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Background This study examined the strength, shape and direction of associations of accelerometer-assessed overall, school- and non-school-based moderate-to-vigorous physical activity (MVPA) and sedentary time (ST) with BMI among adolescents across the world. Second, we examined whether these associations differed by study site and sex. Methods Cross-sectional data from the IPEN Adolescent study, an observational multi-country study, were used. Participants wore an accelerometer for seven days, reported height and weight, and completed a socio-demographic survey. In total, 4852 adolescents (46.6% boys), aged 11–19 years (mean age = 14.6, SD = 1.7 years) were included in the analyses, using generalized additive mixed models. Results Adolescents accumulated on average 41.3 (SD = 22.6) min/day of MVPA and 531.8 (SD = 81.1) min/day of ST, and the prevalence of overweight and obesity was 17.2% (IOTF), but these mean values differed by country. Linear negative associations of accelerometer-based MVPA and ST with standardized BMI scores and the likelihood of being overweight/obese were found. School-based ST and non-school-based MVPA were more strongly negatively associated to the outcomes than non-school based ST and school-based MVPA. Study site moderated the associations; adolescent sex did not. No curvilinear associations were found. Conclusions This multi-country study confirmed the importance of MVPA as a potential protective factor against overweight/obesity in adolescents. Non-school-based MVPA seemed to be the main driver of these associations. Unexpected results were found for ST, calling for further examination in methodologically sound international studies but using inclinometers or pressure sensors to provide more precise ST measures.

MyoD inhibits cell proliferation and promotes muscle differentiation. A paradoxical feature of rhabdomyosarcoma (RMS), a tumor arising from muscle precursors, is the block of the differentiation program and the deregulated proliferation despite MyoD expression. A deficiency in RMS of a factor required for MyoD activity has been implicated by previous studies. We report here that p38 MAP kinase (MAPK) activation, which is essential for muscle differentiation, is deficient in RMS cells. Enforced induction of p38 MAPK by an activated MAPK kinase 6 (MKK6EE) restored MyoD function and enhanced MEF2 activity in RMS deficient for p38 MAPK activation, leading to growth arrest and terminal differentiation. Stress and cytokines could activate the p38 MAPK in RMS cells, however, these stimuli did not promote differentiation, possibly because they activated p38 MAPK only transiently and they also activated JNK, which could antagonize differentiation. Thus, the selective and sustained p38 MAPK activation, which is distinct from the stress-activated response, is required for differentiation and can be disrupted in human tumors.

In activated macrophages, the anti-inflammatory cytokine IL-10 inhibits expression of molecules that propagate inflammation in a manner that depends on transcription factor STAT3. Expression of IL-10 is regulated posttranscriptionally by the RNA-binding protein tristetraprolin (TTP), which destabilizes IL-10 mRNA in activated macrophages. Using LPS-activated bone marrow-derived murine macrophages, we demonstrate that TTP is a negative regulator of the IL-10/STAT3 anti-inflammatory response. LPS-stimulated TTP-deficient macrophages overproduced IL-10, contained increased amounts of activated STAT3, and showed reduced expression of inflammatory cytokines, including cytokines encoded by TTP target mRNAs. Thus, in LPS-stimulated TTP-deficient macrophages, increased IL-10/STAT3 anti-inflammatory control was dominant over the mRNA stabilization of specific TTP targets. The TTP gene promoter contains a conserved STAT3 binding site, and IL-10 induces STAT3 recruitment to this site. Correspondingly, STAT3 was required for efficient IL-10-induced TTP expression. Hence, by inducing TTP expression, STAT3 activates a negative regulatory loop that controls the IL-10/STAT3 anti-inflammatory response.

Hanoteau A, Newton JM, Krupar R, et al . Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy. J Immunother Cancer 2019;7:10. doi: 10.1186/s40425-018-0485-9. Since the online publication of this article, the authors have noticed that the funding acknowledgement is

Exposure of mammalian cells to radiation triggers the ultraviolet (UV) response, which includes activation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B). This was postulated to occur by induction of a nuclear signaling cascade by damaged DNA. Recently, induction of AP-1 by UV was shown to be mediated by a pathway involving Src tyrosine kinases and the Ha-Ras small guanosine triphosphate-binding protein, proteins located at the plasma membrane. It is demonstrated here that the same pathway mediates induction of NF-kappa B by UV. Because inactive NF-kappa B is stored in the cytosol, analysis of its activation directly tests the involvement of a nuclear-initiated signaling cascade. Enucleated cells are fully responsive to UV both in NF-kappa B induction and in activation of another key signaling event. Therefore, the UV response does not require a signal generated in the nucleus and is likely to be initiated at or near the plasma membrane.

Background. A sustainable pattern of participation in physical activity is important in the maintenance of health and prevention of disease. College students are in transition from an active youth to a more sedentary adult behavior pattern. Methods. We assessed self-reported physical activity and other characteristics in a sample of 2,729 male and female students (median age was 20 years) recruited from representative courses and year levels at four Australian College campuses. They were categorized as sufficiently or insufficiently active, using estimates of energy expenditure (kcal/week) derived from self-reported physical activity. Personal factors (self-efficacy, job status, enjoyment), social factors (social support from family/friends), and environmental factors (awareness of facilities, gym membership) were also assessed. Results. Forty-seven percent of females and 32% of males were insufficiently active. For females, the significant independent predictors of being insufficiently active were lower social support from family and friends, lower enjoyment of activity, and not working. For males, predictors were lower social support from family and friends, lower enjoyment of activity, and being older. Conclusions. Factors associated with physical activity participation (particularly social support from family and friends) can inform physical activity strategies directed at young adults in the college setting.

Abstract The B cell-activating factor of the tumor necrosis factor family (BAFF) is a potent B-cell survival factor. We recently found that nurselike cells, which presumably reside in the leukemia-microenvironment, express BAFF, which promotes survival of leukemia cells of patients with chronic lymphocytic leukemia (CLL) cells through activation of the classical NF-kB pathway. To study the influence of BAFF on leukemogenesis, we crossed BAFF transgenic (Tg) mice with either Eμ-TCL-Tg mice, which develop a lymphoproliferative disease resembling human CLL at about 12 months of age, or Ea-MYC-Tg mice, which experience higher rates of apoptosis in their mature B cells, but do not develop overt lymphoproliferative disease per se. We found that BAFF/TCL1-Tg mice had a shorter mean survival than either TCL1-Tg or BAFF-Tg mice due to the early development of a CD5+CD3−CD45Rlo leukemia B-cell population resembling human CLL at the age of about 3–4 months as compared to 7–9 months in TCL1-Tg mice. In contrast none of the BAFF-Tg or wt mice developed lymphoproliferative disease over the 26-month period of observation. The CD5+CD3−CD45Rlo cell population increased in BAFF/TCL1-Tg mice relatively rapidly, coming to represent >99% of the total blood mononuclear cells of 9-month-old double Tg animals. At this age, these mice also developed massive splenomegaly and their spleens were heavily infiltrated with leukemia B cells. Southern blot analyses of splenocytes harvested at various ages detected oligoclonal/monoclonal splenic B cell populations at approximately 4 months of age in the BAFF/TCL1-Tg mice compared to 9–12 months in the TCL1-Tg mice. Similarly, Ea-MYC-Tg mice, generated by inserting a single copy of MYC into the mouse Ig heavy-chain Ca locus, were crossed with the BAFF-Tg mice in order to obtain BAFF/MYC-Tg mice. In contrast to Ea-MYC-Tg mice, the BAFF/MYC-Tg mice developed expansions of CD5+CD3−CD45Rlo CLL-like leukemia B cells in the blood and spleen starting at 4 months of age, resulting in splenomegaly. These cells could be adoptively transferred into syngeneic BAFF-Tg mice, allowing for continued proliferation of such CD5+CD3−CD45Rlo leukemia B-cells and development lymphoproliferative disease. Staining of splenic sections for proliferating-cell nuclear antigen (PCNA) demonstrated similar high-rates of cell-proliferation in Ea-MYC-Tg mice and BAFF/MYC-Tg mice, which were twice greater than those of BAFF-Tg mice or wt mice. In contrast, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) of splenic sections revealed that Ea-MYC-Tg mice had 4 times greater proportions of apoptotic splenocytes than did BAFF/MYC-Tg mice, suggesting that BAFF promoted B cell expansion by inhibiting B cell turnover. Consistent with this, we found that BAFF induced in TCL1-Tg, as well as MYC-Tg mice, high-level B cell expression of anti-apoptotic proteins such as Bcl-XL, Bcl-2, A1/Bfl1, and Pim-2 in leukemia B cells. Also, these leukemia B cells transferred more efficiently into syngeneic BAFF-Tg mice than in mice lacking expression of BAFF. We treated BAFF-Tg mice with intraperitoneal (i.p.) injections of BAFF-neutralizing BR3-Fc or control protein prior to adoptive transfer of leukemia cells of Eμ-TCL1-Tg mice. We found that i.p. injection of 200 mg BR3-Fc into the recipient animals reduced the numbers of circulating CLL cells relative to that found in control-treated mice by nearly 20% (18.2%±5.3%; n=3) within 6 days. These findings indicate that BAFF accelerates development of leukemia in Eμ-TCL1-Tg and Ea-MYC-Tg mice primarily by enhancing leukemia B-cell survival, but not leukemia-cell proliferation, resulting in accelerated rates of tumor development and apparent enhancement of leukemia B cell proliferation in vivo. These findings suggest that targeting BAFF or BAFF-expressing cells within the leukemia microenvironment might be an effective strategy for treatment of CLL and related B-cell malignancies.

Collectively, our findings demonstrate that SOAT1 participates in HCG by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53-deficient HCC.