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1.
Impaired bone marrow microenvironment and stem cells in transfusion-dependent beta-thalassemia.
Zhou, X, Huang, L, Wu, J, Qu, Y, Jiang, H, Zhang, J, Qiu, S, Liao, C, Xu, X, Xia, J, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112548
Abstract
Beta-thalassemia (BT) is a hereditary disease caused by abnormal hemoglobin synthesis with consequent ineffective erythropoiesis. Patients with thalassemia major are dependent on long-term blood transfusions with associated long-term complications such as iron overload (IO). This excess iron can result in tissue damage, impaired organ function, and increased morbidity. Growing evidence has demonstrated that IO contributes to impairment of the bone marrow (BM) microenvironment that largely impacts the function of BM mesenchymal stem cells, hematopoietic stem cells, and endothelial cells. In this article, we review recent progress in the understanding of iron metabolism and the perniciousness induced by IO. We highlight the importance of understanding the cross-talk between BM stem cells and the BM microenvironment, particularly the pathological effect of IO on BM stem cells and BT-associated complications. We also provide an update on recent novel therapies to cure transfusion-dependent beta-thalassemia and iron overload-induced complications for their future clinical application.
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Tetrandrine overcomes drug resistance mediated by bone marrow microenvironment by regulating the expression of P-glycoprotein in acute leukemia.
Zhou, X, Jin, N, Chen, B
Hematology (Amsterdam, Netherlands). 2022;(1):274-279
Abstract
Objectives: To study the effect of TET on the reversal of drug resistance in the bone marrow microenvironment, and to further promote the research on drug reversal.Methods: We established a co-culture system of bone marrow mesenchymal stem cells (BM-MSC) and K562 cell lines, and compared the cell inhibition rate of K562 cells between the co-culture group and K562 singleculture group by daunorubicin (DNR) single-drug intervention with CCK-8 and also compared K562 proliferation in the co-culture group and K562 single-culture group after combined intervention with DNR and TET, then used Western blot and RT-qPCR to verify the expression of P-gp of K562 cells at protein and mRNA levels, confirmed the concentration of DNR in K562 of different experimental groups by HPLC-MS.Results: According to the results of CCK-8, after co-culture with bone marrow mesenchymal stem cells (BM-MSCs), the inhibition rate of DNR on K562 decreased significantly. When TET (1μmol/L) combined with daunorubicin (DNR) treated on the co-culture group, the inhibition rate increased significantly. Then, the results of RT-qPCR and western blot showed a remarkable difference of the expression of P-glycoprotein (P-gp). After co-culture with BM-MSCs, the protein expression of P-gp showed a significant upward trend. After adding TET intervention, the expression of P-gp decreased both in mRNA and protein levels. Also, the DNR concentration in K562 also performed the correspondent trend.Conclusion: The bone marrow microenvironment can promote the MDR of acute leukemia. TET can reverse the MDR mediated by the bone marrow microenvironment by inhibiting the expression of P-glycoprotein.
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Immunoglobulin D-kappa multiple myeloma in a patient with rheumatoid arthritis: a case report and review of the literature.
Tokunaga, T, Hashimoto, H, Yoshida, Y, Sugimoto, T, Mokuda, S, Kosaka, Y, Shimizu, R, Hirata, S, Kumagai, T, Komoto, K, et al
Modern rheumatology case reports. 2021;(1):22-28
Abstract
A 77-year-old Japanese woman with a 21-year history of seropositive, erosive rheumatoid arthritis (RA) and a 10-year history of methotrexate (MTX) therapy was admitted with malaise and mild consciousness disturbance. Laboratory data showed hypercalcemia, acute kidney injury, normocytic anaemia, and thrombocytopenia. As we first assumed drug-induced toxicity by MTX and eldecalcitol, both were discontinued and leucovorin rescue therapy and calcitonin were administered. However, her condition continued to worsen. Serum protein electrophoresis showed only a small M-peak, immunoelectrophoresis of both the serum and urine demonstrated Bence-Jones kappa (κ) type monoclonal protein without immunoglobulin heavy chain, and bone marrow examination revealed proliferation of plasma cells. We diagnosed her with Bence-Jones κ type multiple myeloma (MM) and transferred her to the department of haematology of a higher order medical institution. Conclusively, the diagnosis of immunoglobulin (Ig) D-κ type MM, a rare variant of this disorder, was determined in accordance with serum immunofixation. Several previous studies have suggested that pre-existing RA is a risk factor for MM. Although IgD MM is characterised by its clinical severity and poor prognosis compared to other subtypes, it is often misdiagnosed or mistaken as light chain type MM, as in the present case, because of the low level of IgD M-protein, resulting in delayed diagnosis. Physicians must take MM into consideration as a differential diagnosis when inactive RA patients present with inexplicable elevated calcium, renal failure, anaemia, and bone lesion symptoms and should be aware of IgD MM to establish the correct diagnosis promptly.
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Radiotracers for Bone Marrow Infection Imaging.
Jødal, L, Afzelius, P, Alstrup, AKO, Jensen, SB
Molecules (Basel, Switzerland). 2021;(11)
Abstract
INTRODUCTION Radiotracers are widely used in medical imaging, using techniques of gamma-camera imaging (scintigraphy and SPECT) or positron emission tomography (PET). In bone marrow infection, there is no single routine test available that can detect infection with sufficiently high diagnostic accuracy. Here, we review radiotracers used for imaging of bone marrow infection, also known as osteomyelitis, with a focus on why these molecules are relevant for the task, based on their physiological uptake mechanisms. The review comprises [67Ga]Ga-citrate, radiolabelled leukocytes, radiolabelled nanocolloids (bone marrow) and radiolabelled phosphonates (bone structure), and [18F]FDG as established radiotracers for bone marrow infection imaging. Tracers that are under development or testing for this purpose include [68Ga]Ga-citrate, [18F]FDG, [18F]FDS and other non-glucose sugar analogues, [15O]water, [11C]methionine, [11C]donepezil, [99mTc]Tc-IL-8, [68Ga]Ga-Siglec-9, phage-display selected peptides, and the antimicrobial peptide [99mTc]Tc-UBI29-41 or [68Ga]Ga-NOTA-UBI29-41. CONCLUSION Molecular radiotracers allow studies of physiological processes such as infection. None of the reviewed molecules are ideal for the imaging of infections, whether bone marrow or otherwise, but each can give information about a separate aspect such as physiology or biochemistry. Knowledge of uptake mechanisms, pitfalls, and challenges is useful in both the use and development of medically relevant radioactive tracers.
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Developing a standardized approach for assessing mast cells and eosinophils on tissue biopsies: A Work Group Report of the AAAAI Allergic Skin Diseases Committee.
Zimmermann, N, Abonia, JP, Dreskin, SC, Akin, C, Bolton, S, Happel, CS, Geller, M, Larenas-Linnemann, D, Nanda, A, Peterson, K, et al
The Journal of allergy and clinical immunology. 2021;(4):964-983
Abstract
Mast cells and eosinophils are commonly found, expectedly or unexpectedly, in human tissue biopsies. Although the clinical significance of their presence, absence, quantity, and quality continues to be investigated in homeostasis and disease, there are currently gaps in knowledge related to what constitutes quantitatively relevant increases in mast cell and eosinophil number in tissue specimens for several clinical conditions. Diagnostically relevant thresholds of mast cell and eosinophil numbers have been proposed and generally accepted by the medical community for a few conditions, such as systemic mastocytosis and eosinophilic esophagitis. However, for other mast cell- and eosinophil-associated disorders, broad discrepancies remain regarding diagnostic thresholds and how samples are processed, routinely and/or specially stained, and interpreted and/or reported by pathologists. These discrepancies can obfuscate or delay a patient's correct diagnosis. Therefore, a work group was assembled to review the literature and develop a standardized consensus for assessing the presence of mast cells and eosinophils for a spectrum of clinical conditions, including systemic mastocytosis and cutaneous mastocytosis, mast cell activation syndrome, eosinophilic esophagitis, eosinophilic gastritis/enteritis, and hypereosinophilia/hypereosinophilic syndrome. The intent of this work group is to build a consensus among pathology, allergy, dermatology, hematology/oncology, and gastroenterology stakeholders for qualitatively and quantitatively assessing mast cells and eosinophils in skin, gastrointestinal, and bone marrow pathologic specimens for the benefit of clinical practice and patients.
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Bone Marrow Metabolism Is Impaired in Insulin Resistance and Improves After Exercise Training.
Ojala, R, Motiani, KK, Ivaska, KK, Arponen, M, Eskelinen, JJ, Virtanen, KA, Löyttyniemi, E, Heiskanen, MA, U-Din, M, Nuutila, P, et al
The Journal of clinical endocrinology and metabolism. 2020;(12):e4290-303
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Abstract
CONTEXT Exercise training improves bone mineral density, but little is known about the effects of training on bone marrow (BM) metabolism. BM insulin sensitivity has been suggested to play an important role in bone health and whole-body insulin sensitivity. OBJECTIVE To study the effects of exercise training on BM metabolism. DESIGN Randomized controlled trial. SETTING Clinical research center. PARTICIPANTS Sedentary healthy (n = 28, 40-55 years, all males) and insulin resistant (IR) subjects (n = 26, 43-55 years, males/females 16/10). INTERVENTION Two weeks of sprint interval training or moderate-intensity continuous training. MAIN OUTCOME MEASURES We measured femoral, lumbar, and thoracic BM insulin-stimulated glucose uptake (GU) and fasting free fatty acid uptake (FFAU) using positron-emission tomography and bone turnover markers from plasma. RESULTS At baseline, GU was highest in lumbar, followed by thoracic, and lowest in femoral BM (all Ps < 0.0001). FFAU was higher in lumbar and thoracic than femoral BM (both Ps < 0.0001). BM FFAU and femoral BM GU were higher in healthy compared to IR men and in females compared to males (all Ps < 0.05). Training increased femoral BM GU similarly in all groups and decreased lumbar BM FFAU in males (all Ps < 0.05). Osteocalcin and PINP were lower in IR than healthy men and correlated positively with femoral BM GU and glycemic status (all Ps < 0.05). CONCLUSIONS BM metabolism differs regarding anatomical location. Short-term training improves BM GU and FFAU in healthy and IR subjects. Bone turnover rate is decreased in insulin resistance and associates positively with BM metabolism and glycemic control. CLINICAL TRIAL REGISTRATION NUMBER NCT01344928.
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Vertebral Bone Marrow Fat Is independently Associated to VAT but Not to SAT: KORA FF4-Whole-Body MR Imaging in a Population-Based Cohort.
Hasic, D, Lorbeer, R, Bertheau, RC, Machann, J, Rospleszcz, S, Nattenmüller, J, Rathmann, W, Peters, A, Bamberg, F, Schlett, CL
Nutrients. 2020;(5)
Abstract
The objective of the current study was to assess the relationship of bone marrow adipose tissue (BMAT) content to abdominal fat depots, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), as well as cardiovascular risk factors (CVRF) beyond physical activity in a population-based cohort study undergoing whole-body magnetic resonance (MR) imaging. Subjects of the Cooperative Health Research in the Augsburg Region (KORA) FF4 study without known cardiovascular disease underwent fat fraction quantification in vertebrae (BMATL1/L2) via a 2-point T1-weighted volumetric interpolated breath-hold examination (VIBE) Dixon sequence. The same MR sequence was applied to quantify VAT and SAT volume. Subjects' characteristics, including physical activity, were determined through standardized exams and self-assessment questionnaires. Univariate and multivariate linear regression were applied. In the cohort of 378 subjects (56 ± 9.1years; 42.1% female), BMATL1/L2 was 54.3 ± 10.1%, VAT was 4.54 ± 2.71 L, and SAT was 8.10 ± 3.68 L. VAT differed significantly across BMATL1/L2 tertiles (3.60 ± 2.76 vs. 4.92 ± 2.66 vs. 5.11 ± 2.48; p < 0.001), there was no significant differences for SAT (p = 0.39). In the fully adjusted model, VAT remained positively associated with BMATL1/L2 (β = 0.53, p = 0.03). Furthermore, BMATL1/L2 was associated with age (β = 5.40 per 10-years, p < 0.001), hemoglobin A1c (HbA1c; β = 1.55 per 1%, p = 0.04), lipids (β = 0.20 per 10 mg/dL triglycerides; β = 0.40 per 10 mg/dL low-density lipoprotein (LDL); β =-3.21 lipid-lowering medication; all p < 0.05), and less physical activity (β = 3.7 "no or nearly no exercise" as compared to "≥2 h per week, regularly", p = 0.003); gender was not significantly different (p = 0.57). In the population-based cohort, VAT but not SAT were associated with higher BMATL1/L2 independently of physical activity and other cardiovascular risk factors. Further, BMATL1/L2 increased with older age, less physical activity, higher HbA1c, and increased lipids but decreased with lipid-lowering medication.
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Marrow outside marrow: imaging of extramedullary haematopoiesis.
Malla, S, Razik, A, Das, CJ, Naranje, P, Kandasamy, D, Kumar, R
Clinical radiology. 2020;(8):565-578
Abstract
Extramedullary haematopoiesis (EMH) refers to the formation of non-neoplastic blood cell lines outside the bone marrow and is a common incidental finding when patients with haematological disorders are imaged. EMH presenting as mass (tumefactive EMH) has long been a radiological conundrum as it resembles neoplasms. Several imaging findings have been described in EMH, and these vary depending on the activity of the underlying haematopoiesis. The older lesions are easier to diagnose as they often demonstrate characteristic findings such as haemosiderin and fat deposition. In comparison, the newer, actively haematopoietic lesions often mimic neoplasms. Molecular imaging, particularly 99mTc labelled sulphur colloid scintigraphy, may be helpful in such cases. Although imaging is extremely useful in detecting and characterising EMH, imaging alone is often non-diagnostic as no single mass shows all the typical findings. Hence, a judgement based on the clinical background, combination of imaging findings, and slow interval growth may be more appropriate and practical in making the correct diagnosis. In every case, an effort has to be made in providing an imaging-based diagnosis as it may prevent a potentially risky biopsy. When confident differentiation is not possible, biopsy has to be resorted to. This article describes the causes, pathophysiology, and theories underlying the genesis of EMH, followed by the general and location-specific imaging findings. The purpose is to provide a thorough understanding of the condition as well as enable the clinical radiologist in making an imaging-based diagnosis whenever possible and identify the situations where biopsy has to be performed.
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Direct comparison of diagnostic accuracies of F-18 FDG PET and MRI for detection of bone marrow involvement in lymphoma patients; A meta-analysis.
Kim, K, Kim, SJ
Leukemia research. 2020;:106475
Abstract
BACKGROUND The purpose of the current study was to compare the diagnostic accuracies of F-18 FDG PET or PET/CT and MRI for detection of bone marrow involvement (BMI) in lymphoma patients through a systematic review and meta-analysis. METHODS AND MATERIALS The PubMed, Cochrane database, and EMBASE database, from the earliest available date of indexing through July 31, 2020, were searched for studies evaluating direct comparison of diagnostic performance of F-18 FDG PET or PET/CT and MRI for BMI in lymphoma patients. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR + and LR-), and constructed summary receiver operating characteristic curves. RESULTS Across 5 studies (212 patients), the pooled sensitivity of F-18 FDG PET or PET/CT was 0.65 (95 % CI; 0.42-0.82) a pooled specificity of 0.90 (95 % CI; 0.85-0.94). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 6.4 (95 % CI; 3.3-12.4) and negative likelihood ratio (LR-) of 0.39 (95 % CI; 0.21-0.73). The pooled DOR was 16 (95 % CI; 5-56). The pooled sensitivity of MRI was 0.78 (95 % CI; 0.55-0.91) and a pooled specificity of 0.86 (95 % CI; 0.67-0.95). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 5.6 (95 % CI; 1.8-17.0) and negative likelihood ratio (LR-) of 0.26 (95 % CI; 0.1-0.65). The pooled DOR was 22 (95 % CI; 3-149). In meta-regression analysis, no variable was the source of the study heterogeneity. CONCLUSION F-18 FDG PET or PET/CT and MRI showed similar diagnostic performances for the detection of BMI in lymphoma patients. Further large multicenter studies would be necessary to substantiate the diagnostic accuracy of F-18 FDG PET or PET/CT and MRI for the diagnosis of BMI in lymphoma patients.
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Optimising dual-energy CT scan parameters for virtual non-calcium imaging of the bone marrow: a phantom study.
Müller, FC, Børgesen, H, Gosvig, K, Rodell, A, Booz, C, Schmidt, B, Krauss, B, Boesen, M
European radiology experimental. 2019;(1):46
Abstract
BACKGROUND We investigated the influence of dose, spectral separation, pitch, rotation time, and reconstruction kernel on accuracy and image noise of virtual non-calcium images using a bone marrow phantom. METHODS The phantom was developed at our institution and scanned using a third-generation dual-source dual-energy CT scanner at five different spectral separations by varying the tube-voltage combinations (70 kV/Sn150 kV, 80 kV/Sn150 kV, 90 kV/Sn150 kV, and 100 kV/Sn150 kV, all with 0.6-mm tin filter [Sn]; 80 kV/140 kV without tin filter) at six different doses (volume computed tomography dose index from 1 to 80 mGy). In separate experiments, rotation times, pitch, and reconstruction kernels were varied at a constant dose and tube voltage. Accuracy was determined by measuring the mean error between virtual non-calcium values in the fluid within and outside of the bone. Image noise was defined as the standard deviation of virtual non-calcium values. RESULTS Spectral separation, dose, rotation time, or pitch did not significantly correlate (p > 0.083) with mean error. Increased spectral separation (rs-0.96, p < 0.001) and increased dose (rs-0.98, p < 0.001) correlated significantly with decreased image noise. Increasing sharpness of the reconstruction kernel correlated with mean error (rs 0.83, p = 0.015) and image noise (rs 1.0, p < 0.001). CONCLUSIONS Increased dose and increased spectral separation significantly lowered image noise in virtual non-calcium images but did not affect the accuracy. Virtual non-calcium reconstructions with similar accuracy and image noise could be achieved at a lower tube-voltage difference by increasing the dose.