A Comparison of Delivery Methods of Cognitive-Behavioral Therapy for Panic Disorder: An International Multicenter Trial

Cognitive-behavioral therapy (CBT) is the psychological treatment of choice for panic disorder (PD). However, given limited access to CBT, it must be delivered with maximal cost-effectiveness. Previous researchers have found that a brief computer-augmented CBT was as effective as extended therapist-delivered CBT. To test this finding, this study randomly allocated 186 patients with PD across 2 sites in Scotland and Australia to 12 sessions of therapist-delivered CBT (CBT12), 6 sessions of therapist-delivered (CBT6) or computer-augmented CBT (CBT6-CA), or a waitlist control. On a composite measure, at post-treatment, the outcome for CBT12 was statistically better than the outcome for CBT6. The outcome for CBT6-CA fell between CBT12 and CBT6, but could not be statistically distinguished from either treatment. The active treatments did not differ statistically at 6-month follow-up. The study provided some support for the use of computers as an innovative adjunctive-therapy tool and merits further investigation

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Prognostic indices with brief and standard CBT for panic disorder: II. Moderators of outcome

Background. Despite the growth of reduced therapist-contact cognitive behavioural therapy (CBT) programmes, there have been few systematic attempts to determine prescriptive indicators for such programmes vis-a-vis more standard forms of CBT delivery. The present study aimed to address this in relation to brief (6-week) and standard (12-week) therapist-directed CBT for panic disorder (PD) with and without agoraphobia. Higher baseline levels of severity and associated disability/comorbidity were hypothesized to moderate treatment effects, in favour of the 12-week programme. Method. Analyses were based on outcome data from two out of three treatment groups (n = 72) from a recent trial of three forms of CBT delivery for PD. The dependent variables were a continuous composite panic/anxiety score and a measure of clinical significance. Treatment x predictor interactions were examined using multiple and logistic regression analyses. Results. As hypothesized, higher baseline severity, disability or co-morbidity as indexed by strength of dysfunctional agoraphobic cognitions; duration of current episode of PD; self-ratings of panic severity; and the 36-item Short Form Health Survey (SF-36) (Mental component) score were all found to predict poorer outcome with brief CBT. A similar trend was apparent in relation to baseline level of depression. With high and low end-state functioning as the outcome measure, however, only the treatment x agoraphobic cognitions interaction was found to be significant. Conclusions. While there was no evidence that the above variables necessarily contraindicate the use of brief CRT, they were nevertheless associated with greater overall levels of post-treatment improvement with the 12-week approach

The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling.

Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia

Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab.

To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab. Patient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString. At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti-double-stranded DNA (anti-dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti-dsDNA antibody, C3, and immunoglobulin levels. SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE-1 and ILLUMINATE-2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab

'Now She's Just an Ordinary Baby': The Birth of IVF in the British Press.

The birth of Louise Brown, the first baby born through in vitro fertilisation (IVF), in England in 1978 attracted worldwide media attention. This article examines how the contemporary British news media framed this momentous event. Drawing on the example of the Daily Mail's coverage, it focuses on the way in which the British press depicted Louise's parents' emotions, marital relationship and social class in a context of political and economic crisis and resurgent social conservatism. The British press framed the Browns as ordinary and respectable, noting their work ethic, family orientation and moral values. The article argues that the human-interest angle that the press used to represent this story created a dominant narrative in which IVF was simply a means of helping married heterosexual couples have babies and that this established a frame for subsequent depictions of IVF, as well as contributing to its rapid normalisation