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As a corridor for population movement out of Africa, the southern Levant is a natural laboratory for research exploring the dynamics of the Middle-to-Upper Paleolithic transition. Yet, the number of well-preserved sites dating to the initial millennia of the Early Upper Paleolithic (EUP; ∼45–30 ka) remains limited, restricting the resolution at which we can study the biocultural and techno-typological changes evidenced across the transition. With EUP deposits dating to 45–39 ka cal BP, Mughr el-Hamamah, Jordan, offers a key opportunity to expand our understanding of EUP lifeways in the southern Levant. Mughr el-Hamamah is particularly noteworthy for its large faunal assemblage, representing the first such assemblage from the Jordan Valley. In this paper, we present results from taxonomic and taphonomic analyses of the EUP fauna from Mughr el-Hamamah. Given broader debates about shifts in human subsistence across the Middle-to-Upper Paleolithic transition, we also assess evidence for subsistence intensification, focusing especially on the exploitation of gazelle and the use of small game. Taphonomic data suggest that the fauna was primarily accumulated by human activity. Ungulates dominate the assemblage; gazelle (Gazella sp.) is the most common taxa, followed by fallow deer (Dama mesopotamica) and goat (Capra sp.). Among the gazelle, juveniles account for roughly one-third of the sample. While the focus on gazelle and the frequency of juveniles are consistent with broader regional trends, evidence for the regular exploitation of marrow from gazelle phalanges suggests that the EUP occupants of Mughr el-Hamamah processed gazelle carcasses quite intensively. Yet, the overall degree of dietary intensification appears low—small game is rare and evidence for human capture of this game is more equivocal. As a whole, our results support a growing body of data showing gradual shifts in animal exploitation strategies across the Middle-to-Upper Paleolithic transition in the southern Levant. [ABSTRACT FROM AUTHOR]

Calvarial bone marrow has been found to be central in the brain immune response, being connected to the dura through channels which allow leukocyte trafficking. Temporal bone marrow is thought to play important roles in relation to the inner ear, but is still largely uncharacterized, given this bone complex anatomy. We characterized the geometry and connectivity of rat temporal bone marrow using lightsheet imaging of cleared samples and microCT. Bone marrow was identified in cleared tissue by cellular content (and in particular by the presence of megakaryocytes); since air-filled cavities are absent in rodents, marrow clusters could be recognized in microCT scans by their geometry. In cleared petrosal bone, autofluorescence allowed delineation of the otic capsule layers. Within the endochondral layer, bone marrow was observed in association to the cochlear base and vestibule, and to the cochlear apex. Cochlear apex endochondral marrow (CAEM) was a separated cluster from the remaining endochondral marrow, which was therefore defined as "vestibular endochondral marrow" (VEM). A much larger marrow island (petrosal nonendochondral marrow, PNEM) extended outside the otic capsule surrounding semicircular canal arms. PNEM was mainly connected to the dura, through bone channels similar to those of calvarial bone, and only a few channels were directed toward the canal periosteum. On the contrary, endochondral bone marrow was well connected to the labyrinth through vascular loops (directed to the spiral ligament for CAEM and to the bony labyrinth periosteum for VEM), and to dural sinuses. In addition, CAEM was also connected to the tensor tympani fossa of the middle ear and VEM to the endolymphatic sac. Endochondral marrow was made up of small lobules connected to each other and to other structures by channels lined by elongated macrophages, whereas PNEM displayed larger lobules connected by channels with a sparse macrophage population. Our data suggest that the rat inner ear is surrounded by bone marrow at the junctions with middle ear and brain, most likely with "customs" role, restricting pathogen spread; a second marrow network with different structural features is found within the endochondral bone layer of the otic capsule and may play different functional roles. [ABSTRACT FROM AUTHOR]

Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response. The mechanisms driving B cell differentiation into resident bone marrow plasma cells (BMPC) remain unclear. Here the authors use single cell sequencing and BMPC phenotyping to infer developmental pathways and regulation by IL-21 in germinal centres to promote maintenance of BMPC after vaccination in humans. [ABSTRACT FROM AUTHOR]

The regeneration of critical-size bone defects, especially those with irregular shapes, remains a clinical challenge. Various biomaterials have been developed to enhance bone regeneration, but the limitations on the shape-adaptive capacity, the complexity of clinical operation, and the unsatisfied osteogenic bioactivity have greatly restricted their clinical application. In this work, we construct a mechanically robust, tailorable and water-responsive shape-memory silk fibroin/magnesium (SF/MgO) composite scaffold, which is able to quickly match irregular defects by simple trimming, thus leading to good interface integration. We demonstrate that the SF/MgO scaffold exhibits excellent mechanical stability and structure retention during the degradative process with the potential for supporting ability in defective areas. This scaffold further promotes the proliferation, adhesion and migration of osteoblasts and the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. With suitable MgO content, the scaffold exhibits good histocompatibility, low foreign-body reactions (FBRs), significant ectopic mineralisation and angiogenesis. Skull defect experiments on male rats demonstrate that the cell-free SF/MgO scaffold markedly enhances bone regeneration of cranial defects. Taken together, the mechanically robust, personalised and bioactive scaffold with water-responsive shape-memory may be a promising biomaterial for clinical-size and irregular bone defect regeneration. The regeneration of critical-size bone defects, especially those with irregular shapes, remains a clinical challenge. Here, the authors report a shape-memory, tailorable, self-adaptive and bioactive silk fibroin/magnesium composite scaffold that can quickly match irregular defects by simple trimming and lead to good interface integration. [ABSTRACT FROM AUTHOR]

Stem cell-based therapy plays a significant role in the repair of bone defects. However, traditional stem cell transplantation strategies in bone tissue engineering are characterized by low survival rates and unstable treatment outcomes. In this study, we propose a timely delivery strategy for inflammatory changes in the setting of bone injury to improve the survival rate of transplanted cells and bone repair. The results of cell tracing in vivo showed that this strategy could effectively improve the survival rate of low-dose exogenous transplanted cells in bone defect areas, and CD31 immunofluorescence and histological sections suggested that this strategy effectively promoted vascularization and new bone formation in the calvarial defect area. Subsequently, we analyzed the mechanism of action of the "Two-step" strategy from the perspective of inflammatory microenvironment regulation, and the results suggested that the first batch transplanted stem cells caused localized and transient increases in tissue apoptosis levels and inflammatory factors, and recruited macrophage chemotaxis, and the second batch of cells may promote pro-inflammatory - anti-inflammatory transformation of the tissue. Finally, mRNA sequencing results suggest that the first batch cells in the "Two-step" strategy are important initiators in bone repair, which not only actively regulate the immune microenvironment at the bone defect, but also guide richer cellular activity and more positive biochemical responses. Therefore, the "Two-step" strategy leads to efficient inflammatory environment regulation and superior bone repair effects, which may provide an alternative option for the treatment of bone defects in the future. [ABSTRACT FROM AUTHOR]

Pleuroparenchymal fibroelastosis (PPFE) is a rare, progressive, restrictive lung disease characterized by hypercarbic respiratory failure. In pediatrics, it has been described in patients with a history of malignancy who have received a bone marrow transplant, chemotherapy, or radiotherapy. It is characterized by pleural thickening, fibrosis, subpleural elastosis, and intraalveolar collagen deposits. Survival is poor, and the only therapy is lung transplantation. Here, we report a patient who developed PPFE as a late-onset pulmonary toxicity after treatment with anticancer chemotherapy for high-risk neuroblastoma (NB). [ABSTRACT FROM AUTHOR]

Over the last decades, the survival of multiple myeloma (MM) patients has considerably improved. However, despite the availability of new treatments, most patients still relapse and become therapy-resistant at some point in the disease evolution. The mutation profile has an impact on MM patients' outcome, while typically evolving over time. Because of the patchy bone marrow (BM) infiltration pattern, the analysis of a single bone marrow sample can lead to an underestimation of the known genetic heterogeneity in MM. As a result, interest is shifting towards blood-derived liquid biopsies, which allow for a more comprehensive and non-invasive genetic interrogation without the discomfort of repeated BM aspirations. In this review, we compare the application potential for mutation profiling in MM of circulating-tumor-cell-derived DNA, cell-free DNA and extracellular-vesicle-derived DNA, while also addressing the challenges associated with their use. [ABSTRACT FROM AUTHOR]

Hematopoietic stem and progenitor cells (HSPCs) continuously generate platelets throughout one's life. Inherited Platelet Disorders affect ≈ 3 million individuals worldwide and are characterized by defects in platelet formation or function. A critical challenge in the identification of these diseases lies in the absence of models that facilitate the study of hematopoiesis ex vivo. Here, a silk fibroin‐based bioink is developed and designed for 3D bioprinting. This bioink replicates a soft and biomimetic environment, enabling the controlled differentiation of HSPCs into platelets. The formulation consisting of silk fibroin, gelatin, and alginate is fine‐tuned to obtain a viscoelastic, shear‐thinning, thixotropic bioink with the remarkable ability to rapidly recover after bioprinting and provide structural integrity and mechanical stability over long‐term culture. Optical transparency allowed for high‐resolution imaging of platelet generation, while the incorporation of enzymatic sensors allowed quantitative analysis of glycolytic metabolism during differentiation that is represented through measurable color changes. Bioprinting patient samples revealed a decrease in metabolic activity and platelet production in Inherited Platelet Disorders. These discoveries are instrumental in establishing reference ranges for classification and automating the assessment of treatment responses. This model has far‐reaching implications for application in the research of blood‐related diseases, prioritizing drug development strategies, and tailoring personalized therapies. [ABSTRACT FROM AUTHOR]

Extending the shelf life of exported beef could increase international demand and producer profits. The objective was to evaluate the effects of topically applying combinations of acerola cherry powder and rosemary extract on the shelf life of frozen–thawed bone-in beef short rib and chuck roll steaks. Chuck rolls (IMPS 116A; N = 9) and bone-in short ribs (IMPS 123A; N = 18) were aged (7 d; 0 °C), frozen (30 d; −20 °C), and thawed (60–72 h; 0 °C). Steaks measuring 1.02 cm thick were treated and subjected to a 4 d retail display. Steaks were left untreated (control) or sprayed topically with acerola cherry powder (0.05%; A), rosemary extract (0.10%; R), or a combination (M1 = 0.05% A + 0.1% R; M2 = 0.1% A + 0.1% R; M3 = 0.05% A + 0.2% R; M4 = 0.1% A + 0.2% R). Chuck roll M2- and M4-treated steaks were redder than the control steaks on days 3 and 4 (p = 0.008), and antioxidant-treated steaks had less lipid oxidation on day 4 than the control steaks (p = 0.021). Bone marrow samples treated with R, M3, and M4 were redder than the control on days 1–3 (p = 0.014), and bone marrow treated with M3 was subjectively redder compared to the control on days 0 and 1 (p = 0.033). Topical antioxidants improve the redness and delay the oxidation of frozen–thawed beef. [ABSTRACT FROM AUTHOR]

Simple Summary: Chemoradiation as a standard treatment for locally advanced cervical cancer is known to induce severe hematologic toxicity. This systematic review aims to evaluate the relationship between pelvic bone marrow irradiation and hematologic toxicity in patients undergoing platin-based chemoradiation for locally advanced cervical cancer. We seek to summarize possible dose constraints for optimal bone marrow sparing and optimize clinical strategies to mitigate treatment-related toxicities. The standard treatment for locally advanced cervical cancer typically includes concomitant chemoradiation, a regimen known to induce severe hematologic toxicity (HT). Particularly, pelvic bone marrow dose exposure has been identified as a contributing factor to this hematologic toxicity. Chemotherapy further increases bone marrow suppression, often necessitating treatment interruptions or dose reductions. A systematic search for original articles published between 1 January 2006 and 7 January 2024 that reported on chemoradiotherapy for locally advanced cervical cancer and hematologic toxicities was conducted. Twenty-four articles comprising 1539 patients were included in the final analysis. HT of grade 2 and higher was observed across all studies and frequently exceeded 50%. When correlating active pelvic bone marrow and HT, significant correlations were found for volumes between 10 and 45 Gy and HT of grade 3 and higher. Several dose recommendations for pelvic bone and pelvic bone marrow sparing to reduce HT were established, including V10 < 90–95%, V20 < 65–86.6% and V40 < 22.8–40%. Applying dose constraints to the pelvic bone/bone marrow is a promising approach for reducing HT, and thus reliable implementation of therapy. However, prospective randomized controlled trials are needed to define precise dose constraints and optimize clinical strategies. [ABSTRACT FROM AUTHOR]

In this study of the alterations of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts in Osteoarthritis (OA), the levels of GPCs and Notum in the plasma of 25 patients and 24 healthy subjects were measured. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured over a period of 21 days using both a culture medium and an osteogenic medium. Protein and gene expression levels of GPCs and Notum were determined using ELISA and qPCR at 0, 7, 14 and 21 days. GPC5 and Notum levels decreased in the plasma of OA patients, while the BM-MSCs of OA patients showed downexpression of GPC6 and upregulation of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPCs 2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in patients with OA. Furthermore, the protein levels of GPC2, GPC5 and Notum decreased, while the levels of GPC3 increased. Glypicans and Notum were altered in BM-MSCs and during osteogenic differentiation from patients with OA. The alterations found point to GPC5 and Notum as new candidate biomarkers of OA pathology. [ABSTRACT FROM AUTHOR]

The concept of "stemness" incorporates the molecular mechanisms that regulate the unlimited self-regenerative potential typical of undifferentiated primitive cells. These cells possess the unique ability to navigate the cell cycle, transitioning in and out of the quiescent G0 phase, and hold the capacity to generate diverse cell phenotypes. Stem cells, as undifferentiated precursors endow with extraordinary regenerative capabilities, exhibit a heterogeneous and tissue-specific distribution throughout the human body. The identification and characterization of distinct stem cell populations across various tissues have revolutionized our understanding of tissue homeostasis and regeneration. From the hematopoietic to the nervous and musculoskeletal systems, the presence of tissue-specific stem cells underlines the complex adaptability of multicellular organisms. Recent investigations have revealed a diverse cohort of non-hematopoietic stem cells (non-HSC), primarily within bone marrow and other stromal tissue, alongside established hematopoietic stem cells (HSC). Among these non-HSC, a rare subset exhibits pluripotent characteristics. In vitro and in vivo studies have demonstrated the remarkable differentiation potential of these putative stem cells, known by various names including multipotent adult progenitor cells (MAPC), marrow-isolated adult multilineage inducible cells (MIAMI), small blood stem cells (SBSC), very small embryonic-like stem cells (VSELs), and multilineage differentiating stress enduring cells (MUSE). The diverse nomenclatures assigned to these primitive stem cell populations may arise from different origins or varied experimental methodologies. This review aims to present a comprehensive comparison of various subpopulations of multipotent/pluripotent stem cells derived from stromal tissues. By analysing isolation techniques and surface marker expression associated with these populations, we aim to delineate the similarities and distinctions among stromal tissue-derived stem cells. Understanding the nuances of these tissue-specific stem cells is critical for unlocking their therapeutic potential and advancing regenerative medicine. The future of stem cells research should prioritize the standardization of methodologies and collaborative investigations in shared laboratory environments. This approach could mitigate variability in research outcomes and foster scientific partnerships to fully exploit the therapeutic potential of pluripotent stem cells. [ABSTRACT FROM AUTHOR]

Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages. The role of coagulation system in erythropoiesis is not clear. Here, the authors report that an anticoagulant protein TFPI from erythroblasts directs central macrophages to synthesize heme, which in turn promotes erythropoiesis in bone marrow. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans classically causes pulmonary and central nervous system (CNS) infection in immunocompromised hosts and can lead to disseminated disease. Two cases of atypical cryptococcal infection are presented—an elderly Human Immunodeficiency Virus- (HIV-) negative male with a urinary source of infection and a young HIV-positive male with bone marrow infiltration complicated by haemophagocytic lymphohistiocytosis (HLH). A literature review of systemic cryptococcal infections involving the genitourinary tract and bone marrow was performed. These cases highlight the importance of clinicians considering uncommon manifestations of cryptococcal disease. [ABSTRACT FROM AUTHOR]

ORMDL3 is a prominent member of a family of highly conserved endoplasmic reticulum resident proteins, ORMs (ORM1 and ORM2) in yeast, dORMDL in Drosophila and ORMDLs (ORMDL1, ORMDL2, and ORMDL3) in mammals. ORMDL3 mediates feedback inhibition of de novo sphingolipid synthesis. Expression levels of ORMDL3 are associated with the development of inflammatory and autoimmune diseases including asthma, systemic lupus erythematosus, type 1 diabetes mellitus and others. It has been shown that simultaneous deletions of other ORMDL family members could potentiate ORMDL3-induced phenotypes. To understand the complex function of ORMDL proteins in immunity in vivo, we analyzed mice with single or double deletions of Ormdl genes. In contrast to other single and double knockouts, simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupted blood homeostasis and reduced immune cell content in peripheral blood and spleens of mice. The reduced number of splenocytes was not caused by aberrant immune cell homing. A competitive bone marrow transplantation assay showed that the development of Ormdl1-/-/Ormdl3-/- B cells was dependent on lymphocyte intrinsic factors. Highly increased sphingolipid production was observed in the spleens and bone marrow of Ormdl1-/-/Ormdl3-/- mice. Slight, yet significant, increase in some sphingolipid species was also observed in the spleens of Ormdl3-/- mice and in the bone marrow of both, Ormdl1-/- and Ormdl3-/- single knockout mice. Taken together, our results demonstrate that the physiological expression of ORMDL proteins is critical for the proper development and circulation of lymphocytes. We also show cell-type specific roles of individual ORMDL family members in the production of different sphingolipid species. [ABSTRACT FROM AUTHOR]

Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu. Excessive bone marrow adipocytes accumulation is involved in bone deterioration. Here, the authors show that adipocyte ESRRA abrogation promotes osteogenesis and vascular formation in adipocyte-rich bone marrow via oppositely regulating the expression and secretion of leptin and SPP1. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroblastoma (NB) is a common pediatric solid tumor characterized by extreme heterogeneity; non-high-risk (non-HR) patients have near uniform survival and HR patients experience a fatal demise. Metastatic disease is the principal cause of death among both non-HR and HR NB patients. Previous studies have reported a significant but limited prognostic value of quantitative PCR (qPCR)-based assays, measuring overlapping but different sets of neuroblastoma-associated mRNAs (NB-mRNAs), to detect metastatic disease in both non-HR and HR patient samples. A droplet digital PCR (ddPCR)-based assay measuring seven NB-mRNAs was developed and exhibited a better prognostic value for HR patient samples than qPCR-based assays. However, it remained to be tested on non-HR patient samples. In the present study, we employed the ddPCR-based assay to study peripheral blood (PB) and bone marrow (BM) samples collected at diagnosis from eight non-HR and eleven HR cases and characterized the expression profiles of NB-mRNAs. The most highly expressed NB-mRNAs in PB and BM differed between non-HR and HR cases. The expression levels of NB-mRNAs in PB and BM were 5 to 1000 times lower in non-HR cases than in HR cases. The PB to BM ratio of NB-mRNAs was 10 to 100 times higher in non-HR cases than in HR cases. The present case series suggests that non-HR and HR NB patients have the distinct expression profiles of NB-mRNAs in their PB and BM. Non-high-risk (non-HR) neuroblastoma (NB) patients have excellent outcomes, with more than a 90% survival rate, whereas HR NB patients expect less than a 50% survival rate. Metastatic disease is the principal cause of death among both non-HR and HR NB patients. Previous studies have reported the significant but limited prognostic value of quantitative PCR (qPCR)-based assays, measuring overlapping but different sets of neuroblastoma-associated mRNAs (NB-mRNAs), to detect metastatic disease in both non-HR and HR patient samples. A droplet digital PCR (ddPCR)-based assay measuring seven NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was recently developed and exhibited a better prognostic value for HR patient samples than qPCR-based assays. However, it remained to be tested on non-HR patient samples. In the present study, we employed the ddPCR-based assay to study peripheral blood (PB) and bone marrow (BM) samples collected at diagnosis from eight non-HR and eleven HR cases and characterized the expression profiles of NB-mRNAs. The most highly expressed NB-mRNAs in PB and BM differed between non-HR and HR cases, with the CRMP1 mRNA being predominant in non-HR cases and the GAP43 mRNA in HR cases. The levels of NB-mRNAs in PB and BM were 5 to 1000 times lower in non-HR cases than in HR cases. The PB to BM ratio of NB-mRNAs was 10 to 100 times higher in non-HR cases compared to HR cases. The present case series suggests that non-HR and HR NB patients have the distinct expression profiles of NB-mRNAs in their PB and BM. [ABSTRACT FROM AUTHOR]

We aimed to explore the performance of bone marrow mesenchymal stem cells (BMSCs) in modulating signal transducer and activator of transcription 3 (STAT3)/p-catenin to facilitate alveolar bone remodeling in periodontitis rats in the process of orthodontic tooth movement. Flow cytometry was employed to identify BMSCs isolated, and then their osteogenic capacity was examined by alizarin red staining assay. BMSCs group (n=10), periodontitis + orthodontic tooth movement (PO+OTM) group (n=10), BMSCs+Static group (n=10) and negative control (NC) group (n=10) were set up for random allocation of 40 rats. The PO+OTM group had significantly decreased bone mineral density (BMD), trabecular number (Tb.N), bone volume/total volume (BV/ TV), trabecular thickness (Tb.Th), phosphorylated STAT3 (p-STAT3) ratio in alveolar bone tissues, but increased receptor activator of nuclear factor-KB ligand protein expression, trabecular space (Tb.Sp), cement-enamel junction to alveolar bone crest, and osteoclast count in comparison to those of the NC group (P<0.05). In contrast with the PO+OTM group, the BMSCs group had significantly increased BMD, Tb.N, BV/TV, Tb.Th, p-STAT3/STAT3 ratio, and protein expressions of p-catenin and osteoprotegerin, but decreased Tb.Sp (P<0.05). For periodontitis rats, BMSCs can promote osteogenic differentiation to facilitate alveolar bone remodeling in the process of orthodontic tooth movement. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the outcomes (relapse and mortality rate) and response of the bone marrow in early stages after combination chemotherapy in patients with T-cell Acute Lymphoblastic Leukemia (T-ALL). Methods: A descriptive cross-sectional study was conducted at King Fahad Medical City, from January 2021 to December 2022, to evaluate bone marrow findings at the time of diagnosis and post-chemotherapy in 26 patients diagnosed with T-ALL. The study included all patients diagnosed with T-ALL of any age group during the study period. The patients' bone marrows were examined at 0 days of treatment (diagnosis work-up), followed by examination at day 15 post induction therapy, and day 30 after treatment. Results: In this study, 26 cases of T-lymphoblastic leukemia were analyzed. The mean age at diagnosis was 15.69±14.28 years, and eight cases had central nervous system involvement. The majority of cases (88.5%) were positive for Cytoplasmic-CD3 and CD7. Positive findings by fluorescence in situ hybridization (FISH) were: T cell receptor (TCR) a/õ in 6 (23.1%) of the patients, CDNK2A/CEP9 in five (19.2%), and TRCB in one (3.8%). Examination of the bone marrow on day 15 revealed a decrease in blasts to <1% in nine patients, and to <1% in 19 patients on day 30 post-therapy. Relapse was recorded in five (19.23%) patients. Three (11.53%) patients did not survive during treatment, of which two were <10 years old. The relapse rate for T-ALL was 19.23%, with an overall survival rate of about 64%. The overall mortality rate was 11.53%. Conclusion: The relapse rate for T-ALL in our study was approximately 19%, but the mortality rate was 11.5%. A substantial decrease in blast percentages was observed, suggesting a favorable initial reaction of the bone marrow to the combined chemotherapy. This suggests that the use of aggressive and more effective chemotherapy has led to better outcomes. [ABSTRACT FROM AUTHOR]

This study delves into the impact of mesenchymal stem cells derived from bone marrow (BM‐MSCs) and those sourced from dental pulp (DP‐MSCs) on the recovery of motor function and morphological aspects of the rat's sciatic nerve after crush injuries. The findings highlight that the groups treated with BM‐MSCs, DP‐MSCs or a combination of both (BM + DP‐MSCs) displayed enhanced sciatic functional index values when juxtaposed with the sham group. This points to bettered motor functionalities. A deeper morphological analysis showed that all the groups had retained perineurium structure and fascicular arrangement. Notably, the sham and BM‐MSCs groups had very few inconsistencies. All groups showed standard vascular density. Remarkably, the combined treatment group (BM + DP‐MSCs) presented diminished oedema and a lower count of inflammatory cells. Through immunohistochemical methods, the presence of S100 expression was noted in the groups that underwent treatment. In summation, the study suggests that both BM‐MSCs and DP‐MSCs, whether used singly or in combination, can significantly aid in motor function restoration and morphological enhancements. An interesting observation from our research and earlier studies is that stem cells from dental pulp, which are sourced with less discomfort from milk and wisdom teeth, show a heightened propensity to evolve into nerve cells. This is in contrast to the more uncomfortably acquired BM‐MSCs. [ABSTRACT FROM AUTHOR]

Easy-to-apply liquid biopsy technique and detection of differentially expressed miRNA/lncRNAs (DEGs) may be more beneficial in multiple myeloma (MM) compared to bone marrow (BM) biopsy. We compared the gene expression levels of circulating tumor cells and BM cells in MM patients and showed differentially upregulated circulating tumor cell-derived miRNAs and lncRNAs. DEGs and related biological pathways were identified by using the R-LIMMA package, ShinyGO 0.77, and LncSEA2.0 tools. Three hundred nine lncRNAs/16 miRNAs were detected as differentially upregulated in MM patients’ circulating tumour cells. Among them, miRNAs (mainly has-miR-103a) and lncRNAs (MEG3, NEAT1, PCAT1) were detected, and only a few miRNAs and lncRNAs were related to MM in a limited number of studies. Drugs that interact with these lncRNAs were also identified. The fact that miRNAs/lncRNAs related to MM are also detected in tumor circulating cells indicates that a technically easier liquid biopsy may verify and even replace BM biopsy. [ABSTRACT FROM AUTHOR]

Objectives: T2 STIR MRI sequences can detect preclinical changes associated with periodontal inflammation, i.e. intraosseous edema in the tooth-supporting bone. In this study, we assessed whether MRI can be used for monitoring periodontal disease. Material and methods: In a prospective cohort study, we examined 35 patients with periodontitis between 10/2018 and 04/2019 by using 3D isotropic T2-weighted short tau inversion recovery (STIR) and Fast Field Echo T1-weighted Black bone sequences. All patients received standardized clinical exams before and three months after non-surgical periodontal therapy. Bone marrow edema extent was quantified in the STIR sequence at 922 sites before and after treatment. Results were compared with standard clinical findings. Non-parametric statistical analysis was performed. Results: Non-surgical periodontal treatment caused significant improvement in mean probing depth (p < 0.001) and frequency of bleeding on probing (p < 0.001). The mean depth of osseous edema per site was reduced from a median [IQR] of 2 [1, 3] mm at baseline to 1 [0, 3] mm, (p < 0.001). Periodontal treatment reduced the frequency of sites with edema from 35 to 24% (p < 0.01). Conclusion: The decrease of periodontal bone marrow edema, as observed with T2 STIR MR imaging, is indicative of successful periodontal healing. Clinical relevance statement: T2 STIR hyperintense bone marrow edema in the periodontal bone decreases after treatment and can therefore be used to evaluate treatment success. Furthermore, MRI reveals new options to depict hidden aspects of periodontitis. Key Points: • T2 STIR hyperintense periodontal intraosseous edema was prospectively investigated in 35 patients with periodontitis before and after treatment and compared to clinical outcomes. • The frequency of affected sites was reduced from 35 to 24% (p < 0.001), and mean edema depth was reduced from a median [IQR] of 2 [1, 3] mm at baseline to 1 [0, 3] mm 3 months after treatment. (p < 0.001). • T2 STIR sequences can be used to monitor the posttreatment course of periodontitis. [ABSTRACT FROM AUTHOR]

Background: The goal was to improve the clinical cognition of Ph-positive mixed phenotype acute leukemia and avoid misdiagnosis or delayed diagnosis. Methods: The clinical manifestations and laboratory results (bone marrow cell morphology, multiparameter flow cytometry, and cytogenetics) of a case of Ph-positive mixed phenotype acute leukemia were analyzed, and related literature was reviewed. Results: Blood routine: WBC 386.35 x 109/L, HGB 117.00 g/L, PLT 31 x 109/L; 80% of the original cells can be seen by artificial classification. Morphological examination of bone marrow cells showed that the proliferation of nucleated cells was obviously active, and the original cells accounted for 76%. The size of the original cells was somewhat uniform, most of the cells had less mass, were stained light grayish blue, the cytoplasm particles were not obvious, the nuclei were mostly round or quasi-round, some of them showed distortion and nuclear notch, and the chromatin was coarse. Some of the cells were rich in mass, small azurin granules were seen, the nuclei were regular, most of them were round, the chromatin was fine, the myeloperoxidase and esterase staining were negative, the eosinophils accounted for 2.5%, and the basophils accounted for 0.5%. Flow cytometry immunotyping: Two groups of abnormal cells were seen in the bone marrow. 1. A group included 12.32% of nuclear cells and showed abnormal myeloid primitive cell phenotype. Main expression: CD117, CD34, CD38, HLA-DR, CD33, CD64, CD123, weak expression: CD13, CD19. 2. The other group included 45.61% of the nuclear cells and had a B-lymphoblastic phenotype. Main expression: CD34, CD38, HLA-DR, CD123, CD19, CD10, CD9, cCD79a, TDT, weak expression of CD13, CD22. Mixed phenotype acute leukemia (M/B) immunophenotype was considered. Chromosome: 46,XY,t(9; 22)(q34;q11.2) [20]. BCR-ABL (P210) fusion gene was positive. Conclusions: Mixed phenotype acute leukemia (MPAL) is a rare type of malignant hematologic disease. Its diagnosis is based on the comprehensive evaluation of bone marrow cell morphology, immunophenotype, molecular and cytogenetic features. [ABSTRACT FROM AUTHOR]

Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B+ lung ILC progenitors represent a multi-lineage subset with tissue-resident characteristics and the potential to form lung-derived ILC subsets and liver-resident ILC1s. Loss of GFI1B in bone marrow progenitors led to the selective loss of lung-resident IL-18R+ ILCs and mature ILC2, subsequently preventing the emergence of effector ILCs that could protect the lung against inflammatory or tumor challenge. Editor's summary: Most innate lymphoid cells (ILCs) develop from lineage-restricted ILC progenitors in the bone marrow, but certain tissues such as the lungs are believed to harbor local ILC progenitor populations. How these local ILC progenitor pools are maintained remains unclear. Using dual reporter mice, Huang et al. mapped expression of the paralog transcription factors GFI1 and GFI1B in ILCs and their progenitors. GFI1B expression alone identified bone marrow and lung ILC progenitors that retained potential to differentiate into multiple ILC lineages. Loss of GFI1B-dependent ILCs impaired type 2 ILC development in the lungs, leading to reduced papain-induced inflammation but impaired protection against establishment of lung tumors. Together, these findings identify GFI1B expression as hallmark of lung-resident ILCs that retain multilineage developmental potential. —Claire Olingy [ABSTRACT FROM AUTHOR]

The aim of this study was to review the current literature regarding the effects of intra-articularly applied, fat-derived orthobiologics (FDO) in the treatment of primary knee osteoarthritis over a mid-term follow-up period. A systematic literature search was conducted on the online databases of Scopus, PubMed, Ovid MEDLINE, and Cochrane Library. Studies investigating intra-articularly applied FDO with a minimum number of 10 knee osteoarthritis patients, a follow-up period of at least 2 years, and at least 1 reported functional parameter (pain level or Patient-Reported Outcome Measures) were included. Exclusion criteria encompassed focal chondral defects and techniques including additional arthroscopic bone marrow stimulation. In 28 of 29 studies, FDO showed a subjective improvement in symptoms (pain and Patient-Reported Outcome Measures) up to a maximum follow-up of 7.2 years. Radiographic cartilage regeneration up to 3 years postoperatively, as well as macroscopic cartilage regeneration investigated via second-look arthroscopy, may corroborate the favorable clinical findings in patients with knee osteoarthritis. The methodological heterogeneity in FDO treatments leads to variations in cell composition and represents a limitation in the current state of knowledge. However, this systematic review suggests that FDO injection leads to beneficial mid-term results including symptom reduction and preservation of the affected joint in knee osteoarthritis patients. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal/stem cells (MSCs), which are distributed in many tissues including bone marrow, have been reported to play a critical role in tumor development. While bone marrow, the primary site for hematopoiesis, is important for establishing the immune system, whether MSCs in the bone marrow can promote tumor growth via influencing hematopoiesis remains unclear. We observed that the numbers of MSCs and neutrophils were increased in bone marrow in tumor-bearing mice. Moreover, co-culture assay showed that MSCs strongly protected neutrophils from apoptosis and induced their maturation. G-CSF and GM-CSF have been well-documented to be associated with neutrophil formation. We found a remarkably increased level of G-CSF, but not GM-CSF, in the supernatant of MSCs and the serum of tumorbearing mice. The G-CSF expression can be enhanced with inflammatory cytokines (IFNγ and TNFα) stimulation. Furthermore, we found that IFNγ and TNFα-treated MSCs enhanced their capability of promoting neutrophil survival and maturation. Our results indicate that MSCs display robustly protective effects on neutrophils to contribute to tumor growth in bone niches. [ABSTRACT FROM AUTHOR]

Background: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. Methods: C57BL/6J mice (9–14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45−, TER-119−, CD31−) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. Results: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. Conclusions: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS. [ABSTRACT FROM AUTHOR]

Leukemias and their bone marrow microenvironments undergo dynamic changes over the course of disease. However, little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of CLC dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1–2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: (i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and (ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells. A blood exchange system reveals that leukemia cells clear faster in the blood than circulating tumor cells from solid tumors and that clearance rates can vary in response to tumor and treatment status. [ABSTRACT FROM AUTHOR]

Background: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is characterized by lymphoproliferation and increased risk of malignancy. FDG-PET/CT may represent a helpful diagnostic tool for differentiating these clinical features and correctly diagnosing inborn errors of immunity (IEI). Case report: We present the case of a female patient diagnosed with Hodgkin's lymphoma at 19 years of age, although atypical imaging aspects emerged: baseline FDG-PET/CT revealed several hot lymph nodes with a symmetrical distribution, and increased tracer uptake in spleen, axial, and appendicular bone marrow. Imaging repeated after chemotherapy and autologous stem cell transplantation showed persistent increased FDG uptake at multiple supradiaphragmatic nodes and in bone marrow. After the diagnosis of APDS2 and rapamycin treatment, FDG-PET/CT confirmed complete metabolic normalization of all sites. Conclusions: In the IEI scenario, FDG-PET/CT plays an effective role in differentiating malignant proliferation and immune dysregulation phenotypes. Atypical patterns at FDG-PET/CT should be interpreted as a red flag for the need of an early immunological evaluation. [ABSTRACT FROM AUTHOR]

Background: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are associated with chronic organ enlargement, bone manifestations, and inflammation. Tartrate-resistant acid phosphatase type 5 (TRAP5 protein, ACP5 gene) has long been a nonspecific biomarker of macrophage/GCs activation; however, the discovery of two isoforms of TRAP5 has expanded its significance. The discovery of TRAP5′s two isoforms revealed that it is more than just a biomarker of macrophage activity. While TRAP5a is highly expressed in macrophages, TRAP5b is secreted by osteoclasts. Recently, we have shown that the elevation of TRAP5b in plasma is associated with osteoporosis in GD. However, the role of TRAP isoforms in GD and how the accumulation of Gb-1 and Lyso-Gb-1 affects TRAP expression is unknown. Methods: 39 patients with GD were categorized into cohorts based on bone mineral density (BMD). TRAP5a and TRAP5b plasma levels were quantified by ELISA. ACP5 mRNA was estimated using RT-PCR. Results: An increase in TRAP5b was associated with reduced BMD and correlated with Lyso-Gb-1 and immune activator chemokine ligand 18 (CCL18). In contrast, the elevation of TRAP5a correlated with chitotriosidase activity in GD. Lyso-Gb-1 and plasma seemed to influence the expression of ACP5 in macrophages. Conclusions: As an early indicator of BMD alteration, measurement of circulating TRAP5b is a valuable tool for assessing osteopenia–osteoporosis in GD, while TRAP5a serves as a biomarker of macrophage activation in GD. Understanding the distinct expression pattern of TRAP5 isoforms offers valuable insight into both bone disease and the broader implications for immune system activation in GD. [ABSTRACT FROM AUTHOR]

Background: Bilateral suprarenal neuroblastoma (BSN) is a rare presentation. Few previously published literature showed BSN patients to have favorable pattern and prognosis. This study aim was to evaluate clinical and biological features in relation to outcome of Egyptian patients with BSN. Methods: Included patients were diagnosed from 2007 to 2017, retrospectively. Tissue biopsy, imaging and bone marrow were evaluated at presentation. Clinical, demographic, biological variables and risk group were determined and analyzed in relation to overall (OS) and event-free-survival (EFS). Results: BSN patients (n = 33) represented 2% of hospital patients with neuroblastoma during the 10-year study period, 17 were males and 16 were females. Twenty-four patients (72.7%) were infants, and 9 patients (27.3%) were above 1 year of age (range: 1 month to 3 years). Metachronous disease was present in only one patient. Amplified MYCN was found in 10 patients. Initially, most patients (n = 25) had distant metastasis, 6 had stage 3 versus 2 stage 2. Fifteen were high risk (HR), 15 intermediate (IR), 1 low risk (LR) and 2 were undetermined due to inadequate tissue biopsy. Three-year OS for HR and IR patients were 40.5% and 83.9% versus 23.2% and 56.6% EFS; respectively. Conclusion: BSN treatment is similar to unilateral disease. A more conservative surgical approach with adrenal tissue preservation on less extensive side should be considered. Biological variables and extent of disease are amongst the most important prognostic determinants. Future studies are warranted to further address the biologic profiling of BSN and highlight prognostic significance of size difference between both adrenal sides. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian insufficiency (POI) is a major cause of infertility. In this study, we aimed to investigate the effects of the combination of bone marrow mesenchymal stem cells (BMSCs) and moxibustion (BMSCs-MOX) on POI and evaluate the underlying mechanisms. Methods: A POI rat model was established by injecting different doses of cyclophosphamide (Cy). The modeling of POI and the effects of the treatments were assessed by evaluating estrous cycle, serum hormone levels, ovarian weight, ovarian index, and ovarian histopathological analysis. The effects of moxibustion on BMSCs migration were evaluated by tracking DiR-labeled BMSCs and analyzing the expression of chemokines stromal cell-derived factor 1 (Sdf1) and chemokine receptor type 4 (Cxcr4). Mitochondrial function and mitophagy were assessed by measuring the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, and the mitophagy markers (Drp1, Pink1, and Parkin). Furthermore, the mitophagy inhibitor Mdivi-1 and the mitophagy activator CCCP were used to confirm the role of mitophagy in Cy-induced ovarian injury and the underlying mechanism of combination therapy. Results: A suitable rat model of POI was established using Cy injection. Compared to moxibustion or BMSCs transplantation alone, BMSCs-MOX showed improved outcomes, such as reduced estrous cycle disorders, improved ovarian weight and index, normalized serum hormone levels, increased ovarian reserve, and reduced follicle atresia. Moxibustion enhanced Sdf1 and Cxcr4 expression, promoting BMSCs migration. BMSCs-MOX reduced ROS levels; upregulated MMP and ATP levels in ovarian granulosa cells (GCs); and downregulated Drp1, Pink1, and Parkin expression in ovarian tissues. Mdivi-1 significantly mitigated mitochondrial dysfunction in ovarian GCs and improved ovarian function. CCCP inhibited the ability of BMSCs-MOX treatment to regulate mitophagy and ameliorate Cy-induced ovarian injury. Conclusions: Moxibustion enhanced the migration and homing of BMSCs following transplantation and improves their ability to repair ovarian damage. The combination of BMSCs and moxibustion effectively reduced the excessive activation of mitophagy, which helped prevent mitochondrial damage, ultimately improving ovarian function. These findings provide a novel approach for the treatment of pathological ovarian aging and offer new insights into enhancing the efficacy of stem cell therapy for POI patients. [ABSTRACT FROM AUTHOR]

Diffuse large B cell lymphoma (DLBCL) is one of the most prevalent subtypes of non-Hodgkin lymphoma (NHL) and is known for commonly infiltrating extra-nodal sites. The involvement of the bone marrow by lymphoma cells significantly impacts the staging, treatment, and prognosis among the extra-nodal sites in DLBCL. Bone marrow biopsy has been considered the standard diagnostic procedure for detecting bone marrow involvement. However, advancements in imaging techniques, such as positron emission tomography-computed tomography (PET-CT), have shown an improved ability to detect bone marrow involvement, making the need for bone marrow biopsy debatable. This review aims to emphasize the importance of bone marrow evaluation in adult patients newly diagnosed with DLBCL and suggest an optimal diagnostic approach to identify bone marrow involvement in these patients. [ABSTRACT FROM AUTHOR]

This research was conducted to test the effect of oxygen content (low O2, high O2, air) during hermetic seed storage at 20±2℃ over 8 and 12 months on seed germination and seedling root and shoot length in tomato, onion, cabbage, and marrow seeds. Samples with low oxygen storage had higher seed germination as well as longer root and shoot lengths than both control and high oxygen storage. When the storage period extended from 8 to 12 months, the germination percentages also reduced. However, these results varied among the species. The greatest advantage of low oxygen storage was obtained in tomatoes, which exhibited 15% and 9% higher germination compared to the control after 8 and 12 months of storage, respectively. The longest root and shoot lengths of 6.4 cm and 11.6 cm, respectively, were obtained from the low oxygen storage treatments. A similar positive effect of low oxygen storage was observed in onion and cabbage seeds but not in marrows. Results indicated that oxygen level in the packets during storage can be an effective component to maintain high seed germination and seedling growth potential (seed vigour). The difference in the effect on different species is a matter of further research. [ABSTRACT FROM AUTHOR]

Human Respiratory Syncytial Virus (RSV) is a common cause of respiratory tract infections. Usually associated with infants and children, an increasing amount of evidence suggests that RSV can cause substantial morbidity and mortality in immunocompromised individuals, including recipients of bone marrow transplantation (BMT). The present systematic review was therefore designed in accordance with the PRISMA guidelines to collect available evidence about RSV infections in BMT recipients. Three medical databases (PubMed, Embase, and MedRxiv) were therefore searched for eligible observational studies published up to 30 September 2023 and collected cases were pooled in a random-effects model. Heterogeneity was assessed using I2 statistics. Reporting bias was assessed by means of funnel plots and regression analysis. Overall, 30 studies were retrieved, including 20,067 BMT cases and 821 RSV infection episodes. Of them, 351 were lower respiratory tract infections, and a total of 78 RSV-related deaths were collected. A pooled attack rate of 5.40% (95% confidence interval [95%CI] 3.81 to 7.60) was identified, with a corresponding incidence rate of 14.77 cases per 1000 person-years (95%CI 9.43 to 20.11), and a case fatality ratio (CFR) of 7.28% (95%CI 4.94 to 10.60). Attack rates were higher in adults (8.49%, 95%CI 5.16 to 13.67) than in children (4.79%, 95%CI 3.05 to 7.45), with similar CFR (5.99%, 95%CI 2.31 to 14.63 vs. 5.85%, 95%CI 3.35 to 10.02). By assuming RSV attack rates as a reference group, influenza (RR 0.518; 95%CI 0.446 to 0.601), adenovirus (RR 0.679, 95%CI 0.553 to 0.830), and human metapneumovirus (RR 0.536, 95%CI 0.438 to 0.655) were associated with a substantially reduced risk for developing corresponding respiratory infection. Despite the heterogeneous settings and the uneven proportion of adult and pediatric cases, our study has identified high attack rates and a substantial CFR of RSV in recipients of BMT, stressing the importance of specifically tailored preventive strategies and the need for effective treatment options. [ABSTRACT FROM AUTHOR]

Background & Objective: Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults with various signs, symptoms, and types of progression. In this study, we have investigated the frequency and correlation of laboratory findings including peripheral blood smear, bone marrow aspiration and biopsy, and cellular immunophenotyping in CLL patients. Methods: In this cross-sectional and retrospective study, the laboratory information of all 161 patients with definite diagnoses of CLL was extracted, and the frequency and correlation between different laboratory data were analyzed by descriptive statistics methods and Jamovi software version 2022. Results: Demographic factors such as age and gender, and laboratory factors such as anemia, thrombocytopenia, white blood cell count, percentage of lymphocytes, and patterns of bone marrow involvement were evaluated for 161 patients. There was a significant relationship between the bone marrow iron storage and the percentage of FMC7 marker expression with the percentage of atypical lymphocytes in the peripheral blood. Conclusion: Chronic lymphocytic leukemia, a prevalent form of leukemia associated with substantial mortality and morbidity, can be detected through a range of diagnostic techniques. Analyzing the results of these diagnostic tests and examining the prevalence of these indicators in patients afflicted with the condition can prove highly beneficial for prompt disease diagnosis, and prognosis determination among affected individuals. [ABSTRACT FROM AUTHOR]

The relevance of this study is conditioned by the widespread use of stem cells in veterinary medicine, a wide range of studies and ambiguous data on the oncoprotective properties of stem cells of different origins. In this regard, the purpose of this study was to investigate the course of the tumour process in Lewis lung carcinoma and the specific features of the effect of allogeneic mesenchymal stem cells of red bone marrow culture on it. The leading approach to investigating this problem was the method of modelling Lewis lung carcinoma in C57BL6 mice and the use of stem cells. The use of allogeneic mesenchymal stem cells from the bone marrow culture of C57BL6 mice with transplanted epidermoid metastatic carcinoma of the Lewis lung contributed to the activation of the tumour process. Under the influence of allogeneic mesenchymal stem cells of red bone marrow culture from Day 14 to Day 24 of the study, the body weight of mice decreased by 7.0-12.1% (P < 0.05) compared to the control, the diameter of the primary tumour increased by 1.43-1.51 times (P < 0.05), which is conditioned by the activation of primary tumour growth. The number of lymphocytes as producers of vascular growth factor in primary tumour tissue under the influence of allogeneic mesenchymal stem cells of red bone marrow culture significantly increased by 1.47 and 1.52 times on Day 18 of the experiment compared to animals of the control group and placebo (P < 0.05), respectively. This promoted angiogenesis in the primary tumour node and metastasis through the circulatory system. After administration allogeneic mesenchymal cells of red bone marrow culture to mice, a larger volume of lung metastases was recorded, which was 41.52 ± 7.9 mm3 compared to the values in the control and placebo groups, respectively, 17.94 ± 6.59 and 16.43 ± 5.32 mm3. The morphological picture of the histological sections of the primary tumour of Lewis lung carcinoma confirms all the signs of qualitative and quantitative indicators of its progression. The findings obtained are of both theoretical and practical value for clinical veterinary medicine on the use of allogeneic bone marrow mesenchymal stem cells in tumour processes. [ABSTRACT FROM AUTHOR]

The generation of bone-marrow-derived dendritic cells is a widely used approach in immunological research to study antigen processing and presentation, as well as T-cell activation responses. However, the initial step of isolating the bone marrow can be time-consuming, especially when larger numbers of precursor cells are required. Here, we assessed whether an accelerated bone marrow isolation method using centrifugation is suitable for the differentiation of FMS-like tyrosine kinase 3 ligand-driven dendritic cells. Compared to the conventional flushing method, the centrifugation-based isolation method resulted in a similar bone marrow cell yield on Day 0, increased cell numbers by Day 8, similar proportions of dendritic cell subsets, and consequently a higher number of type 1 conventional dendritic cells (cDC1) from the culture. Although the primary purpose of this method of optimization was to improve experimental efficiency and increase the output of cDC1s, the protocol is also compatible with the differentiation of other dendritic cell subsets such as cDC2 and plasmacytoid dendritic cells, with an improved output cell count and a consistent phenotype. [ABSTRACT FROM AUTHOR]

Oncolytic viruses and combinatorial immunotherapy for cancer (this Special Issue) are both part of cancer treatment at IOZK. This review focusses on an individual multimodal cancer immunotherapy concept developed by IOZK, Cologne, Germany. The scientific rationale for employing three main components is explained: (i) oncolytic Newcastle disease virus, (ii) modulated electrohyperthermia and (iii) individual tumor antigen and oncolytic virus modified dendritic cell vaccine (IO-VACR). The strategy involves repeated cancer-immunity cycles evoked in cancer patients by systemic oncolytic virus exposure plus hyperthermia pretreatment to induce immunogenic cell death followed by intradermal IO-VACR vaccination. As an example of the experience at IOZK, we present the latest results from combining the immunotherapy with standard treatment of patients suffering from glioblastoma multiforme. The promising clinical results in terms of overall survival benefit of additional individualized multimodal immunotherapy are presented. The cancer-immunity cycle, as introduced 10 years ago, describes key important steps occurring locally at the sites of both tumor and draining lymph nodes. This view is extended here towards systemic events occuring in blood where immunogenic cell death-induced tumor antigens are transported into the bone marrow. For 20 years it has been known that bone marrow is an antigen-responsive organ in which dendritic cells present tumor antigens to T cells leading to immunological synapse formation, tumor antigen-specific T cell activation and memory T cell formation. Bone marrow is known to be the most prominent source of de novo cellular generation in the body and to play an important role for the storage and maintenance of immunological memory. Its systemic activation is recommended to augment cancer-immunity cycles. [ABSTRACT FROM AUTHOR]

Purpose This study aims to investigate the diagnostic significance of positron emission tomography/computed tomography (PET/CT) in assessing bone marrow (BM) involvement through a comparison of PET/CT findings with BM biopsy in extranodal natural killer/T-cell lymphoma. Materials and Methods The medical records of 193 patients were retrospectively reviewed. Patients were categorized as having early-stage (PET-ES) or advanced-stage (PET-AS) disease based on PET/CT results. The BM involvement was classified into three groups according to BM biopsy: gross BM involvement, minimal BM involvement (defined as the presence of a limited number of Epstein-Barr virus-positive cells in BM), and no involvement. Calculations of the accuracy of PET/CT in detecting BM involvement and analysis of the clinical outcomes (progression-free survival [PFS] and overall survival [OS]) according to the BM biopsy status were performed. Results PET/CT exhibited a sensitivity of 64.7% and a specificity of 96.0% in detecting gross BM involvement. For detecting any (both gross and minimal) BM involvement, the sensitivity was 30.4%, while the specificity was 99.0%. Only one patient (0.7%) demonstrated gross BM involvement among the PET-ES group. Survival outcomes of the PET-ES group with minimal BM involvement (3-year PFS, 55.6%; OS, 77.0%) were closer to those of the PET-ES group with no BM involvement (3-year PFS, 62.2%; OS, 80.6%) than to those of the PET-AS group (3-year PFS, 20.1%; OS, 29.9%). Conclusion PET/CT exhibits high specificity, but moderate and low sensitivity in detecting gross and minimal BM involvement, respectively. The clinical significance of minimal BM involvement for patients in the PET-ES group may be limited. [ABSTRACT FROM AUTHOR]

Objectives: MR imaging-based proton density fat fraction (PDFF) and T2* imaging has shown to be useful for the evaluation of degenerative changes in the spine. Therefore, the aim of this study was to investigate the influence of myelotoxic chemotherapy on the PDFF and T2* of the thoracolumbar spine in comparison to changes in bone mineral density (BMD). Methods: In this study, 19 patients were included who had received myelotoxic chemotherapy (MC) and had received a MR imaging scan of the thoracolumbar vertebrates before and after the MC. Every patient was matched for age, sex, and time between the MRI scans to two controls without MC. All patients underwent 3-T MR imaging including the thoracolumbar spine comprising chemical shift encoding-based water-fat imaging to extract PDFF and T2* maps. Moreover, trabecular BMD values were determined before and after chemotherapy. Longitudinal changes in PDFF and T2* were evaluated and compared to changes in BMD. Results: Absolute mean differences of PDFF values between scans before and after MC were at 8.7% (p = 0.01) and at −0.5% (p = 0.57) in the control group, resulting in significantly higher changes in PDFF in patients with MC (p = 0.008). BMD and T2* values neither showed significant changes in patients with nor in those without myelotoxic chemotherapy (p = 0.15 and p = 0.47). There was an inverse, yet non-significant correlation between changes in PDFF and BMD found in patients with myelotoxic chemotherapy (r = −0.41, p = 0.12). Conclusion: Therefore, PDFF could be a useful non-invasive biomarker in order to detect changes in the bone marrow in patients receiving myelotoxic therapy. Clinical relevance statement: Using PDFF as a non-invasive biomarker for early bone marrow changes in oncologic patients undergoing myelotoxic treatment may help enable more targeted countermeasures at commencing states of bone marrow degradation and reduce risks of possible fragility fractures. Key Points: Quantifying changes in bone marrow fat fraction, as well as T2* caused by myelotoxic pharmaceuticals using proton density fat fraction, is feasible. Proton density fat fraction could potentially be established as a non-invasive biomarker for early bone marrow changes in oncologic patients undergoing myelotoxic treatment. [ABSTRACT FROM AUTHOR]

The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9–based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3+ progenitors up-regulated pro-inflammatory and macrophage-specific genes but failed to induce the DC differentiation program. Collectively, these data elucidate mechanisms that control Flt3L-driven differentiation of the entire DC lineage and identify Trim33 as its essential regulator. Editor's summary: Dendritic cells (DCs) differentiate from bone marrow progenitors through a process guided by the cytokine Flt3 ligand (Flt3L). Using CRISPR-Cas9–based screening, Tiniakou et al. identified key regulators of murine Flt3L-driven DC differentiation including the arginine methyltransferase Carm1, mTOR-negative regulators TSC and GATOR1, and the transcriptional repressor Trim33. Trim33-deficient mice displayed a near-complete loss of multiple DC subsets with minimal impact on monocytes or granulocytes. During DC differentiation, Trim33 repressed expression of type I interferon and genes associated with other myeloid lineages. These findings identify Trim33 as a key transcriptional regulator of the Flt3L-driven pathway of DC differentiation. —Claire Olingy [ABSTRACT FROM AUTHOR]

Alternative polyadenylation can occur in introns, termed intronic polyadenylation (IPA), has been implicated in diverse biological processes and diseases, as it can produce noncoding transcripts or transcripts with truncated coding regions. However, a reliable method is required to accurately characterize IPA. Here, we propose a computational method called InPACT, which allows for the precise characterization of IPA from conventional RNA-seq data. InPACT successfully identifies numerous previously unannotated IPA transcripts in human cells, many of which are translated, as evidenced by ribosome profiling data. We have demonstrated that InPACT outperforms other methods in terms of IPA identification and quantification. Moreover, InPACT applied to monocyte activation reveals temporally coordinated IPA events. Further application on single-cell RNA-seq data of human fetal bone marrow reveals the expression of several IPA isoforms in a context-specific manner. Therefore, InPACT represents a powerful tool for the accurate characterization of IPA from RNA-seq data. Intronic polyadenylation (IPA) can produce transcripts with truncated coding regions and has been implicated in diverse biological processes and diseases. Here, the authors present a computational method for the accurate delineation of IPA events using RNA-sequencing data. [ABSTRACT FROM AUTHOR]

In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression. The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression. [ABSTRACT FROM AUTHOR]

This review focuses on non-surgical treatment options for rotator cuff injuries and highlights the potential of mesenchymal stem cells (MSCs) as a potential regenerative approach. MSCs, sourced from various tissues like bone marrow and adipose tissue, exhibit promising mechanisms in vitro, influencing tendon-related gene expression and microenvironment modulation. Animal studies support this, showcasing MSCs' ability to reduce inflammation, improve tissue remodeling, and enhance repaired tendon strength. Human trials, while varied and limited, suggest that MSCs might lower retear rates and enhance post-repair outcomes, but randomized controlled trials yield mixed results, emphasizing the necessity for standardized investigations. Ultimately, while cell-based therapies demonstrate an excellent safety profile, more rigorous clinical trials are necessary to determine their efficacy in improving patient outcomes and achieving lasting structural changes in rotator cuff injuries. [ABSTRACT FROM AUTHOR]

Simple Summary: B-cell acute lymphoblastic leukemia is genetically diverse, with one of the most commonly altered genes being PAX5. Recently, alterations in PAX5 have been identified not merely as secondary events, but also as the oncogenic drivers, with newly defined genetic subtypes like PAX5alt and PAX5 P80R. Studying a consecutive cohort of 99 B-ALL patients, we found PAX5 alterations in over a third of patients, mostly involving copy number variations. Seven of our patients exhibited the PAX5alt genetic profile and one carried the P80R variant, and these patients showed intermediate outcomes. We also discovered that patients within the hyperdiploid group that carried extra copies of PAX5 did not respond as well to the treatment. Overall, our study highlights widespread PAX5 alterations affecting treatment response, particularly in specific genetic subtypes, underlining the need to identify these alterations for improved treatment strategies. In this study, we aimed to identify patients within our B-ALL cohort with altered PAX5. Our objective was to use a comprehensive analysis approach to characterize the types of genetic changes, determine their origin (somatic/germline), and analyze the clinical outcomes associated with them. A consecutive cohort of 99 patients with B-ALL treated at the Children's Hospital of the UMC Ljubljana according to the ALL IC-BFM 2009 protocol was included in our study. We used RNA sequencing data for gene expression analysis, fusion gene detection and single nucleotide variant identification, multiplex-ligation dependent probe amplification for copy number variation assessment, and Sanger sequencing for germline variant detection. PAX5 was impacted in 33.3% of our patients, with the genetic alterations ranging from CNVs and rearrangements to SNVs. The most common were CNVs, which were found in more than a third of patients, followed by point mutations in 5.2%, and gene rearrangements in 4.1%. We identified eight patients with a PAX5-associated genetic subtype that were previously classified as "B-other", and they showed intermediate outcomes. We showed higher minimal residual disease values at the end of induction and poorer event-free survival in hyperdiploid cases carrying duplications in PAX5 compared to other hyperdiploid cases. We also report an interesting case of a patient with PAX5::FKBP15 and a pathogenic variant in PTPN11 who underwent an early relapse with a monocytic switch. In conclusion, this study provides valuable insights into the presence, frequency, and prognostic significance of diverse PAX5 alterations in B-ALL patients, highlighting the complexity of genetic factors and their impact on patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is associated with chronic low-grade inflammation of adipose tissue (AT) and an increase of AT macrophages (ATMs) that is linked to the onset of type 2 diabetes. We have recently shown that neutralization of interleukin (IL)-6 in obese AT organ cultures inhibits proliferation of ATMs, which occurs preferentially in alternatively activated macrophage phenotype. Methods: In this study, we investigated AT biology and the metabolic phenotype of mice with myeloid cell-specific IL-6Ra deficiency (Il6raΔmyel) after normal chow and 20 weeks of high-fat diet focusing on AT inflammation, ATM polarization and proliferation. Using organotypical AT culture and bone marrow derived macrophages (BMDMs) of IL-4Ra knockout mice (Il4ra-/-) we studied IL-6 signaling. Results: Obese Il6raΔmyel mice exhibited no differences in insulin sensitivity or histological markers of AT inflammation. Notably, we found a reduction of ATMs expressing the mannose receptor 1 (CD206), as well as a decrease of the proliferation marker Ki67 in ATMs of Il6raΔmyel mice. Importantly, organotypical AT culture and BMDM data of Il4ra-/- mice revealed that IL-6 mediates a shift towards the M2 phenotype independent from the IL-6/IL-4Ra axis. Discussion: Our results demonstrate IL-4Ra-independent anti-inflammatory effects of IL-6 on macrophages and the ability of IL-6 to maintain proliferation rates in obese AT. [ABSTRACT FROM AUTHOR]