Proton beam therapy with concurrent chemotherapy is feasible in children with newly diagnosed rhabdomyosarcoma

BackgroundThe optimal treatment for rhabdomyosarcoma (RMS) requires multidisciplinary treatment with chemotherapy, surgery, and radiotherapy. Surgery and radiotherapy are integral to the local control (LC) of RMS. However, postsurgical and radiotherapy-related complications could develop according to the local therapy and tumor location. In this study, we conducted a single-center analysis of the outcomes and toxicity of multidisciplinary treatment using proton beam therapy (PBT) for pediatric RMS.Materials and methodsRMS patients aged younger than 20 years whose RMS was newly diagnosed and who underwent PBT at University of Tsukuba Hospital (UTH) during the period from 2009 to 2019 were enrolled in this study. The patients’ clinical information was collected by retrospective medical record review.ResultsForty-eight patients were included. The 3-year progression-free survival (PFS) and overall survival (OS) rates of all the patients were 68.8% and 94.2%, respectively. The 3-year PFS rates achieved with radical resection, conservative resection, and biopsy only were 65.3%, 83.3%, and 67.6%, respectively (p = 0.721). The 3-year LC rates achieved with radical resection, conservative resection, and biopsy only were 90.9%, 83.3%, and 72.9%, respectively (p = 0.548). Grade 3 or higher mucositis/dermatitis occurred in 14 patients. Although the days of opioid use due to mucositis/dermatitis during the chemotherapy with PBT were longer than those during the chemotherapy without PBT [6.1 and 1.6 (mean), respectively, p = 0.001], the frequencies of fever and elevation of C-reactive protein were equivalent.ConclusionsMultidisciplinary therapy containing PBT was feasible and provided a relatively fair 3-year PFS, even in children with newly diagnosed RMS without severe toxicity.     

The gene expression landscape of thermogenic skunk cabbage suggests critical roles for mitochondrial and vacuolar metabolic pathways in the regulation of thermogenesis

Floral thermogenesis has been described in several plant species. Because of the lack of comprehensive gene expression profiles in thermogenic plants, the molecular mechanisms by which floral thermogenesis is regulated remain to be established. We examined the gene expression landscape of skunk cabbage (Symplocarpus renifolius) during thermogenic and post-thermogenic stages and identified expressed sequence tags from different developmental stages of the inflorescences using super serial analysis of gene expression (SuperSAGE). In-depth analysis suggested that cellular respiration and mitochondrial functions are significantly enhanced during the thermogenic stage. In contrast, genes involved in stress responses and protein degradation were significantly up-regulated during post-thermogenic stages. Quantitative comparisons indicated that the expression levels of genes involved in cellular respiration were higher in thermogenic spadices than in Arabidopsis inflorescences. Thermogenesis-associated genes seemed to be expressed abundantly in the peripheral tissues of the spadix. Our results suggest that cellular respiration and mitochondrial metabolism play key roles in heat production during floral thermogenesis. On the other hand, vacuolar cysteine protease and other degradative enzymes seem to accelerate senescence and terminate thermogenesis in the post-thermogenic stage.     

Higher serum bone alkaline phosphatase as a predictor of mortality in male hemodialysis patients

AimsHigher serum alkaline phosphatase predicts lower mortality in chronic kidney disease and hemodialysis patients without liver dysfunction because it reflects high bone turnover. The purpose of our study was to compare the significance of serum bone alkaline phosphatase (BAP) with that of other bone markers in prediction of all-cause mortality(ACM) in male hemodialysis patients.Main methodsThe study was performed for 5 years. Serum BAP, intact osteocalcin (iOC), ß-CrossLaps (CTX), and intact parathyroid hormone (iPTH) were measured in 196 male hemodialysis patients without radiographic fracture. Their day-to-day variation during 5 consecutive days and diurnal variation were determined in 13 healthy males.Key findingsThe patients were divided into higher and lower groups based on serum levels of bone markers(mean ± SD: iPTH 218.6 ± 214.5 pg/ml, BAP 23.6 ± 12.2U/L, iOC 42.8 ± 45.2 ng/ml, CTX 1.71 ± 1.23 nmol/L BCE). In Kaplan–Meier analysis, the higher BAP group had significantly higher ACM than the lower BAP group (P = 0.013), whereas mortality did not differ between the higher and lower groups in other markers. Cox regression hazard analysis identified higher log BAP as a significant independent predictor [hazard ratio(HR) 8.32(95%CI:1.18–58.98)] for ACM after adjustment for various factors including pre-existing cardiovasucular disease, presence of DM. The significant association of mortality with serum BAP alone, in contrast with other markers including CTX [HR0.64 (95%CI:0.16–2.47)], iOC [HR0.97(95%CI:0.36–2.64)], iPTH [HR0.84(95%CI:0.44–1.60)],it may be due to the narrower day-to-day variation and the absence of diurnal variation in serum BAP compared to other markers.SignificanceHigher serum BAP may be a predictor of ACM in male hemodialysis patients.     

Differential encoding of factors influencing predicted reward value in monkey rostral anterior cingulate cortex

Background

The value of a predicted reward can be estimated based on the conjunction of both the intrinsic reward value and the length of time to obtain it. The question we addressed is how the two aspects, reward size and proximity to reward, influence the responses of neurons in rostral anterior cingulate cortex (rACC), a brain region thought to play an important role in reward processing.

Methods and Findings

We recorded from single neurons while two monkeys performed a multi-trial reward schedule task. The monkeys performed 1–4 sequential color discrimination trials to obtain a reward of 1–3 liquid drops. There were two task conditions, a valid cue condition, where the number of trials and reward amount were associated with visual cues, and a random cue condition, where the cue was picked from the cue set at random. In the valid cue condition, the neuronal firing is strongly modulated by the predicted reward proximity during the trials. Information about the predicted reward amount is almost absent at those times. In substantial subpopulations, the neuronal responses decreased or increased gradually through schedule progress to the predicted outcome. These two gradually modulating signals could be used to calculate the effect of time on the perception of reward value. In the random cue condition, little information about the reward proximity or reward amount is encoded during the course of the trial before reward delivery, but when the reward is actually delivered the responses reflect both the reward proximity and reward amount.

Conclusions

Our results suggest that the rACC neurons encode information about reward proximity and amount in a manner that is dependent on utility of reward information. The manner in which the information is represented could be used in the moment-to-moment calculation of the effect of time and amount on predicted outcome value.     

Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells

Drosophila male germline stem cells (GSCs) divide asymmetrically, balancing self-renewal and differentiation. Although asymmetric stem cell division balances between self-renewal and differentiation, it does not dictate how frequently differentiating cells must be produced. In male GSCs, asymmetric GSC division is achieved by stereotyped positioning of the centrosome with respect to the stem cell niche. Recently we showed that the centrosome orientation checkpoint monitors the correct centrosome orientation to ensure an asymmetric outcome of the GSC division. When GSC centrosomes are not correctly oriented with respect to the niche, GSC cell cycle is arrested/delayed until the correct centrosome orientation is reacquired. Here we show that induction of centrosome misorientation upon culture in poor nutrient conditions mediates slowing of GSC cell proliferation via activation of the centrosome orientation checkpoint. Consistently, inactivation of the centrosome orientation checkpoint leads to lack of cell cycle slowdown even under poor nutrient conditions. We propose that centrosome misorientation serves as a mediator that transduces nutrient information into stem cell proliferation, providing a previously unappreciated mechanism of stem cell regulation in response to nutrient conditions.     

Porphyromonas gingivalis SerB-mediated dephosphorylation of host cell cofilin modulates invasion efficiency

Porphyromonas gingivalis, a host-adapted opportunistic pathogen, produces a serine phosphatase, SerB, known to affect virulence, invasion and persistence within the host cell. SerB induces actin filament rearrangement in epithelial cells, but the mechanistic basis of this is not fully understood. Here we investigated the effects of SerB on the actin depolymerizing host protein cofilin. P. gingivalis infection resulted in the dephosphorylation of cofilin in gingival epithelial cells. In contrast, a SerB-deficient mutant of P. gingivalis was unable to cause cofilin dephosphorylation. The involvement of cofilin in P. gingivalis invasion was determined by quantitative image analysis of epithelial cells in which cofilin had been knocked down or knocked in with various cofilin constructs. siRNA-silencing of cofilin led to a significant decrease in numbers of intracellular P. gingivalis marked by an absence of actin colocalization. Transfection with wild-type cofilin or constitutively active cofilin both increased numbers of intracellular bacteria, while constitutively inactive cofilin abrogated invasion. Expression of LIM kinase resulted in reduced P. gingivalis invasion, an effect that was reversed by expression of constitutively active cofilin. These results show that P. gingivalis SerB activity induces dephosphorylation of cofilin, and that active cofilin is required for optimal invasion into gingival epithelial cells.     

CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells

Foxp3(+)CD25(+)CD4(+) regulatory T cells (Treg) mediate immunological self-tolerance and suppress immune responses. A subset of dendritic cells (DCs) in the intestine is specialized to induce Treg in a TGF-beta- and retinoic acid-dependent manner to allow for oral tolerance. In this study we compare two major DC subsets from mouse spleen. We find that CD8(+) DEC-205/CD205(+) DCs, but not the major fraction of CD8(-) DC inhibitory receptor-2 (DCIR2)(+) DCs, induce functional Foxp3(+) Treg from Foxp3(-) precursors in the presence of low doses of Ag but without added TGF-beta. CD8(+)CD205(+) DCs preferentially express TGF-beta, and the induction of Treg by these DCs in vitro is blocked by neutralizing Ab to TGF-beta. In contrast, CD8(-)DCIR2(+) DCs better induce Foxp3(+) Treg when exogenous TGF-beta is supplied. In vivo, CD8(+)CD205(+) DCs likewise preferentially induce Treg from adoptively transferred, Ag-specific DO11.10 RAG(-/-) Foxp3(-)CD4(+) T cells, whereas the CD8(-)DCIR2(+) DCs better stimulate natural Foxp3(+) Treg. These results indicate that a subset of DCs in spleen, a systemic lymphoid organ, is specialized to differentiate peripheral Foxp3(+) Treg, in part through the endogenous formation of TGF-beta. Targeting of Ag to these DCs might be useful for inducing Ag-specific Foxp3(+) Treg for treatment of autoimmune diseases, transplant rejection, and allergy.     

Small intestine CD4+ T cells are profoundly depleted during acute simian-human immunodeficiency virus infection, regardless of viral pathogenicity

To analyze the relationship between acute virus-induced injury and the subsequent disease phenotype, we compared the virus replication and CD4(+) T-cell profiles for monkeys infected with isogenic highly pathogenic (KS661) and moderately pathogenic (#64) simian-human immunodeficiency viruses (SHIVs). Intrarectal infusion of SHIV-KS661 resulted in rapid, systemic, and massive virus replication, while SHIV-#64 replicated more slowly and reached lower titers. Whereas KS661 systemically depleted CD4(+) T cells, #64 caused significant CD4(+) T-cell depletion only in the small intestine. We conclude that SHIV, regardless of pathogenicity, can cause injury to the small intestine and leads to CD4(+) T-cell depletion in infected animals during acute infection.