Promyelocytic leukemia protein in mesenchymal stem cells is essential for leukemia progression

The dynamic interactions between leukemic cells and cells resident within the bone marrow microenvironment are vital for leukemia progression. The lack of detailed knowledge about the cellular and molecular mechanisms involved in this cross-talk restricts the design of effective treatments. Guarnerio et al. (2018) by using state-of-the-art techniques, including sophisticated Cre/loxP technologies in combination with leukemia mouse models, reveal that mesenchymal stem cells via promyelocytic leukemia protein (Pml) maintain leukemic cells in the bone marrow niche. Strikingly, genetic deletion of Pml in mesenchymal stem cells raised survival of leukemic mice under chemotherapeutic treatment. The emerging knowledge from this research provides a novel target in the bone marrow niche for therapeutic benefit in leukemia.     

Stimulation of collagenase 3 expression in synovial fibroblasts of patients with rheumatoid arthritis by contact with a three-dimensional collagen matrix or with normal cartilage when coimplanted in NOD/SCID mice

OBJECTIVE: To study the expression of collagenase 3 (matrix metalloproteinase 13 [MMP-13]) and collagenase 1 (MMP-1) in synovial fibroblasts from patients with rheumatoid arthritis (RA) when cultured within 3-dimensional collagen gels or coimplanted with normal cartilage in immunodeficient NOD/SCID mice. METHODS: Messenger RNA (mRNA) and protein expression of collagenase 3 and collagenase 1 were characterized in synovial and skin fibroblasts by Northern blot and Western blot analysis. The mRNA expression of both collagenases in cell-cartilage implants in NOD/SCID mice was investigated by in situ hybridization in combination with immunohistochemistry of human fibroblasts. RESULTS: Synovial fibroblasts coimplanted with normal cartilage in NOD/SCID mice deeply invaded adjacent cartilage tissue. In this in vivo system of cartilage destruction, collagenase 3 mRNA was induced in synovial fibroblasts at sites of cartilage erosion, while the expression of collagenase 1 mRNA could not be detected. Culture of synovial fibroblasts within 3-dimensional collagen gels was associated with a marked increase in collagenase 3 mRNA expression and proenzyme production. This stimulatory effect was 1 order of magnitude higher in comparison with a 2-4-fold increase upon treatment with interleukin-1beta or tumor necrosis factor a. In contrast, mRNA expression and proenzyme production of collagenase 1 were increased strongly, and to a similar extent, either by contact with 3-dimensional collagen or by proinflammatory cytokines. CONCLUSION: The expression of collagenase 3, in contrast to that of collagenase 1, is preferentially stimulated in synovial fibroblasts by 3-dimensional collagen rather than by proinflammatory cytokines. The induction of collagenase 3 by cell-matrix interactions represents a potential mechanism contributing to the invasive phenotype of synovial fibroblasts at sites of synovial invasion into cartilage in RA.     

Additive effects of simulated climate changes,elevated CO2, and nitrogen deposition on grassland diversity

Biodiversity responses to ongoing climate and atmospheric changes will affect both ecosystem processes and the delivery of ecosystem goods and services. Combined effects of co-occurring global changes on diversity, however, are poorly understood. We examined plant diversity responses in a California annual grassland to manipulations of four global environmental changes, singly and in combination: elevated CO2, warming, precipitation, and nitrogen deposition. After 3 years, elevated CO2 and nitrogen deposition each reduced plant diversity, whereas elevated precipitation increased it and warming had no significant effect. Diversity responses to both single and combined global change treatments were driven overwhelmingly by gains and losses of forb species, which make up most of the native plant diversity in California grasslands. Diversity responses across treatments also showed no consistent relationship to net primary production responses, illustrating that the diversity effects of these environmental changes could not be explained simply by changes in productivity. In two- to four-way combinations, simulated global changes did not interact in any of their effects on diversity. Our results show that climate and atmospheric changes can rapidly alter biological diversity, with combined effects that, at least in some settings, are simple, additive combinations of single-factor effects.     

Prevalence and reliability of treatment-based classification for subgrouping patients with low back pain

Objectives: To observe the distribution of patients who presented with low back pain (LBP) and to determine the between therapists’ interrater reliability of assessments in a private outpatient setting using treatment-based classification (TBC) subgroups.

Methods: An observational and methodological study was conducted. Four hundred and twenty-nine patients (231 male; 198 female) presenting LBP symptoms and referred to conservative treatment were assessed by 13 physical therapists who conducted a 60-min examination process utilizing TBC subgroups. Interrater reliability analyses from six raters were assessed using Fleiss’ kappa and previously recorded data (n = 30).

Results: In this study, 65.74% of patients were classified in only one subgroup, the most prevalent being stabilization (21.91%), followed by extension (15.38%), traction (11.89%), flexion (10.96%), manipulation (5.13%), and lateral shift (0.47%). Approximately 20.98% of patients were classified in two subgroups, where the most frequent overlaps were flexion + stabilization (7.46%), extension + stabilization (6.06%), flexion + traction (4.20%), extension + manipulation (1.86%), and 13.29% of patients were not classified in any TBC subgroup. Analysis of interrater reliability showed a kappa value of 0.62 and an overall agreement of 66% between raters.

Discussion: LBP is a heterogeneous clinical condition and several classification methods are proposed in the attempt to observe better outcomes for patients. Eighty-five percent of patients assessed were able to be classified when using the TBC assessment and reliability analysis showed a substantial agreement between raters.

Level of Evidence: 2c.     

Health Policy,Ethics, and the Kansas Legislative Health Academy

We describe a unique program, the Kansas Legislative Health Academy, that brings together state legislators from across the political spectrum to build their capacity in advancing policies that can improve the health of Kansans.To that end, the academy helps legislators develop new skills to deliberate the ethics of health policy, use systems thinking to understand the long- and short-term effects of policy action and inaction, and engage in acts of civic leadership. The academy also seeks to foster an environment of respectful open dialogue and to build new cross-chamber and cross-party relationships.Among the most important outcomes cited by program participants is the value of sustained, personal interaction and problem solving with individuals holding differing political views.Health policy often elicits controversy. Recent examples include the uproar over recommendations for mammography screening for women 40 to 49 years old and human papillomavirus vaccination for adolescent girls and boys. Perhaps the most dramatic controversy relates to the passage of the Patient Protection and Affordable Care Act (Pub L No. 111-148); despite being signed into law in 2010 and found substantially constitutional by the US Supreme Court in 2012 (Medicaid expansion was made optional for states), this legislation remains subject to vigorous dissent. Such controversies, although no doubt a function of interest-driven politics, also reflect deep differences in ethical values.Ethical values and premises underpin all public policy.1,2 Ideas about individual liberty, personal responsibility, solidarity, justice, and the role of the government are just a few of the moral constructs that often clash in the making of policy. Policy analysis often ignores these dimensions of policy-making, although that is beginning to change.3–5Here we describe a project based in part on the premise that training policymakers to recognize and talk openly about the ethical values entailed in health policy might improve its content and process. This project, the Kansas Legislative Health Academy (hereafter Health Academy), brought together state legislators from across the political spectrum to build their capacity to respond to complex health policy challenges in Kansas. To that end, the curriculum sought to help legislators develop new skills in 3 areas: health policy ethics, systems thinking, and civic leadership. The Health Academy also sought to foster an environment of open, respectful dialogue and to build new cross-chamber and cross-party relationships.To our knowledge, the Health Academy is a unique program. Many educational programs exist for legislators to focus on leadership development or specific health policy issues, but none we are aware of are specifically designed to cover a broad range of health policy issues while also addressing underlying barriers to effective policy-making within legislative bodies. In what follows, we describe the Health Academy’s origins, structure, substance, and lessons learned.