SUMMARY
Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.
Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-lossinduced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a "pro-senescence" approach for cancer prevention and therapy.
The purpose of our study was to define the signal characteristics and clinical circumstances associated with emboli detected in the middle cerebral artery using 2-MHz pulsed transcranial Doppler ultrasound in patients undergoing carotid endarterectomy. Signals designating emboli were transients displaying harmonic qualities the signatures of which were clearly different from those of mechanical and electronic artifacts. We reviewed the audio/video tape recordings from 91 patients for signals of air bubble emboli occurring upon release of common carotid artery crossclamps; recordings from 35 patients (38%) demonstrated air bubble emboli. Transients with signatures identical to those of air bubble emboli were also discovered when bubbles in the bloodstream were improbable; we defined these transients as representing formed-element emboli. Such signals were found in recordings from 24 patients (26%), and they occurred before (both spontaneously and upon common carotid artery compression), during, and after surgical dissection. Signals indicating formed-element emboli were associated with intraluminal platelet thrombus, with ulcerations in the carotid artery, and with transient ischemic attacks or stroke. Most postoperative formed-element emboli did not cause symptoms but, when persisting for hours, they were associated with strokes and cerebral infarction. This Doppler ultrasound method of detecting emboli will be useful in the study of stroke mechanisms and as a clinical test to guide the medical and surgical treatment of patients at risk of stroke. (Stroke 1990*21:415-423)
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