Pre- and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro- or macro-metastatic disease.

BACKGROUND: There are phase 3 clinical trials underway evaluating anti-PD-L1 antibodies as adjuvant (postoperative) monotherapies for resectable renal cell carcinoma (RCC) and triple-negative breast cancer (TNBC); in combination with antiangiogenic VEGF/VEGFR2 inhibitors (e.g., bevacizumab and sunitinib) for metastatic RCC; and in combination with chemotherapeutics as neoadjuvant (preoperative) therapies for resectable TNBC. METHODS: This study investigated these and similar clinically relevant drug combinations in highly translational preclinical models of micro- and macro-metastatic disease that spontaneously develop after surgical resection of primary kidney or breast tumours derived from orthotopic implantation of murine cancer cell lines (RENCAluc or EMT-6/CDDP, respectively). RESULTS: In the RENCAluc model, adjuvant sunitinib plus anti-PD-L1 improved overall survival compared to either drug alone, while the same combination was ineffective as early therapy for unresected primary tumours or late-stage therapy for advanced metastatic disease. In the EMT-6/CDDP model, anti-PD-L1 was highly effective as an adjuvant monotherapy, while its combination with paclitaxel chemotherapy (with or without anti-VEGF) was most effective as a neoadjuvant therapy. CONCLUSIONS: Our preclinical data suggest that anti-PD-L1 plus sunitinib may warrant further investigation as an adjuvant therapy for RCC, while anti-PD-L1 may be improved by combining with chemotherapy in the neoadjuvant but not the adjuvant setting of treating breast cancer.

A compromise solution between overlapping and overlooking DSM personality disorders in Chinese psychiatric practice.

OBJECTIVE: This study aimed to examine the overlaps between the Diagnostic and Statistical Manual-5 (DSM-5) Personality Disorders (PDs) in a high-risk clinical population and to explore a transitional model for implementing DSM-5 PDs. METHOD: A sample population of 982 outpatients with at least one diagnosed PD was selected from 3,075 outpatients of the Shanghai Mental Health Center. The diagnostic process comprised of a personality diagnostic questionnaire and a structured clinical interview. RESULTS: 685 (22.3%) patients were diagnosed with at least one of six PDs (antisocial, avoidant, borderline, narcissistic, obsessive-compulsive, and schizotypal) under the alternative DSM-5 model for personality disorders proposed in Section III of the DSM-5. Nearly 20.3% of the subjects with PD met criteria for at least two PDs (of the 685 PD patients/6 PD model). Cluster and principal component analyses suggest a transitional model for the 7 specific PD categories (among the 722 PD patients, the overlapping rate was 24.1%) will be more appropriate for PD diagnosis in China. CONCLUSIONS: Using the simplified PD categories in the alternative DSM-5 model for personality disorders will reduce the overlaps in PD diagnoses in Chinese psychiatric practice, and should be preferred over the DSM-5 PD diagnostic system.

Faux pas recognition performance in a help-seeking population at clinical high risk of psychosis.

There is a growing body of evidence suggesting that patients with psychosis show impaired theory of mind (ToM). However, much remains to be understood as to whether ToM deficits occur in the premorbid or post-onset period of psychosis. Our primary aim was to examine empirically impairment on ToM tasks in a group of individuals with clinical high risk (CHR) of psychosis. Fifty CHR participants identified through the Structured Interview for Prodromal Syndromes and 52 age-/education-matched controls were assessed with a complete standard neuropsychological battery (the MCCB, MATRICS Consensus Cognitive Battery) and a social cognition assessment (Faux Pas Test, FPT). We then examined the association of baseline FPT performance with conversion to psychosis at 12-month follow-up. Compared with controls, the CHR group showed significantly poorer performances on the FPT and most MCCB domains. Significant positive correlations were found between faux pas detection and the MCCB domains of Attention/Vigilance and Working Memory in CHR participants when controlling for age and years of education. Mean scores on the FPT in 14 converters who were diagnosed with full-blown psychosis within 12 months were significantly lower than they were for non-converters. Impairments in ToM ability are acquired earlier in the prodromal stage of psychosis, along with general cognition (such as memory function) deficits. Declines in ToM ability may overlap with the progress of psychosis (the gradual loss insight), sharing similar neural substrates, and reflected by impairments in basic cognitive function.

Co-morbidity of personality disorder in schizophrenia among psychiatric outpatients in China: data from epidemiologic survey in a clinical population.

BACKGROUND: The reported rates of personality disorder (PD) in subjects with schizophrenia (SZ) are quite varied across different countries, and less is known about the heterogeneity of PD among subjects with SZ. We examined the co-morbidity of PD among patients who are in the stable phase of SZ. METHOD: 850 subjects were randomly sampled from patients diagnosed with SZ in psychiatric and psycho-counseling clinics at Shanghai Mental Health Center. Co-morbidity of PDs was assessed through preliminary screening and patients were administered several modules of the SCID-II. Evidence of heterogeneity was evaluated by comparing patients diagnosed with SZ with those who presented with either affective disorder or neurosis (ADN). RESULTS: 204 outpatients (24.0 %) in the stable phase of SZ met criteria for at least one type of DSM-IV PD. There was a higher prevalence of Cluster-A (odd and eccentric PD) and C (anxious and panic PD) PDs in SZ (around 12.0 %). The most prevalent PD was the paranoid subtype (7.65 %). Subjects with SZ were significantly more likely to have schizotypal PD (4.4 % vs. 2.1 %, p = 0.003) and paranoid PD (7.6 % vs. 5.4 %, p = 0.034), but much less likely to have borderline, obsessive-compulsive, depressive, narcissistic and histrionic PD. CONCLUSIONS: These findings suggest that DSM-IV PD is common in patients with SZ than in the general population. Patterns of co-morbidity with PDs in SZ are different from ADN.

Temsirolimus Maintenance Therapy After Docetaxel Induction in Castration-Resistant Prostate Cancer.

LESSONS LEARNED: Temsirolimus maintenance therapy after docetaxel induction chemotherapyis safe in patients with castration-resistant prostate cancer, although biochemical or tumor responses are rare;does not diminish quality of life; anddelays radiological and/or symptomatic progression by approximately 6 months. BACKGROUND: No standard therapy is available for men with castration-resistant prostate cancer (CRPC) who have responded to docetaxel and do not yet have disease progression. Hence, we designed a single-arm phase II trial to explore whether the mTOR inhibitor temsirolimus can maintain the response to docetaxel without compromising quality of life. METHODS: After successful docetaxel induction (75 mg/m(2) every 3 weeks; 6-10 cycles), 21 CRPC patients underwent temsirolimus maintenance treatment (25 mg weekly; 4 weeks per cycle). The primary endpoint was the time to treatment failure (TTTF) (i.e., radiological and/or symptomatic progression). The secondary endpoints included the tumor response rate (RECIST 1.0), safety (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0), quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P]), pain (Present Pain Intensity [PPI] scale), prostate-specific antigen (PSA) parameters, including time to PSA progression (TTPP) according to Prostate Cancer Clinical Trials Working Group criteria, and serial enumeration of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs). RESULTS: Patients received a median of 7 cycles of temsirolimus (range, 1-28), resulting in a median TTTF of 24.3 weeks (95% confidence interval [CI], 16.1-33.0), 1 partial tumor response (4.8%), 1 PSA response (4.8%), and a median TTPP of 12.2 weeks (95% CI, 7.8-23.9). Grade 3-4 adverse events were infrequent, and FACT-P and PPI scores remained stable during treatment. CECs did not predict clinical benefit, and CEPs were not consistently detectable. CONCLUSION: Temsirolimus maintenance therapy after successful docetaxel induction is feasible, does not adversely affect quality of life, and, in this exploratory single-arm phase II study, resulted in a median TTTF of 24.3 weeks.

In vivo passage of human prostate cancer cells in mice results in stable gene expression changes affecting numerous cancer-associated biological processes.

BACKGROUND: While therapeutic resistance is difficult to model in vitro in its entirety, in vivo passage and re-derivation of treatment resistant prostate cancer cell variants is a strategy to study therapeutic resistance more comprehensively. However, the process of in vivo passage itself may result in gene expression changes that could confound the analysis of such resistant cell variants compared to their parental cell lines. METHODS: We compared the expression profiles of parental PC-3 human prostate cancer cells and PC-3 cells re-derived after in vivo passage in athymic nude mice. Whole transcriptome information was obtained using the SOLiD 4 system (Applied Biosystems). Differentially expressed genes were mapped to genes in the Database for Annotation, Visualization and Integrated Discovery for gene enrichment and functional annotation analysis. The expression of a panel of these genes was validated using quantitative RT-PCR. RESULTS: Altogether, 21,032 distinct transcripts were found in PC-3 and/or NS1.1. Of these, 906 were differentially regulated (≥2-fold) in NS1.1 versus PC-3. 337 transcripts were upregulated, and 569 were downregulated, including genes previously associated with various aspects of prostate carcinogenesis such as TLR4 and IGFBP5, respectively. Gene ontology analysis of the differentially expressed transcripts revealed enrichment for biological processes such as cell adhesion, migration, and angiogenesis. CONCLUSIONS: When using in vivo as opposed to in vitro derived prostate cancer cell variants for comparative genetic studies of complex traits such as therapeutic resistance, one may be better served to use similarly in vivo passaged control cell variants instead of parental cell lines.

Preclinical analysis of resistance and cross-resistance to low-dose metronomic chemotherapy.

Low-dose metronomic chemotherapy is an emerging form of chemotherapy with distinct mechanisms of action from conventional chemotherapy (e.g., antiangiogenesis). Although developed to overcome resistance to conventional chemotherapy, metronomic chemotherapy is subject to resistance on its own. However, there is a paucity of information on mechanisms of resistance, on cross-resistance between metronomic regimens using different cytotoxic drugs, and on cross-resistance between metronomic versus conventional chemotherapy, or versus targeted antiangiogenic therapy. Herein we show that PC-3 human prostate cancer xenografts were sensitive to both metronomic cyclophosphamide and metronomic docetaxel, but resistant to metronomic topotecan. Conventional docetaxel was only moderately active in parental PC-3 and in metronomic cyclophosphamide resistant PC-3 tumors. However, in metronomic cyclophosphamide resistant PC-3 tumors combining conventional docetaxel or bolus cyclophosphamide therapy with continued metronomic cyclophosphamide was superior to each treatment alone. Furthermore, bevacizumab had single-agent activity against metronomic cyclophosphamide resistant PC-3 tumors. Microarray analyses identified altered regulation of protein translation as a potential mechanism of resistance to metronomic cyclophosphamide. Our results suggest that sensitivity to metronomic chemotherapy regimens using different cytotoxic drugs not only depends on shared mechanisms of action such as antiangiogenesis, but also on as yet unknown additional antitumor effects that appear to be drug-specific. As clinically observed with targeted antiangiogenic agents, the continued use of metronomic chemotherapy beyond progression may amplify the effects of added second-line therapies or vice versa. However, metronomic chemotherapy is no different from other systemic therapies in that predictive biomarkers will be essential to fully exploit this novel use of conventional chemotherapeutics.

Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy.

ATG4B belongs to the autophagin family of cysteine proteases required for autophagy, an emerging target of cancer therapy. Developing pharmacological ATG4B inhibitors is a very active area of research. However, detailed studies on the role of ATG4B during anticancer therapy are lacking. By analyzing PC-3 and C4-2 prostate cancer cells overexpressing dominant negative ATG4B(C74A)in vitro and in vivo, we show that the effects of ATG4B(C74A) are cell type, treatment, and context-dependent. ATG4B(C74A) expression can either amplify the effects of cytotoxic therapies or contribute to treatment resistance. Thus, the successful clinical application of ATG4B inhibitors will depend on finding predictive markers of response.

Childhood maltreatment profile in a clinical population in China: a further analysis with existing data of an epidemiologic survey.

To determine the lifetime prevalence and diverse profiles of types of childhood maltreatment (CM) in a high-risk clinical sample using standardized assessment tools (Child Trauma Questionnaire, CTQ) in China, Shanghai, 2090 subjects were sampled from the Shanghai Mental Health Centre. Personality disorder (PD) was assessed using the Personality Diagnostic Questionnaire (PDQ-4+) and subjects were interviewed using the Structured Clinical Interview (SCID-II). CTQ was used to assess CM in five domains (emotional abuse, EA; physical abuse, PA; sexual abuse, SA; emotional neglect, EN; and physical neglect, PN). The prevalence estimate of EA in the sample is 22.2%, followed by 17.8% of PA, and 12.5% of SA. The prevalence estimate was more frequent in PN (65.0%) and in EN (34.0%) than in childhood abuse (EA, PA and SA). It seems that males reported more PA and females reported more SA, the older subjects reported more neglect and the younger subjects reported more abuse. There was a higher prevalence of EA and SA in borderline PD patients (44.4%, 22.5%), PA in antisocial PD patients (38.9%). Multi-PD patients reported more forms of CM in childhood. Additionally, factor analysis of CTQ items confirmed factorial validity by identifying a five-factor structure that explained 50% of the total variance. These findings support the view that prevalence of CM was commonly experienced in clinical population during their childhood, especially for subjects with PDs. Factorial validity in PN needs to be further improved, and can in part be culturally explained.

Role of childhood traumatic experience in personality disorders in China.

BACKGROUND: There has been no large-scale examination of the association between types of childhood abuse and personality disorders (PDs) in China using standardized assessment tools and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Hence, this study aimed to explore the relationship between retrospective reports of various types of childhood maltreatments and current DSM-IV PDs in a clinical population in China, Shanghai. METHOD: One thousand four hundred two subjects were randomly sampled from the Shanghai Psychological Counselling Centre. PDs were assessed using the Personality Diagnostic Questionnaire, Fourth Edition Plus. Participants were also interviewed using the Structured Clinical Interview for DSM-IV axis II. The Child Trauma Questionnaire (CTQ) was used to assess childhood maltreatment in 5 domains (emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect). RESULTS: According to Pearson correlations, childhood maltreatment had a strong association with most PDs. Subsequently, using partial correlations, significant relationships were also demonstrated between cluster B PDs and all the traumatic factors except physical neglect. A strongest positive correlation was found between cluster B PD and CTQ total scores (r = .312, P < .01). Using the Kruskal-Wallis rank sum test, significant differences in 4 groups of subjects (clusters A, B, and C PD and non-PD) in terms of emotional abuse (χ(2) = 34.864, P < .01), physical abuse (χ(2) = 14.996, P < .05), sex abuse (χ(2) = 9.211, P < .05), and emotional neglect (χ(2) = 17.987, P < .01) were found. Stepwise regression analysis indicated that emotional abuse and emotional neglect were predictive for clusters A and B PD, and sexual abuse was highly predictive for cluster B PD; only emotional neglect was predictive for cluster C PD. CONCLUSION: Early traumatic experiences are strongly related to the development of PDs. The effects of childhood maltreatment in the 3 clusters of PDs are different. Childhood trauma has the most significant impact on cluster B PD.

Prevalence of personality disorders using two diagnostic systems in psychiatric outpatients in Shanghai, China: a comparison of uni-axial and multi-axial formulation.

OBJECTIVE: To compare multi-axial (DSM-IV) with uni-axial diagnostic system (CCMD-3, Chinese Classification and Diagnostic Criteria of Mental Disorders) as diagnostic methods to determine the prevalence of personality disorders (PDs) in Chinese psychiatric outpatients. METHOD: 3,075 outpatients were randomly sampled from clinical settings in China. CCMD-3 PDs were evaluated as per routine psychiatric practice. DSM-IV PDs were assessed using both self-reported questionnaire and structured clinical interview. RESULTS: The prevalence estimate for any type of PD in the total sample is 31.93% as reflected in the DSM-IV. This figure is nearly 110 times as large as the prevalence estimate for the CCMD-3. Only 9 outpatients were diagnosed with PD based on the CCMD-3. Amongst the 10 forms of DSM-IV PDs, avoidant (8.1%), obsessive-compulsive (7.6%), paranoid (6.0%), and borderline (5.8%) PDs were the most prevalent subtypes. This study found that PDs are commonly associated with the following: (i) the younger aged; (ii) single marital status; (iii) those who were not raised by their parents; (iv) introverted personalities; (v) first-time seekers of psycho-counseling treatment; and (vi) patients with co-morbid mood or anxiety disorders. CONCLUSIONS: PDs are easily overlooked when the diagnosis is made based on the CCMD-3 uni-axial diagnostic system. However, it was found that personality pathology is common in the Chinese psychiatric community when using the DSM-IV classification system. Existing evidence suggest, at least indirectly, that there are important benefits of moving towards a multi-axial diagnostic approach in psychiatric practice.

Molecular characterization of human homologs of yeast MOB1.

MOB (Mps one binder) was originally identified in yeast as a regulator of mitotic exit and cytokinesis, and was later identified as a tumor suppressor and a component of an emerging Hippo-LATS tumor suppressor pathway in Drosophila (D). So far, 7 human homologs of yeast MOB (hMOB1A, 1B, 2A, 2B, 2C, 3, 4) have been identified. Although hMOB1A/B has been extensively studied, the biological features of other hMOBs are largely unknown. In addition, while hMOB1 has been reported to interact with and activate LATS (Large tumor suppressor)/Warts tumor suppressor, the functional significance of this is unknown. In this study, we have characterized, for the first time, the cellular and biochemical function of all human MOBs. By examining hMOB mRNAs expression in various human tissues, we found that hMOBs demonstrated different expression patterns. Further biochemical characterization of hMOBs showed that only hMOB1A and hMOB1B interact with both LATS1 and LATS2 in vitro and in vivo. Significantly, we have discovered that overexpression of hMOB1 in human cancer cells activated LATS activity and inhibited cell proliferation or caused apoptosis while hMOB1, targeting the plasma membrane, led to a more significant phenotype. Reciprocally, short-hairpin (sh) RNA-mediated suppression of hMOB1 causes increased cell proliferation. Our findings provided evidence that hMOB1A and hMOB1B are 2 LATS-binding proteins that may function as tumor suppressors in human cancer cells.

Immunostimulatory and anti-tumor metronomic cyclophosphamide regimens assessed in primary orthotopic and metastatic murine breast cancer.

The impressive successes of immune checkpoint blockade antibodies to treat various types of cancer are limited to minor subsets of patients. Combination therapy strategies, including with chemotherapy, are being explored to possibly improve the efficacy of immunotherapies. Here we report results regarding the use of an immunostimulatory regimen of metronomic cyclophosphamide (CTX). We show that in orthotopic models of syngeneic murine triple-negative breast cancer (EMT6), CTX administered at 140 mg/kg every 6 days (CTX140 1q6d) is superior at inhibiting primary tumor growth when compared to maximum tolerated dose or daily oral (continuous) low-dose CTX. In SCID or SCID beige mice, anti-tumor effects of CTX140 1q6d are reduced, reinforcing the therapeutic contribution of the adaptive and innate immune systems. In a second breast cancer model (SP1-AC2M2), CTX140 1q6d again showed clear superiority in anti-tumor effects, causing complete tumor regressions; however, these mice were not protected from subsequent tumor re-challenge, suggesting absence of immune memory. We also show that in an aggressive and metastatic cisplatin-resistant variant (EMT6-CDDP), CTX140 1q6d is superior and invokes an influx of intra-tumoral CD4+ and CD8+ T cells. CTX increases expression of tumor cell PD-L1; however, when combined with concomitant PD-L1 antibody therapy none of the CTX regimens showed increased benefit. This work sheds light on the potential use of metronomic CTX for the treatment of breast cancer, in particular using the quasi-weekly regimen, but also underscores the complexity of the anti-tumor mechanisms and potential to improve immune checkpoint therapy efficacy.

Therapeutic impact of Nintedanib with paclitaxel and/or a PD-L1 antibody in preclinical models of orthotopic primary or metastatic triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, in part because of the current lack of any approved molecularly targeted therapy. We evaluated various combinations of three different drugs: nintedanib, an antiangiogenic TKI targeting VEGF receptors, paclitaxel (PTX), or a PD-L1 antibody, using models of orthotopic primary or advanced metastatic TNBC involving a metastatic variant of the MDA-MB-231 human cell line (called LM2-4) in SCID mice and two mouse lines (EMT-6 and a drug-resistant variant, EMT-6/CDDP) in immunocompetent mice. These drugs were selected based on the following: PTX is approved for TNBC; nintedanib combined with docetaxel has shown phase III clinical trial success, albeit in NSCLC; VEGF can act as local immunosuppressive factor; and PD-L1 antibody plus taxane therapy was recently reported to have encouraging phase III trial benefit in TNBC. METHODS: Statistical analyses were performed with ANOVA followed by Tukey's Multiple Comparison Test or with Kruskal-Wallis test followed by Dunn's Multiple Comparison Test. Survival curves were analyzed using a Log-rank (Mantel Cox) test. Differences were considered statistically significant when p values were < 0.05. RESULTS: Toxicity analyses showed that nintedanib is well tolerated when administered 5-days ON 2-days OFF; PTX toxicity differed in mice, varied with cell lines used and may have influenced median survival in the metastatic EMT6/CDDP model; while toxicity of PD-L1 therapy depended on the cell lines and treatment settings tested. In the LM2-4 system, combining nintedanib with PTX enhanced overall antitumor efficacy in both primary and metastatic treatment settings. In immunocompetent mice, combining nintedanib or PTX with the PD-L1 antibody improved overall antitumor efficacy. Using the advanced metastatic EMT-6/CDDP model, optimal efficacy results were obtained using the triple combination. CONCLUSIONS: These results suggest circumstances where nintedanib plus PTX may be potentially effective in treating TNBC, and nintedanib with PTX may improve PD-L1 therapy of metastatic TNBC.

Progressive decline of cognition during the conversion from prodrome to psychosis with a characteristic pattern of the theory of mind compensated by neurocognition.

The association between neurocognition and the theory of mind (ToM) abilities during the progression of psychosis is unclear. This study included 83 individuals with attenuated psychosis syndrome (APS), from which 26 converted to psychosis (converters) after a follow up period of 18months. Comprehensive cognitive tests (including MATRICS Consensus Cognitive Battery, Faux-Pas Task, and Reading-Mind-in-Eyes Tasks) were administered at baseline. A structural equation modeling (SEM) analysis was conducted to estimate the effects of neurocognition on the ToM functioning in both APS and healthy controls (HC) datasets. At baseline, the converters and non-converters groups differed significantly on several domains of cognitive performance. The SEM analysis demonstrated that the path from neurocognition to ToM was statistically significant in the APS dataset (p<0.001). However, in the HC dataset, the result of the same analysis was not significant (p=0.117). Positive correlations between neurocognition and ToM were observed, and the most obvious correlations were found in the converters group compared with the non-converters group (p=0.064) and compared with the HC group (p=0.002). The correlation between ToM abilities and neurocognition may be increased during the progression of the condition, especially for individuals who convert to psychosis after a short period.

Impact of Chemical-Induced Mutational Load Increase on Immune Checkpoint Therapy in Poorly Responsive Murine Tumors.

A recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26, and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Although tumor PD-L1 expression was upregulated in in vivo chemotherapy-exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically "hot" or "cold" tumors with a high mutational load, to which certain chemotherapy agents may contribute, on immunotherapy outcomes. Mol Cancer Ther; 17(4); 869-82. ©2018 AACR.

Efficacy of Cotargeting Angiopoietin-2 and the VEGF Pathway in the Adjuvant Postsurgical Setting for Early Breast, Colorectal, and Renal Cancers.

Antiangiogenic tyrosine kinase inhibitors (TKI) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III clinical trials. Angiopoietin-2 (Ang2) is a proangiogenic and proinflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models. In the MDA-MB-231.LM2-4 human breast cancer model, adjuvant sunitinib was ineffective, whereas adjuvant CVX-060 delayed the progression of pulmonary or distant lymphatic metastases; however, overall survival was only improved with the adjuvant use of a VEGF-A/Ang2-bispecific CovX-body (CVX-241) but not when CVX-060 is combined with sunitinib. Adjuvant CVX-241 also showed promise in the EMT-6/CDDP murine breast cancer model, with or without an immune checkpoint inhibitor (anti-PD-L1). In the RENCA model of mouse renal cancer, however, combining CVX-060 with sunitinib in the adjuvant setting was superior to CVX-241 as treatment for postsurgical lung metastases. In the HCT116 and HT29 xenograft models of colorectal cancer, both CVX-060 and regorafenib inhibited liver metastases. Overall, our preclinical findings suggest differential strategies by which Ang2 blockers can be successfully combined with VEGF pathway targeting in the adjuvant setting to treat micrometastatic disease-particularly, in combination with VEGF-A blockers (but not VEGFR2 TKIs) in resected breast cancer; in combination with VEGFR2 TKIs in resected kidney cancer; and as single agents or with VEGFR2 TKIs in resected colorectal cancer. Cancer Res; 76(23); 6988-7000. ©2016 AACR.

Theory of Mind Impairments in Youth at Clinical High Risk of Psychosis.

OBJECTIVE: The normal maturational processes of theory of mind (ToM) capacity are ongoing during adolescence and even early adulthood. However, research has shown that ToM ability also declines among adults suffering from prodromal psychotic experiences. The goal of this study was to investigate the characteristics of ToM performance in youth with clinical high risk (CHR) of psychosis. METHODS: The Reading Mind in Eyes Task (RMET), including own-race and other-race eyes, was administered to 40 CHR youth; 42 age-, gender-, and education-matched healthy controls (HCs); and 62 adult patients with schizophrenia (SZ). Nine-month follow-up data were collected from 31 CHR subjects, of whom 7 (22.6%) had made the transition to psychosis. RESULTS: CHR youth showed significant impairment in RMET performance compared to HC youth but performed better than did SZ patients. Moreover, they were significantly slower than were HC youth in responding to the RMET, with a response time similar to that of SZ patients. In particular, they had significantly poorer accuracy in interpreting positive and neutral eye expressions compared to the HC group, but not in interpreting negative eye expressions. Preliminary follow-up data showed a trend toward significance (p = 0.079) for RMET performance between those who transitioned to psychosis and those who did not. CONCLUSIONS: Our findings illustrate that deficits in ToM capacity, specifically the ability to interpret people's mental state from eye expressions, occur early on in prodromal psychosis in youth. Early interventions for CHR youth focusing on ToM enhancement may halt progress toward psychosis.