Investigations of Beck's cognitive therapy for depression

Beck's cognitive model of depression suggests that negative thinking can play an important role in the development and maintenance of clinical depression. It follows from this that interventions which reduce the frequency or intensity of depressing thoughts will also reduce depression. This prediction forms the basis of cognitive-behavioural therapy (CBT) for depression, as developed by Beck and his colleagues. The cognitive model of depression, and cognitive therapy, are described. The development of a questionnaire (the Cognitions Questionnaire -- CQ) is then presented, designed to assess various dimensions of depressive thinking in relation to positive, negative and neutral hypothetical events. Relationships between scores on the questionnaire and level of depression in psychiatric and community samples are examined, and possible indices of continuing cognitive vulnerability to depression following an episode are explored. As an alternative to the traditional outcome trial, a within-subject experimental design is proposed, designed to test the central prediction of the cognitive model outlined above by examining the immediate effects on depressive thinking and on depression of specified cognitive therapy interventions. A series of experiments is presented, which demonstrated that in patients low in endogeneity, a brief, standardised distraction procedure reliably reduced the frequency of depressing thoughts, compared to a control procedure. As would be predicted from the cognitive model of depression, this was accompanied by significant reductions in depression. A study using non depressed student subjects showed that these effects could not be attributed to the direct impact of the two procedures on depressed mood. Similar results were not found in depressed patients high in endogeneity. The nature of this difference in responsiveness to distraction is explored, and its implications for the theory and practice of CBT for depression are discussed.<p

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead