Active Bone Marrow Research Articles

Comparison of Hematologic Toxicity and Bone Marrow Compensatory Response in Head and Neck vs. Cervical Cancer Patients Undergoing Chemoradiotherapy.

Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy.Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m2. We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18F-fluorodeoxyglucose positron emission tomography/computed tomography.Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, −0.06 [−0.09, −0.031]; platelets,−0.028 [-0.051, −0.0047]; ANC, −0.043 [−0.075, −0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 103 per μL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury.Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity.

A Multi-atlas Approach for Active Bone Marrow Sparing Radiation Therapy: Implementation in the NRG-GY006 Trial

Sparing active bone marrow (ABM) can reduce acute hematologic toxicity in patients undergoing chemoradiotherapy for cervical cancer, but ABM segmentation based on positron emission tomography/computed tomography (PET/CT) is costly. We sought to develop an atlas-based ABM segmentation method for implementation in a prospective clinical trial. A multiatlas was built on a training set of 144 patients and validated in 32 patients from the NRG-GY006 clinical trial. ABM for individual patients was defined as the subvolume of pelvic bone greater than the individual mean standardized uptake value on registered 18F-fluorodeoxyglucose PET/CT images. Atlas-based and custom ABM segmentations were compared using the Dice similarity coefficient and mean distance to agreement and used to generate ABM-sparing intensity modulated radiation therapy plans. Dose-volume metrics and normal tissue complication probabilities of the two approaches were compared using linear regression. Atlas-based ABM volumes (mean [standard deviation], 548.4 [88.3] cm3) were slightly larger than custom ABM volumes (535.1 [93.2] cm3), with a Dice similarity coefficient of 0.73. Total pelvic bone marrow V20 and Dmean were systematically higher and custom ABM V10 was systematically lower with custom-based plans (slope: 1.021 [95% confidence interval (CI), 1.005-1.037], 1.014 [95% CI, 1.006-1.022], and 0.98 [95% CI, 0.97-0.99], respectively). We found no significant differences between atlas-based and custom-based plans in bowel, rectum, bladder, femoral heads, or target dose-volume metrics. Atlas-based ABM segmentation can reduce pelvic bone marrow dose while achieving comparable targetandother normal tissue dosimetry. This approach may allow ABM sparing in settings where PET/CT is unavailable.

Dose\u2013volume parameters of MRI-based active bone marrow predict hematologic toxicity of chemoradiotherapy for rectal cancer

PurposeMagnetic resonance imaging (MRI) is routinely used for locoregional staging of rectal cancer and offers promise for the prediction of hematologic toxicity. The present study compares the clinical utility of MRI-based active bone marrow (BMact) delineation with that of CT-based bone marrow total (BMtot) delineation for predicting hematologic toxicity.MethodsA prospective cohort study was performed. Eligible patients had stage II/III rectal cancer and qualified for preoperative chemoradiotherapy. The BMact areas on T1-weighted MRI were contoured. The impact of the dose–volume parameters of BMact/BMtot and clinical data on hematologic toxicity were assessed. Basic endpoints were the occurrence of grade 3/4 hematologic toxicity and peripheral blood parameters reaching a nadir. Linear regression models were generated for the nadirs and receiver operating characteristic (ROC) curves for the occurrence of grade 3/4 hematologic toxicity.ResultsThirty-five patients were enrolled. Women presented higher dose–volume parameters of BMact, BMtot, and lymphocyte nadir (ALCnadir%) than men. Models for the prediction of ALCnadir% (V5-V20BMtot, V5-V30BMact) and platelet nadir (PLTnadir%; V5-V10BMtot, V5-V20BMact) were statistically significant. In the ROC curves, a baseline lymphocyte level of 1.81 × 103/ml was adopted as the cutoff for predicting grade 3/4 lymphopenia, with specificity of 77.8% and sensitivity of 73.1%. The multivariate linear regression model for ALCnadir% had R2 = 0.53, p = 0.038. In the tenth step of selection, V5BMact (p = 0.002) and gender (p = 0.019) remained. The multivariate linear regression model for PLTnadir% had R2 = 0.20, p = 0.34. In the sixth step of selection, V15BMact remained (p = 0.026).ConclusionThe dose–volume parameters of BMact serve as better predictors of ALCnadir% and PLTnadir% than BMtot.

Gammagrafía con leucocitos marcados y SPECT/TC en el diagnóstico de infección de prótesis vasculares

AimVascular graft infection is a rare complication with a high morbidity and mortality. Early diagnosis is essential to establish an adequate treatment. We assess the accuracy of 99mTc-WBC scintigraphy with SPECT/CT in the diagnosis of vascular graft infection. Materials and methodsWe retrospectively analyzed thirty 99mTc-WBC scintigraphies with SPECT/CT performed in thirty patients with suspicion of vascular prosthesis infection. Studies were considered positive for graft infection if the intensity of activity involving the graft was greater than the liver or bone marrow activity (spine and pelvis). ResultsFinal diagnosis of infection was established in 10 patients, based on Fitzgerald criteria. Scintigraphy was positive in 11 patients. No false negatives were obtained. The values of sensitivity and specificity were 100% and 95%, respectively, with a PPV of 91% and a NPV of 100%.Twenty five patients had a CT performed prior to scintigraphy, in 9 cases the result was positive and in the remaining 16 was negative. CT sensitivity and specificity obtained in our study were 62.5% and 76% respectively, with a PPV of 55.6% and a NPV of 81.3%.Diagnosis of infection led to prosthesis exeresis in 8 cases (all of them had a positive microbiological study of the extracted material), while the remaining 2 patients were treated with antibiotic therapy alone due to high surgical risk. ConclusionOur results suggest a high accuracy for 99mTc-WBC scintigraphy with SPECT/CT in the assessment of clinically suspected arterial graft infection.

Diagnostic performance of plain radiography for sacroiliitis in patients with suspected axial spondyloarthritis: a systematic review and meta-analysis.

Plain radiography serves a pivotal role in diagnosing axial spondyloarthritis. However, a broad range of diagnostic performance of plain radiography has been reported. To perform a systematic review and meta-analysis to measure the diagnostic performance of plain radiography for sacroiliitis in patients suspected of having axial spondyloarthritis using magnetic resonance imaging (MRI) findings as the reference standard. Studies comparing radiography and MRI in the diagnosis of sacroiliitis in patients suspected of having axial spondyloarthritis were searched in PubMed and EMBASE. Additionally, studies analyzed SPondyloaArthritis Caught Early (SPACE), DEvenir des Spondylarthropathies Indifferenciées Récentes (DESIR), GErman Spondyloarthritis Inception Cohort (GESPIC), and South Swedish Arthritis Treatment Group (SSATG) cohorts were manually searched. Pooled sensitivity and specificity of radiography were calculated by using a bivariate random-effects model. Meta-regression analyses were performed to identify the sources of heterogeneity. Eight eligible studies with 1579 patients were included. The pooled sensitivity and specificity of radiography were 0.55 (95% confidence interval [CI] = 0.40-0.69) and 0.87 (95% CI = 0.72-0.95). The meta-regression analyses showed prospective study design and criteria for MRI positivity considering only active bone marrow edema were associated with lower sensitivity. The plain radiography showed low sensitivity and reasonable specificity in diagnosis of sacroiliitis in patients suspected of having axial spondyloarthritis.

Phase IIa study of marrow infiltrating lymphocytes (MILs), an adoptive T cell therapy, alone or in combination with nivolumab in non-small cell lung cancer (NSCLC).

TPS9630 Background: Primary or secondary resistance to anti-PD-1 may be due to loss of T cell function. Persistent antigen stimulation can lead to impaired CD8+ T cell function, which often results in acquired resistance to PD-1 inhibition. It is unclear whether reinvigoration of tumor infiltrating cells or recruitment of novel T cells impart the activity of anti-PD-1 therapy. The bone marrow is a reservoir for antigen experienced memory T cells. We have previously shown that MILs can be generated for patients with hematologic malignancies and solid tumors including patients with NSCLC. MILs are the product of the activation and expansion of bone marrow T cells with a polyantigenic memory phenotype that recognize tumor antigens, are cytotoxic to autologous tumor and are able to persist over a long period of time. In a pre-clinical study of NSCLC, MILs were able to be expanded in all patients tested. Furthermore, all of the NSCLC products tested showed specificity to shared NSCLC antigens. The combination of adoptive cell therapy (ACT) with checkpoint inhibitors (CPIs) has distinctive positive effects on CD8 and CD4 T cell subsets, with the possibility for complete tumor control. We hypothesize that patients with NSCLC who have relapsed on anti-PD-1 treatment could benefit from an infusion of non-exhausted, central memory-enhanced, antigen specific T cells i.e. MILs which can delay the induction of tumor-associated anergy and augment the overall effectiveness of immunotherapy. Methods: Patients with advanced NSCLC who have progressed following prior anti-PD-1 therapy, with sufficient bone marrow reserve and an ECOG 0-1 are eligible. In eligible patients, bone marrow (200 mL) will be harvested and processed. Patients will undergo lymphodepletion (fludarabine 300 mg/m2/day and cyclophosphamide 30 mg/m2/day on days -5,-4,-3) followed by infusion of MILs on day 0. In Part 1, up to 6 patients will be administered MILs alone on day 0. In Part 2, approximately 20 subjects will be administered MILs on day 0 followed by NIVO 480 mg Q4W starting on day 1. The objectives of the study are to assess safety of MILs alone and in combination with NIVO, as well as efficacy. The first patient was treated in December 2019. Clinical trial information: NCT04069936 .

Real-world burden of chemotherapy-induced myelosuppression: Results of a U.S. online survey of patients with cancer.

e19299 Background: Research into the real-world impact of chemotherapy (CT)-induced myelosuppression on patients’ lives is limited. This study aimed to investigate the impact of CT-induced myelosuppression on patients with lung, breast, or colorectal cancer (CRC). Methods: Following Institutional Review Board approval to proceed with exception, a survey of participants identified from an online U.S. patient panel was conducted in Nov/Dec 2019. Participants who had been treated with CT in the past year and experienced ≥1 episode of myelosuppression (‘a decrease in bone marrow activity resulting in the reduced production of blood cells’) were eligible for participation. The survey was administered with predominantly close-ended questions, and lay definitions of key terms were provided to aid response selection. Descriptive statistics were used to summarize key findings. P values were calculated using the Chi-square test. Results: 301 participants completed the online survey (breast cancer, n = 153 [51%]; lung cancer, n = 100 [33%]; CRC, n = 48 [16%]). Most participants were aged &gt; 40 years, 60% were female, 60% were currently employed, and 75% had been diagnosed with cancer within the last 3 years. Anemia, neutropenia, lymphopenia, and thrombocytopenia were reported by 61%, 59%, 37%, and 34% of participants, respectively. Fatigue was the most commonly noted side-effect of CT (reported by 72% of participants), with 55% of participants rating it as highly bothersome (9 or 10 on a 1–10 scale of ‘bothersomeness’). Most participants (89%) considered myelosuppression to have a moderate or major impact on life (major life impact, 40%; moderate life impact, 49%; minor life impact, 12%). Patient-reported impact of myelosuppression was significantly higher among participants aged &lt; 50 years vs those aged ≥50 years (p = 0.01); however, no significant differences were observed when participants were stratified by sex, employment status, comorbidities (depression, diabetes, hypertension), or type of cancer. Significantly more participants with fatigue, considering themselves to have a weakened immune system, or noticing easy bruising/bleeding reported a major life impact vs those without these side effects (44% vs 27%, 52% vs 26%, and 50% vs 34%, respectively; all p &lt; 0.01). Conclusions: These data provide further insights into the substantial real-world patient burden of symptoms arising from CT and associated with myelosuppression. Preventing or proactively managing CT-induced myelosuppression could have a major impact on patients’ quality of life.

Induction of blood-circulating bile acids supports recovery from myelosuppressive chemotherapy

AbstractChemotherapeutic agents can reduce bone marrow (BM) activity, causing myelosuppression, a common life-threatening complication of cancer treatment. It is challenging to predict the patients in whom prolonged myelosuppression will occur, resulting in a delay or discontinuation of the treatment protocol. An early indicator of recovery from myelosuppression would thus be highly beneficial in clinical settings. In this study, bile acids (BAs) were highly increased in the systemic circulation as a natural response during recovery from myelosuppression, supporting regeneration of BM cells. BA levels in the blood of pediatric cancer patients and mice treated with chemotherapeutic agents were increased, in synchrony with early proliferation of BM cells and recovery from myelosuppression. In a mouse model of altered BA composition, Cyp8b1 knockout mice, a subset of mice recovered poorly after chemotherapy. The poor recovery correlated with low levels and changes in composition of BAs in the liver and systemic circulation. Conversely, BA supplementation in chemotherapy-treated wild-type mice resulted in significantly improved recovery. The results suggest that part of the mechanism by which BAs support recovery is the suppression of endoplasmic reticulum stress pathways in expanding and recovering hematopoietic cells. The findings propose a novel role of BAs as early markers of recovery and active components of the recovery process after chemotherapy.

STINGing the tumor microenvironment to promote therapeutic tertiary lymphoid organogenesis

Abstract Classical tertiary lymphoid structures (TLS) are non-encapsulated aggregates of B cells, T cells and dendritic cells (DCs) that form around high endothelial venules (HEVs) in tissue sites affected by chronic inflammation. Homeostatic chemokines/cytokines CCL19, CCL21, lymphotoxin α, lymphotoxin β, IL-36γ, type I interferons, CXCL9 and CXCL10 have collectively been implicated in secondary lymphoid organogenesis as well as in formation of TLSs. As these factors can be produced by appropriately activated dendritic cells (DC), we posit that conditioning of intratumoral DCs/stromal cells can lead to TLS formation, improved immune cell infiltration and slowed tumor growth. We report that STING activation in bone marrow derived CD11c+ DCs leads to the production of various TLS forming factors through a STING-TBK1-IRF3 signaling cascade. In vivo, B16.F10 bearing mice treated intratumorally with a human/murine STING agonist, ML-RR-S2-CDA, showed slowed tumor growth dependent on CD8+ T cells. Immunofluorescent imaging of treated tumors showed increased aggregation of CD11c+ DCs with CD3+ T cells around PNAd+/MAdCAM1+ HEVs as early as 5 days post-treatment. These changes occurred in association with evidence for normalization of the tumor vasculature based on enhanced PDGFRβ+ pericyte coverage of CD31+ VECs. Future studies will analyze how the presence of TLS shapes the evolving local (tumor) vs. systemic therapeutic anti-tumor T cell repertoire.

IRF8 Regulates Gram-Negative Bacteria-Mediated NLRP3 Inflammasome Activation and Cell Death.

Inflammasomes are intracellular signaling complexes that are assembled in response to a variety of pathogenic or physiologic stimuli to initiate inflammatory responses. Ubiquitously present LPS in Gram-negative bacteria induces NLRP3 inflammasome activation that requires caspase-11. We have recently demonstrated that IFN regulatory factor (IRF) 8 was dispensable for caspase-11-mediated NLRP3 inflammasome activation during LPS transfection; however, its role in Gram-negative bacteria-mediated NLRP3 inflammasome activation remains unknown. In this study, we found that IRF8 promotes NLRP3 inflammasome activation in murine bone marrow-derived macrophages (BMDMs) infected with Gram-negative bacteria such as Citrobacter rodentium, Escherichia coli, or Pseudomonas aeruginosa mutant strain ΔpopB Moreover, BMDMs deficient in IRF8 showed substantially reduced caspase-11 activation and gasdermin D cleavage, which are required for NLRP3 inflammasome activation. Mechanistically, IRF8-mediated phosphorylation of IRF3 was required for Ifnb transcription, which in turn triggered the caspase-11-dependent NLRP3 inflammasome activation in the infected BMDMs. Overall, our findings suggest that IRF8 promotes NLRP3 inflammasome activation during infection with Gram-negative bacteria.

The synergy of TLR and STING in cancer immunity

Abstract Adjuvants are essential components of cancer vaccine formulations to promote effective immune responses. We initially screened multiple immune-activating targets, including TLR and STING adjuvants using in-vitro assays to test their ability to activate bone marrow DC (BMDC) and showed STING had the most potent activation (i.e., MHC and co-stimulatory molecules) on DCs. Since STING and TLR signaling is non-redundant, TLR and STING adjuvants were combined to enhance DC activation. We utilized the multidimensional synergy of combinations (MuSyc), a novel synergy algorithm, to assess molecular synergy in combining STING and TLR adjuvants, and we noted that the combination of R848 (TLR7-8) plus STING agonists provided a synergistic efficacious and potent response on BMDCs. From this data-set, we generated a MuSYC synergy strategy where we will utilize max signal dose for STING adjuvant and ten times less of max signal dose for R848 (TLR7-8) to determine synergy for other assays. We tested this same MuSYC strategy for activation of human monocytic cell line THP-1 and determined that the synergy strategy induced similar or better activation effects compared to the max signal dose for both adjuvants. Finally, we tested the in-vivo anti-tumor immune response for the B16 melanoma and MOC2 head/neck tumor-bearing vaccination models that resulted in an improved anti-tumor response for the combinatorial STING-TLR adjuvanted vaccines compared to the single agents.

Retinoic acid exerts disease stage-dependent and tissue-specific effects on pristane-induced lupus

Abstract We previously showed that all-trans-retinoic acid (tRA) exacerbated pre-existing autoimmunity in lupus; however, its effects before disease onset are unknown. Here, using a pristane-induced model, we show that tRA exerts tissue-specific effects when given at the initiation vs. continuation phase of lupus. Pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow CD11b- conventional dendritic cells, increasing the splenic CD4:CD8 ratio, and upregulating the interaction of ICAM-1 and LFA-1 that led to the infiltration of inflammatory cells to the spleen. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated genes associated with cell differentiation, activation, and migration. Moreover, compared to pristane alone, tRA pre-treatment potentiated, whereas tRA post-treatment significantly suppressed, the renal expression of proinflammatory TNF-α, IL-1β, CCL2, and CCL3. While it may benefit the kidney, post-pristane treatment with tRA worsened the onset and severity of pristane-induced arthritis through promoting neutrophil and mononuclear cell infiltration into the joints. Together, these findings suggest that tRA supplementation regardless of the time of administration promotes chemokine-driven migration and tissue-specific infiltration of inflammatory cells, thereby exacerbating lupus-associated kidney or joint inflammation. Interestingly, both pre- and post-treatments with tRA modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.

Organ-on-Chip Meets Immunology: Let’s Start with the Lungs

Abstract Organs-on-chips are biomimetic, microfluidic, cell culture devices created with microchip manufacturing methods that contain continuously perfused hollow microchannels inhabited by living tissue cells arranged to simulate organ-level physiology. By recapitulating the multicellular architectures, tissue-tissue interfaces, chemical gradients, mechanical cues, and vascular perfusion of the body, these devices produce levels of tissue and organ functionality not possible with conventional 2D or 3D culture systems. They also enable high-resolution, real-time imaging and in vitro analysis of biochemical, genetic and metabolic activities of living human cells in a functional human tissue and organ context. Here, we discuss development of ‘Human Lung Small Airway-on-a-Chip’ – an engineered cell-by-cell reconstituted microfluidic device with living human tissues to model airway inflammation in the context of debilitating lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). In addition, we will present our preliminary data on recreating a hematopoietically active bone marrow niche in vitro (‘BM-on-a-Chip’) for microphysiological integration with the Small Airway-on-a-Chip to emulate innate immune cell egress into circulation (from the BM) and their recruitment to the lung airway.

Seaweed polysaccharide derived bioaldehyde nanocomposite: Potential application in anticancer therapeutics

In the present study, we have demonstrated synthesis of agar aldehyde (Aald) from seaweed polysaccharide and its further successful application for preparation of Aald mediated solid silver nanocomposite (Aald–AgNPs). Aald–AgNPs were characterized for biophysical properties by FTIR, XRD, SEM, TEM, XPS, and UV–vis spectroscopy. Aald–AgNPs were further tested in vitro and in vivo for anticancer activity. The results of the in vitro study revealed that Aald–AgNPs exhibited activity against 3 cancer cell lines. Aald–AgNPs were found to act through causing dose dependent increase in cell size, inducing anueploidy, mitochondrial disintegration and increasing septa formation in cell cytoplasm. Results of in vivo anticancer activity against ME–180, Colon–26, and HL–60 xenograft mice tumor models showed 64 %, 27.3 % and 51 % reduction in tumor volume, respectively with 83–100 % survival rate. Aald–AgNPs exhibited excellent antibacterial activity. It was interesting to note that Aald–AgNPs did not exhibit any significant detrimental effect on viability and metabolic activity of normal bone marrow derived mesenchymal stem cells. This study opens new areas of research for chemists and biologists to use seaweed-derived polymers to develop nanocomposites for cancer therapeutics.

Breast cancer bone metastases are attenuated in a Tgif1-deficient bone microenvironment

BackgroundOsteoclast activation is a hallmark of breast cancer-induced bone disease while little is known about the role of osteoblasts in this process. Recently, we identified the homeodomain protein TG-interacting factor-1 (Tgif1) as a crucial regulator of osteoblast function. In this study, we demonstrate that lack of Tgif1 also restricts the progression of breast cancer bone metastases.MethodsTranswell migration assays were used to investigate the osteoblast-breast cancer cell interaction in vitro. Molecular analyses included RNA sequencing, immunoblotting, and qRT-PCR. To determine the role of Tgif1 in metastatic bone disease, 4T1 breast cancer cells were injected intracardially into mice with a germ line deletion of Tgif1 (Tgif1−/−) or control littermates (Tgif1+/+). Progression of bone metastases and alterations in the bone microenvironment were assessed using bioluminescence imaging, immunofluorescence staining, confocal microscopy, and histomorphometry.ResultsMedium conditioned by osteoblasts stimulated breast cancer cell migration, indicating a potential role of osteoblasts during bone metastasis progression. Tgif1 expression was strongly increased in osteoblasts upon stimulation by breast cancer cells, demonstrating the implication of Tgif1 in the osteoblast-breast cancer cell interaction. Indeed, conditioned medium from osteoblasts of Tgif1−/− mice failed to induce breast cancer cell migration compared to control, suggesting that Tgif1 in osteoblasts augments cancer cell motility. Semaphorin 3E (Sema3E), which is abundantly secreted by Tgif1−/− osteoblasts, dose-dependently reduced breast cancer cell migration while silencing of Sema3E expression in Tgif1−/− osteoblasts partially restored the impaired migration. In vivo, we observed a decreased number of breast cancer bone metastases in Tgif1−/− mice compared to control littermates. Consistently, the presence of single breast cancer cells or micro-metastases in the tibiae was reduced in Tgif1−/− mice. Breast cancer cells localized in close proximity to Endomucin-positive vascular cells as well as to osteoblasts. Although Tgif1 deficiency did not affect the bone marrow vasculature, the number and activity of osteoblasts were reduced compared to control. This suggests that the protective effect on bone metastases might be mediated by osteoblasts rather than by the bone marrow vasculature.ConclusionWe propose that the lack of Tgif1 in osteoblasts increases Sema3E expression and attenuates breast cancer cell migration as well as metastases formation.

Dynamics of Red Blood Cell Indices among Donor Samples in Kisii County, Western Kenya

Blood specimens are used to study the aetiology, diagnosis, treatment, prognosis, and prevention of blood diseases that includes research purposes. The primary health care worldwide calls for ideal systems that can provide accurate results but it is challenging to analyse the samples immediately. Thus, the primary objective of this study was to determine the changes in the red cell indices when stored at room temperatures. To accept such samples that have delayed after collections for some time as from zero (0) hours, at 6 hours, 12 hours, 24 hours and 48 hours requires testing and confirming the results validations. Therefore, this research analysed samples of blood to validate the results after storage at room temperature in different hours within 48 hours of storage at room temperature. Samples collected from donors aged 16-65 years at Kisii Teaching and Referral Hospital in Kisii County, Western Kenya were tested in this study. The technique of Flow cytometry was used to analyse results of blood obtained through Venepuncture procedure from donors and placed in 4 ml Ethylene Diamine Tetra Acetic (EDTA) Vacutainer tubes of standardised anticoagulant ratio. A cross-sectional study with laboratory experiment was employed to analyse the data between the month of April and August 2018. Percentile male and female blood samples were analysed at 48% and 52% respectively. The analytes of obtained were used to determine the two red blood cell parameters in controlled room temperature within 48 hours on Packed Cell Volume (PCV) and Total Red Cell counts. Statistical analysis with computerized applications package (SPSS, version 21.0) was used to determine the changes that occurred during the study with repeated Analysis of Variation (ANOVA). Comparative mean values were calculated for each blood samples. The results were insignificant at sixth and twelfth hours of storage for most indices except from the RBC total counts, which had a deviation between 6-48 hours. In conclusion blood sample analysis is safe for tests results up 12 hours of storage at room temperature when not tested immediately after collection. This study recommends further finds for Reticulocytes Production Index to assess bone marrow activities.

Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus.

We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.

Increased Bone Marrow 18F-Choline Uptake in a Patient with Hepatocellular Carcinoma and Thalassemia Intermedia

A 57-year-old male with history of thalassemia intermedia and hepatocellular carcinoma underwent a positron emission tomography/computed tomography (PET/CT) scan with 18F-choline before radioembolization procedure with 90Y-microspheres. The PET/CT scan with 18F-choline demonstrated highly increased tracer incorporation within a gross lesion in the hepatic dome coupled with diffuse activity in bone marrow, this latter aspect was probably due to the compensatory hematopoiesis stimulation induced by chronic hemolysis. This pattern of skeletal 18F-choline uptake should be considered as a peculiar PET/CT finding in thalassemic patients.

Chlorella sorokiniana Extract Prevents Cisplatin-Induced Myelotoxicity In Vitro and In Vivo.

Cisplatin chemotherapy causes myelosuppression and often limits treatment duration and dose escalation in patients. Novel approaches to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. Chlorella sorokiniana (CS) is a freshwater unicellular green alga and exhibits encouraging efficacy in immunomodulation and anticancer in preclinical studies. However, the efficacy of CS on chemoprotection remains unclear. We report here, for the first time, that CS extract (CSE) could protect normal myeloid cells and PBMCs from cisplatin toxicity. Also, cisplatin-induced apoptosis in HL-60 cells was rescued through reservation of mitochondrial function, inhibition of cytochrome c release to cytosol, and suppression of caspase and PARP activation. Intriguingly, cotreatment of CSE attenuated cisplatin-evoked hypocellularity of bone marrow in mice. Furthermore, we observed the enhancement of CSF-GM activity in bone marrow and spleen in mice administered CSE and cisplatin, along with increased CD11b levels in spleen. In conclusion, we uncovered a novel mechanism of CSE on myeloprotection, whereby potentially supports the use of CSE as a chemoprotector against cisplatin-induced bone marrow toxicity. Further clinical investigation of CSE in combination with cisplatin is warranted.

Automated hematology and radiology synergy in diagnosing anemia in children

Aim: This review aims to evaluate the role of automated hematology analyzers and radiological imaging techniques in the diagnosis and management of anemia in children, highlighting traditional and advanced parameters. Methods: A comprehensive literature review was conducted, focusing on automated hematological parameters such as hemoglobin, RBC indices, reticulocyte counts, and novel metrics from modern analyzers, alongside radiological assessments such as bone marrow imaging and organ evaluation. The quasi-morphological approach, reticulocyte kinetic analysis, and imaging technologies like digital imaging and artificial intelligence were examined. Results: Traditional parameters, including RDW and MCV, provide initial insights into anemia classification. Advanced metrics, such as reticulocyte hemoglobin content and immature reticulocyte fractions, improve iron status assessment and therapeutic response evaluation. Radiological imaging offers valuable insights into bone marrow activity and organ health, complementing hematological findings. The use of automated analyzers and imaging techniques demonstrates high reproducibility and rapid results, though challenges in standardization persist. Conclusion: Automated hematology analyzers and radiological imaging techniques significantly enhance the diagnostic landscape for pediatric anemia, yet clinical integration and ongoing refinement of reference ranges are essential. Future developments in technology and standardization may further elevate the efficacy of anemia management in children.