Excised DNA circles from V(D)J recombination promote relapsed leukaemia

Extrachromosomal DNA amplification is associated with poor cancer prognoses1 . Large numbers of excised signal circles (ESCs) are produced as by-products of antigen receptor rearrangement during V(D)J recombination2,3 . However, current dogma states that ESCs are progressively lost through cell division4 . Here we show that ESCs replicate and persist through many cell generations and share many properties in common with circular extrachromosomal DNAs. Increased ESC copy numbers at diagnosis of B cell precursor acute lymphoblastic leukaemia were highly correlated with subsequent relapse. By taking advantage of the matching recombination footprint that is formed upon the generation of each ESC, we measured ESC persistence and replication and found increased ESC replication in patients who later relapsed. This increased replication is controlled by cell-intrinsic factors and corresponds to increased expression of DNA replication- and repair-associated genes. Consistent with high ESC levels having a role in disease progression, the number of mutations typical of those caused by the V(D)J recombinase–ESC complex was significantly increased at diagnosis in patients who later relapsed. The number of such mutations in genes associated with relapse increased between diagnosis and relapse, and corresponded to clonal expansion of cells with high ESC copy numbers. These data demonstrate that the by-product of V(D)J recombination, when increased in abundance, potently associates with the V(D)J recombinase to cause adverse disease outcomes

The evidence for pharmacologic treatment of neuropathic cancer pain: beneficial and adverse effects

Item does not contain fulltextCONTEXT: The prevalence of neuropathic pain in patients with cancer pain has been estimated to be around 40%. Neuropathic pain may be caused by tumor invasion and is considered as mixed nociceptive-neuropathic pain, or caused by an anticancer treatment and considered as purely neuropathic pain. The use of adjuvant analgesics in patients with cancer is usually extrapolated from their efficacy in nononcological neuropathic pain syndromes. OBJECTIVES: In this systematic review, we sought to evaluate the evidence for the beneficial and adverse effects of pharmacologic treatment of neuropathic cancer pain. METHODS: A systematic review of the literature in PubMed and Embase was performed. Primary outcome measures were absolute risk benefit (ARB), defined as the number of patients with a defined degree of pain relief divided by the total number of patients in the treatment group, and absolute risk harm (ARH), defined as the fraction of patients who dropped out as a result of adverse effects. RESULTS: We identified 30 articles that fulfilled our inclusion criteria. Overall, ARB of antidepressants, anticonvulsants, other adjuvant analgesics, or opioids greatly outweighed ARH. There were no significant differences in ARB or ARH between the four groups of medication or between patients with mixed vs. purely neuropathic pain. Because of the low methodological quality of the studies, we could not draw conclusions about the true treatment effect size of the four groups of medications. CONCLUSION: Once a diagnosis of neuropathic pain has been established in patients with cancer, antidepressants, anticonvulsants, or other adjuvant analgesics should be considered in addition to or instead of opioids

Pacioli and humanism: pitching the text in Summa Arithmetica

Despite the wide cross-disciplinary influence of Fra' Luca Pacioli's Summa de Arithmetica, Geometria, Proportioni et Proportionalita (Summa), it has been criticized as being both difficult to read and written in a mixture of bad Italian and bad Latin; but, paradoxically, intellectuals of Pacioli's day praised the style of writing in Summa. Can both viewpoints be correct? The answer to this question is sought by identifying what may have inspired Pacioli to write Summa in the manner he did. In doing so, the article considers the times in which he lived and, in particular, the impact that Renaissance Humanism and Humanist Education may have had upon his writing style. The article finds both views were correct in their own timeframes and contexts and that Pacioli's writing style was both an appropriate one with which to address a contemporary merchant society and one which would impress and gain the approval of his fellow humanist educators and patrons