Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course.

Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as "functional" prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients

Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL.

NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface receptors, which include several members of the TNF/TNF receptor family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors

Sports Participation in Youth with Inflammatory Bowel Diseases: The Role of Disease Activity and Subjective Physical Health Symptoms

Background: Physical activity is important for youth with inflammatory bowel diseases (IBD), and sports participation is a common way in which youth are physically active. Yet, studies examining sports participation in youth with IBD and barriers to sports participation are lacking. This study examined the role of disease complications, body mass index (BMI), subjective physical health, and psychosocial functioning in influencing sports participation in a large sample of youth with IBD participating in the Crohn's and Colitis Foundation of America Partners (CCFA Partners) Kids and Teens Registry. Methods: CCFA Partners Kids and Teens is an internet-based cohort study in which participants and their parents self-report demographics, disease characteristics, anthropometrics, and validated assessments of physical health, psychosocial functioning, and perceived impairment in sports participation. We performed a cross-sectional analysis of 450 cohort participants, age 12-17 years. Results: Nearly two-thirds of the sample reported that their IBD resulted in some impairment in sports participation. IBD disease activity was associated with perceived impairment in sports participation. In a forward regression analysis controlling for disease activity, fatigue, pain, and past IBD-related surgery emerged as the most salient correlates of impairment in sports participation. Conclusions: Disease activity and subjective physical health symptoms were the most salient correlates of impairment in sports participation. Whether these barriers interfere with physical activity more generally deserves further study, as does replication of these findings longitudinally. Ultimately, a greater understanding of potential barriers to sports participation may be useful for generating targeted physical activity recommendations for youth with IBD

Backward pion-nucleon scattering

A global analysis of the world data on differential cross sections and polarization asymmetries of backward pion-nucleon scattering for invariant collision energies above 3 GeV is performed in a Regge model. Including the $N_\alpha$, $N_\gamma$, $\Delta_\delta$ and $\Delta_\beta$ trajectories, we reproduce both angular distributions and polarization data for small values of the Mandelstam variable $u$, in contrast to previous analyses. The model amplitude is used to obtain evidence for baryon resonances with mass below 3 GeV. Our analysis suggests a $G_{39}$ resonance with a mass of 2.83 GeV as member of the $\Delta_{\beta}$ trajectory from the corresponding Chew-Frautschi plot.Comment: 12 pages, 16 figure

The effects of probiotics administration on the gut microbiome in adolescents with anorexia nervosa—A study protocol for a longitudinal, double-blind, randomized, placebo-controlled trial

Objective Knowledge on gut?brain interaction might help to develop new therapies for patients with anorexia nervosa (AN), as severe starvation-induced changes of the microbiome (MI) do not normalise with weight gain. We examine the effects of probiotics supplementation on the gut MI in patients with AN. Method This is a study protocol for a two-centre double-blind randomized-controlled trial comparing the clinical efficacy of multistrain probiotic administration in addition to treatment-as-usual compared to placebo in 60 patients with AN (13?19 years). Moreover, 60 sex- and age-matched healthy controls are included in order to record development-related changes. Assessments are conducted at baseline, discharge, 6 and 12 months after baseline. Assessments include measures of body mass index, psychopathology (including eating-disorder-related psychopathology, depression and anxiety), neuropsychological measures, serum and stool analyses. We hypothesise that probiotic administration will have positive effects on the gut microbiota and the treatment of AN by improvement of weight gain, gastrointestinal complaints and psychopathology, and reduction of inflammatory processes compared to placebo. Conclusions If probiotics could help to normalise the MI composition, reduce inflammation and gastrointestinal discomfort and increase body weight, its administration would be a readily applicable additional component of multi-modal AN treatment

Methodology and Implementation of a Randomized Controlled Trial (RCT) for Early Post-concussion Rehabilitation: The Active Rehab Study

Background: Sports-related concussion (SRC) is a complex injury with heterogeneous presentation and management. There are few studies that provide guidance on the most effective and feasible strategies for recovery and return to sports participation. Furthermore, there have been no randomized studies of the feasibility, safety, and efficacy of early rehabilitation strategies across multiple sports and age groups. This international cluster-randomized pragmatic trial evaluates the effectiveness of early multi-dimensional rehabilitation integrated with the current return to sport strategy vs. the current return to sport strategy alone. Methods: The study is a cluster-randomized pragmatic trial enrolling male and female athletes from 28 sites. The sites span three countries, and include multiple sports, levels of play (high school, college, and professional), and levels of contact. The two study arms are Enhanced Graded Exertion (EGE) and Multidimensional Rehabilitation (MDR). The EGE arm follows the current return to sport strategy and the MDR arm integrates early, MDR strategies in the context of the current return to sport strategy. Each arm employs a post-injury protocol that applies to all athletes from that site in the event they sustain a concussion during their study enrollment. Participants are enrolled at pre-season baseline. Assessment timepoints include pre-season baseline, time of injury (concussion), 24–48 h post-injury, asymptomatic, and 1-month post-injury. Symptoms and activity levels are tracked post injury through the return to play process and beyond. Injury and recovery characteristics are obtained for all participants. Primary endpoints include time to medical clearance for full return to sport and time to become asymptomatic. Secondary endpoints include symptom, neurocognitive, mental status, balance, convergence insufficiency, psychological distress, and quality of life trajectories post-injury. Discussion: Outputs from the trial are expected to inform both research and clinical practice in post-concussion rehabilitation across all levels of sport and extend beyond civilian medicine to care for military personnel. Ethics and Dissemination: The study is approved by the data coordinating center Institutional Review Board and registered at clinicaltrials.gov. Dissemination will include peer-reviewed publications, presentation to patients and public groups, as well as dissemination in other healthcare and public venues of interest. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02988596 Trial Funding: National Football League

Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics

Published: April 13, 2023With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.Madeline G. Dans, Henni Piirainen, William Nguyen, Sachin Khurana, Somya Mehra, Zahra Razook, Niall D. Geoghegan, Aurelie T. Dawson, Sujaan Das, Molly Parkyn Schneider, Thorey K. Jonsdottir, Mikha Gabriela, Maria R. Gancheva, Christopher J. Tonkin, Vanessa Mollard, Christopher Dean Goodman, Geoffrey I. McFadden, Danny W. Wilson, Kelly L. Rogers, Alyssa E. Barry, Brendan S. Crabb, Tania F. de Koning-Ward, Brad E. Sleebs, Inari Kursula, Paul R. Gilso

Defects and rescue of the minor salivary glands in Eda pathway mutants

AbstractDespite their importance to oral health, the mechanisms of minor salivary gland (SG) development are largely unexplored. Here we present in vivo and in vitro analyses of developing minor SGs in wild type and mutant mice. Eda, Shh and Fgf signalling pathway genes are expressed in these glands from an early stage of development. Developing minor SGs are absent in Eda pathway mutant embryos, and these mice exhibit a dysplastic circumvallate papilla with disrupted Shh expression. Supplementation of Eda pathway mutant minor SG explants with recombinant EDA rescues minor SG induction. Supplementation with Fgf8 or Shh, previously reported targets of Eda signalling, leads to induction of gland like structures in a few cases, but these fail to develop into minor SGs