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Cancer Discovery Jun 2024Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell...
Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months.
PubMed: 38867349
DOI: 10.1158/2159-8290.CD-23-1376 -
Pediatric Dermatology Jun 2024Development of periungual pyogenic granulomas (pPGs) has been associated with several systemic treatments, including retinoids, taxanes, epidermal growth factor receptor...
Development of periungual pyogenic granulomas (pPGs) has been associated with several systemic treatments, including retinoids, taxanes, epidermal growth factor receptor inhibitors, and vascular endothelial growth factor inhibitors. We present the case of an 8-year-old girl with a personal history of acute myelomonocytic leukemia treated with a haploidentical hematopoietic stem cell transplant who developed pPGs 2 months after starting ravulizumab. Ravulizumab is a monoclonal antibody directed against C5 protein. No previous reports of pPGs development have been described with ravulizumab.
PubMed: 38858093
DOI: 10.1111/pde.15675 -
Emerging Microbes & Infections Dec 2024Tuberculosis (TB) remains a leading cause of mortality among individuals coinfected with HIV, characterized by progressive pulmonary inflammation. Despite TB's hallmark...
Tuberculosis (TB) remains a leading cause of mortality among individuals coinfected with HIV, characterized by progressive pulmonary inflammation. Despite TB's hallmark being focal granulomatous lung lesions, our understanding of the histopathological features and regulation of inflammation in HIV & TB coinfection remains incomplete. In this study, we aimed to elucidate these histopathological features through an immunohistochemistry analysis of HIV & TB co-infected and TB patients, revealing marked differences. Notably, HIV & TB granulomas exhibited aggregation of CD68 + macrophage (Mφ), while TB lesions predominantly featured aggregation of CD20+ B cells, highlighting distinct immune responses in coinfection. Spatial transcriptome profiling further elucidated CD68+ Mφ aggregation in HIV & TB, accompanied by activation of IL6 pathway, potentially exacerbating inflammation. Through multiplex immunostaining, we validated two granuloma types in HIV & TB versus three in TB, distinguished by cell architecture. Remarkably, in the two types of HIV & TB granulomas, CD68 + Mφ highly co-expressed IL6R/pSTAT3, contrasting TB granulomas' high IFNGRA/SOCS3 expression, indicating different signaling pathways at play. Thus, activation of IL6 pathway may intensify inflammation in HIV & TB-lungs, while SOCS3-enriched immune microenvironment suppresses IL6-induced over-inflammation in TB. These findings provide crucial insights into HIV & TB granuloma formation, shedding light on potential therapeutic targets, particularly for granulomatous pulmonary under HIV & TB co-infection. Our study emphasizes the importance of a comprehensive understanding of the immunopathogenesis of HIV & TB coinfection and suggests potential avenues for targeting IL6 signaling with SOCS3 activators or anti-IL6R agents to mitigate lung inflammation in HIV & TB coinfected individuals.
Topics: Humans; Coinfection; HIV Infections; Macrophages; STAT3 Transcription Factor; Granuloma; Lung; Receptors, Interleukin-6; Suppressor of Cytokine Signaling 3 Protein; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Signal Transduction; Tuberculosis, Pulmonary; Male; Tuberculosis; Female; Adult; Interleukin-6; CD68 Molecule
PubMed: 38855910
DOI: 10.1080/22221751.2024.2366359 -
Clinical Case Reports Jun 2024Chronic myelomonocytic leukemia, a rare case of hematological malignancy mainly affects the elderly and may present with life threatening pericardial effusion as an...
KEY CLINICAL MESSAGE
Chronic myelomonocytic leukemia, a rare case of hematological malignancy mainly affects the elderly and may present with life threatening pericardial effusion as an initial manifestation. High index of suspicion is hence key for early management.
ABSTRACT
We present a case of an 81-year-old African male who presented with progressive cough, respiratory distress and bilateral lower limb swelling, and was diagnosed with life-threatening pericardial effusion resulting from chronic myelomonocytic leukemia following complete blood count, peripheral blood film, bone marrow aspirate with trephine biopsy, and flow cytometry studies.
PubMed: 38855083
DOI: 10.1002/ccr3.9048 -
Skin Health and Disease Jun 2024In the two common inflammatory skin diseases, Atopic Dermatitis (AD) and Psoriasis (Ps), keratinocytes (KCs) respond to immune insults through activation of...
BACKGROUND
In the two common inflammatory skin diseases, Atopic Dermatitis (AD) and Psoriasis (Ps), keratinocytes (KCs) respond to immune insults through activation of proinflammatory transcription factors (TFs) and their translocation to the cell's nucleus. Therein, the TFs induce expression of genes encoding mediators of skin inflammation. The Nuclear Transport Checkpoint Inhibitors (NTCIs) were developed to regulate nuclear translocation of activated TFs, the essential step of inflammatory response. This new class of cell-penetrating peptide therapeutics controls inflammation caused by allergic, autoimmune, metabolic, and microbial insults. In preclinical model of AD, the treatment with NTCI, cSN50.1 peptide, suppressed the expression of Thymic Stromal Lymphopoietin (), the key gene in the development of allergic inflammation, among the 15 genes silenced by the NTCI. Here, we report the mechanism of anti-inflammatory action of NTCI in human skin-derived KCs.
OBJECTIVES
We aimed to determine whether the NTCI treatment can protect human KCs from harmful inflammatory insults.
METHODS
Human primary KCs were pretreated with NTCI and challenged with the mix of cytokines Tumour Necrosis Factor alpha (TNF-α) and Interleukin (IL)-17A, or with Phorbol 12-Myristate 13-Acetate (PMA), and analysed for nuclear content of TFs and the expression of genes encoding mediators of inflammation.
RESULTS
The nuclear import of TFs, Nuclear Factor ĸB (NF-ĸB) and Signal Transduction and Activator of Transcription 3 (STAT3), was inhibited in cells treated with NTCI. The expression of along with genes encoding the core mediators of inflammation (, , and ) was suppressed by NTCI. Noteworthy, NTCI silenced genes encoding Granulocyte-Macrophage Colony-Stimulating Factor (), and chemokine IL-8 (), responsible for skin infiltration by the eosinophils and other myelomonocytic cells.
CONCLUSION
The control of inflammatory response in human KCs by NTCI is attributed to the inhibition of nuclear import of proinflammatory TFs. The protection of human KCs by NTCI, adds new perspectives to the completed Phase two clinical trial of the NTCI (AMTX-100 CF) for AD (NCT04313400).
PubMed: 38846687
DOI: 10.1002/ski2.356 -
BMC Cancer May 2024Recent studies have shown that blue light-emitting diode (LED) light has anti-tumor effects, suggesting the possibility of using visible light in cancer therapy....
Recent studies have shown that blue light-emitting diode (LED) light has anti-tumor effects, suggesting the possibility of using visible light in cancer therapy. However, the effects of blue light irradiation on cells in the tumor microenvironment, including tumor-associated macrophages (TAMs), are unknown. Here, THP-1 cells were cultured in the conditioned medium (CM) of HCT-116 cells to prepare TAMs. TAMs were divided into LED-irradiated and control groups. Then, the effects of blue LED irradiation on TAM activation were examined. Expression levels of M2 macrophage markers CD163 and CD206 expression were significantly decreased in LED-irradiated TAMs compared with the control group. While control TAM-CM could induce HCT-116 cell migration, these effects were not observed in cells cultured in TAM-CM with LED irradiation. Vascular endothelial growth factor (VEGF) secretion was significantly suppressed in LED-exposed TAMs. PD-L1 expression was upregulated in HCT-116 cells cultured with TAM-CM but attenuated in cells cultured with LED-irradiated TAM-CM. In an in vivo model, protein expression levels of F4/80 and CD163, which are TAM markers, were reduced in the LED-exposed group. These results indicate that blue LED light may have an inhibitory effect on TAMs, as well as anti-tumor effects on colon cancer cells.
Topics: Humans; Colonic Neoplasms; Tumor-Associated Macrophages; Light; Animals; HCT116 Cells; Mice; Tumor Microenvironment; Cell Movement; Culture Media, Conditioned; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Vascular Endothelial Growth Factor A; Receptors, Cell Surface; Macrophages; Phototherapy; Macrophage Activation; Blue Light
PubMed: 38822331
DOI: 10.1186/s12885-024-12440-1 -
Scientific Reports May 2024The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and...
The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and the time scale at which such effects can occur following irradiation. To explore these phenomena, we exposed atheroprone ApoE mice to a single dose of 0, 0.05, 0.5 or 1 Gy of Cs (γ) administered at a 10.35 mGy min dose rate and evaluated short-term (1-10 days) and long-term consequences (100 days). Bone marrow-derived macrophages were derived from mice 1 day after exposure. Irradiation was associated with a significant skewing of M0 and M2 polarized macrophages towards the M2 phenotype, as demonstrated by an increased mRNA expression of Retnla, Arg1, and Chil3 in cells from mice exposed to 0.5 or 1 Gy compared with non-irradiated animals. Minimal effects were noted in M1 cells or M1 marker mRNA. Concurrently, we observed a reduced secretion of IL-1β but enhanced IL-10 release from M0 and M2 macrophages. Effects of irradiation on circulating monocytes were most marked at day 10 post-exposure, when the 1 Gy dose was associated with enhanced numbers of both Ly6C and Ly6 cells. By day 100, levels of circulating monocytes in irradiated and non-irradiated mice were equivalent, but anti-inflammatory Ly6C monocytes were significantly increased in the spleen of mice exposed to 0.05 or 1 Gy. Long term exposures did not affect atherosclerotic plaque size or lipid content, as determined by Oil red O staining, whatever the dose applied. Similarly, irradiation did not affect atherosclerotic plaque collagen or smooth muscle cell content. However, we found that lesion CD68+ cell content tended to decrease with rising doses of radioactivity exposure, culminating in a significant reduction of plaque macrophage content at 1 Gy. Taken together, our results show that short- and long-term exposures to low to moderate doses of ionizing radiation drive an anti-inflammatory response, skewing bone marrow-derived macrophages towards an IL-10-secreting M2 phenotype and decreasing plaque macrophage content. These results suggest a low-grade athero-protective effect of low and moderate doses of ionizing radiation.
Topics: Animals; Macrophages; Plaque, Atherosclerotic; Mice; Cesium Radioisotopes; Apolipoproteins E; Gamma Rays; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Atherosclerosis; Male; Mice, Knockout; CD68 Molecule
PubMed: 38816571
DOI: 10.1038/s41598-024-63084-x -
Biochemical Pharmacology Jul 2024Relaxin's role in differentiated thyroid cancer (DTC) has been suggested but its characterization in a large clinical sample remains limited. We performed...
Relaxin's role in differentiated thyroid cancer (DTC) has been suggested but its characterization in a large clinical sample remains limited. We performed immunohistochemistry for relaxin-2 (RLN2), CD68 (total macrophages), CD163 (M2 macrophages) on tissue microarrays from 181 subjects with non-distant metastatic DTC, and 185 subjects with benign thyroid tissue. Mean pixels/area for each marker was compared between tumor and adjacent tissue via paired-t test and between DTC and benign subjects via t-test assuming unequal variances. RNA qPCR was performed for expression of RLN2, RLN1, and RXFP1 in cell lines. Amongst 181 cases, the mean age was 46 years, 75 % were females. Tumoral tissue amongst the DTC cases demonstrated higher mean expression of RLN2 (53.04 vs. 9.79; p < 0.0001) compared to tumor-adjacent tissue. DTC tissue also demonstrated higher mean expression of CD68 (14.46 vs. 4.79; p < 0.0001), and CD163 (23.13 vs. -0.73; p < 0.0001) than benign thyroid. These markers did not differ between tumor-adjacent and benign thyroid tissue groups; and amongst cases, did not differ by demographic or clinicopathologic features. RLN1 and RXFP1 expression was detected in a minority of the cell lines, while RLN2 was expressed by 6/7 cell lines. In conclusion, widespread RLN2 expression in DTC tissue and most cell lines demonstrates that RLN2 acts in a paracrine manner, and that RLN1 and RXFP1 are probably not involved in thyroid cancer cell signaling. RLN2 is a biomarker for thyroid carcinogenesis, being associated with but not secreted by immunosuppressive macrophages. These findings will guide further investigations for therapeutic avenues against thyroid cancer.
Topics: Humans; Relaxin; Thyroid Neoplasms; Female; Middle Aged; Male; Biomarkers, Tumor; Adult; Receptors, G-Protein-Coupled; Cell Line, Tumor; Antigens, CD; Aged; Receptors, Peptide; Antigens, Differentiation, Myelomonocytic
PubMed: 38815632
DOI: 10.1016/j.bcp.2024.116323 -
Haematologica May 2024Not available.
Not available.
PubMed: 38813703
DOI: 10.3324/haematol.2024.285326