Enhancer activation from transposable elements in extrachromosomal DNA.

Extrachromosomal DNA (ecDNA) is a hallmark of aggressive cancer, contributing to both oncogene amplification and tumor heterogeneity. Here, we used Hi-C, super-resolution imaging, and long-read sequencing to explore the nuclear architecture of MYC-amplified ecDNA in colorectal cancer cells. Intriguingly, we observed frequent spatial proximity between ecDNA and 68 repetitive elements which we called ecDNA-interacting elements or EIEs. To characterize a potential regulatory role of EIEs, we focused on a fragment of the L1M4a1#LINE/L1 which we found to be co-amplified with MYC on ecDNA, gaining enhancer-associated chromatin marks in contrast to its normally silenced state. This EIE, in particular, existed as a naturally occurring structural variant upstream of MYC, gaining oncogenic potential in the transcriptionally permissive ecDNA environment. This EIE sequence is sufficient to enhance MYC expression and is required for cancer cell fitness. These findings suggest that silent repetitive genomic elements can be reactivated on ecDNA, leading to functional cooption and amplification. Repeat element activation on ecDNA represents a mechanism of accelerated evolution and tumor heterogeneity and may have diagnostic and therapeutic potential.

The Role of Staging in Planning Psychotherapeutic Interventions in Depression.

CONTEXT: The purpose of this critical review is to examine the role of staging in planning a psychotherapeutic intervention in depressive disorders. EVIDENCE ACQUISITION: English-language studies concerned with staging in depressive disorders were identified in MEDLINE, PsycINFO, and Web of Science and by manual search of the literature. Selection of articles was based on their methodological quality and implications for clinical practice. RESULTS: Staging may allow clinicians to apply a psychotherapeutic intervention to specific phases of the development of depressive disorders: certain psychotherapeutic approaches, such as well-being therapy and mindfulness-based cognitive therapy, appear to be uniquely suited for addressing the residual phase of depression, whereas interpersonal psychotherapy has been mainly tested in the acute phase. Cognitive-behavioral treatment appears to be suitable for all phases, but with chronic or double depression, its modifications (eg, cognitive-behavioral analysis system of psychotherapy) appear to be indicated. Staging may also allow clinicians to assess past and potential resistance to treatment. CONCLUSIONS: Treatment options, including psychotherapy, need to be filtered by clinical judgment and patient-specific problems that take into account individual staging classifications of the depressive illness.

Treatment of recurrent depression.

Approximately eight out of ten people experiencing a major depressive episode will have one or more further episodes during their lifetime: a recurrent major depressive disorder. Prolongation or lifelong pharmacotherapy has emerged as the main therapeutic tool for preventing relapse in depression. However, outcome after discontinuation of antidepressants does not seem to be affected by the duration of their administration. Loss of clinical effects, despite adequate compliance, has also emerged as a vexing clinical problem. Use of intermittent pharmacotherapy with follow-up visits is another therapeutic option that would leave patients with periods free of drugs and side effects, in consideration of the fact that a high proportion of patients would discontinue the antidepressant anyway. However, the problems of resistance (the fact that a drug treatment may be associated with a diminished chance of response in those patients who successfully responded to it, but discontinued it) and of discontinuation syndromes are a substantial disadvantage of this therapeutic option. In recent years, several controlled trials have suggested that a sequential use of pharmacotherapy in the treatment of the acute episode and psychotherapy in its residual phase may improve long-term outcome. However, patients should be motivated for psychotherapy and skilled therapists should be available. It is important to discuss with the patient the various therapeutic options and to adapt strategies to the specific needs of patients.

Routine radiographic screening of the chest in pregnant women: is it indicated?

Experience with routine antepartum chest radiographic screening from July 1, 1976, through June 30, 1977, in a city-county hospital which serves a predominantly black indigent population was reviewed. The 5422 routine screening chest radiographs produced an extremely low yield of pathology (11 cases), and only 3 of the 11 cases were not suspected from the history of physical examination. Only 2 cases of active pulmonary tuberculosis were discovered, and both patients were recent immigrants from countries with a much higher incidence of tuberculosis. This low case finding probably reflects the general decline in incidence of pulmonary tuberculosis in the United States and suggests that routine screening chest radiographs (done primarily to exclude tuberculosis) are not longer indicated in our pregnant population (AU)