environmental settings where relations are always less good and complicated by many factors. An experiment was designed where environmental settings are more controlled, the best outside laboratory, to assess the transferability from lab to outdoor. A field experiment was carried out to evaluate the use of electric resistivity tomography (ERT) for monitoring soil moisture dynamics over a period of 67 days. A homogeneous site in the central part of The Netherlands was selected consisting of grass pasture on an aeolian sand soil profile. ERT values were correlated to gravimetric soil moisture samples for five depths at three different dates. Correlations ranged from 0.43 to 0.73 and were best for a soil depth of 90 cm. Resistivity patterns over time (time-lapse ERT) were analyzed and related to rainfall events where rainfall infiltration patterns could be identified. Duplicate ERT measurements showed that the noise level of the instrument and measurements is low and generally below 3% for the soil profile below the mixed layer but above the groundwater. Although the majority of the measured resistivity patterns could be well explained, some artefacts and dynamics were more difficult to clarify, even so in this homogeneous field situation. The presence of an oak tree with its root structure and a ditch with surface water with higher conductivity may have an impact on the resistivity pattern in the soil profile and over time. We conclude that ERT allows for detailed spatial measurement of local soil moisture dynamics resulting from precipitation although field experiments do not yield accuracies similar to laboratory experiments. ERT approaches are suitable for detailed spatial analyses where probe or sample-based methods are limited in reach or repeatability.

Kinome capture sequencing of high-grade serous ovarian carcinoma reveals novel mutations in the JAK3 gene.

High-grade serous ovarian carcinoma (HGSOC) remains the deadliest form of epithelial ovarian cancer and despite major efforts little improvement in overall survival has been achieved. Identification of recurring "driver" genetic lesions has the potential to enable design of novel therapies for cancer. Here, we report on a study to find such new therapeutic targets for HGSOC using exome-capture sequencing approach targeting all kinase genes in 127 patient samples. Consistent with previous reports, the most frequently mutated gene was TP53 (97% mutation frequency) followed by BRCA1 (10% mutation frequency). The average mutation frequency of the kinase genes mutated from our panel was 1.5%. Intriguingly, after BRCA1, JAK3 was the most frequently mutated gene (4% mutation frequency). We tested the transforming properties of JAK3 mutants using the Ba/F3 cell-based in vitro functional assay and identified a novel gain-of-function mutation in the kinase domain of JAK3 (p.T1022I). Importantly, p.T1022I JAK3 mutants displayed higher sensitivity to the JAK3-selective inhibitor Tofacitinib compared to controls. For independent validation, we re-sequenced the entire JAK3 coding sequence using tagged amplicon sequencing (TAm-Seq) in 463 HGSOCs resulting in an overall somatic mutation frequency of 1%. TAm-Seq screening of CDK12 in the same population revealed a 7% mutation frequency. Our data confirms that the frequency of mutations in kinase genes in HGSOC is low and provides accurate estimates for the frequency of JAK3 and CDK12 mutations in a large well characterized cohort. Although p.T1022I JAK3 mutations are rare, our functional validation shows that if detected they should be considered as potentially actionable for therapy. The observation of CDK12 mutations in 7% of HGSOC cases provides a strong rationale for routine somatic testing, although more functional and clinical characterization is required to understand which nonsynonymous mutations alterations are associated with homologous recombination deficiency.

Testicular cancer: Determinants of cisplatin sensitivity and novel therapeutic opportunities.

Testicular cancer (TC) is the most common solid tumor among men aged between 15 and 40 years. TCs are highly aneuploid and the 12p isochromosome is the most frequent chromosomal abnormality. The mutation rate is of TC is low, with recurrent mutations in KIT and KRAS observed only at low frequency in seminomas. Overall cure rates are high, even in a metastatic setting, resulting from excellent cisplatin sensitivity of TCs. Factors contributing to the observed cisplatin sensitivity include defective DNA damage repair and a hypersensitive apoptotic response to DNA damage. Nonetheless, around 10-20% of TC patients with metastatic disease cannot be cured by cisplatin-based chemotherapy. Resistance mechanisms include downregulation of OCT4 and failure to induce PUMA and NOXA, elevated levels of MDM2, and hyperactivity of the PI3K/AKT/mTOR pathway. Several pre-clinical approaches have proven successful in overcoming cisplatin resistance, including specific targeting of PARP, MDM2 or AKT/mTOR combined with cisplatin. Finally, patient-derived xenograft models hold potential for mechanistic studies and pre-clinical validation of novel therapeutic strategies in TC. While clinical trials investigating targeted drugs have been disappointing, pre-clinical successes with chemotherapy and targeted drug combinations fuel the need for further investigation in clinical setting.

A meta-analysis of client-therapist perspectives on the therapeutic alliance: Examining the moderating role of type of measurement and diagnosis.

BACKGROUND: Clients and therapists often have different perspectives on their therapeutic alliance (TA), affecting the process and outcome of therapy. The aim of the present meta-analysis was to assess the mean differences between clients' and therapists' estimations of TA among clients with severe disturbances, while focusing on two potential moderators: client diagnosis and alliance instrument. METHOD: We conducted a systematic literature search of studies examining both client perspective and therapist perspective on TA in psychotherapy among people with schizophrenia spectrum disorders, personality disorders, and substance misuse disorders. We then analyzed the data using a random-effects meta-analytic model with Cohen's d standardized mean effect size. RESULTS: Heterogeneity analyses (k = 22, Cohen's d = -.46, 95% confidence interval = .31-1.1) produced a significant Q-statistic (Q = 94.96) and indicated high heterogeneity, suggesting that moderator analyses were appropriate. CONCLUSIONS: Our findings show that the type of TA instrument moderates the agreement on TA between client and therapist, but there was no indication of the client's diagnosis moderating the effect. The agreement between client and therapist estimations seems to be dependent on the instrument that is used to assess TA. Specific setting-related instruments seem to result in higher agreement between clients' and therapists' estimations than do more general instruments that are applied to assess TA.

Molecular Imaging of PD-L1 Expression and Dynamics with the Adnectin-Based PET Tracer 18F-BMS-986192.

18F-BMS-986192, an adnectin-based human programmed cell death ligand 1 (PD-L1) tracer, was developed to noninvasively determine whole-body PD-L1 expression by PET. We evaluated the usability of 18F-BMS-986192 PET to detect different PD-L1 expression levels and therapy-induced changes in PD-L1 expression in tumors. Methods: In vitro binding assays with 18F-BMS-986192 were performed on human tumor cell lines with different total cellular and membrane PD-L1 protein expression levels. Subsequently, PET imaging was performed on immunodeficient mice xenografted with these cell lines. The mice were treated with interferon γ (IFNγ) intraperitoneally for 3 d or with the mitogen-activated protein kinase kinase inhibitor selumetinib by oral gavage for 24 h. Afterward, 18F-BMS-986192 was administered intravenously, followed by a 60-min dynamic PET scan. Tracer uptake was expressed as percentage injected dose per gram of tissue. Tissues were collected to evaluate ex vivo tracer biodistribution and to perform flow cytometric, Western blot, and immunohistochemical tumor analyses. Results:18F-BMS-986192 uptake reflected PD-L1 membrane levels in tumor cell lines, and tumor tracer uptake in mice was associated with PD-L1 expression measured immunohistochemically. In vitro IFNγ treatment increased PD-L1 expression in the tumor cell lines and caused up to a 12-fold increase in tracer binding. In vivo, IFNγ affected neither PD-L1 tumor expression measured immunohistochemically nor 18F-BMS-986192 tumor uptake. In vitro, selumetinib downregulated cellular and membrane levels of PD-L1 in tumor cells by 50% as measured by Western blotting and flow cytometry. In mice, selumetinib lowered cellular, but not membrane, PD-L1 levels of tumors, and consequently, no treatment-induced change in 18F-BMS-986192 tumor uptake was observed. Conclusion:18F-BMS-986192 PET imaging allows detection of membrane-expressed PD-L1 as soon as 60 min after tracer injection. The tracer can discriminate a range of tumor cell PD-L1 membrane expression levels.

Elements that enhance therapeutic alliance and short-term outcomes in metacognitive reflection and insight therapy: A session-by-session assessment.

OBJECTIVE: Preliminary evidence has found metacognitive capacity is associated with therapeutic alliance and with other outcomes in psychotherapy among persons with schizophrenia. The current study explored: (a) before to after changes in clients' metacognition capacity following Metacognitive Reflection and Insight Therapy (MERIT) and (b) whether the use of specific therapeutic elements of MERIT were followed by higher ratings of therapeutic alliance at the end of each session as well as with short-term outcome as measured prior to the next session, in a session-by-session intensive data collection. METHOD: Two hundred twenty-one sessions of 10 completers with schizophrenia who took part in an ongoing MERIT trial were analyzed. Measures of therapeutic alliance (short version of the Working Alliance Inventory), general outcome (Outcome Rating Scale), and metacognition (Metacognition Assessment Scale-Abbreviated) were used. RESULTS: Findings showed significant change in 2 domains of metacognition, self-reflectivity and mastery, following therapy. In addition, the presence of 2 specific MERIT elements, the introduction of the therapist's mind and reflecting on the progress in therapy within a given session, were related to better outcomes in the following week. Finally, reflecting on the progress was also followed by higher therapeutic alliance. CONCLUSIONS: Metacognitively oriented therapy may positively affect both therapeutic alliance and short-term outcome. Specifically discussing the therapist's and client's experiences of what is occurring in therapy may positively affect short-term outcome and could be applicable to other psychotherapy approaches. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Measuring personal recovery in people with a psychotic disorder based on CHIME: A comparison of three validated measures.

Living well in spite of residual symptoms of mental illness is measured with the construct of personal recovery. The CHIME framework might be suitable to evaluate personal recovery measures and guide instrument choice. Three validated measures were evaluated in Dutch patients with a psychotic disorder (N = 52). We compared the Recovery Assessment Scale (RAS), the Mental Health Recovery Measure (MHRM), and the Netherlands Empowerment List (NEL). The measures were assessed on six criteria: content validity (based on CHIME), convergent validity with a social support measure, internal consistency, floor and ceiling effects, item interpretability, and ease of administration. The MHRM scored high on content validity with a balanced distribution of items covering the CHIME framework. The MHRM and the NEL showed moderate convergent validity with social support. In all three measures, internal consistency was moderate and floor and ceiling effects were absent. The NEL scores demonstrated a high degree of item interpretability. Ease of administration was moderate for all three measures. Finally, the CHIME framework demonstrated good utility as a framework in guiding instrument choice and evaluation of personal recovery measures. The MHRM showed the best overall result. However, differences between measures were minimal. Generalization of the results is limited by cultural and linguistic factors in the assessment for the subjective measures (i.e. content validity and item interpretability). The broad and multidimensional construct of personal recovery might lead to ambiguous interpretations. Scientific consensus on a well-defined personal recovery construct is needed.