Explore the vast range of titles available.

\"In a future world ravaged by global warming, people have lost the ability to dream, and the dreamlessness has led to widespread madness. The only people still able to dream are North America's indigenous population--and it is their marrow that holds the cure for the rest of the world. But getting the marrow--and dreams--means death for the unwilling donors. Driven to flight, a 15-year-old and his companions struggle for survival, attempt to reunite with loved ones, and take refuge from the 'recruiters' who seek them out to bring them to the marrow-stealing 'factories'\"-- Provided by publisher.

In this study of unrelated-donor transplantation for hematologic cancers, survival was similar with bone marrow and peripheral-blood stem-cell grafts. However, graft failure was more common with the former, and chronic graft-versus-host disease with the latter. In the early days of allogeneic hematopoietic stem-cell transplantation, the only graft source available was bone marrow harvested from the pelvis of a donor under anesthesia. When studies showed that an increased dose of bone marrow cells correlated with more robust hematopoietic engraftment and lower mortality from infectious complications, transplantation centers began to use filgrastim-stimulated peripheral blood, which has a much higher content of blood progenitor cells than bone marrow, although there was concern that the higher T-cell content might increase the risk of graft-versus-host disease (GVHD). 1 – 5 Several large, randomized trials of transplantation between HLA-identical siblings showed that peripheral-blood . . .

Objective Braces used to treat (PF) osteoarthritis (OA) may reduce contact stress across the PF joint. We hypothesised that in PF OA, braces would decrease knee pain and shrink PF bone marrow lesions (BMLs). Methods Eligible subjects had painful PF OA. Subjects were randomly allocated to brace or no brace for 6 weeks. Knee MRIs were acquired at baseline and 6 weeks. We measured BMLs on post-contrast fat suppressed sagittal and proton density weighted axial images. The primary symptom outcome was change in pain at 6 weeks during a preselected painful activity, and the primary structural outcome was BML volume change in the PF joint. Analyses used multiple linear regression. Results We randomised 126 subjects aged 40–70 years (mean age 55.5  years; 72 females (57.1%)). Mean nominated visual analogue scale (0–10 cm) pain score at baseline was 6.5 cm. 94 knees (75%) had PF BMLs at baseline. Subjects wore the brace for a mean of 7.4 h/day. 6 subjects withdrew during the trial. After accounting for baseline values, the brace group had lower knee pain than the control group at 6 weeks (difference between groups −1.3 cm, 95% CI −2.0 to −0.7; p<0.001) and reduced PF BML volume (difference −490.6 mm3, 95% CI −929.5 to −51.7; p=0.03) but not tibiofemoral volume (difference −53.9 mm3, 95% CI −625.9 to 518.2; p=0.85). Conclusions A PF brace reduces BML volume in the targeted compartment of the knee, and relieves knee pain. Trial registration number UK. ISRCTN50380458.

ObjectivesTo explore the effects of tofacitinib—an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)—with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand.MethodsIn this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with p<0.05 (vs MTX monotherapy) were considered significant.ResultsIn total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were −1.55 (90% CI −2.52 to −0.58) for tofacitinib + MTX and −1.74 (−2.72 to −0.76) for tofacitinib monotherapy (both p<0.01 vs MTX monotherapy). Numerical improvements in RAMRIS synovitis at month 3 were −0.63 (−1.58 to 0.31) for tofacitinib + MTX and −0.52 (−1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy.ConclusionsThese results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage.Trial registration numberNCT01164579.

Objectives To compare the effect of a single infusion of zoledronic acid (ZA) with placebo on knee pain and bone marrow lesions (BMLs). Methods Adults aged 50–80 years (n=59) with clinical knee osteoarthritis and knee BMLs were randomised to receive either ZA (5 mg/100 ml) or placebo. BMLs were determined using proton density-weighted fat saturation MR images at baseline, 6 and 12 months. Pain and function were measured using a visual analogue scale (VAS) and the knee injury and osteoarthritis outcome score (KOOS) scale. Results At baseline, mean VAS score was 54 mm and mean total BML area was 468 mm2. VAS pain scores were significantly reduced in the ZA group compared with placebo after 6 months (−14.5 mm, 95% CI −28.1 to −0.9) but not after 3 or 12 months. Changes on the KOOS scales were not significant at any time point. Reduction in total BML area was greater in the ZA group compared with placebo after 6 months (−175.7 mm2, 95% CI −327.2 to −24.3) with a trend after 12 months (−146.5 mm2, 95% CI −307.5 to +14.5). A greater proportion of those in the ZA group achieved a clinically significant reduction in BML size at 6 months (39% vs 18%, p=0.044). Toxicity was as expected apart from a high rate of acute phase reactions in treatment and placebo arms. Conclusions ZA reduces knee pain and areal BML size and increases the proportion improving over 6 months. Treatment of osteoarthritis may benefit from a lesion specific therapeutic approach. Clinical trial registration number ACTRN 12609000399291.

Immune rejection may limit the therapeutic use of induced pluripotent stem cells (iPSCs); here, terminally differentiated mouse iPSCs are shown to generate negligible immune rejection in their host. No immune reaction to iPSCs Induced pluripotent stem cells (iPSCs) derived from a patient's own somatic cells could have great therapeutic potential. The hope is that iPSC-derived differentiated cells would avoid any immunogenic responses. In this study, Masumi Abe and colleagues assess the immunogenicity of skin and bone marrow tissues derived from a large set of isogenic mouse embryonic stem cell and iPSC lines. Their results are consistent with negligible immune rejection by the host. The advantages of using induced pluripotent stem cells (iPSCs) instead of embryonic stem (ES) cells in regenerative medicine centre around circumventing concerns about the ethics of using ES cells and the likelihood of immune rejection of ES-cell-derived tissues 1 , 2 . However, partial reprogramming and genetic instabilities in iPSCs 3 , 4 , 5 , 6 could elicit immune responses in transplant recipients even when iPSC-derived differentiated cells are transplanted. iPSCs are first differentiated into specific types of cells in vitro for subsequent transplantation. Although model transplantation experiments have been conducted using various iPSC-derived differentiated tissues 7 , 8 , 9 , 10 and immune rejections have not been observed, careful investigation of the immunogenicity of iPSC-derived tissue is becoming increasingly critical, especially as this has not been the focus of most studies done so far. A recent study reported immunogenicity of iPSC- but not ES-cell-derived teratomas 11 and implicated several causative genes. Nevertheless, some controversy has arisen regarding these findings 12 . Here we examine the immunogenicity of differentiated skin and bone marrow tissues derived from mouse iPSCs. To ensure optimal comparison of iPSCs and ES cells, we established ten integration-free iPSC and seven ES-cell lines using an inbred mouse strain, C57BL/6. We observed no differences in the rate of success of transplantation when skin and bone marrow cells derived from iPSCs were compared with ES-cell-derived tissues. Moreover, we observed limited or no immune responses, including T-cell infiltration, for tissues derived from either iPSCs or ES cells, and no increase in the expression of the immunogenicity-causing Zg16 and Hormad1 genes in regressing skin and teratoma tissues. Our findings suggest limited immunogenicity of transplanted cells differentiated from iPSCs and ES cells.

Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche. Boyd et al. monitored the effects of patient-derived acute myeloid leukaemia (AML) cells on human HSPCs in vivo and found that AML impairs bone marrow adipocyte differentiation, and this in turn impedes healthy endogenous haematopoiesis.

Multiple myeloma (MM) is an incurable malignancy characterized by the proliferation of abnormal plasma cells within the bone marrow, followed by potential dissemination to extramedullary sites. The bone marrow barrier (BMB) plays a pivotal role in plasma cell homing and disease progression. Bone marrow endothelial cells (BMECs) and bone marrow stromal cells (BMSCs), through their interactions with MM cells, secrete adhesion molecules, angiogenic cytokines, anti-apoptotic factors, and growth-promoting signals that support MM cell survival and proliferation. This review examines the components of the BMB and the major pathways involved in MM pathogenesis. Targeting the interactions between MM cells and the BMB may offer novel therapeutic opportunities.

Background Previous studies have shown that hyaluronic acid can delay the progression of knee osteoarthritis. Existing research has extracted a bright red fluid called cell-free fat extract from human adipose tissue, which may play an important role in delaying the progression of osteoarthritis. By comparing with intra-articular injection of hyaluronic acid, this study aimed to evaluate the effects of intra-articular injection of CEFFE on both clinical efficacy and the reduction of bone marrow edema in patients with early to mid-stage knee osteoarthritis. Methods A total of 48 patients with KOA (Kellgren-Lawrence grade II-III) symptoms were randomly divided into CEFFE group (24 cases) and HA group (24 cases). The patients in the CEFFE group received five injections of CEFFE (2 ml, 1 time/week), and the patients in the HA group received five injections of HA (2 ml, 1 ml/10 mg, 1 time/week). All the patients underwent clinical assessments using rating scales, including VAS, WOMAC and Lysholm Knee Score. These assessments were conducted at pre-treatment and at 3-week, 6-week, 3-month, and 6-month follow-up timepoints post-treatment. The clinical efficacy was evaluated at the 6-month follow-up after the treatment. The changes in subchondral bone marrow edema before and 6 months after treatment were assessed by grading BME on MRI of the affected knees. Results A total of 52 knees from 46 patients were included in the final analysis. Comparison of VAS score, WOMAC score, and Lysholm score between the two groups revealed that the differences between pre-treatment and 3 weeks post-treatment were not statistically significant ( P  > 0.05). For the VAS score and WOMAC score at 6 weeks, 3 months, and 6 months post-treatment, the CEFFE group was lower than the HA group ( P  < 0.05). For the Lysholm score, the CEFFE group was higher than the HA group ( P  < 0.05). Compared with pre-treatment, VAS scores and WOMAC scores were lower and Lysholm scores were higher at all post-treatment time points ( P  < 0.05). At 6 months post-treatment, the clinical efficacy of the CEFFE group was significantly better than that of the HA group ( P  < 0.05). At 6 months post-treatment, MRI grading showed that subchondral BME was reduced to different degrees in both groups, with the reduction being more pronounced in the CEFFE group ( P  < 0.05). Conclusion This study demonstrated that intra-articular injection of CEFFE into the knee joint could enhance the durability of tissue-specific cells (especially chondrocytes) and improve cellular metabolic processes, preventing the continued progression of osteoarthritis. Both CEFFE and HA were found to improve clinical symptoms and reduced subchondral bone marrow edema in the treatment of early to mid-stage knee osteoarthritis. However, CEFFE was more effective than HA in achieving these outcomes.

Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell \"mass cytometry\" to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention.