Cooperative STAT/NF-κB signaling regulates lymphoma metabolic reprogramming and aberrant GOT2 expression.

Knowledge of stromal factors that have a role in the transcriptional regulation of metabolic pathways aside from c-Myc is fundamental to improvements in lymphoma therapy. Using a MYC-inducible human B-cell line, we observed the cooperative activation of STAT3 and NF-κB by IL10 and CpG stimulation. We show that IL10 + CpG-mediated cell proliferation of MYClow cells depends on glutaminolysis. By 13C- and 15N-tracing of glutamine metabolism and metabolite rescue experiments, we demonstrate that GOT2 provides aspartate and nucleotides to cells with activated or aberrant Jak/STAT and NF-κB signaling. A model of GOT2 transcriptional regulation is proposed, in which the cooperative phosphorylation of STAT3 and direct joint binding of STAT3 and p65/NF-κB to the proximal GOT2 promoter are important. Furthermore, high aberrant GOT2 expression is prognostic in diffuse large B-cell lymphoma underscoring the current findings and importance of stromal factors in lymphoma biology.

Synergy of interleukin 10 and toll-like receptor 9 signalling in B cell proliferation: Implications for lymphoma pathogenesis.

A network of autocrine and paracrine signals defines B cell homeostasis and is thought to be involved in transformation processes. Investigating interactions of these microenvironmental factors and their relation to proto-oncogenes as c-Myc (MYC) is fundamental to understand the biology of B cell lymphoma. Therefore, B cells with conditional MYC expression were stimulated with CD40L, insulin-like growth factor 1, α-IgM, Interleukin-10 (IL10) and CpG alone or in combination. The impact of forty different interventions on cell proliferation was investigated in MYC deprived cells and calculated by linear regression. Combination of CpG and IL10 led to a strong synergistic activation of cell proliferation (S-phase/doubling of total cell number) comparable to cells with high MYC expression. A synergistic up-regulation of CDK4, CDK6 and CCND3 expression by IL10 and CpG treatment was causal for this proliferative effect as shown by qRT-PCR analysis and inhibition of the CDK4/6 complex by PD0332991. Furthermore, treatment of stimulated MYC deprived cells with MLN120b, ACHP, Pyridone 6 or Ruxolitinib showed that IL10/CpG induced proliferation and CDK4 expression were JAK/STAT3 and IKK/NF-κB dependent. This was further supported by STAT3 and p65/RELA knockdown experiments, showing strongest effects on cell proliferation and CDK4 expression after double knockdown. Additionally, chromatin immunoprecipitation revealed a dual binding of STAT3 and p65 to the proximal promotor of CDK4 after IL10/CpG treatment. Therefore, the observed synergism of IL10R and TLR9 signalling was able to induce proliferation in a comparable way as aberrant MYC and might play a role in B cell homeostasis or transformation.

The Health Assessment Longitudinal File imperative: foundation for improving the health of the force.

A smaller active duty force and an increased operational tempo have made the Reserve components (RC) essential elements in the accomplishment of the mission of the U.S. Army. One critical factor in meeting mission is maintaining the optimal health of each soldier. Baseline health data about the RC is currently not being collected, even though increasing numbers of reserve soldiers are being activated. The Annual Health Certification and Survey is being developed as a way to meet the RCs' statutory requirement for annual certification of health while at the same time generating and tracking baseline data on each reservist in a longitudinal health file, the Health Assessment Longitudinal File. This article discusses the Annual Health Certification Questionnaire/Health Assessment Longitudinal File, which will greatly enhance the Army's ability to accurately certify the health status of the RC and track health in relation to training, mission activities, and deployment.

Pain management of older adults after discharge from outpatient surgery.

Older adults manage their pain at home after outpatient surgery. Yet the experience and management of postoperative pain outside the hospital is largely unknown. The purpose of this study was to examine older adults' experiences of postoperative pain and their methods of pain management after discharge from outpatient surgery. A telephone-based interview of 93 older adults (ages 60-84) showed that pain intensity reached a level of 5 (0 to 10 scale) for 66% of participants on the first morning and for 42% on the third evening after discharge. Pain interfered with activities for almost one-fourth of the participants. Reasons for high pain intensity scores included improper and inadequate dosage of pain medication. More than half of the participants chose to take only one pain tablet at a time and 66% waited until their pain intensity reached a rating of 5 or above before taking their analgesic medication. The participants who took pain medications at higher levels of pain intensity reported taking larger amounts of medication but receiving less pain relief. This finding substantiates the idea that it takes a larger dose of pain medication to decrease severe pain. Pain management instructions did not make a difference in the way pain was managed. Overall, findings indicate that older postoperative patients are not adequately medicating themselves for pain after discharge. Furthermore, when participants were asked, "From this list of nonpharmacologic activities, which activities helped relieve pain?" the most frequently selected answer was "to stay still or not move." This finding requires further investigation to determine if older adults are using immobility as a way to control their pain.