Acupuncture for pain and pain-related disability in deep infiltrating endometriosis

ObjectivesTo evaluate the efficacy of acupuncture in relieving symptoms (dysmenorrhea, dyspareunia, pelvic pain and dyschezia) intensity, improving functional disability, reducing the number of days per months of dysmenorrhea, the frequency and the efficacy of analgesic use in deep infiltrating endometriosis (DIE). The safety profile was also evaluated.MethodsThe study sample was 34 patients with DIE; for 2 months (T-2, T-1) the women recorded diary notes on the numbers of days of menstruation, the presence, intensity, and disability related to dysmenorrhea, dyspareunia, pelvic pain, and dyschezia. They then received a total of 15 acupuncture treatments over 6 months (T1–T6; once a week for 12 weeks, then once a month for 3 months).ResultsDysmenorrhea intensity was decreased during treatment. A decrease of at least 50% in number of days of dysmenorrhea, and a decrease in moderate-to-severe disability starting from T1 to T6 was recorded for 58.6% of patients. Dyspareunia intensity steadily decreased starting at T2; the percentage of women with moderate-to-severe disability declined from 73.3% at T-2, to 36.9% at T3, T4, and T5. A decrease in pelvic pain score was noted starting at T1; the percentage of disability decreased from 83.3% at T-2 to 33.3% at T3 and T6. The intensity of dyschezia decreased from T-2 to T3 and T4 and then increased slightly. Analgesic drug use was lower during treatment and its efficacy appeared to be greater.ConclusionsThe limitations notwithstanding our study-findings show that acupuncture was safe and effective in reducing pain intensity and symptoms-related disability. Larger-scale studies are needed to compare acupuncture and pharmacotherapy for endometriosis-related pain

Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma

Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressive program induced by oncogenic NPM-ALK. While inhibiting the expression of T cell molecules, NPM-ALK activates surrogate TCR signaling by directly inducing pathways downstream the TCR. CD45 is a tyrosine phosphatase that plays a central role in T cell activation by controlling the TCR signaling and regulating the cytokine responses through the JAK/STAT pathway and exists in different isoforms depending on the stage of T-cell maturation, activation and differentiation. ALK+ ALCL cells mainly express the isoform CD45RO in keeping with their mature/memory T cell phenotype. Because of its regulatory effect on the JAK/STAT pathway that is essential for ALK+ ALCL, we investigated whether CD45 expression was affected by oncogenic ALK. We found that most ALK+ ALCL cell lines express the CD45RO isoform with modest CD45RA expression and that NPM-ALK regulated the expression of these CD45 isoforms. Regulation of CD45 expression was dependent on ALK kinase activity as CD45RO expression was increased when NPM-ALK kinase activity was inhibited by treatment with ALK tyrosine kinase inhibitors (TKIs). Silencing ALK expression through shRNA or degradation of ALK by the PROTAC TL13-112 caused upregulation of CD45RO both at mRNA and protein levels with minimal changes on CD45RA, overall indicating that oncogenic ALK downregulates the expression of CD45. CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance in vitro to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL