Bipotential B-neutrophil progenitors are present in human and mouse bone marrow and emerge in the periphery upon stress hematopoiesis.

Hematopoiesis is a tightly regulated process that gets skewed toward myelopoiesis. This restrains lymphopoiesis, but the role of lymphocytes in this process is not well defined. To unravel the intricacies of neutrophil responses in COVID-19, we performed bulk RNAseq on neutrophils from healthy controls and COVID-19 patients. Principal component analysis revealed distinguishing neutrophil gene expression alterations in COVID-19 patients. ICU and ward patients displayed substantial transcriptional changes, with ICU patients exhibiting a more pronounced response. Intriguingly, neutrophils from COVID-19 patients, notably ICU patients, exhibited an enrichment of immunoglobulin (Ig) and B cell lineage-associated genes, suggesting potential lineage plasticity. We validated our RNAseq findings in a larger cohort. Moreover, by reanalyzing single-cell RNA sequencing (scRNAseq) data on human bone marrow (BM) granulocytes, we identified the cluster of granulocyte-monocyte progenitors (GMP) enriched with Ig and B cell lineage-associated genes. These cells with lineage plasticity may serve as a resource depending on the host's needs during severe systemic infection. This distinct B cell subset may play a pivotal role in promoting myelopoiesis in response to infection. The scRNAseq analysis of BM neutrophils in infected mice further supported our observations in humans. Finally, our studies using an animal model of acute infection implicate IL-7/GM-CSF in influencing neutrophil and B cell dynamics. Elevated GM-CSF and reduced IL-7 receptor expression in COVID-19 patients imply altered hematopoiesis favoring myeloid cells over B cells. Our findings provide novel insights into the relationship between the B-neutrophil lineages during severe infection, hinting at potential implications for disease pathogenesis. IMPORTANCE: This study investigates the dynamics of hematopoiesis in COVID-19, focusing on neutrophil responses. Through RNA sequencing of neutrophils from healthy controls and COVID-19 patients, distinct gene expression alterations are identified, particularly in ICU patients. Notably, neutrophils from COVID-19 patients, especially in the ICU, exhibit enrichment of immunoglobulin and B cell lineage-associated genes, suggesting potential lineage plasticity. Validation in a larger patient cohort and single-cell analysis of bone marrow granulocytes support the presence of granulocyte-monocyte progenitors with B cell lineage-associated genes. The findings propose a link between B-neutrophil lineages during severe infection, implicating a potential role for these cells in altered hematopoiesis favoring myeloid cells over B cells. Elevated GM-CSF and reduced IL-7 receptor expression in stress hematopoiesis suggest cytokine involvement in these dynamics, providing novel insights into disease pathogenesis.

Changing frontline AML treatment patterns from 2013 to 2022.

The treatment patterns for patients with newly diagnosed acute myeloid leukemia (AML) were compared between 2013 and 16 and 2021-22 in a real-world setting. A significantly higher proportion of patients age 70 and over received non-intensive therapy (NIT) in 2021-22 as compared with 2013-16 (65 % vs 44 %, p = 0.014), with a corresponding reduction in the proportion receiving either intensive therapy or no antileukemic treatment. Treatment patterns among patients < age 70 were unchanged. The complete response rate in the NIT group was 69 % in 2021-22 vs. 24 % in 2013-16 (p < 0.001); the overall survival (OS) of NIT patients was 11.5 months in 2021-22 vs. 7.8 months in 2013-16. Older patients from rural areas were more likely to decline therapy than those from urban regions. The increase in the proportion of patients opting for NIT may be related to the availability of more effective treatment options. Although outcomes are improving, the OS with NIT remains suboptimal.

Depletion of polyfunctional CD26highCD8+ T cells repertoire in chronic lymphocytic leukemia.

BACKGROUND: CD8+ T cells play an essential role against tumors but the role of human CD8+CD26+ T cell subset against tumors, in particular, haematological cancers such as chronic lymphocytic leukemia (CLL) remains unknown. Although CD4+CD26high T cells are considered for adoptive cancer immunotherapy, the role of CD8+CD26+ T cells is ill-defined. Therefore, further studies are required to better determine the role of CD8+CD26+ T cells in solid tumors and haematological cancers. METHODS: We studied 55 CLL and 44 age-sex-matched healthy controls (HCs). The expression of CD26 on different T cell subsets (e.g. naïve, memory, effector, and etc.) was analyzed. Also, functional properties of CD8+CD26+ and CD8+CD26- T cells were evaluated. Finally, the plasma cytokine/chemokine and Galectin-9 (Gal-9) levels were examined. RESULTS: CD26 expression identifies three CD8+ T cell subsets with distinct immunological properties. While CD26negCD8+ T cells are mainly transitional, effector memory and effectors, CD26lowCD8+ T cells are mainly naïve, stem cell, and central memory but CD26high T cells are differentiated to transitional and effector memory. CD26+CD8+ T cells are significantly reduced in CLL patients versus HCs. CD26high cells are enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161TVα7.2 and IL-18Rα. Also, CD26high cells have a rich chemokine receptor profile (e.g. CCR5 and CCR6), profound cytokine (TNF-α, IFN-γ, and IL-2), and cytolytic molecules (Granzyme B, K, and perforin) expression upon stimulation. CD26high and CD26low T cells exhibit significantly lower frequencies of CD160, 2B4, TIGIT, ICOS, CD39, and PD-1 but higher levels of CD27, CD28, and CD73 versus CD26neg cells. To understand the mechanism linked to CD26high depletion, we found that malignant B cells by shedding Galectin-9 (Gal-9) contribute to the elevation of plasma Gal-9 in CLL patients. In turn, Gal-9 and the inflammatory milieu (IL-18, IL-12, and IL-15) in CLL patients contribute to increased apoptosis of CD26high T cells. CONCLUSIONS: Our results demonstrate that CD26+ T cells possess a natural polyfunctionality to traffic and exhibit effector functions and resist exhaustion. Therefore, they can be proposed for adoptive cancer immunotherapy. Finally, neutralizing and/or inhibiting Gal-9 may preserve CD26highCD8+ T cells in CLL.

Expanded antigen-experienced CD160+CD8+effector T cells exhibit impaired effector functions in chronic lymphocytic leukemia.

BACKGROUND: T cell exhaustion compromises antitumor immunity, and a sustained elevation of co-inhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). However, the role of CD160, a glycosylphosphatidylinositol-anchored protein, as one of these co-inhibitory receptors has been contradictory in T cell function. Therefore, we decided to elucidate how CD160 expression and/or co-expression with other co-inhibitory receptors influence T cell effector functions in patients with CLL. METHODS: We studied 56 patients with CLL and 25 age-matched and sex-matched healthy controls in this study. The expression of different co-inhibitory receptors was analyzed in T cells obtained from the peripheral blood or the bone marrow. Also, we quantified the properties of extracellular vesicles (EVs) in the plasma of patients with CLL versus healthy controls. Finally, we measured 29 different cytokines, chemokines or other biomarkers in the plasma specimens of patients with CLL and healthy controls. RESULTS: We found that CD160 was the most upregulated co-inhibitory receptor in patients with CLL. Its expression was associated with an exhausted T cell phenotype. CD160+CD8+ T cells were highly antigen-experienced/effector T cells, while CD160+CD4+ T cells were more heterogeneous. In particular, we identified EVs as a source of CD160 in the plasma of patients with CLL that can be taken up by T cells. Moreover, we observed a dominantly proinflammatory cytokine profile in the plasma of patients with CLL. In particular, interleukin-16 (IL-16) was highly elevated and correlated with the advanced clinical stage (Rai). Furthermore, we observed that the incubation of T cells with IL-16 results in the upregulation of CD160. CONCLUSIONS: Our study provides a novel insight into the influence of CD160 expression/co-expression with other co-inhibitory receptors in T cell effector functions in patients with CLL. Besides, IL-16-mediated upregulation of CD160 expression in T cells highlights the importance of IL-16/CD160 as potential immunotherapy targets in patients with CLL. Therefore, our findings propose a significant role for CD160 in T cell exhaustion in patients with CLL.

Repair of Frontoethmoidal Encephalocele in the Philippines: An Account of 30 Cases Between 2008-2013.

BACKGROUND: Frontoethmoidal encephalocele is a congenital abnormality of the anterior skull base involving herniation of cranial contents through a midline skull defect. Patency of the foramen cecum, along with other multifactorial variables, contributes to the development of frontoethmoidal encephaloceles. Because of limited resources, financial constraints, and lack of surgical expertise, repair of frontoethmoidal encephaloceles is limited in developing countries. METHODS: Between 2008 and 2013 an interdisciplinary team composed of neurosurgeons, craniofacial surgeons, otolaryngologists, plastic surgeons, and nursing personnel, conducted surgical mission trips to Davao City in Mindanao, Philippines. All patients underwent a combined extracranial/intracranial surgical approach, performed in tandem by a neurosurgeon and a craniofacial surgeon, to detach and remove the encephalocele. This procedure was followed by reconstruction of the craniofacial defects. RESULTS: A total of 30 cases of frontoethmoidal encephalocele were repaired between 2008 and 2013 (20 male; 10 female). The average age at operation was 8.7 years, with 7 patients older than 17 years. Of the 3 subtypes, the following breakdown was observed in patients: 18 nasoethmoidal; 9 nasofrontal; and 3 naso-orbital. Several patients showed concurrent including enlarged ventricles, arachnoid cysts (both unilateral and bilateral), and gliotic changes, as well as orbit and bulbus oculi (globe) deformities. There were no operative-associated mortalities or neurologic deficits, infections, or hydrocephalus on follow-up during subsequent trips. CONCLUSIONS: Despite the limitations of performing advanced surgery in a developing country, the combined interdisciplinary surgical approach has offered effective treatment to improve physical appearance and psychological well-being in afflicted patients.

Tessier No. 3 and No. 4 clefts: Sequential treatment in infancy by pre-surgical orthopedic skeletal contraction, comprehensive reconstruction, and novel surgical lengthening of the ala base-canthal distance.

BACKGROUND: Repair of facial clefts implies wide tissue mobilization with multi-stage surgical treatment. Authors propose pre-surgical orthopedic correction for naso-oro-ocular clefts and a novel surgical option for Tessier No. 3 cleft. METHODS: Two male infants, a Tessier No. 3 cleft (age 7 months) and another Tessier No. 4 (age 3 months), were treated with a modified orthopedic Latham device with additional septo-premaxillary molding and observed to age four years. Tessier No. 3 orthopedic measurements were obtained by image corrected cephalometric analysis. Subsequent repair included tissue expansion on Tessier No. 4 and naso-frontal Rieger flap combined with myocutaneous upper lid flap on Tessier No. 3. RESULTS: Orthopedic movements ranged from 18.5 mm in bi-planar to 33 mm in oblique analyses. Tissue margins became aligned with platform normalization. Tissue expansion on Tessier No. 4 improved distances from ala base-lower lid and subalar base-lip. The naso-frontal flap combined with myocutaneous upper lid flap on Tessier No. 3 had similar achievement, but also sufficiently lengthened ala base-canthal distance. CONCLUSIONS: Repairs were facilitated by pre-surgical orthopedic correction. The naso-frontal flap combined with an upper lid myocutaneous flap seems viable as a single-stage option to lengthen ala base-canthal distance to advance repair achievement in unilateral Tessier No. 3.