Pre-emptive detection and evolution of relapse in acute myeloid leukemia by flow cytometric measurable residual disease surveillance.

Measurable residual disease (MRD) surveillance in acute myeloid leukemia (AML) may identify patients destined for relapse and thus provide the option of pre-emptive therapy to improve their outcome. Whilst flow cytometric MRD (Flow-MRD) can be applied to high-risk AML/ myelodysplasia patients, its diagnostic performance for detecting impending relapse is unknown. We evaluated this in a cohort comprising 136 true positives (bone marrows preceding relapse by a median of 2.45 months) and 155 true negatives (bone marrows during sustained remission). At an optimal Flow-MRD threshold of 0.040%, clinical sensitivity and specificity for relapse was 74% and 87% respectively (51% and 98% for Flow-MRD ≥ 0.1%) by 'different-from-normal' analysis. Median relapse kinetics were 0.78 log10/month but significantly higher at 0.92 log10/month for FLT3-mutated AML. Computational (unsupervised) Flow-MRD (C-Flow-MRD) generated optimal MRD thresholds of 0.036% and 0.082% with equivalent clinical sensitivity to standard analysis. C-Flow-MRD-identified aberrancies in HLADRlow or CD34+CD38low (LSC-type) subpopulations contributed the greatest clinical accuracy (56% sensitivity, 90% specificity) and notably, by longitudinal profiling expanded rapidly within blasts in > 40% of 86 paired MRD and relapse samples. In conclusion, flow MRD surveillance can detect MRD relapse in high risk AML and its evaluation may be enhanced by computational analysis.

Short life fission products extracted from molten salt reactor fuel for radiopharmaceutical applications.

This work studies the potential of using short life fission product (AFp) radioisotopes e.g. 82Br, 86Rb, (90Sr) - 90mY, (99Mo) - 99mTc, 103Ru - 103mRh, 111Ag, 127Sb - 127(m)Te, 126I, 131I, 133Xe, 136Cs, 141Ce, 143Ce, 143Pr, 147Nd - 147Pm, 149Pm, 153Sm, 156Eu, 159Gd and 161Tb, extracted from a molten salt reactor and their separation using specific thermodynamic and radiochemical conditions. Their utilisation for coupled radiodiagnostics and radiotherapy is a key consideration. A molten salt reactor produces fission products during operation. These radioisotopes can be separated at line from the liquid fuel by evaporation/distillation, chemical reduction (using H2 doped gas), electro-deposition and/or chemical oxidation (using Cl2 doped gas). They can be refined and chemically treated for radiopharmaceutical use for imaging and radiodiagnostics utilising γ radioscopy or positron emission tomography, and potentially in radiotherapy to target specific cancers or viral diseases using ß- emitters. Some of the AFp isotopes are currently used for radiodiagnostics because they emit γ rays of energy 50-200 keV. However, some may also be used in parallel for radiotherapy utilising their ß- (EMean ≈ 100 keV) emission whose mean free pathway of c.a. 100 nm in biological tissue is much smaller than their penetration depth. Focus is given to 86Rb, 90Y, 99mTc, 131I and 133Xe as well as on the ALn isotopes (141Ce, 143Ce - 143Pr, 147Nd - 147Pm, 149Pm and 153Sm) because of their strong potential for complexation with bio-ligands (e.g. DOTA) or for their ability to form micro-nano-spheres, and because of their potential for dual radiodiagnostics and radiotherapy. It is shown that these radio-lanthanides could also replace 177Lu for the treatment of specific cancers.

Pathways to lung cancer diagnosis among individuals who did not receive lung cancer screening: a qualitative study.

BACKGROUND: Although early detection of lung cancer through screening is associated with better prognosis, most lung cancers are diagnosed among unscreened individuals. We therefore sought to characterize pathways to lung cancer diagnosis among unscreened individuals. METHODS: Participants were individuals with lung cancer who did not undergo asymptomatic lung cancer screening (n = 13) and healthcare providers who may be involved in the pathway to lung cancer diagnosis (n = 13). We conducted semi-structured interviews to identify themes in lung cancer patients' narratives of their cancer diagnoses and providers' personal and/or professional experiences of various pathways to lung cancer diagnoses, to identify delays in diagnosis. We audio-recorded, transcribed, and coded interviews in two stages. First, we conducted deductive coding using three time-period intervals from the Models of Pathways to Treatment framework: appraisal, help-seeking, and diagnostic (i.e., excluding pre-treatment). Second, we conducted inductive coding to identify themes within each time-period interval, and classified these themes as either barriers or facilitators to diagnosis. Coding and thematic summarization were completed independently by two separate analysts who discussed for consensus. RESULTS: Eight of the patient participants had formerly smoked, and five had never smoked. We identified eight barrier/facilitator themes within the three time-period intervals. Within the appraisal interval, the barrier theme was (1) minimization or misattribution of symptoms, and the facilitator theme was (2) acknowledgment of symptoms. Within the help-seeking interval, the barrier theme was (3) hesitancy to seek care, and the facilitator theme was (4) routine care. Within the diagnosis interval, barrier themes were (5) health system challenges, and (6) social determinants of health; and facilitator themes were (7) severe symptoms and known risk factors, and (8) self-advocacy. Many themes were interrelated, including minimization or misattribution of symptoms and hesitancy to seek care, which may collectively contribute to care and imaging delays. CONCLUSIONS: Interventions to reduce hesitancy to seek care may facilitate timely lung cancer diagnoses. More prompt referral to imaging-especially computed tomography (CT)-among symptomatic patients, along with patient self-advocacy for imaging, may reduce delays in diagnosis.

Rubella virus-associated necrotizing granulomatous inflammation with extensive eyelid, ocular, and orbital involvement.

We present a case of cutaneous granulomatous disease associated with rubella virus in a 4-year-old girl without an identifiable immunodeficiency. In this case, a combination of anti-inflammatory, anti-viral, and anti-neutrophil therapies successfully treated vision-threatening eyelid, conjunctival, scleral, and orbital inflammation.

Pathways to ovarian cancer diagnosis: a qualitative study.

BACKGROUND: Ovarian cancer is often diagnosed at a late stage, when survival is poor. Qualitative narratives of patients' pathways to ovarian cancer diagnoses may identify opportunities for earlier cancer detection and, consequently, earlier stage at diagnosis. METHODS: We conducted semi-structured interviews of ovarian cancer patients and survivors (n = 14) and healthcare providers (n = 11) between 10/2019 and 10/2021. Interviews focused on the time leading up to an ovarian cancer diagnosis. Thematic analysis was conducted by two independent reviewers using a two-phase deductive and inductive coding approach. Deductive coding used a priori time intervals from the validated Model of Pathways to Treatment (MPT), including self-appraisal and management of symptoms, medical help-seeking, diagnosis, and pre-treatment. Inductive coding identified common themes within each stage of the MPT across patient and provider interviews. RESULTS: The median age at ovarian cancer diagnosis was 61.5 years (range, 29-78 years), and the majority of participants (11/14) were diagnosed with advanced-stage disease. The median time from first symptom to initiation of treatment was 2.8 months (range, 19 days to 4.7 years). The appraisal and help-seeking intervals contributed the greatest delays in time-to-diagnosis for ovarian cancer. Nonspecific symptoms, perceptions of health and aging, avoidant coping strategies, symptom embarrassment, and concerns about potential judgment from providers prolonged the appraisal and help-seeking intervals. Patients and providers also emphasized access to care, including financial access, as critical to a timely diagnosis. CONCLUSION: Interventions are urgently needed to reduce ovarian cancer morbidity and mortality. Population-level screening remains unlikely to improve ovarian cancer survival, but findings from our study suggest that developing interventions to improve self-appraisal of symptoms and reduce barriers to help-seeking could reduce time-to-diagnosis for ovarian cancer. Affordability of care and insurance may be particularly important for ovarian cancer patients diagnosed in the United States.

Women with Rheumatoid Arthritis have similar rates of postpartum maternal outcomes compared to women without autoimmune disease.

OBJECTIVE: Limited data exist on the effect of rheumatoid arthritis (RA) on maternal postpartum outcomes. Using a real-world, electronic health record (EHR) cohort, we assessed maternal postpartum outcomes in RA. METHODS: In a large, de-identified EHR, we identified possible RA deliveries using ≥1 delivery ICD-9 or ICD-10-CM codes and a validated RA algorithm. RA cases were required to be diagnosed by a rheumatologist on chart review. Maternal postpartum outcomes included rates of blood transfusion, rates of infection up to 6 weeks postpartum defined by a clinician, and length of hospital stay. We also identified deliveries to women without autoimmune diseases. RESULTS: We identified 202 deliveries occurring after RA diagnosis and 596 deliveries to controls without autoimmune diseases. Postpartum infection rates were similar among RA patients and controls (8% vs. 4%, p = 0.10), as were red blood cell transfusion rates (2% vs. 2%, p = 1.00). RA case status was not significantly associated with postpartum infection (OR = 2.10, 95% CI 0.88 - 4.98, p = 0.09) but was significantly associated with preterm birth (OR = 2.11, 95% CI 1.38 - 3.23, p = 0.001). Corticosteroid use during pregnancy was common at 41%, while tumor necrosis factor inhibitor use was 13%. After adjusting for age at delivery and race, corticosteroid use at delivery was not associated with postpartum maternal infections but was associated with a significantly lower birthweight in RA cases. CONCLUSION: Women with RA have an increased risk of adverse pregnancy outcomes, particularly preterm birth. Our study highlights, however, that maternal postpartum outcomes such as postpartum infection and blood transfusion are not significantly increased in RA patients.

Emerging immune checkpoint inhibitors for the treatment of head and neck cancers.

Introduction: The benefits of immune checkpoint inhibitors (ICIs) in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have been demonstrated through multiple studies to improve overall survival (OS) with decreased side effects when compared to the standard of care (SOC) treatment regimens in place for decades, leading to the approval of two ICIs, nivolumab and pembrolizumab. There has been a subsequent influx in the development of novel immunotherapy agents for the treatment of HNSCC. Areas covered: Data for anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies in treatment of R/M HNSCC will be reviewed. Emerging immune checkpoint inhibitors as well as combined therapies in HNSCC will be discussed. The role of predictive biomarkers, HPV-status, PD-L1 expression, and challenges related to treating patients with ICIs will be summarized. Expert opinion: A shift toward ICIs as SOC for the treatment of R/M HNSCC will continue as emerging immune checkpoints and combination therapies are evaluated. Response rates are variable in this patient population underlying the importance of identifying predictive biomarkers to aid in patient selection for ICI treatment.

Addressing Healthcare Professional Burnout: A Quality Improvement Intervention.

BACKGROUND: Burnout is a substantial phenomenon across healthcare settings, affecting more than half of healthcare professionals and leading to negative patient and health system outcomes. Infusion center professionals (ICPs) are at increased risk of burnout attributed to high patient volume and acuity levels. Strategies to address burnout have been developed and prioritized by the American Medical Association (AMA), the World Health Organization, and other organizations. AIMS: This quality improvement project aimed to address perceived burnout, job-related stress, and job satisfaction among nurses, physician assistants, and medical assistants at a large pediatric hospital through integration of two infusion center (IC)-based staff engagement interventions. METHODS: A pre- and post-test study design was used. Existing team huddles in the IC were modified based on the AMA STEPS Forward program recommendations to incorporate appreciative inquiry and recognition into team and department events. Peer recognition was tailored toward institutional core values. The Mini-Z Burnout survey was administered before and 3 months after implementation of both interventions. FINDINGS: Pre- to post-intervention responses revealed a higher percentage of staff reporting no burnout (57.7% vs. 75%), low levels of job-related stress (58.8% vs. 65.5%), and satisfaction with current job (70.6% vs. 82.8%). Most participants agreed or strongly agreed that structured huddles (69%) and recognition events (82.8%) were beneficial and recommended continuation (65.5% and 82.8%, respectively). Open-ended responses regarding workplace stressors focused heavily on staffing and patient acuity. LINKING EVIDENCE TO ACTION: Project outcomes support the integration of tailored interventions to reduce burnout among pediatric ICPs. Organizational commitment to addressing burnout can provide incentive to scale up institution-wide staff engagement interventions. Further study is needed to assess the efficiency and effectiveness of such tailored interventions across diverse settings.

Lifetime Economic Burden of Crohn's Disease and Ulcerative Colitis by Age at Diagnosis.

BACKGROUND & AIMS: Understanding the burden of Crohn's disease (CD) and ulcerative colitis (UC) is important for measuring treatment value. We estimated lifetime health care costs incurred by patients with CD or UC by age at diagnosis. METHODS: We collected data from 78,620 patients with CD, 85,755 with UC, and propensity score-matched control subjects from the Truven Health MarketScan insurance claims databases (2008‒2015). Total medical (inpatient, outpatient) and pharmacy costs were captured. Cost variations over a lifetime were estimated in cost-state Markov models by age at diagnosis, adjusted to 2016 U.S. dollars and discounted at 3% per annum. We measured lifetime total and lifetime incremental cost (the difference between costs of CD or UC patients vs matched controls). RESULTS: For CD, the lifetime incremental cost was $707,711 among patients who received their diagnosis at 0‒11 years, and $177,614 for patients 70 years or older, averaging $416,352 for a diagnosis at any age. Lifetime total cost was $622,056, consisting of outpatient ($273,056), inpatient ($164,298), pharmacy ($163,722), and emergency room (ER) ($20,979) costs. For UC, the lifetime incremental cost was $369,955 among patients who received their diagnosis at 0‒11 years, and $132,396 for individuals 70 years or older, averaging $230,102 for a diagnosis at any age. Lifetime total cost was $405,496, consisting of outpatient ($163,670), inpatient ($123,190), pharmacy ($105,142), and ER ($13,493) costs. Therefore, the prevalent populations of patients with CD or UC in the United States in 2016 are expected to incur lifetime total costs of $498 billion and $377 billion, respectively. CONCLUSIONS: Using a Markov model, we estimated lifetime costs for patients with CD or UC to exceed previously published estimates. Individuals who receive a diagnosis of CD or UC at an early age (younger than 11 years) incur the highest lifetime cost burden. Advancing management strategies may significantly improve patient outcomes and reduce lifetime health care spending.

Tumour size criteria for Group D and E eyes in the International Classification System for Retinoblastoma: effects on rates of globe salvage and high-risk histopathologic features.

PURPOSE: To determine the significance of large tumour size as a criteria for classifying advanced intraocular retinoblastoma, analysing rates of globe survival and high-risk (HE) histopathologic features. METHODS: Retrospective chart review of 212 eyes diagnosed with Group D (111 eyes) or Group E (101 eyes) retinoblastoma in at least one eye from January 1, 2006 to December 31, 2016 using the Los Angeles (LA) Classification System (no tumour size criteria for Group E). The 111 Group D tumours were then reclassified to Group E using 10, 12, 14, 16, 18 mm tumour size criteria, as determined by ultrasound or magnetic resonance imaging dimensions. RESULTS: For eyes in the original LA classification, 66.7% of Group D and 10.5% of Group E eyes undergoing globe preservation therapy avoided enucleation or radiotherapy (p < 0.0001; median follow-up of 33.0 months). In the LA classification, 8.5% of Group D and 26.3% of Group E enucleated globes had HE histopathologic features (p = 0.0065). When Group D eyes with tumours meeting the size criteria were reclassified to Group E, 65.7-74.4% of Group D and 16.1-36.7% of Group E eyes avoided enucleation or radiotherapy. Applying the tumour size criteria, 0-10.9% of Group D and 20.7-23.8% of Group E eyes had HE histopathologic features. CONCLUSION: Our retrospective analysis suggests that a large tumour size criteria for Group E retinoblastoma have no clinical basis, given that the LA classification system provided the greatest separation in globe salvage rates between Group D and E eyes. The LA classification system was also able to show a statistically significant difference in the rates of HE histopathologic features between Group D and E eyes. To avoid discrepancies in the literature, we recommend that centres use one uniform system for classifying advanced intraocular retinoblastoma.

Putting Evidence Academies into action: Prostate cancer, nutrition, and tobacco control science.

A well-documented challenge in moving public health research into practice is the extended time it takes to implement findings in clinical practice and communities. The Evidence Academy model (Rohweder et al., 2016), developed and first used in North Carolina, is a pragmatic, action-oriented model that aims to shorten this timeline by communicating cutting-edge findings directly to those who can use them and convening individuals working in a single topic area to network and plan activities for the future. The University of Pennsylvania Collaborating Center of the Cancer Prevention and Control Research Network (CPCRN) held three conferences based on the Evidence Academy model: one about prostate cancer in 2015, a second on food access and obesity prevention in 2017, and a third about tobacco control science in 2018. A diverse planning committee of stakeholders helped shape the content, focus,and format of each conference. Local and national experts presented findings to regional audiences of researchers, practitioners, government leaders, and community members. Each Evidence Academy included collaborators and speakers from other Prevention Research Centers (PRCs) and CPCRN network sites. Evaluations and outcomes indicated that the events were successful in achieving their goals and fostered ongoing relationships among attendees. This paper illustrates how the Evidence Academy model was used in a different region and describes lessons learned and follow-up activities that were initiated via the Evidence Academy and with input from participants. Lessons learned may be helpful in developing and evaluating future adaptations of the Evidence Academy model and/or the effectiveness of its components.

The economic burden of switching targeted disease-modifying anti-rheumatic drugs among rheumatoid arthritis patients.

AIMS: To estimate real world healthcare costs and resource utilization of rheumatoid arthritis (RA) patients associated with targeted disease modifying anti-rheumatic drugs (tDMARD) switching in general and switching to abatacept specifically. MATERIALS AND METHODS: RA patients initiating a tDMARD were identified in IMS PharMetrics Plus health insurance claims data (2010-2016), and outcomes measured included monthly healthcare costs per patient (all-cause, RA-related) and resource utilization (inpatient stays, outpatient visits, emergency department [ED] visits). Generalized linear models were used to assess (i) average monthly costs per patient associated with tDMARD switching, and (ii) among switchers only, costs of switching to abatacept vs tumor necrosis factor inhibitors (TNFi) or other non-TNFi. Negative binomial regressions were used to determine incident rate ratios of resource utilization associated with switching to abatacept. RESULTS: Among 11,856 RA patients who initiated a tDMARD, 2,708 switched tDMARDs once and 814 switched twice (to a third tDMARD). Adjusted average monthly costs were higher among patients who switched to a second tDMARD vs non-switchers (all-cause: $4,785 vs $3,491, p < .001; RA-related: $3,364 vs $2,297, p < .001). Monthly RA-related costs were higher for patients switching to a third tDMARD compared to non-switchers remaining on their second tDMARD ($3,835 vs $3,383, p < .001). Switchers to abatacept had significantly lower RA-related monthly costs vs switchers to TNFi ($3,129 vs $3,436, p = .021), and numerically lower all-cause costs ($4,444 vs $4,741, p = 0.188). Switchers to TNFi relative to abatacept had more frequent inpatient stays after switch (incidence rate ratio (IRR) = 1.85, p = .031), and numerically higher ED visits (IRR = 1.32, p = .093). Outpatient visits were less frequent for TNFi switchers (IRR = 0.83, p < .001) compared to switchers to abatacept. LIMITATIONS AND CONCLUSIONS: Switching to another tDMARD was associated with higher healthcare costs. Switching to abatacept, however, was associated with lower RA-related costs, fewer inpatient stays, but more frequent outpatient visits compared to switching to a TNFi.

Interprofessional palliative care education for pediatric oncology clinicians: an evidence-based practice review.

OBJECTIVE: Clinician education and expertise in palliative care varies widely across pediatric oncology programs. The purpose of this evidence-based practice review was to identify interprofessional palliative care education models applicable to pediatric oncology settings as well as methods for evaluating their impact on clinical practice. RESULTS: Based on a literature search in PubMed, CINAHL and Embase, which identified 13 articles meeting inclusion/exclusion criteria, the following three themes emerged: (1) establishment of effective modalities and teaching strategies, (2) development of an interprofessional palliative care curriculum, and (3) program evaluation to assess impact on providers' self-perceived comfort in delivering palliative care and patient/family perceptions of care received. Remarkably, health professionals reported receiving limited palliative care training, with little evidence of systematic evaluation of practice changes following training completion. Improving palliative care delivery was linked to the development and integration of an interprofessional palliative care curriculum. Suggested evaluation strategies included: (1) eliciting patient and family feedback, (2) standardizing care delivery measures, and (3) evaluating outcomes of care.

Lurking below: massive choroidal invasion under a calcified tumor after attempted conservative therapy for retinoblastoma.

BACKGROUND: In the conservative management of retinoblastoma, detection of tumor activity beneath large, calcified tumors presents a challenging aspect of care as local consolidation is limited in this area. Routine imaging modalities, including magnetic resonance imaging, B-scan ultrasound, and optical coherence tomography, are also limited in providing appropriate surveillance for recurrent disease. MATERIALS AND METHODS: Medical records were reviewed to evaluate patients' demographic data, ophthalmic exams, imaging studies, and histopathologic reports. RESULTS: Three patients (two females and one male) were diagnosed with retinoblastoma (two bilateral and one unilateral) and managed with intravenous chemotherapy and local consolidation. In all three cases, the initial tumors regressed to form large, predominantly calcified tumors. However, it was observed that there continued to be nodular recurrences on the surface of the calcium without visible clinical activity at the base of the calcified lesion. All three cases ultimately required enucleation for these active nodular recurrences and massive choroidal invasion was noted under the calcified tumor. Ophthalmic exams and imaging studies did not provide consistent indication of choroidal disease in these cases, and the extensive calcification prevented detection of active disease at the tumor base on fundoscopy. CONCLUSIONS: Active choroidal disease at the base of large, calcified tumors cannot be ruled out with ophthalmologic examination and noninvasive imaging; suspicion of disease activity at the base should remain high for patients presenting with multiple recurrent nodules over a calcified tumor.

Impact of Deprescribing Interventions in Older Hospitalised Patients on Prescribing and Clinical Outcomes: A Systematic Review of Randomised Trials.

BACKGROUND: Polypharmacy and potentially inappropriate medications (PIMs) are prevalent in older adults in hospital, and are associated with negative outcomes including adverse drug reactions, falls, confusion, hospitalisation and death. Deprescribing may reduce inappropriate polypharmacy and use of inappropriate medications. OBJECTIVE: The aim of this systematic review was to investigate the efficacy of deprescribing interventions in older inpatients to reduce PIMs and impact on clinical outcomes. METHODS: Ovid MEDLINE, Embase, Informit, International Pharmaceutical Abstracts, Scopus, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL were searched for randomised controlled trials (RCTs) from 1996 to April 2017. RCTs reporting on deprescribing interventions to reduce PIMs in older hospitalised adults were eligible. Data were extracted, and study quality assessed. The primary outcome was reduction in PIMs. Where available, clinically relevant outcomes were assessed. RESULTS: Nine RCTs (n = 2522 subjects) met the inclusion criteria. Deprescribing interventions were either pharmacist-led (n = 4), physician-led (n = 4) or multidisciplinary team-led (n = 1). Seven of the nine studies reported a statistically significant reduction in PIMs in the intervention group. There was no change in one study where there were zero PIMs on admission and discharge, and in the other study a reduction in PIMs that was not statistically significant was observed. There was significant heterogeneity in outcome measures and reporting. Few studies reported on the impact of deprescribing interventions on clinical outcomes. Reported clinical outcomes included drug-related problems (n = 3), quality of life (n = 2), mortality (n = 3), hospital readmissions (n = 4), falls (n = 3) and functional status (n = 2). Most studies reported a benefit in the intervention group that was not statistically significant. No notable harm was observed in the intervention group. There was a high risk of bias in the included studies. CONCLUSIONS: The evidence available suggests that deprescribing interventions in hospital are feasible, generally effective at reducing PIMs and safe. However, the current evidence is limited, of low quality and the impact on clinical outcomes is unclear.

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation.

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217-30. ©2017 AACR.

Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6.

Macrophage polarization plays a central role in both protective immunity and immunopathology. While the role of cytokines in driving macrophage polarization is well characterized, less is understood about the role of chemokines. The purpose of this study was to determine if CC chemokine 2 (CCL2/MCP1) could influence macrophage polarization in response to subsequent activation with cytokines and microbial products. Treatment of bone marrow-derived macrophages with CCL2 alone did not result in increased expression of either classical or alternatively-activated macrophage genes as compared to standard skewing cytokines or Toll-like receptor agonists. However, subsequent stimulation of CCL2 pre-treated macrophages with classical activation stimuli resulted in enhanced expression of genes associated with classical activation. This enhancement correlated with increased phosphorylation of ERK1/2 kinases, a decrease in expression of the ERK phosphatase Dusp6 and enhanced expression of miR-9. These results indicate that CCL2 supports the classical activation of macrophages, with miR-9 mediated down-regulation of Dusp6 and enhanced ERK-mediated signal transduction possibly mediating this enhanced pro-inflammatory gene expression.